The Human Auditory System Fundamental Organization and Clinical Disorders [1st Edition] 9780444626295, 9780444626301

Table of contents :
Content:
Series PagePage ii
CopyrightPage iv
Handbook of Clinical Neurology 3rd SeriesPages v-vi
ForewordPage viiMichael J. Aminoff, François Boller, Dick F. Swaab
PrefacePages ix-xGastone G. Celesia, Gregory Hickok
ContributorsPages xi-xiii
Chapter 1 - Auditory pathways: anatomy and physiologyPages 3-25James O. Pickles
Chapter 2 - Anatomic organization of the auditory cortexPages 27-53Troy A. Hackett
Chapter 3 - Development of the auditory systemPages 55-72Ruth Litovsky
Chapter 4 - Representation of loudness in the auditory cortexPages 73-84Christoph E. Schreiner, Brian J. Malone
Chapter 5 - Temporal coding in the auditory cortexPages 85-98Luc H. Arnal, David Poeppel, Anne-lise Giraud
Chapter 6 - Sound localizationPages 99-116John C. Middlebrooks
Chapter 7 - New perspectives on the auditory cortex: learning and memoryPages 117-147Norman M. Weinberger
Chapter 8 - Neural basis of speech perceptionPages 149-160Gregory Hickok, David Poeppel
Chapter 9 - Role of the auditory system in speech productionPages 161-175Frank H. Guenther, Gregory Hickok
Chapter 10 - White-matter pathways for speech and language processingPages 177-186Angela D. Friederici
Chapter 11 - Neural basis of music perceptionPages 187-205Petr Janata
Chapter 12 - Music and language: relations and disconnectionsPages 207-222Nina Kraus, Jessica Slater
Chapter 13 - Invasive recordings in the human auditory cortexPages 225-244Kirill V. Nourski, Matthew A. Howard III
Chapter 14 - Electromagnetic recording of the auditory systemPages 245-255David Poeppel, Gregory Hickok
Chapter 15 - Hemodynamic imaging of the auditory cortexPages 257-275Ann Hall Deborah, Susi Karima
Chapter 16 - Imaging white-matter pathways of the auditory system with diffusion imaging tractographyPages 277-288Chiara Maffei, Guadalupe Soria, Alberto Prats-Galino, Marco Catani
Chapter 17 - Electrophysiologic auditory testsPages 289-311Alan D. Legatt
Chapter 18 - Psychophysical and behavioral peripheral and central auditory testsPages 313-332Frank E. Musiek, Gail D. Chermak
Chapter 19 - Neurocognitive development in congenitally deaf childrenPages 335-356Elizabeth Fitzpatrick
Chapter 20 - Aging of the auditory systemPages 357-373Thomas Nicolas Roth
Chapter 21 - Decreased sound tolerance: hyperacusis, misophonia, diplacousis, and polyacousisPages 375-387Pawel J. Jastreboff, Margaret M. Jastreboff
Chapter 22 - Auditory synesthesiasPages 389-407Pegah Afra
Chapter 23 - TinnitusPages 409-431Robert A. Levine, Yahav Oron
Chapter 24 - Auditory hallucinationsPages 433-455Jan Dirk Blom
Chapter 25 - PalinacousisPages 457-467Madeline C. Fields, Lara V. Marcuse
Chapter 26 - Musicogenic epilepsyPages 469-477John Stern
Chapter 27 - Deafness in cochlear and auditory nerve disordersPages 479-494Kathryn Hopkins
Chapter 28 - Auditory neuropathyPages 495-508Arnold Starr, Gary Rance
Chapter 29 - Hearing disorders in brainstem lesionsPages 509-536Gastone G. Celesia
Chapter 30 - Central auditory processing disorders in children and adultsPages 537-556Teri James Bellis, Jennifer D. Bellis
Chapter 31 - Auditory neglect and related disordersPages 557-571Alexander Gutschalk, Andrew R. Dykstra
Chapter 32 - Auditory agnosiaPages 573-587L. Robert slevc, Alison R. Shell
Chapter 33 - Congenital amusiasPages 589-605B. Tillmann, P. Albouy, A. Caclin
Chapter 34 - Acquired amusiaPages 607-631Camilla N. Clark, Hannah L. Golden, Jason D. Warren
Chapter 35 - Hearing disorders in strokePages 633-647Doris Eva Bamiou
Chapter 36 - Hearing disorders in multiple sclerosisPages 649-665Miriam Furst, Robert A. Levine
Chapter 37 - Hearing and music in dementiaPages 667-687Julene K. Johnson, Maggie L. Chow
Chapter 38 - Future advancesPages 689-692Gastone G. Celesia, Gregory Hickok
IndexPages 693-704

Citation preview

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 129

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2015

ELSEVIER B.V. Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 225 Wyman Street, Waltham, MA 02451, USA © 2015, Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). ISBN: 9780444626301 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. The Publisher

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Handbook of Clinical Neurology 3rd Series Available titles Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 9780444513571 Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 9780444514905 Vol. 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016 Vol. 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941 Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009 Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933 Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104 Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996 Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965 Vol. 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972 Vol. 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989 Vol. 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958 Vol. 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081 Vol. 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036 Vol. 93, Stroke – Part II: Clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043 Vol. 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050 Vol. 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081 Vol. 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159 Vol. 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392 Vol. 98, Sleep disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067 Vol. 99, Sleep disorders Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074 Vol. 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142 Vol. 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315 Vol. 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039 Vol. 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927 Vol. 104, Neuro-oncology Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385 Vol. 105, Neuro-oncology Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023 Vol. 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029 Vol. 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988 Vol. 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995 Vol. 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378 Vol. 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015 Vol. 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919 Vol. 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107 Vol. 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652 Vol. 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds. ISBN 9780444534903 Vol. 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022 Vol. 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972 Vol. 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910 Vol. 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016 Vol. 119, Neurologic aspects of systemic disease Part I, J. Biller and J.M. Ferro, eds. ISBN 9780702040863 Vol. 120, Neurologic aspects of systemic disease Part II, J. Biller and J.M. Ferro, eds. ISBN 9780702040870 Vol. 121, Neurologic aspects of systemic disease Part III, J. Biller and J.M. Ferro, eds. ISBN 9780702040887 Vol. 122, Multiple sclerosis and related disorders, D.S. Goodin, ed. ISBN 9780444520012 Vol. 123, Neurovirology, A.C. Tselis and J. Booss, eds. ISBN 9780444534880

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Foreword

It is curious how little attention most neurologists direct at hearing, despite the fact that its impairment disrupts communication and can lead to social withdrawal and isolation. Our ability to hear sounds and clothe them with meaning forms the basis of language, music, learning, and culture. In other words, it helps to define humankind. We have long felt the need for a volume on the human auditory system in the Handbook of Clinical Neurology series. Such a volume could summarize the basic aspects of the auditory system, detail the methods that have been used to establish our current knowledge and further our understanding of how the system functions, review the various clinical disorders that result from gross or subtle abnormalities in the auditory system, and perhaps predict future developments in the field. It is therefore with great pleasure that we welcome this new volume to the series, edited by Gastone G. Celesia, former Professor and Chair of the Department of Neurology, Loyola University, Stritch School of Medicine, Chicago, and past Editor-in-Chief of the journal Electroencephalography and Clinical Neurophysiology, who has long had an interest in sensory systems and their integration centrally, and by Gregory Hickok, Professor and Director of the Center for Language Sciences at the University of California at Irvine, and former President of the Society for the Neurobiology of Language. Both are world authorities in their respective fields and together have made an outstanding team to develop and edit this authoritative volume. The volume contains 38 chapters divided into three sections. The first section, which contains 12 chapters, discusses the anatomy and physiology of the human auditory system and also includes chapters on speech perception, production, and processing and on the perception of music. The second section contains six chapters on methodologies and techniques for investigating the auditory system. In a final section, 20 chapters discuss various disorders involving the auditory system, from such common problems as tinnitus or deafness from cochlear and auditory nerve disorders to less commonly encountered abnormalities such as congenital and acquired amusias and musicogenic epilepsy. The volume editors have added a final chapter in this section, dedicated to future advances in the field and thus providing insight into what might be expected in the years ahead. Professors Celesia and Hickok have gathered about them a group of international experts to contribute to the present compendium, which they have crafted to ensure that the various contributions fit seamlessly together to produce a truly valuable appraisal and synthesis of the literature. We are grateful to them and to all the contributors. We have read and commented on each of the chapters in our capacity as series editors and believe that both clinicians and basic scientists will find much to appeal to them in this volume. Furthermore, the availability of the volume electronically on Elsevier’s Science Direct site should ensure its ready accessibility and facilitate searches for specific information. As always, it is a pleasure to thank Elsevier, our publishers – and in particular Mica Haley, Michael Parkinson, and Kristi Anderson – for their assistance in the development and production of this volume. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

Preface

Nature has given man one tongue, but two ears, that we may hear twice as much as we speak. Epictetus (c. AD 50–138), Fragment VI At the beginning of recorded history, philosopher/physicians began to observe and record the human ability to hear, see, smell, and taste. Alcmaeon of Croton (sixth–fifth century BC) was the first to write about hearing, as reported by Theophrastus (371–287 BC) in De Sensibus: Hearing is by means of the ears, he [Alcmaeon] says, because within them is an empty space, and this empty space resounds. A kind of noise is produced by the cavity, and the internal air re-echoes this sound. The first historical document that reported impaired hearing is found in a set of tablets excavated in Epidaurus dating to the fourth century BC. Sigerist in his History of Medicine states that two cases of deafness were listed among the 70 cases found. Around 385 BC Plato stated that deaf Athenians used a “sign language” to communicate, although at that time it was believed that deaf people could not be educated. It was only 2000 years later, during the Renaissance, that systematic studies of the anatomy of hearing began and the stigma of deafness started to change. Pedro Ponce de Leon (1510?–1584), a Benedictine monk, is recognized as the first teacher interested in helping deaf children. Progress in knowledge of the auditory system has been slow but steady; we have now come a long way. In the last 50 years, the literature on the anatomy and physiology of hearing and its disorders has reached encyclopedic proportion. Yet most of the knowledge of the human auditory systems is scattered among diverse publications and from different disciplines: from neurophysiology to audiology, from otolaryngology to neuropsychology, and from neurology to psychiatry. It is the task of this volume of the Handbook of Clinical Neurology to assemble current knowledge into a single volume with the collaboration of world-renowned experts from the basic and clinical sciences. The reader will have the opportunity to obtain information on the auditory pathways and auditory cortex, on the relationship between sound, music, and language, and on how the human auditory system can be tested. The various disorders of audition from the cochlea to the cortex are detailed, providing a comprehensive description of their clinical features, diagnosis, and therapy. Section 1 of the volume describes the anatomy and physiology of the human auditory system. It includes descriptions of auditory pathways and the organization of the auditory cortex as well as an account of the development, and of learning and memory, of the auditory system. The representation of pitch, loudness, sound localization, and temporal coding is emphasized and based on human data. Speech perception, production, music perception, and the relationship of music and language are described. Section 2 reviews the methodology and techniques used to study the system. It includes direct recording of the human auditory cortex as well as non-invasive electromagnetic and electrophysiologic testing of the system. Psychophysical and behavioral auditory testing is included. Neuroimaging techniques of the auditory cortices and the whitematter pathways are described. Section 3 describes disorders of the auditory system. This section includes neurocognitive development in deaf children, aging of the system, central auditory processing disorders, and altered perceptions of sound from hyperacusis, diplacousis, tinnitus, auditory synesthesias, hallucinations, and palinacousis. Musicogenic epilepsy, auditory neglect, agnosia, and word deafness are described. Deafness in cochlear and auditory nerve disorders is covered as well as auditory neuropathy, hearing disorders in brainstem lesions, congenital and acquired amusias. Hearing

x

PREFACE

difficulties in strokes, multiple sclerosis, and dementia are described. Lastly, the subject of future advances is addressed, with the knowledge that they are difficult to predict, and only educated guesses are possible. We hope to have been successful in our endeavors and that this handbook will serve as the benchmark summarizing present knowledge and inspiring future research. Gastone G. Celesia Gregory Hickok

Contributors

P. Afra Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA P. Albouy Auditory Cognition and Psychoacoustics Team and Brain Dynamics and Cognition Team, Lyon Neuroscience Research Center, and University Lyon 1, Lyon, France L.H. Arnal Department of Neurosciences, University Medical Centre, Geneva, Switzerland and Department of Psychology, New York University, New York, NY, USA D.E. Bamiou Ear Institute, University College London and Neurootology Department, National Hospital for Neurology and Neurosurgery, London, UK J.D. Bellis Auditory Neuroscience Laboratory, Department of Communication Sciences and Disorders, University of South Dakota, Vermillion, SD, USA T.J. Bellis Department of Communication Sciences and Disorders, USD Speech-Language-Hearing Clinics and Division of Basic Biomedical Sciences, University of South Dakota, Vermillion, SD, USA J.D. Blom Parnassia Psychiatric Institute, The Hague and University of Groningen, Groningen, The Netherlands

G.G. Celesia Department of Neurology, Loyola University of Chicago; Chicago Council for Science and Technology, Chicago, IL, USA G.D. Chermak Department of Speech and Hearing Sciences, Washington State University Spokane, Spokane, WA, USA M.L. Chow School of Medicine, University of California, San Francisco, CA, USA C.N. Clark Dementia Research Centre, UCL Institute of Neurology, University College London, Queen Square, London, United Kingdom A.R. Dykstra Department of Neurology, Ruprecht-Karls-Universita¨t Heidelberg, Heidelberg, Germany M.C. Fields Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA E. Fitzpatrick Faculty of Health Sciences, University of Ottawa and Children’s Hospital of Eastern Ontario Research Institute, Otttawa, ON, Canada A.D. Friederici Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany

A. Caclin Brain Dynamics and Cognition Team, Lyon Neuroscience Research Center and University Lyon 1, Lyon, France

M. Furst School of Electrical Engineering, Tel Aviv University, Tel Aviv, Israel

M. Catani NatBrainLab, Institute of Psychiatry, King’s College London, London, UK

A-L. Giraud Department of Neurosciences, University Medical Centre, Geneva, Switzerland

xii CONTRIBUTORS H.L. Golden and Physiology and Department of Otolaryngology, Dementia Research Centre, UCL Institute of Neurology, Northwestern University, Evanston, IL, USA University College London, Queen Square, London, A.D. Legatt United Kingdom Departments of Neurology and Neuroscience, Montefiore Medical Center and Albert Einstein College F.H. Guenther of Medicine, Bronx, NY, USA Departments of Speech, Language, and Hearing Sciences and Biomedical Engineering, Boston R.A. Levine University, Boston, MA, USA Department of Ear, Nose and Throat and Head and Neck Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, A. Gutschalk Israel Department of Neurology, Ruprecht-Karls-Universita¨t Heidelberg, Heidelberg, Germany T.A. Hackett Department of Hearing and Speech Sciences, Vanderbilt University School of Medicine and Department of Psychology, Vanderbilt University, Nashville, TN, USA D.A. Hall National Institute for Health Research, Nottingham Hearing Biomedical Research Unit, University of Nottingham, Nottingham, UK G. Hickok Department of Cognitive Sciences, Center for Language Science and Center for Cognitive Neuroscience, University of California, Irvine, CA, USA K. Hopkins School of Psychological Sciences, University of Manchester, Manchester, UK M.A. Howard III Department of Neurosurgery, University of Iowa, Iowa City, IA, USA P. Janata Center for Mind and Brain and Department of Psychology, University of California, Davis, CA, USA M.M. Jastreboff JHDF, Inc., Ellicott City, MD, USA P.J. Jastreboff Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA J.K. Johnson Institute for Health and Aging, University of California, San Francisco, CA, USA N. Kraus Auditory Neuroscience Laboratory, Department of Communication Sciences, Department of Neurobiology

R. Litovsky Binaural Hearing and Speech Laboratory, Waisman Center, University of Wisconsin-Madison, Madison, WI, USA C. Maffei NatBrainLab, Institute of Psychiatry, King’s College London, London, UK B.J. Malone Center for Integrative Neuroscience and Coleman Memorial Laboratory, Department of Otolaryngology – Head and Neck Surgery, University of California San Francisco, San Francisco, CA, USA L.V. Marcuse Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA J.C. Middlebrooks Departments of Otolaryngology, Neurobiology and Behavior, Cognitive Sciences, and Biomedical Engineering, University of California at Irvine, Irvine, CA, USA F.E. Musiek Department of Communication Sciences and Department of Surgery (Otolaryngology), School of Medicine, University of Connecticut, Farmington, CT, USA K.V. Nourski Department of Neurosurgery, University of Iowa, Iowa City, IA, USA Y. Oron Department of Otolaryngology, Head and Neck Surgery, E. Wolfson Medical Centre, Holon, Israel J.O. Pickles Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia

CONTRIBUTORS xiii D. Poeppel L.R. Slevc Department of Psychology, New York University, Department of Psychology, University of Maryland, New York, NY, USA College Park, MD, USA A. Prats-Galino Laboratory of Surgical NeuroAnatomy, Human Anatomy and Embryology Unit, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain G. Rance School of Audiology, University of Melbourne, Melbourne, Australia T.N. Roth Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Zurich, Zurich, Switzerland

G. Soria Experimental 7T MRI Unit, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain A. Starr Departments of Neurology and Neurobiology, University of California, Irvine, CA, USA J. Stern Department of Neurology, Geffen School of Medicine, University of California, Los Angeles, CA, USA K. Susi Division of Psychology, School of Social Sciences, Nottingham Trent University, Nottingham, UK

C.E. Schreiner Center for Integrative Neuroscience and Coleman Memorial Laboratory, Department of Otolaryngology – Head and Neck Surgery, University of California San Francisco, San Francisco, CA, USA

B. Tillmann Auditory Cognition and Psychoacoustics Team, Lyon Neuroscience Research Center and University Lyon 1, Lyon, France

A.R. Shell Department of Psychology, University of Maryland, College Park, MD, USA

J.D. Warren Dementia Research Centre, UCL Institute of Neurology, University College London, Queen Square, London, United Kingdom

J. Slater Auditory Neuroscience Laboratory and Department of Communication Sciences, Northwestern University, Evanston, IL, USA

N.M. Weinberger Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, CA, USA

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 1

Auditory pathways: anatomy and physiology JAMES O. PICKLES* Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia

INTRODUCTION AND OVERVIEW The auditory brainstem, midbrain, and cortex have a multiplicity of parallel and overlapping pathways, which have parallel but overlapping and interrelated functions. In addition, the stages of analysis of the auditory signal are not as clearly separated or as clearly comprehensible as in for instance the visual system. It is difficult therefore to use a simple functional framework to help understand the anatomic and physiologic results. It is hoped that this chapter will provide a scheme by which the auditory system can be more easily approached and understood. The auditory signal is a time-dependent variation in sound pressure. From the one-dimensional stimuli as received by each ear, the whole multifeatured auditory world is constructed. Therefore the auditory system accomplishes an outstanding feat of both analysis and synthesis. This chapter will describe some of the anatomy and physiology that underlies this. The issues described in this chapter are also described in more detail in An Introduction to the Physiology of Hearing, to which the reader is referred for further information (Pickles, 2012).

THE OUTER AND MIDDLE EARS The input impedance of the cochlea (defined as the pressure required to produce a unit displacement of the oval window) is some 200 times greater than that of free air (Nakajima et al., 2009). If the sound vibrations met the oval window directly, we can calculate that most of the energy would be reflected, with only 2% of the energy being transmitted. However, the outer and middle ears increase this transmission substantially. The increase in transmission is accomplished at two stages. Firstly, the outer ear acts as a directionally sensitive ear trumpet, collecting sound pressures over the area of the pinna, and by a set of resonances, increasing

the sound pressure at the rather smaller tympanic membrane. The frequency peaks of the major resonances are complementary, so that the pressure at the eardrum is raised relatively uniformly, by 15–20 dB, over the frequency range from 2 to 8 kHz, with transmission being similarly raised. Secondly, there is an impedance transformer in the middle ear; this stage makes the major contribution. The middle-ear transformer has two components. Firstly, the largest factor arises from the ratio of the area of the tympanic membrane to the area of the footplate of the stapes in the oval window. The two areas are 60 mm2 and 3.2 mm2 respectively. The pressure on the oval window, and hence the pressure/displacement ratio, is therefore increased 60/3.2 ¼ 18.75 times. The second factor is the lever action: the arm of the malleus (i.e., the umbo) is 2.1 times longer than the arm of the stapes. Therefore the force at the round window, and hence the pressure, is increased 2.1 times, while the displacement is decreased 2.1 times. The impedance ratio, being pressure/displacement, is therefore increased 2.12 ¼ 4.4 times. The overall impedance change of the driving stimulus is therefore increased by 18.75  4.4 times ¼ 82.5 times. The overall effect of the outer and middle ears is to increase the transmission efficiency, at its optimum frequency of 1 kHz, to 35% (Rosowski, 1991). Most of the losses in transmission are due to friction in the middle ear.

The absolute threshold and relation to outer- and middle-ear transmission Over a wide range of frequencies, and in a variety of mammals, including human beings, the auditory absolute threshold corresponds to a power of the order of 10–18 W absorbed by the inner ear (Rosowski, 1991). Since at threshold we integrate energy for approximately

*Correspondence to: James O. Pickles, Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Qld, Australia. E-mail: [email protected]

4 J.O. PICKLES 300 ms to make a decision, this equals an energy detecresolution, but without the long temporal “ringing” that tion threshold of 3  10–19 J. This corresponds to the would normally accompany such a high degree of freenergy in a single quantum of red light. Therefore the quency resolution. fundamental energy sensitivities of the eye and the ear The input vibrations of the cochlea produce the wellare comparable. known traveling wave on the basilar membrane, which In young human beings with good hearing, the threspeaks more basally for stimuli of higher frequencies, hold of 10–18 W delivered to the cochlea applies over the and more apically for stimuli of lower frequencies range of 450 Hz to at least 10 kHz. Therefore, within this (Fig. 1.2A). Therefore stimulus frequency is mapped range the shape of the audiogram, i.e., the variation in on to place of stimulation in the cochlea. As originally the threshold of hearing as a function of frequency, measured by Be´ke´sy in human cadavers (see Be´ke´sy, can be described by the variation in the efficiency of 1960), the traveling wave was relatively small and broad, transmission through the outer and middle ears to the and showed poor frequency selectivity as the frequency inner ear. At higher and lower frequencies, however, was changed. It is now recognized that when the cochlea other factors come into play. The upper frequency limit is in good physiologic condition, the traveling wave is of hearing in human beings is commonly taken as 20 kHz much larger and more sharply peaked, showing a much in young children and 15 kHz in young adults (e.g., greater frequency selectivity (Fig. 1.2B; for review see Dadson and King, 1952). The upper frequency limit of Robles and Ruggero, 2001). hearing arises because the cochlea itself becomes unreThe sharp tuning and great sensitivity arise because sponsive to stimuli of higher frequency (Ruggero and the organ of Corti acts as a regenerative mechanical Temchin, 2002). At low frequencies (70 dB HL), essentially preventing them from detecting speech sounds without specialized hearing technology (hearing aids or cochlear implants). In this cohort, 7% presented with ANSD. Consideration of the subgroup of 285 children identified since the implementation of UNHS reveals strikingly similar results. This chapter is concerned with congenital hearing loss of a permanent nature, the overwhelming majority being sensorineural in origin, but there is one important caveat. In studies conducted prior to UNHS, children diagnosed with hearing loss before age 2–3 years were frequently

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assumed to have congenital disorders in the absence of any specific information regarding delayed onset. Thus, specifically isolating the effects of congenital hearing loss is difficult until sufficient studies become available from newborn screening cohorts that report data separately for children with congenital and lateronset hearing loss.

Hearing loss and additional disabilities One of the complexities of determining the effects of hearing loss on development is that it does not necessarily occur in isolation, independently of other conditions that affect children’s neurodevelopment outcomes. Several reports indicate that up to 30–40% of children with hearing disorders have at least one additional disability (Van Naarden et al., 1999; Picard, 2004; Gallaudet Research Institute, 2011). A recent review of population-based clinical data showed that 82 (23%) of 363 children identified with permanent hearing disorders in a 10-year period had at least one additional developmental disability; disabilities were associated with a syndrome for 26 (32%) children (Fitzpatrick and Doucet, 2013). Table 19.2 provides an overview of the broad range of developmental conditions documented for the children with non-syndromic deafness. In the presence of other disabilities, particularly when associated with cognitive delay, disentangling the specific consequences of hearing loss on spoken language and other neurodevelopmental areas is complicated. For example, the majority of children with Down syndrome have some level of hearing loss (permanent conductive loss due to middle-ear disorders or sensorineural loss) which persists throughout childhood and which can have an additive or even multiplicative effect for cognitive and speech language development (Rasore Quartino, 2011). There is now an extensive literature on children with additional disabilities associated with developmental delay who have profound deafness and were fitted with cochlear implants. There is evidence to suggest that these Table 19.2 Clinical profile of 56 children with additional documented developmental disabilities Developmental condition

Percent

Motor disability Communication-related disability Autism spectrum disorder Cognitive disability Attention-deficit hyperactivity disorder Learning disability Other (various conditions)

33.9% 10.8% 7.1% 7.1% 3.6% 3.6% 33.9%

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E. FITZPATRICK

children achieve lower language skills than would be expected according to their cognitive abilities (Meinzen-Derr et al., 2011). Overall, children with severe cognitive delay have shown minimal progress in the development of auditory skills and spoken language (Olds et al., 2005; Meinzen-Derr et al., 2011).

EFFECTS OF PERMANENT CHILDHOOD HEARING LOSS ON THE CHILD AND FAMILY The most apparent and understandable effect of congenital hearing loss is disruption in the typical acquisition of spoken language. Consequences of delayed language skills are also manifested, at least for some children, in later difficulties in literacy, academic and social functioning (Wake et al., 2004; Geers, 2006). In addition to the more obvious cascade effects of deafness resulting in language, educational, and quality-of-life concerns, early auditory access seems to contribute substantially to the beginning stages of the child’s perceptual and cognitive development (Ruff et al., 1992; Perone et al., 2008; Fagan and Pisoni, 2009). Therefore, in addition to providing an important foundation for spoken language development, hearing plays an important role in the development of cognitive abilities in domains such as attention, learning, and memory (Pisoni et al., 2008). It follows, then, that children with congenital loss are especially susceptible to disruptions in language development due to a lack of auditory stimulation in early infancy, a sensitive period for language acquisition.

Auditory plasticity Evidence has accumulated from neuroscience to show that the developing brain depends on multiple sensory inputs for typical maturation. There is evidence from animal studies that deafness during the early years of life interferes with or disrupts typical auditory cortical

development by delaying or preventing the formation of neuronal connections and the maturation of cortical layers (Kral and O’Donoghue, 2010; Kral and Sharma, 2012). Research points to a sensitive period for auditory cortical development, suggesting that after this period the brain reorganizes itself, that is, cross-modal reorganization takes place to adapt to information from other sensory modalities (Kral, 2007; Kral and O’Donoghue, 2010). Consequently, auditory cortical areas become reassigned to other types of non-auditory sensory input, decreasing the brain’s efficiency in processing auditory input (Sharma et al., 2009). A series of studies using cortical auditory evoked potentials in children with profound deafness fitted with cochlear implants at various ages lend support to a “sensitive” period for maximal auditory development (Sharma et al., 2002, 2005; Sharma and Dorman, 2006). By measuring cortical auditory evoked potential (P1) responses in children who received cochlear implants at different ages, Sharma and Dorman (2006) summarized convincing evidence for the importance of early auditory stimulation. In studies of 107 individuals (104 children) with either congenital deafness or onset in the first year, age 3.5 years emerged as the approximate upper boundary for normal cortical responses while children implanted after 7.0 years demonstrated abnormal responses following several years of stimulation with their implant (Fig. 19.2). Children fitted with cochlear implants between these two ages showed a range of response latencies. Studies in individuals with long-term deafness suggest that visual processing may occur in cortical regions usually dedicated to auditory processing. For example, as shown in Figure 19.3 from Neville et al. (1998), in adults with congenital deafness who were primarily users of sign rather than spoken language, processing of sign language (visual stimuli) activates areas in the auditory cortex. Functional studies of individuals with congenital deafness who were

Fig. 19.2. (A) P1 latencies as a function of age for normal-hearing children. The line of best fit and the 95% confidence interval are superimposed on the raw data. (B) P1 latencies as a function of chronologic age for children with cochlear implants. The solid functions are the 95% confidence limits for normal-hearing children. P1 latencies for children implanted before age 3.5 years (early-implanted group) are shown as circles. P1 latencies for children implanted between age 3.5 years and 6.5 years (middleimplanted group) are shown as crosses. P1 latencies for children implanted after age 7 years (late-implanted group) are shown as triangles. (Reproduced from Sharma et al., 2002.)

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Fig. 19.3. Cortical areas displaying activation (P < 0.005) for American Sign Language (ASL) sentences (versus non-signs) for three subject groups. These results (from Neville et al., 1998) suggest that spoken language acquisition is not a requirement for establishing specialized language systems in the left hemisphere. When processing sentences in ASL versus non-signs, normalhearing adults who were not sign language users showed no differences in activation (A); deaf adult users of ASL showed significant left-hemisphere activation as well as right-hemisphere activation (B); similarly, normal hearing adults who were native signers also showed significant left-hemisphere activation as well as right-hemisphere recruitment (C). (Reproduced with permission from Neville et al., 1998. Copyright (1998) National Academy of Sciences, USA.)

implanted as adolescents or adults show limited ability for auditory-only speech recognition for words and phrases relative to post-linguistically deafened adults or early-implanted children (Schramm et al., 2002; Waltzman et al., 2002).

Sensitive period for language learning In addition to the concept of a “critical period” specifically for auditory stimulation, children seem to be

organically ready to develop language (Chomsky, 1986), the length of the period varying depending on the particular aspect of language (Ruben, 1997). Language acquisition occurs at remarkably similar timelines across children from different social and cultural backgrounds. Arshavsky (2009) proposes that early language experience is required to “activate” genetic programs that underlie language acquisition during early brain development. The existence of a time window for language development is supported by naturally occurring

340 E. FITZPATRICK experiments of children who were disconnected from speech, that is, use more requests and commands in comlinguistic environments in the early years and who, when municating with their child rather than usual infantdiscovered as adolescents, were unable to acquire nordirected talk. mal language (Curtis, 1977; Singh and Zingg, 1996). There is considerable evidence from studies related to Studies in infant speech perception have revealed children with normal hearing in early development prothat, from the first few months, infants are programmed grams that mothers’ responsiveness is a key factor in to listen to speech and prefer speech over non-speech early linguistic development. In fact, some studies have sounds (Vouloumanos and Werker, 2007; shown that responsiveness has a far greater impact on Vouloumanos et al., 2009). Research indicates that, durearly child development than specific therapeutic intering the first 6 months, infants essentially function as univentions undertaken to enhance language development, versal language receptors; that is, they appear to even stronger than the intervention specifically on the differentiate between all phonemic categories (for child’s development. There is strong support from other example, pa versus ba contrast), even those not used literature for the role that parents play in enhancing cogin their native language (Werker and Tees, 2005). Hownitive development. For example, studies have shown ever, by their first birthday, children’s brains undergo that parent responsiveness is an important predictor of reorganization to discriminate phonemes specific to children’s developmental age and intelligence quotient the languages to which they are exposed in their daily scores (Fewell et al., 1996; Landry et al., 1997). For examenvironments (Werker and Yeung, 2005). During this ple, Landry et al., in their study of 299 full-term and lowperceptual fine-tuning period, the infant appears to birth-weight children, reported that children had higher “sharpen” the phonetic contrasts required for language cognitive-language ages at 18 months of age if their and to ignore differences that are not relevant in the lanmothers’ interactions were characterized by high proporguage spoken around the infant. Most children with contions of maintaining interest (P ¼ 0.002) (e.g., engaging genital hearing loss will not have normal access to speech and responding to child’s attempt to attract attention). and therefore cannot fully experience this foundation In contrast, mothers’ use of more restrictive interactions period for language learning unless hearing technology (P ¼ 0.002) such as attempting to stop their child’s is provided within the first days or weeks of life. attempts at communicating, was highly associated with In typically developing infants, perception of speech lower cognitive-linguistic ages. Furthermore, higher sounds, phonologic development, and vocabulary interlevels of restrictive behaviors were related to lower act are viewed as cognitive-linguistic blocks on which social initiating ages for these children, particularly later receptive and expressive language and even literacy for the 73 children categorized as medically high-risk. are built (Jusczyk, 1997). It seems that, for most children These parent behaviors have also emerged as critical in with hearing loss, there is likely at least some disconnect research related to children with developmental disabilin this early synergy among various components of lanities (Mahoney et al., 2004). guage development. Capitalizing on these periods when Mahoney et al. (2007) suggested parent responsivechildren are developmentally “programmed” to learn ness increases the frequency that children use certain language appears to offer the greatest chance for natural pivotal behaviors, behaviors considered as foundations language acquisition. for social and cognitive developmental learning. Their study of 45 mother–child dyads (pairs) showed that, in children under age 3 with developmental delays, heightImpact on child’s experience in the family ened mother responsiveness enhanced the use of the As described above, reduced hearing that leads to child’s pivotal behaviors such as attention, initiation, perdelayed and degraded acoustic inputs can be expected sistence, cooperation, and joint attention. Furthermore, to have repercussions for the developing child by intermore frequent use of these behaviors was associated fering with brain maturation of the auditory cortex at with higher rate of social communication and cognitive a sensitive developmental period. Also of paramount development. The authors conclude that, regardless of importance is that hearing loss not only impacts the child, type of developmental disability, parents’ ability to but also affects how the family interacts with the child in respond to their child is key to nurturing children’s overthis early learning period. There is some evidence showall learning and development. Other research with chiling that families, primarily mothers, of children with dren with disabilities has shown that intervention was hearing loss alter how they interact with their children in fact ineffective if it did not enhance parents’ respon(Cole, 1992; Calderon and Greenberg, 2003; Cole and siveness with their children (Mahoney et al., 2004). Flexer, 2011). For example, in the absence of typical feedA study of 32 mothers and their preschool children with back from a child, parents may spend less time talking cochlear implants revealed that mothers’ involvement with the child, be less engaged, and use more directive and their sense of self-efficacy were highly related to

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Table 19.3 Associations between maternal self-efficacy and involvement and facilitative language techniques Facilitative language techniques Parallel talk Expansion Recast Open–ended question Linguistic mapping Closed-ended question Imitation Label Directive Comment

Maternal self-efficacy cochlear implant

Maternal involvement cochlear implant

Maternal self-efficacy speech language

Maternal involvement speech language

–0.03 –0.11 –0.35 0.27

0.04 0.08 –0.23 0.14

0.45* 0.22 0.08 0.10

0.56† 0.39* –0.31 0.30

–0.36

–0.09

–0.63†

–0.37

0.13

–0.35

0.12

–0.05

–0.01 –0.07 –0.18 0.15

0.36 0.08 –0.39 –0.03

–0.63* –0.29 –0.52* –0.39

–0.56* –0.51* –0.53* –0.40*

P < 0.05; †P < 0.01. Reproduced from Desjardin and Eisenberg (2007).

*

the quantity and quality of linguistic input they provided (Desjardin and Eisenberg, 2007). Table 19.3 details the associations reported in this study between mothers’ use of facilitative language techniques and their sense of self-efficacy and involvement with both their child’s cochlear implant device and speech-language development. Taken together, these studies lead to the conclusion that any interference with natural experiences, including reduced linguistic and social exposure from parents, can have a negative “experiential” effect on communication, learning, and social development. It seems reasonable to infer that young children with hearing loss, whose parents learn about the disorder in the early developing years, are particularly at risk. Not only are affected children receiving reduced or poorer-quality sensory information through hearing technology but it can be a difficult emotional time for caregivers. Fewer than 10% of children with hearing loss have parents who are themselves deaf (Mitchell and Karchmer, 2004), so most families are adjusting to the shock and diagnosis of hearing loss (English, 2011). Parent interviews about their early experiences with learning about deafness suggest that it can indeed be a fragile period wrought with emotions such as guilt and grief (Young and Tattersall, 2007; Fitzpatrick et al., 2008) and the early months and years can be characterized by a period of particular vulnerability, guilt, and grief (Luterman, 2008). Of importance is that parents are living these poignant experiences and learning about deafness and new technology in a period that is understood to be a sensitive

learning period for all children acquiring spoken language. As reflected in parent interviews (Fitzpatrick et al., 2007b), this can be a particularly taxing time. This information suggests that investment in informing, teaching, coaching, and emotionally supporting parents during this period is extremely important to encourage auditory and general cognitive stimulation of the brain centers (Fitzpatrick and Doucet, 2013). Interestingly, what many parents report that they need most at this period is support from other parents (Fitzpatrick et al., 2008; English, 2011). A recent international consensus statement (Moeller et al., 2013) supports family-centered practice as the best approach to facilitating enriching developmental experiences in the early years. One of the best practice principles outlined in the statement is that service providers and families work together to establish optimal learning environments. This implies that families learn to enhance their child’s communication and developmental skills through natural techniques during routine daily experiences. The risk for families, and by default for the child, is well recognized in the Joint Committee on Infant Hearing (2007) guidelines that recommend that all families of children with any degree of hearing loss should be considered eligible for early intervention support. This recognizes the prominent role the family plays in fostering the child’s overall neurocognitive development and that rehabilitation for a young child cannot be considered separately from the family context. One of the greatest challenges for families in the early months after diagnosis is achieving full-time use of

342

E. FITZPATRICK

hearing technology (Moeller et al., 2009), an outcome considered so necessary to maximizing auditory input, language, and early cognitive skills. Particularly vulnerable groups are children with mild and unilateral hearing loss, with studies showing 40–50% not achieving consistent use of amplification devices (MacKay et al., 2008; Fitzpatrick et al., 2010). To conclude, it is well accepted that the trajectory for language and literacy is established in infancy. That is, quality stimulation in the early years is requisite for laying the groundwork for later cognitive, linguistic, literacy, academic, and social competence (Hart and Risley, 1995; Mustard, 2006). For example, in a landmark longitudinal study of families and children from different socioeconomic strata, Hart and Risley demonstrated the incredible impact that the quantity of language exposure has on children’s verbal skills. Embellished experiences are likely even more critical for children with congenital hearing loss who do not have a “buffer.” Recognition of the neurophysiologic and range of cognitive benefits from enriched input in the early years has provided a compelling argument for investments in early identification of hearing loss to facilitate early access to auditory and linguistic stimulation.

CURRENT CONTEXT FOR CHILDREN WITH HEARING LOSS Two key developments in the last two decades are largely credited with dramatically transforming neurodevelopmental outcomes and expectations for future progress for children with congenital hearing loss: early intervention in the first few months of life and the availability of improved hearing technology, particularly cochlear implants for children with severe to profound hearing loss.

Neonatal hearing screening Early intervention has become possible because of worldwide UNHS initiatives. This movement has been fueled by comparison studies that showed improved developmental outcomes in children who benefitted from early detection (Yoshinaga-Itano et al., 1998a; Moeller, 2000). Until the 1990s, the average age of identification of hearing loss was 2–2.5 years (Durieux-Smith et al., 2008), with an inverse relationship between severity of loss and age of identification. Developments in screening technologies, notably otoacoustic emissions testing and automation of auditory brainstem response testing, contributed to the feasibility, accuracy, and affordability of population-based screening. These events, coupled with convincing evidence from neuroscience about the effects of auditory deprivation on the

developing brain, have significantly changed the landscape of deafness. The overarching goal of screening as defined by the Joint Committee on Infant Hearing (2007) is to reduce or prevent delays in development. The recommended timelines are screening by 1 month of age, identification by 3 months, and intervention by 6 months. While there is good evidence that UNHS has significantly lowered the age of detection for children with moderate and greater hearing losses (Nelson et al., 2008), documenting evidence that early detection translates to improved developmental outcomes, as discussed in a subsequent section, is more tenuous (Nelson et al., 2008; Colgan et al., 2012).

Cochlear implantation The second key development, pediatric cochlear implantation, has unequivocally dramatically improved the amount and quality of auditory information available to children with severe to profound hearing loss (Thoutenhoofd et al., 2005; Bond et al., 2009). Since first approved for children in the United States in 1990, pediatric cochlear implantation has become standard care for this population of children. While in the first decade unilateral cochlear implantation was common practice, there has been a trend toward bilateral implants in recent years (Papsin and Gordon, 2008). As will be discussed in subsequent sections of this chapter, cochlear implantation has provided a unique opportunity to examine neurodevelopmental outcomes in children who previously had little or no auditory stimulation. Since the widespread use of cochlear implants, degree of hearing loss is no longer a barrier to accessing spoken language, even for congenital deafness. Clinical candidacy criteria have expanded to include less severe hearing loss (Fitzpatrick et al., 2009; Leigh et al., 2011) and younger ages at implantation (Dettman et al., 2007). Several researchers have equated hearing via cochlear implants to be roughly equivalent to hearing by children with moderate or moderately severe hearing loss using hearing aids (Sarant et al., 2009; Spencer and Marschark, 2010). However, cochlear implantation does not constitute a cure for hearing loss and it is well recognized that even children who undergo this intervention very early require specialized rehabilitation therapy and that families require ongoing guidance to optimize neurocognitive development.

Expectations A third but and perhaps less perceptible shift shaping the current context is professionals’ (e.g., otolaryngologists’, audiologists’ and language, and other health and education specialists’) expectations that auditory speech reception and spoken language development

NEUROCOGNITIVE DEVELOPMENT IN CONGENITALLY DEAF CHILDREN 343 ● Families need specific guidance to provide optimal stimulation, and therefore intervention should be family-centered to provide children with embellished experiences for language learning. ● Increasingly, children with normal cognitive abilities who receive early technology and neurocognitive rehabilitation have the potential to develop language skills comparable to those of their hearing peers.

are now a possibility for the overwhelming majority of children with congenital hearing loss, irrespective of degree of hearing loss. These attitudes directly and indirectly influence environmental factors, such as policies, funding, and type of intervention offered. There is now an “investment” in making speech accessible to all children from an early age if parents choose hearing technology options. Early intervention for children with hearing loss encompass comprehensive services that include audiologic, medical, language, cognitive, and social interventions that aim to improve the development of the child and family (Jerger et al., 2001; Joint Committee on Infant Hearing, 2007). Despite greater and easier access to “hearing” than ever before, hearing has not been restored.

Summary To summarize, in the current context of neonatal screening and early intervention, there is a consensus that: ●

●

Intervention should begin as early as possible to take advantage of neuroplasticity of the auditory system and to provide optimal stimulation synchrony with the typical language acquisition period in the first 3 years of life. Hearing technology alone is insufficient for most children and children need specialized intervention.

FACTORS AFFECTING NEUROCOGNITIVE DEVELOPMENT Figure 19.4 provides a framework (Fitzpatrick, 2010), adapted from the World Health Organization (WHO) International Classification of Functioning and Disability (World Health Organization, 2001), of the multitude of factors potentially affecting neurocognitive development in children with hearing loss. In the WHO model, body functions and structure (e.g., hearing loss) affect an individual’s outcomes that in turn impact participation in society. Outcomes in this expanded model include not only neurodevelopmental outcomes such as communication and cognition, but also process and family outcomes, all of which have emerged in research with families as important aspects to consider (Tattersall and Young, 2006; Fitzpatrick et al., 2007b; Nelson et al., 2008). Consistent with the WHO model, multiple

Infant Hearing

OUTCOMES COMMUNICATION Hearing Access Speech-Language Cognition Literacy Social

Body Functions and Structure

FAMILY Guilt Anxiety Stress Acceptance of loss

Participation

PROCESS Seamless transition to health services Smooth transition to intervetion

Environmental Factors Service Provider

Geography

-Coordinated care -Parent support -Hearing technology

Service Model

-Access to intervention -Type of intervention -Information

Family Factors -Family functioning -Socio-economic status -Family resources -Previous experience

Child Factors -Age of diagnosis -Hearing age -Degree/type of loss -Developmental level -Temperament

Fig. 19.4. Conceptual framework of outcomes and factors related to development in children with hearing loss. (Adapted with permission from Fitzpatrick, 2010.)

344 E. FITZPATRICK environmental and personal (both family and child) faca need to demonstrate the efficacy and effectiveness tors interact to shape the child’s experience and affect of a new biomedical device. With convincing evidence developmental outcomes. that even children with congenital and early-onset profound deafness could process information through Approaches to neurodevelopmental audition alone, researchers also became interested in rehabilitation examining the benefits of this new intervention for language development. More recently, as described Despite the important gains in research on language in subsequent sections, there has been increasing acquisition in children with hearing loss, particularly interest in examining other aspects of development since the availability of cochlear implants, many outbeyond hearing and language and in investigating other standing questions remain about how spoken communineurocognitive functions to better understand variabilcation develops, the most effective intervention methods ity in outcomes and to provide children who use for facilitating language development, and the contribucochlear implants with more customized interventions tion of various factors to language outcomes. Overall, (Peterson et al., 2010). there is considerable optimism about neurocognitive development opportunities for the current generation of children with early-identified hearing disorders. Since Children with mild to severe degrees most children now have the potential to develop spoken of hearing loss language, the subsequent sections will focus on neuroChildren with mild to severe degrees of hearing loss cognitive development where spoken language is the account for 70% or more of clinical populations with goal of intervention. Historically, there has been no conbilateral hearing loss. Clinical practices for children with sensus on how best to achieve desired outcomes in chilmoderate to severe loss are well defined (Bagatto et al., dren with hearing loss whose parents choose spoken 2010; King, 2010) and they are typically fitted with language. Intervention methods range from auditoryacoustic hearing aids to improve their access to speech based approaches such as auditory-verbal practice, and environmental sounds. Although hearing aids and focused on listening and inclusion of the child into regspecialized systems that facilitate listening in difficult ular education programs, to programs that include sign listening situations such as the classroom have less dralanguage to support spoken language development matically impacted auditory and speech-language out(Durieux-Smith and Fitzpatrick, 2011). Despite a long comes than cochlear implants, technologic advances in history of approaches and techniques, the evidence suphearing devices have occurred and pediatric-focused porting the effectiveness of any particular intervention techniques have been developed (Bagatto et al., 2011). approach is relatively weak due to the lack of goodMoeller et al. (2007) called attention to the lack of quality comparative studies (Schachter et al., 2002; research on this new generation of children who do Spencer and Marschark, 2010). not use cochlear implants but who have benefitted from earlier intervention and modern hearing technologies. In AUDITION AND SPOKEN LANGUAGE a series of papers in a special issue, these authors The overwhelming focus of research on neurocognitive highlighted that hearing loss across the spectrum of development is related to speech recognition (e.g., idenseverity affects children’s development in multiple tification of words, sentences) and language outcomes, domains. A review of language outcomes at that time not a surprising finding given the important and marked for this population of children found that most of the litimpact of hearing disorders on early auditory developerature pertained to children who were late identified, ment and subsequent spoken-language skills. Since the making it difficult to define realistic expectations. Sim1990s, much of pediatric hearing outcomes research ilarly, although there is an extensive literature on literacy has been divided into two somewhat distinct categories development in children with severe to profound hearing determined by the type of hearing technology used, hearimpairment, again Moeller et al. (2007) found very liming aids or cochlear implants, which roughly corresponds ited information, but the few studies suggested that chilto mild to severe and severe to profound hearing loss. dren lag behind their hearing peers. There has been a proliferation of research documenting A number of studies that have investigated outcomes the effectiveness of cochlear implants. In the early years, in this population in recent years combine results for less considerable research was focused on speech recognisevere children with those for children with cochlear tion measures such as the percentage of phonemes, implants, making it difficult to draw conclusions specifwords, or sentences correctly identified, as the best ically about the group with less severe loss. Data from proxy of hearing restoration with a cochlear implant. 51 children with congenital or assumed congenital losses This specific focus on auditory benefit was driven by recruited from three Canadian auditory-verbal clinics

NEUROCOGNITIVE DEVELOPMENT IN CONGENITALLY DEAF CHILDREN

345

5

3 2

0 5

HA/CI (71-90 dB)

Number of Children

1

4 3 2 1 0 5

CI/HA (> 90 dB)

4 3 2 1

140

PLS-AC Standard Score (mean, 95% CI)

HA ( ≤ 70 dB)

4

130 120 110 100 90 80 70 60 50 40 36 months

0 40.0

50.0

60.0

70.0

80.0

PLS-4 Expressive Communication Standard Score

Fig. 19.5. Distribution of expressive language scores (Preschool Language Scale (PLS), Expressive Communication) for children according to severity of hearing loss. Dotted lines indicate scores within 1 SD of test normative data. HA, hearing aids; CI, cochlear implant. (Reproduced from Fitzpatrick et al., 2011a.)

48 months

60 months

Age at Assessment

90.0 100.0 110.0 120.0 130.0 140.0 150.0 160.0

Fig. 19.6. Mean scores for language comprehension (Preschool Language Scale, Auditory Comprehension (PLSAC)) at age 3, 4, and 5 years. Dotted lines indicate scores within 1 SD of test normative data.

Child

130

105 112 121 125 128 130 132 137 144 149

120

110 PLS-AC Standard Score

(focus on developing spoken language through audition) showed that 94–100% of children with hearing loss 90 dB with cochlear implants showed more variable results than their hearing peers (Fitzpatrick et al., 2011a). Overall, 65–85% (depending on the test measure) of the 51 children obtained scores within 1 SD of their normal-hearing peers. Figure 19.6 provides an example of clinical language comprehension results for 22 children identified at a mean age of 13.4 months followed in one familycentered rehabilitation program with a strong emphasis on auditory development. As shown, average group scores at 3, 4, and 5 years of age were within 1 SD of the normative mean (mean 100, SD 15 for this measure). An examination of individual results for the subgroup of 10 children with known congenital loss shows considerable individual variability in outcomes over the three test intervals (Fig. 19.7). This example serves to illustrate the patterns of language development that can be observed in children with hearing loss. Children who are following a typical developmental trajectory would be expected to obtain average test scores (mean 100, SD 15 for the measure shown) at each age. In contrast, these children show a wide range of trajectories, with most lagging behind normal-hearing peers at age 3 years, but eventually catching up.

100

90

80

70

60

50 36 months

48 months

60 months

Age at Assessment

Fig. 19.7. Individual profiles in language comprehension (Preschool Language Scale, Auditory Comprehension (PLSAC)) for 10 children with congenital hearing loss at age 3, 4, and 5 years.

Recent reports on early-identified children are beginning to contribute further understanding of the difficulties related to hearing loss of lesser severity. Koehlinger et al. (2013) examined grammatic aspects of language for 100 children with mild to severe hearing loss, 60 assessed at age 3, and 40 at age 6 recruited through Early Hearing Detection and Intervention programs in the United States. Results were compared to 23 (age 3) and 17 (age 6) normal-hearing children. The authors reported that, on average, children lagged behind

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normal-hearing peers based on analysis of mean length of utterance (MLU) and percent correct of morphologic markers for verbs (e.g., use of past tense -ed, plurals -s) from spontaneous language samples. MLU is well accepted as a robust marker of early language acquisition (Brown, 1973). More than 50% of the children achieved below the 25th percentile for typically developing children. Similar gaps in grammatic development were documented for 3- and 6-year-olds compared to normal-hearing children, leading to concerns that these children are at risk for later difficulties. In an earlier study examining vocalizations of young children with hearing loss, 24-month-olds were found to produce significantly fewer words than normal-hearing children. Language samples of the children with hearing loss were described as comprised of primarily unintelligible utterances compared to normal-hearing 24-month olds who used words and phrases (Moeller et al., 2007). Taken together, these studies suggest that ageappropriate spoken-language skills in children with mild to severe hearing loss, while attainable, cannot be taken for granted and, despite early intervention, children require significant focused rehabilitation. Additional information can be gleaned from studies in the last decade that have examined outcomes in early- versus late-identified children. These studies are shedding more light on developmental outcomes across the spectrum of hearing loss and confirm that congenital and early-onset deafness negatively impact children’s development in multiple domains. Interestingly, while age at identification was a dominant factor in early newborn screening outcome studies (Yoshinaga-Itano et al., 1998a, 2001), the specific contribution of age at identification or intervention has become less clear. In the last decade, age of identification has been associated with some areas of development measured, but only in some studies (Kennedy et al., 2006; Sininger et al., 2010), but has not emerged as a significant predictor in other studies (Fitzpatrick et al., 2007a; Korver et al., 2010; Ching et al., 2013). A second notable point emerging from an examination of several of these studies is that severity of hearing loss has a significant effect on several language development outcomes, such as vocabulary, and receptive and expressive language (Wake et al., 2004; Fitzpatrick et al., 2007a; Sininger et al., 2010; Ching et al., 2013). A third important finding from these earlyidentification studies is that there are a substantial number of children who do not achieve language levels aligned with their hearing peers (Ching et al., 2013). It is common practice in most studies to exclude children with additional disabilities that would be expected to interfere with typical language development. Population-level research in childhood hearing loss has a relatively recent history. In the largest

population-based study to date of 451 children, Ching et al. (2013) found that the presence of additional disabilities, severity of hearing loss, and maternal education, but not age at hearing-aid fitting, predicted spokenlanguage development at 3 years of age. Age at cochlear implant activation was however associated with better developmental outcomes in 134 children with cochlear implants; by age 3 years, cochlear implants were used by most children with hearing loss greater than 75 dB HL. On average, this population of children had global outcome scores (comprised of auditory function, receptive and expressive language, and speech production measures) 1 SD below the normative mean even after adjusting for additional disabilities. On individual test measures, including a social functional measure, children’s abilities were at or below 1 SD of the mean. As noted previously, about 30–40% of children with permanent hearing loss are affected with additional disabilities that can reduce the auditory and language gains from hearing technology (Edwards, 2007; Meinzen-Derr et al., 2011; Eze et al., 2013). Lower non-verbal cognitive abilities are associated with poorer language skills (Sarant et al., 2009). Based more on expert opinion rather than empiric evidence, many language specialists working with children stress the need for continued intervention even for children whose standardized test scores suggest their skills are aligned with those of hearing peers (Fitzpatrick and Doucet, 2012). In other words, individuals working with these children on a day-to-day basis in real-world environments judge them to be at risk for difficulties in terms of auditory and linguistic skills and observe that they require ongoing practice to maintain and solidify these skills, to access advanced academic concepts, and to foster social development (Fitzpatrick and Olds, 2014).

Children with mild bilateral and unilateral hearing loss Children with mild bilateral and unilateral hearing loss represent a subgroup of children with hearing loss that merit a separate discussion point because: (1) they are frequently not a targeted group for early identification; (2) they receive amplification later, even when early identified; and (3) the effect of early-identified hearing loss of this degree is largely unknown. Children with mild bilateral or unilateral hearing loss have historically been identified late, often at school age, when the effects of reduced hearing access may become more evident in noisy environments (Fitzpatrick et al., 2014). Studies of late-identified children with milder losses showed that they were not immune to the effects of hearing disorders on development and that they were at risk for language,

NEUROCOGNITIVE DEVELOPMENT IN CONGENITALLY DEAF CHILDREN 50 40 Pre-UNHS

Median = 5.0 years 30

10

Children with cochlear implants

0 50 40 Median = 0.8 years

Post-UNHS

Number of Children

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amplification is much longer than for children with moderate or greater losses. These results suggest that questions remain about the effects of this degree of hearing loss on neurocognitive development and whether amplification can prevent difficulties observed in the past.

30 20 10 0 0

15.0 5.0 10.0 Age at Confirmation (years)

20.0

Fig. 19.8. Age at identification of mild bilateral and unilateral hearing loss the year before (n ¼ 244) and after universal newborn hearing screening (UNHS) (n ¼ 102).

cognitive, and behavioral difficulties (Tharpe, 2008; Porter and Bess, 2011). Figure 19.8 shows the dramatic difference in age at identification for this particular population when milder degrees of hearing loss 40 dB hearing loss as the cut-off for newborn hearing screening programs. There is some evidence that even early-identified children in this category may experience difficulties compared to their hearing peers. For example, up to one-third of children have been reported to experience some degree of language delay in the early years (Yoshinaga-Itano et al., 2008). Children with unilateral hearing loss have been reported to have poorer language scores than their siblings and to be receiving speechlanguage services (Lieu et al., 2010), and are considered to be at risk for later difficulties. Furthermore, recent examination of newborn screening data showed that 32% of children with mild bilateral or unilateral loss experienced deterioration in hearing from diagnosis to later years and that 11% with unilateral loss progressed to bilateral loss (Fitzpatrick et al., 2014). There is considerable uncertainty about best practices in managing these children’s losses through technology. Data show that approximately 90% eventually receive amplification but that there is considerable uncertainty around when to fit technology such that time from identification to

As noted, there is now a vast body of literature on children with severe to profound hearing loss who have received cochlear implants over the last two decades. Overall, research indicates that children with cochlear implants develop better spoken language and with substantially greater ease than previous generations of children with profound loss who used hearing aids (Geers et al., 2008; Geers and Nicholas, 2013; Tobey et al., 2013). Convincing evidence has accumulated to suggest that, while cochlear implants provide only partial access to auditory cues important for speech processing, children develop high-level spoken language skills, some achieving scores on standardized language measures comparable to peers with normal hearing (Nicholas and Geers, 2007; Fitzpatrick et al., 2011a; Leigh et al., 2013). However, overall, findings from large studies show that on average their language skills are not comparable to their hearing peers (Niparko et al., 2010; Ching et al., 2013; Tobey et al., 2013) and delays persist throughout the school years (Geers and Nicholas, 2013). Common to most pediatric cochlear implantation outcomes are two key points: (1) average development in multiple language domains tends to show gaps compared to normal-hearing children; and (2) there is great variability in performance on language tests. The important and unexplained variability in results has led researchers to examine factors predictive of neurodevelopmental outcomes. Key factors associated with differences reported in the vast cochlear implant literature include: ● ● ● ● ●

age of identification of hearing loss age at implantation amount of “hearing” experience before implant type of rehabilitation/communication language experience and family involvement.

The influence receiving the greatest attention has been age at implantation. Providing auditory input during the sensitive language development period for children with normal hearing is associated with better language outcomes (Ching et al., 2013; Tobey et al., 2013). However, age at implantation did not emerge as a predictor in one of the largest cochlear implants studies of 181 8- and 9-year-olds who received implants prior to age 5. Reports on whether early implantation effects are lasting are mixed. For example, Geers and Nicholas

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(2013) found that the effects of early implantation on language scores recorded at 4.5 years were maintained at 10.5 years. In contrast, Dunn et al. (2014) reported that the positive effects of age of implantation in preschool were no longer significant for receptive and expressive language at ages 7–10 years, depending on the outcome measured. The concept of a sensitive period and promising outcomes from early implantation has led some investigators to advocate for early cochlear implantation before the Food and Drug Administration approved 12-month lower age-limit criteria. There is accumulating evidence that children implanted before their first birthday can attain typical developmental milestones in speechlanguage. Studies show advantages in language and speech production for children implanted before 1 year of age compared to those implanted between 1 and 2 years (Holman et al., 2013; Leigh et al., 2013). These findings have resulted in expectations that very earlyimplanted children can develop language skills equivalent to children with normal hearing. However, Hof et al. (2013) have raised a note of caution regarding overly aggressive cochlear implant management of preterm infants during the first year of life. In a study of 14 neonates who were diagnosed with hearing loss ranging from 40 to 105 dB after referral from newborn screening, 9 of 14 infants’ hearing improved (to normal hearing for 4 and to moderate loss for 5). These findings led the authors to raise concerns related to delayed maturation of the auditory system in this population and to recommend ongoing audiologic assessment until at least 80 weeks’ gestational age before proceeding with surgical decisions.

REASONS FOR LATE IMPLANTATION While age at implantation is widely advocated to take advantage of the neurodevelopmental window, a review

of studies indicates that overall average age of implantation in developed countries is well beyond 1 year of age. For example, mean age at cochlear implant activation was 29 months in a large study of 160 children implanted between 6 months and 5 years of age (Tobey et al., 2013). An examination of implantation in a Canadian program since the availability of newborn screening indicated that, of 163 children implanted after the implementation of UNHS, 61.3% (100) received implants more than 12 months after identification of hearing loss. A review of the reasons detailed in Figure 19.9 indicated that the primary reason was progressive hearing, which was documented for 58% of children with late implantation. Figure 19.9 provides an overview of the multiple reasons accounting for late implantation in children. The findings that children with additional and complex disabilities also receive implants later are consistent with other reports in the literature as the decision-making and counseling process for these children is frequently more complicated, given complex medical issues and the need to adjust expectations for language-related outcomes (Fitzpatrick et al., 2011b; McCracken and Turner, 2012). Of importance in this discussion is that later implantation does not necessarily equate to lack of auditory stimulation if children were receiving adequate benefit from hearing aids prior to deterioration of hearing. This information may help explain why, in some studies, age at implantation has not necessarily been associated with greater linguistic benefits. These findings further confirm the difficulty of disentangling the true effects of age of implantation and to what extent some amount of residual hearing may impact early speech-language development. They also point to the importance of carefully monitoring all children with hearing loss to decide at what point cochlear implant intervention offers the best option to maximize hearing potential.

Fig. 19.9. Reasons for late implantation (>12 months after identification of hearing loss). id, identification.

NEUROCOGNITIVE DEVELOPMENT IN CONGENITALLY DEAF CHILDREN 349 As described above, even children with congenital Literacy development deafness, when provided with early access to sound Language acquisition is viewed as an important pathway through cochlear implantation, show auditory cortical to literacy, academics, social development, and employresponses similar to those of hearing children. However, ment. A comprehensive description of the impact of little is known about the broader and long-term effects hearing loss on these areas of functioning is beyond of early or extended periods of auditory deprivation the scope of this chapter. However, it is important to on language and overall neurocognitive development. highlight that historically achievement levels in reading It is important to remember that not only are children have shown important gaps, with reading skills of hearreceiving delayed access to sound but that the quality, ing peers with average grade 4 reading levels documenand in some cases the quantity, of auditory input is ted at high-school graduation (Babbidge, 1965; Traxler, not comparable to that experienced by normal-hearing 2000). It is well established in normal-hearing children infants. Language inexperience (relative to adults) that solid language abilities, phonologic awareness, means that, even in normal-hearing children, phonemic and print awareness are associated with good reading representation is not robust. Furthermore, they are parskills (National Reading Panel, 2000; Robertson, 2014). ticularly vulnerable when there is disruption of the audiChildren with hearing loss appear to follow the same tory signal, for example in background noise (Neuman sequence of literacy development as normal-hearing et al., 2010). At this point, it is not clear whether the gaps children (Williams, 2004; Mayer, 2007). They are at risk in development between normal-hearing children and for delayed reading skills because late or poor-quality those with hearing loss are related to environmental defaccess to hearing in the early years weakens these undericits and simply time lost that needs to be “made up,” or lying language abilities. In particular, hearing difficulwhether there are neural changes caused by weaker early ties can interfere with decoding skills, a fundamental sensory experiences that have a lasting effect on other skill for reading. Furthermore, difficulties with distance cognitive areas of development. In other words, are coghearing and incidental learning interfere with the develnitive processes altered, due to later and poor-quality opment of conceptual knowledge, known to be associauditory stimulation and if so, are these changes amenaated with reading comprehension (Robertson, 2014). In ble to treatment? New information on early neurocognivarious studies, difficulties in phonologic processing, tive development may help to better “customize” vocabulary, sentence structure, and conversation have intervention and improve spoken language and overall been associated with reading delays in children with development (Pisoni et al., 2008). hearing disorders (Perfetti and Sandak, 2000; Moeller Researchers have attended to the connection between et al., 2007; Geers and Hayes, 2011). For an indepth discognitive functioning and language for many years, cussion of literacy and hearing loss, the reader is deafness being a prime example of how these two conreferred to Robertson (2014). cepts are interwoven (Marschark and Hauser, 2008; Spencer and Marschark, 2010). Differences in play COGNITION AND LEARNING behaviors, for example, have been documented in preStarting in infancy, children develop cognitive abilities school children compared to children with hearing through a range of early sensory experiences, including (Yoshinaga-Itano et al., 1998b; Spencer and visual, tactile, and auditory interactions with their surMarschark, 2010). Lower levels of language functioning rounding environment. As described by Fagan and were felt to interfere with mothers’ abilities to structure Pisoni (2009), typically developing infants receive multisymbolic play and other cognitive abilities. It has been modal sensory input through their everyday learning suggested that the additional time and visual input environments. As early as the first months of life, required by children with hearing loss to follow play infants learn to assimilate various inputs to process interactions and sequences could interfere with typical information and to initiate the beginnings of expressive cognitive development unless measures are taken to communication, for example, smiling, cooing, and later overcome them (Spencer and Marschark, 2010). This babbling. In contrast, in infants with hearing loss, the points to the importance of family-centered intervention auditory component of multimodal processing may be and the impact of parents on the early development of seriously compromised or even absent in the case of the child with hearing loss. severe and profound hearing loss prior to intervention. Poor average academic achievements such as low This can result in absent or reduced sound awareness reading levels reported historically for children who (knowing sounds are present), sound association (for are deaf (Traxler, 2000) have undoubtedly motivated example, associating a sound pattern with mother’s verongoing examination of cognitive functioning. Marked sus father’s voice, associating sounds with environmendifferences between students who are deaf and those tal occurrences), sound localization, and delayed vocal who are hearing have been revealed in areas such behavior (for example, babbling at 6–9 months of age). as visual perception, memory, and problem solving

350 E. FITZPATRICK (Marschark and Hauser, 2008). However, Marschark at the Indiana University School of Medicine have conand Hauser (2008) underscore that research has not tributed an extensive body of research to this field had the expected contribution as it has been largely (Pisoni et al., 2008). It seems reasonable to assume that undertaken in a piecemeal approach in independent children with various degrees of hearing loss severity are domains, including cognitive, social, and academic outaffected by many of the same factors as those who use comes, limiting understanding of how these various cochlear implants. However, the tremendous difference aspects of learning are intertwined. between deaf and “hearing” that seemed to result from It is common knowledge that verbal cognitive meacochlear implants and the attention captured in the medsures frequently show lower scores, a result that is genical community have likely triggered a strong interest in erally attributed to differences in language abilities this population. Researchers have used the opportunities rather than cognitive functioning (Spencer and presented through cochlear implantation to further Marschark, 2010). While it has been well recognized that study neurocognitive processes such as working memdeafness does not directly interfere with intelligence, ory and attention. New investigations and perspectives based on non-verbal scores of cognitive abilities, appear to be largely fueled by the incredible variability Marschark and Hauser (2008) suggest that, regardless observed in both auditory and language-based outcomes of whether children’s primary communication mode documented in children with cochlear implants (Peterson has been visual or oral language, they may have different et al., 2010). Pisoni et al. (2008, p. 54) describe the typical knowledge and learning experiences. As summarized by speech recognition and language outcomes collected in Marschark and Hauser (2008), there is some evidence cochlear implant studies as the “endpoint of a long series from studies of children who are deaf and use sign lanof neural and neurocognitive processes.” Achieving a guage as their primary communication that they have more integrated understanding of these differences conceptual knowledge that is less richly anchored than might in turn assist in shaping more focused treatments their hearing peers. In turn, these different experiences for children. potentially result in cognitive differences such as visual Variability in language development in children with perception, memory, and problem solving. For example, normal hearing and understanding its causes and consechildren with significant hearing loss have fewer opporquences are central issues in the field of language disortunities for overhearing, incidental learning, following ders more generally (Marchman and Fernald, 2013). For group conversations, and accessing information in a example, early processing speed of familiar words by fast-paced classroom environment. They frequently 2-year-old children has been found to be significantly require additional processing time to understand speech. related to early receptive and expressive vocabulary In addition, as children mature, more of their learning skills at age 2 (Fernald et al., 2006) and to be predictive necessarily takes place in degraded acoustic environof long-term cognitive (working memory) and language ments such as classrooms (Bradley and Sato, 2008; skills at 8 years of age (Marchman and Fernald, 2008). Klatte et al., 2010). Studies showing that normal-hearing These and other findings suggest that differences in children’s listening comprehension is poorer in backearly speech processing capacities may have implications ground speech or in babble than in other background for later language development (Marchman and Fernald, noise (Klatte et al., 2010; Prodi et al., 2013) may be indic2013). Although the source of this variability is unknown, ative that higher-level cognitive processes are affected the investigators propose there is some evidence to sugand that cognitive and auditory processes are integrated. gest that early language experience may be at least partly Children with hearing loss are more vulnerable in responsible. Given that children with hearing loss have adverse listening conditions. Ignoring irrelevant speech later and potentially lower-quality early language expelikely involves even more cognitive resources and riences, they are particularly at risk. greater listening effort than in their normal-hearing As cochlear implantation has become standard care, peers. They may therefore have different learning expethere has been increasing interest in learning more about riences that in turn may lead to different cognitive orgacognitive correlates that affect information processing nization and strategies in learning. that in turn is relevant to language learning. Research in children with normal hearing has established the link between cognitive processes such as working memory Cognitive functioning in children and linguistic-related tasks, including word recognition, with cochlear implants vocabulary and language development (Gathercole In the past decade, considerable attention has been and Baddeley, 1990; Gathercole et al., 1997). There is accorded to the relationship between neurocognitive accumulating evidence in cochlear implant studies to functions and language acquisition in children with suggest that deafness, weaker auditory experiences, cochlear implants. In particular, a team of researchers and possibly disrupted early learning experiences affect

NEUROCOGNITIVE DEVELOPMENT IN CONGENITALLY DEAF CHILDREN 351 neurocognitive functions in addition to spoken language identification and recent technologies, a more integrated skills (Pisoni et al., 2008). understanding of the neurodevelopmental effects of For example, using digit span forward and digit span congenital deafness on these developmental areas backward tests to measure aspects of working memory should emerge. Sensory deprivation and less than optiin school-age children with cochlear implants, mal quality of sensory input when it becomes available researchers have shown that children with cochlear seem to have long-lasting consequences for cognitive, implants have shorter memory and working memory language, and social development. To date, substantial skills compared to children with normal hearing evidence has been collected on children who use cochlear (Pisoni et al., 2008). One of the early studies more than implants. Given that children with severe hearing loss a decade ago investigated memory capacity in 176 chilnow receive implants (Fitzpatrick et al., 2009; Ching dren with cochlear implants who were part of a large et al., 2013), it seems reasonable to assume that children study investigating multiple outcomes of speech, lanwith less severe hearing loss and hearing aids experience guage, and reading in 8- and 9-year-old children some of the same difficulties. (Pisoni and Geers, 2001) implanted before age 5. Significantly shorter digit spans were measured for the Theory of mind and social development children with cochlear implants compared to normalAnother area of early cognitive development that hearing age-matched peers. In the same study, verbal rehearsal speed (speaking rate) was found to account has received some attention is theory of mind for much of the variability in speech and language scores (ToM). Considered an important indicator of cognitive in the cochlear implant group. Several subsequent studdevelopment in the preschool years, ToM refers to the ies described in various reports (Peterson et al., 2010; ability to move beyond one’s own beliefs and realize Houston et al., 2012) provided further evidence for the that others have different desires and perspectives interference of deafness in neurocognitive processes (Nelson, 2007). It has been described as a socialcognitive achievement that is observed in typically such as working memory, verbal rehearsal speech, and developing children by about 4–5 years of age. In other perceptual encoding, suggesting that a period of auditory deprivation and delayed language interfered with words, young children through the course of normal the development of foundation cognitive processes interactions learn to attach meaning to what other peowhich in turn affected children’s speech perception, lanple around them feel and think. Also referred to as guage development, and learning after cochlear “mentalizing” in typically developing children, ToM implantation. is considered an important metric that requires a rich Researchers in this area of study propose that these language context. The ability to recognize other perspectives broadens opportunities for social interactions foundation neurocognitive functions are a prime area and is one of the core constructs that allow children to for targeted intervention as part of rehabilitation programs. For further details concerning the large body participate in their cultural world (Nelson et al., 1998; of research, readers are referred to research summaries Nelson, 2007). Children’s mastery of mental state tasks from the University of Indiana group (Pisoni et al., 2008; is related to the quantity of experience with mental state Peterson et al., 2010; Houston et al., 2012). conversations; in other words, how much parents and Overall, this promising area of research suggests that siblings use advanced levels of cognitive talk with auditory and spoken-language development relies them (Perner et al., 1994). Studies have shown that children with hearing loss of heavily on neurocognitive skills and that these underlyhearing parents are delayed relative to typically developing skills may account for at least some of the variability measured in traditional cochlear implant outcomes. ing children in developing ToM abilities (Moeller and What is unknown and difficult to disentangle from hetSchick, 2006; Schick et al., 2007). In contrast, the develerogeneous groups of children with cochlear implants opment of this mental state in children who have deaf with different onsets of profound loss and different parents appears to be more closely aligned with that of ages at implantation is the extent to which these differnormal-hearing peers (Courtin, 2000; Schick et al., ences are related to sensory deprivation prior to cochlear 2007). These differences between children with and without hearing and between children with deaf parents have implantation. Listening and learning with degraded been attributed to limited language delays and reasoning input through electric or acoustic or combined stimulation modes and exposure to even more degraded signals skills and to less exposure to talk about mental in classroom learning situations with auditory stressors states (Moeller and Schick, 2006; Schick et al., 2007). such as reverberation, noise, and distance may also conChildren who sign and have deaf parents are richly tribute to these differences. As evidence accumulates immersed in conversations in the course of their natural related to children who have benefitted from early environments.

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Moeller and Schick (2006) examined the extent to which 28 hearing mothers with children with hearing loss (using sign and spoken language) and 26 with normalhearing children converse with their children about mental states. This study supported the notion that mothers of children with normal hearing used a greater quantity of and more diverse mental terms than hearing mothers of children with hearing loss. Better use of mental state verbs by mothers was positively associated with children’s ToM development scores. Therefore, children of hearing parents who are developing either spoken or sign language or some combination of both are at risk of having fewer opportunities to naturally learn these skills (Moeller and Schick, 2006). Children who are learning sign are often exposed to less fluent and less confident sign language users. Children with hearing loss learning spoken language appear to be disadvantaged because of missed opportunities to hear at a distance, overhear, or “drop in” on conversations, all of which can limit social interactions. Given that incidental learning and social interactions are more limited, they likely have fewer opportunities to naturally engage in or learn about mental state conversations when developing spoken language.

SUMMARY Large national and population-based studies are beginning to provide a clearer snapshot of broader developmental outcomes in children with hearing loss. Smaller clinical studies add useful context-specific information that may help sort out the myriad of factors impacting neurocognitive development. Despite the growing evidence that early interventions and improved technology have improved neurocognitive developmental outcomes in children with hearing loss, there remain considerable language gaps. Although there is a large body of literature substantiating the effectiveness of cochlear implantation in developing auditory and language functions, many children still do not achieve language proficiency aligned with their hearing peers. Much remains to be learned in relation to underlying cognitive skills that intersect with language development for children across the entire spectrum of hearing disorders. Early intervention has two principal goals: to reduce and prevent, if possible, irreversible damage or disruption to the typically developing auditory system. To date, the bulk of the evidence on development suggests that early hearing access through timely detection and advanced hearing technologies has made important progress in reducing the impact of congenital hearing loss. With ongoing technologic advances coupled with increased understanding from neuroscience, it seems

reasonable to expect that preventing difficulties in language acquisition is a reasonable goal.

ACKNOWLEDGMENTS Preparation of this chapter and research reported were partly supported by a Canadian Institutes of Health Research New Investigator award and a Canadian Child Health Clinician Scientist Career Enhancement award. The author is grateful to Julia Ham and JoAnne Whittingham for assistance with compiling data and figures.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 20

Aging of the auditory system THOMAS NICOLAS ROTH* Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Zurich, Zurich, Switzerland

GENERAL ASPECTS OFAGING From a biologic point of view, an individual life cycle begins with the fusion of two chromosome sets, continues with proliferation and differentiation, and ends with the loss of cell and organ function, leading to death. Hence, life can be considered a genetic program depending on innumerable factors and interacting with just as many promoting, as well as potentially destroying, influences. This process of development is controlled meticulously by mechanisms responding to the need of the cell and the organ. These mechanisms oscillate between proliferation and degeneration in order to maintain a dynamic equilibrium in the continuous cycle of metabolism. The ability of proliferation requires the capability to deplete the ancient state of function and to create a new condition that permits mutation in another state. Hence, in this mutation process, various actions, such as inhibition and stimulation, agonists and antagonists, degeneration and proliferation, are all present at the same time throughout the body and interact in a multitude of feedback mechanisms. In a more general aspect the growth of any species is a controlled development of different organs and structures that on the one hand depend on one another and on the other hand permit the species to interact with other species. In large, complex, multicellular organisms, each part of the body has its specific function, leading to a balanced and interconnected system able to survive in the prevailing circumstances and to respond to both internal and external factors. As proliferation is a genetically controlled process that depends in a certain way on the senescence of the antecedent cellular state, aging is in a comparable way a genetic process that affects cells, organs, or the whole

organism itself. The rare syndrome of progeria that describes the premature senescence emphasizes the genetic impact in the process of aging (Coppede`, 2013). Illnesses and pathologies develop due to disturbed regulation or overwhelmed adaptation mechanisms. Pathologic decline of specific organs may entail deleterious knock-on effects on other organs. For example, diabetes mellitus, whilst being a primarily exocrine pancreatic problem, leads to a multitude of distant effects, including accelerated arteriosclerosis and polyneuropathy. To what extent aging itself is “pathologic” is debatable. Certain age-related changes are normally regarded as physiologic, for example the growth spurt of puberty, the involution of the thymus, or even the menopause. Such changes may be viewed as positive for the body and have protecting reasons, e.g., for the hosting female organism and for the potentially new embryo as well. The specific aging mechanisms of the inner ear include genetic and environmental/systemic factors. leading to a progressive hearing loss of significant individually variation (Walters and Zuo, 2013). Beyond the cochlea itself, changes in the auditory pathway and brain also significantly affect our sense of hearing. In this chapter, general and epidemiologic aspects as well as histologic changes based on Schuknecht’s classification are discussed. Furthermore, some molecular biologic considerations, e.g., oxidative stress, endocochlear potential, the role of mitochondria and supporting elements such as fibrocytes and their effect on presbycusis, are discussed with the aim of giving further insights to the age-related cellular metabolism that may explain histologic changes and the clinical characteristics of age-related hearing loss (ARHL). Furthermore, some aspects of age-related changes in the central nervous system are also considered. Finally, management of the consequences of ARHL is discussed.

*Correspondence to: Thomas Nicolas Roth, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Zurich, Frauenklinikstr. 24, 8091 Zurich, Switzerland. E-mail: [email protected]

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DEFINITION AND TERMINOLOGY Presbyacusis is a term that literally translates to “hearing in the older age.” It includes all factors and structural changes leading to hearing loss in elderly people. Nowadays the term “age-related hearing loss,” abbreviated ARHL, is used preferably. The disorder is characterized by high-frequency-dominated hearing loss, reduced speech understanding (particularly in noisy environments), slowed central processing of acoustic information, and impaired localization of sound sources. These difficulties have a direct impact on lifestyle and social activities by impairing communication (Gates and Mills, 2005). Additional terms may complement the description of the clinical presentation of ARHL. The term “sensory hearing loss” refers to an elevated hearing threshold level as measured in pure-tone audiometry demanding a higher acoustic level to excite the organ of Corti, while “sensorineural hearing loss” includes the signal transduction of sensory cells, their synapses, and the cochlear nerve. ARHL seems to belong mainly to this latter category. The term “perceptual” derives from the Latin verb percipere, signifying to understand or to hold something, and includes perceiving or catching on to the meaning of spoken words or other acoustic messages; this term may include a disturbed central auditory process in conjunction with age-related changes of the sensory and neural parts of the auditory system. Finally, the term “central” restricts the origin of the hearing disorder to the central nervous system, including the auditory cortex. Patients with presbycusis typically describe two types of difficulty: on the one hand they complain, “I do not hear well” or “My hearing has become worse,” whereas on the other hand, “I can hear, but I can’t understand in a noisy environment.” The observation of these two different aspects implies that it is not only the peripheral cochlear part with decreased hearing threshold that plays an important role in the aging process of the auditory pathway, but that other elements in neurophysiologic signal transduction – including the central neural framework – are involved, leading to hearing difficulties, especially in noisy situations (Otto and McCandless, 1982). Consequently, auditory perception presupposes both a well-functioning peripheral part and a wellinterconnected central framework of modulating and sensory areas. The age-related decline in function of the peripheral hearing organ is related to an individual’s genetics background and the cumulative damage of noise, middle-ear inflammation, medication, exposure to toxins including nicotine, and cardiovascular and rheumatologic factors. Indeed, innumerable factors influence the severity and

onset of ARHL, and there is no generally accepted single etiologic factor. Even a multifactorial analysis is extremely complex and likely an oversimplification, though some of the factors thought to be most significant are discussed below in more detail. Aging also affects central nervous function in general by slowing down processing speed and making task-related inhibition less effective. Poorer speech understanding in ARHL often has both peripheral and central components and it is often difficult to assess which is the most significant contributor (Otto and McCandless, 1982; Gates and Popelka, 1992). Moreover, patients with disease-related impairment of the central nervous system typically exhibit deficits in other cognitive functions affecting daily life more severely than patients with an isolated hearing loss.

EPIDEMIOLOGY It is difficult to assess the prevalence and epidemiology of ARHL because of manifold influences and different factors contributing to hearing loss and due to a variety of sociocultural, behavioral, and psychologic aspects. Furthermore, difficulties arise because of a lack of standardization and different selection criteria that have their impact on hearing function. The lack of consistent definitions prevents the compiling of accurate data on hearing loss. Epidemiologic data are easy to measure for certain types of information, for example mortality, or welldefined and measurable states, such as whether a pathohistologic diagnosis of cancer exists. In contrast, ARHL is on a continuous scale without a clear border between normal and impaired function. Furthermore, such objective measures do not necessarily correlate with subjective complaints and perceived handicaps. For example, a professional musician will notice hearing impairment more strongly than someone who does not rely on hearing for a profession. Any definition of ARHL is unavoidably subjected to arbitrary limits due to the vast variety of factors, and this gives rise to methodologic problems. An evident and primary difficulty in comparing reported prevalence data is the different measures and cut-offs for hearing impairment. There is also a difficulty in defining chronologic “age” itself related to the prevalence of ARHL. While several international systems of hearing loss classification exist, they do not include age in their definitions. Even if a chronologic age may have limited biologically relevance, definitions are necessary to obtain clear epidemiologic data. International classification systems such as those of the European Union or the World Health Organization (WHO) differ considerably. Standard age limits may be even more difficult to define than limits of

AGING OF THE AUDITORY SYSTEM Table 20.1 Standardized hearing loss categories Categorization

WHO classification

Normal Mild Moderate Severe Profound

dBHL < 26 26  dBHL < 40 41  dBHL < 60* 61  dBHL < 80 80 < dBHL

* According to the World Health Organization (WHO), hearing impairment of the better ear >41 dB has been defined as disabling.

hearing loss. For example, ISO-7029 is a statistical distribution of hearing threshold as a function of age from the International Organization for Standardization (ISO); this standard is based on a linear model for ages 18–70 years (ISO, 2000), but does not include older ages with their non-linear increase in hearing loss. A single and widely accepted universal classification of ARHL is needed to collect epidemiologic data and to compare prevalence in different countries. Because no system has clear advantages over the other, the WHO classification system is recommended to be used for future data collection (Table 20.1). In addition to problems associated with a lack of standardized methods for defining ARHL, a recent systematic review of epidemiologic data on the prevalence of ARHL in Europe revealed significant information gaps, for example, heterogeneity of selection criteria and differences in cut-offs for grades of hearing impairment (Roth et al., 2011). Neither geographic distributions nor developments over time could be extracted to a reasonable degree. Nevertheless, the studies reflect the

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well-known patterns of a non-linear increase of hearing loss, with age affecting men more than women. If the data are crudely averaged and interpolated, roughly 30% of men and 20% of women in Europe have a hearing loss of 30 dB HL or more at age 70 years, and 55% of men and 45% of women at age 80 years. The geographic distribution of European studies showed a relative paucity of studies in the middle, southern, and eastern parts of Europe; this may reflect differences in public health systems which attach more or less importance to ARHL in different regions (Table 20.2). Differences in the language spoken in different regions may also impact epidemiologic data for ARHL. For example, vowels have a distinct perceptual advantage over consonants in determining speech intelligibility (Kewley-Port et al., 2007; Fogerty and Kewley-Port, 2009), which could affect the prevalence of selfreported hearing impairment across different languages (Roth et al., 2011). In the United States, the overall prevalence of ARHL, defined as hearing loss of more than 25 dB HL in speech frequency, was reported to be 39% for men and 17% for women at the age range of 60–69 years, and 63% for men and 48% for women at the age range of 70–79 years (Agrawal et al., 2008). Another estimate reported a prevalence of 23% of American people aged between 65 and 75 years and 40% of people over 75 years of age, illustrating the vastly different results obtained in different studies (Seidman et al., 2002). Considerations about the difference between men and women are discussed in the section below. Another interesting aspect of the American data is that Afro-Americans seem to be considerably less affected by ARHL than white people (Agrawal et al., 2008; Lin et al., 2011).

Table 20.2 Prevalence of age-related hearing loss in Europe* Reference

Country

Prevalence with nearest cut-offs for HL and age

Bergmann and Rosenhall, 2001 Borchgrevink et al., 2005 Davis, 1989 Davis, 1995 Hietanen et al., 2005 Hietanen et al., 2004 Johansson and Arlinger, 2003 Moller, 1981 Quaranta et al., 1996 Rahko et al., 1985 Rosenhall and Karlsson Espmark, 2003 Wilson et al., 1993

Sweden Norway UK UK Denmark, Sweden, Finland Finland Sweden Sweden Italy Finland Sweden UK

> 19% (70 years at 30–39 dB) > 14.2% (60–64 years at 35 dB) > 7.4% (61–70 years at 45 dB) > 24.5% (61–70 years at 30 dB) >16.5% (75 years at 40–69 dB) >28.3% (80 years at 40–69 dB) > 8.8% (60–70 years at 35 dB) 9% (70 years at 35 dB) 6.7% (61–70 years at 45 dB) 10.3% (65 years at 30 dB) 24% (70 years at 30–39 dB) 54.3% (65 years at 35 dB)

*

This table lists the minimum prevalence in men and women for minimum better-ear hearing loss (HL) of 30 dB and lower age interval border of 60 years.

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These epidemiologic data confirm that ARHL is a major health concern in the aging population. They also demonstrate the need for standardized collection of epidemiologic data on hearing loss. Epidemiology and etiology are intimately related in that population-based endogenous factors will be exposed to geographically varying exogenous factors. Given the variable epidemiologic data and the complex interaction of etiologic factors and their influence on ARHL, it is not surprising that meaningful connections between epidemiology and etiologic factors are difficult to be established. The most relevant factors in the etiology of ARHL seem to be heredity (that may contribute up to 50%), noise exposure, history of chronic middle-ear inflammation, and cardiovascular factors, including diabetes, smoking, and hypertension. Additional relevant factors are hormones (including gender-related differences), exposure to ototoxic medication or chemicals and comorbidities, such as rheumatologic disease (Murdin et al., 2008; George and Pradhan, 2009). All these factors may cause oxidative stress as a common end molecular pathway. Such stress leads to alteration of cochlear homeostasis and to changes of the different anatomic structures accelerating the aging process.

HISTOPATHOLOGIC CHANGES AND SCHUKNECHT’S CLASSIFICATION Different components of the cochlea have specific functions in inner-ear homeostasis and are prone to agerelated changes; for example, the spiral ligament with its cellular and fibrous part as well as the important role of fibroblasts on the basilar membrane or the stria vascularis, considered as the “cochlear battery,” with its impact on the electrolyte homeostasis in the endolymphatic liquid. The inner and outer hair cells with their stereocilia covered by the tectorial membrane are also vulnerable to aging. Beyond the organ of Corti, the poorly understood neural framework of afferent and efferent fibers, the spiral ganglion, and the cochlear nucleus of the brainstem exhibit age-related changes (Frisina and Walton, 2006; Makary et al., 2011). Furthermore, there is evidence that age-related pathologies of the central nervous system have a negative impact on the peripheral cochlear organ (Otto and McCandless, 1982; Eckert et al., 2012). The classification of Schuknecht is based on the agerelated changes of the cochlea. In correlation with rather crude audiometric data archived in his laboratory, Schuknecht described in various temporal bone studies degeneration or age-related changes of the organ of Corti, ganglion cell, stria vascularis and basilar membrane. This led to a classification of ARHL in sensory,

neural, strial or metabolic and cochlear-conductive categories. Two more categories, indeterminate and mixed, were also added. The latter was reported to be responsible for up to 25% of cases. This classification is called the Schuknecht’s typology of ARHL and has been revised recently by Merchant and Nadol (Nadol, 2010) as follows.

Sensory presbycusis Histopathologically, this diagnosis rests on the finding of hair cell loss at the beginning of the basal end of the cochlea. Schuknecht connected this kind of histopathologic finding to audiograms showing typically an abrupt high-tone hearing loss (Fig. 20.1) (Schuknecht and Gacek, 1993). The earliest notable degenerative changes in hair cells affected the sterocilia, followed by slightly distorted and flattened organ of Corti, and subsequently loss of hair cells and supporting cells. Both cell types accumulate lipofuscin in the apical cytoplasm. This accumulation correlates with the presence of lysosomes, indicating exhausted enzyme activity.

Neural presbycusis When the loss of cochlear neurons was more than 50%, the term neural presbycusis was used. The progressive loss of neurons was observed throughout the cochlea (Fig. 20.2). There is a debate about the causes of spiral ganglion cell loss and whether it is primary or secondary. Loss of inner hair cells, supporting elements, and injury to dendritic fibers are proposed factors for secondary degeneration, but primary degeneration has been identified in different entities, e.g., sudden deafness, Friedreich’s ataxia, Me´nie`re’s disease, or Usher’s syndrome, and age-related primary degeneration has been reported in both humans and animals. dB −10

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Atrophy of the spiral ligament Schuknecht observed a degeneration of the spiral ligament as a function of age, beginning in childhood. The atrophy was most severe in the apical region of the cochlea. Degeneration of the enzyme-producing spiral ligament seems to play an important role in the development of presbycusis in animal studies. Degeneration of fibrocytes preceded the loss of hair cells and neurons. In humans as well, the earliest alteration is the loss of fibrocytes; these changes were more frequent in ears exhibiting descending audiometric patterns. Figures 20.6–20.9 show differences between a young and an aged gerbil in the spiral ligament.

The characteristic clinical finding is a progressive loss of word discrimination, termed phonemic regression. Elderly people with rapidly progressive neural presbycusis exhibit signs of general central neurodegeneration, including motor weakness, coordination problems, irritability, loss of memory, and intellectual deterioration.

Strial presbycusis Strial presbycusis is defined as a loss of 30% or more of the strial tissue. When strial loss exceeded this percentage, threshold levels deteriorated in the tone audiogram. The stria vascularis is considered to have an important functional role in inner-ear homeostasis, particularly in the generation and maintenance of the endocochlear potential. Strial atrophy was noted to have a familial correlation, and hence may have a genetic predisposition. The main audiometric characteristic is a flat or slightly descending threshold level (Fig. 20.3). Usually patients do not complain of discomfort with loud sounds. The histologic changes are predominantly in the apical and basal turn of the cochlea (Figs 20.4 and 20.5).

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Fig. 20.4. Strial atrophy and spiral ligament pathologies. Examples of lateral wall in the lower cochlear base of young B6 albino (A), old B6 albino (B), and old BALB/c (C). Age, gender, and basal turn endocochlear potential are indicated). Aging was associated with strial thinning and marginal cell loss in both strains. Severity of capillary loss and ligament thinning in (B) are atypical for this strain. BALB (C) features greater loss of marginal cells along the luminal surface. Marginal cells in (C) inset show dense staining and retraction of processes. Arrow in (C) denotes somewhat unusual strial atrophy. (Reproduced from Ohlemiller, 2009.)

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Fig. 20.5. Strial microvascular pathologies in 24-month-old male gerbil. Sequential sections (A–H) proceeding apically from the upper base of a 24-month-old male gerbil, showing progressive merging of strial capillaries, leaving the stria completely avascular over a span of 80 mm. Dashed arrows in A–F show how capillaries progressively merge, ultimately forming a blind loop. The first completely avascular segment (G) features well-organized regions (inset a), as well as regions with increased numbers of poorly differentiated cells (inset b). The arrow in G shows the wall of the last capillary loop. By 80 mm (H), the stria is still present but thin, and shows hyperplasia of undefined cell types over most of its length (inset c). Traces of degenerated capillaries can still be seen (inset d, arrows). The ligament at this location appears normal. TI, type I fibrocytes; TII, type II fibrocytes; B, basal cells; I, intermediate cells; M, marginal cells; EP, endocochlear potential. (Reproduced from Ohlemiller et al., 2008.)

Indeterminant presbycusis When no significant age-related change of any structure was present, the term “indeterminant presbycusis” was used. Twenty-five percent of all clinical cases of human presbycusis do not exhibit cochlear changes by light microscopy. However, degeneration of the dendritic arborization in the spiral ganglion cells and alteration of the tip links on hair cells have been described in electron microscopy. Changes of altered enzymatic pathways at molecular levels on the lateral cochlear wall

have been put forward as a possible pathophysiologic explanation. These pathways seem to exhibit an important role in inner-ear homeostasis and maintenance of cellular function. Other hypotheses are age-related changes affecting more central parts of the hearing pathway, e.g., the cochlear nuclei.

Mixed presbycusis When significant age-related changes are observed in more than one structure, they are classified as mixed

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Fig. 20.8. Spiral ligament of a young adult gerbil. The spiral ligament under outer sulcus cells (OSC) of a young adult gerbil exhibits congregated type IIc fibrocytes containing many mitochondria. Abundant processes of these rather stellate cells intermingle in loose stroma devoid of the dense bands that border IIb fibrocytes. Magnification  4800. Apical region. (Reproduced from Spicer and Schulte, 2002.) Fig. 20.6. Spiral ligament of a young gerbil. In the spiral ligament of a young control, elongated type IIb fibrocytes display elaborately pleated foldings that greatly amplify the cell surface (arrows and inset). The fibrocytes enclose numerous large mitochondria bordering the nucleus and infiltrating primary processes (P), together with prominent Golgi zones (G). Magnification  6000. Basal region. (Reproduced from Spicer and Schulte, 2002.)

Fig. 20.9. Spiral ligament pathologies of an aged gerbil. An empty-looking zone encircles the stellate profile of a type IIc fibrocyte from a gerbil. Numerous small to large vacuoles populate the cytosol in the cell body and in nearby cell processes (arrows). Magnification  4800. Basal region. (Reproduced from Spicer and Schulte, 2002.)

presbycusis. Unfortunately, this type exhibits no consistent audiometric patterns.

Cochlear conductive presbycusis Fig. 20.7. Spiral ligament pathologies of an aged gerbil. Type IIb fibrocytes from aged gerbil 1 exhibit shrunken cell bodies heavily infiltrated with variable-sized clear vacuoles. Emptylooking spaces separate the cells and their plasmalemmal projections. A thick layer of dense substance lines the periphery (arrows) of a root process (RP) paralleling a vacuolated fibrocyte. Neighboring root processes enclosing a few vacuole-like spaces (arrowheads) lack the marginal dense deposits. Magnification  2800. Basal region. (Reproduced from Spicer and Schulte, 2002.)

Cochlear conductive presbycusis is based on both clinical and pathologic criteria. It can be considered an interesting hypothesis of a mechanism leading to sensorineural hearing loss, but there is, however, no convincing evidence of a cochlear conductive defect. Hence this remains an unproven theory. Schuknecht described age-related thickening and hyaline degeneration of the basilar membrane and deposition of calcium salts in the basal portion of the membrane. A possible

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explanation concerning these findings will be considered in the section below, focusing on the role of fibrocytes and inner-ear homeostasis. Even though the classic types of presbycusis, i.e., sensory, neural, and strial persbycusis could be correlated with defined shapes of audiograms (Figs 20.1–20.3), a clear pathophysiologic explanation or pathohistologic pattern for the other types is lacking. Hence, Schuknecht’s classification is considered vague and imprecise because most aging human and animal cochleas exhibit a mix of pathologies; furthermore, it was somewhat criticized because the classification concentrates on morphology of the peripheral hearing organ, excluding many functional and central aspects of hearing processing (Ohlemiller, 2004). Therefore, and due to the fact that several causes overlap and interfere with each other, further explanations may be given by molecular biology and genetic analyses, opening a vast field in the modern area of research on ARHL. A brief overview of some of these mechanisms is presented in the next section, with the aim of contributing some insights to the underlying cellular processes, which may lead to the above-mentioned histopathologic alterations of the cochlea.

AGING OF THE PERIPHERAL AUDITORY SYSTEM Aging is not only determined by genetics, but also influenced by oxidative stress (Fig. 20.10). Several factors,

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Fig. 20.11. Causes of oxidative stress in the inner ear. Many factors lead to disturbed intracellular homeostasis and therefore to oxidative stress. Overexposure to sound causes oxidative stress in the inner ear as well as systemic factors, e.g., diabetes, vascular and rheumatic factors, and some medication. Furthermore, infection, chronic inflammation, and irradiation therapy have a negative effect on inner-ear homeostasis.

e.g., infection of the middle ear, noise, and systemic diseases, cause oxidative stress that damages inner-ear structures and leads to premature aging (Fig. 20.11). Based on the above-mentioned histologic changes, some of the cellular parts of the inner ear are pointed out with respect to age-related changes. First, the role of oxidative stress and the damaging free radicals is highlighted and then some genetic aspects are summarized with respect to the damage caused by the oxidative stress. Furthermore some mechanisms of inner-ear homeostasis and metabolic factors that influence cell aging are described.

Oxidative stress Genetics

Aging

Fig. 20.10. Aging is a lifelong process which can be visualized as a wheel that is promoted by genetics. Various endogenous and exogenous factors lead to oxidative stress, which may overwhelm compensatory mechanisms and accelerate aging.

Oxidative stress is determined by the imbalance between the production of oxygen metabolites and the cellular ability to detoxify reactive metabolites. These reactive oxygen metabolites and free radicals are highly toxic to many cellular components, even though some of them act as cellular messengers. Thus, if the cell is unable to repair the damage or to restore normal homeostasis, oxidative stress disturbs normal cellular signaling and leads to cell injury or even to cell death (Fig. 20.12). Mitochondria exhibit an important function in maintaining the production and consumption of these toxic metabolites. Reduced activity of mitochondria increases the reactive metabolites and causes DNA damage that in turn reduces the mitochondrial activity on its own (Seidman, 2000).

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Fig. 20.12. Oxidative stress is due to the accumulation of free radicals during cell respiration. When the cell is unable to detoxify, cell metabolism is injured by these free radicals, leading to cell aging or even cell death. Mitochondria have an important role in detoxifying the cell, but mitochondria on their own are vulnerable to overwhelming oxidative stress. The disturbed calcium regulation due to mitochondrial injury leads to altered cell signaling with adverse effects on the surrounding cells.

Many factors cause oxidative stress (Fig. 20.11). In terms of cochlear pathology, bacterial toxins and noise overexposure cause acute oxidative stress in the cochlea and labyrinth and disturb inner-ear homeostasis with subsequent cell damage, resulting in sensorineural hearing loss and vertigo. Chronic inflammation or infection leads to oxidative stress and negatively affects the cochlea. The accumulation of free radicals in stressed cells on one hand has a toxic effect to bacteria that is advantageous for survival of the organ, but on the other hand damages cellular structures and in some way accelerates the genetic process of aging.

Genetics As mentioned above, progeria as well as other pathologies, e.g., muscular dystrophies, scleroderma, and cardiomyopathies, belong to the group called laminopathies. They are determined by a genetic defect of the LMNA gene, producing aberrant nuclear proteins (lamin). These proteins lead to abnormal shape of the cellular nucleus and, therefore, have a wide range of effects on cellular function, leading to a broad presentation of clinical symptoms and the manifestation of premature aging (Zhang et al., 2013). To date, no studies are available in the literature investigating the effect of laminopathies on the inner ear. Another protein, called klotho, was discovered in 1997 and acts as an aging suppressor gene (Kuro-o

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et al., 1997). It was named after the Greek goddess who spins the thread of life. The gene mutation in the klotho mouse exhibited multiple disorders resembling human premature aging (Kuro-o, 2008), but the protein acts in a different manner than those causing the syndromes of laminopathies. The klotho gene encodes for a secreted protein and has therefore an extracellular function which seems to be involved in the regulation of oxidative stress and senescence. Klotho is expressed predominantly in tissues involved in the regulation of calcium homeostasis and was found in the stria vascularis and the vestibular dark cells of the inner ear (Kamemori et al., 2002; Takumida et al., 2009). Due to the distribution of klotho close to the Na-K-Cl co-transporter and the involvement of klotho with other proteins that regulate calcium homeostasis, e.g., transient receptor potential (TRPV), it was suggested that klotho participates in the regulation of the ionic composition of the endolymph; furthermore, the expression of klotho in the inner-ear sensory cell of the mouse led to the hypothesis that klotho is involved in signal transduction in the inner ear (Takumida et al., 2009). The expression of klotho was found to be closely related to the lifespan of the organism and klotho seems to have a protective effect against oxidative stress and to increase cell resistance to the subsequent damage (Yamamoto et al., 2005; Ikushima et al., 2006). Telomeres consist of a series of non-coding, hexanucleotide repeats found at the end of chromosomes, and serve to ensure genomic stability during cell division. Telomeres and telomerase have been investigated not only in cancer development but also in their role of cellular senescence in mitotic cells (Smith et al., 2013). The corresponding enzyme, telomerase, is responsible for maintaining telomere length. It has been reported that telomeres and telomerase are a preferential target of DNA damage under oxidative and genotoxic conditions (Hewitt et al., 2012). Hence, defective DNA leads to a defective cell cycle, with the well-known adverse effects that gradually affect cell and organ structure and function, including cellular aging as well.

Mitochondria As a consequence of the mechanisms mentioned above, an important aspect of aging can be attributed to mitochondria. Mitochondria exhibit a key role in cell cycle: on the one hand they provide energy and on the other hand they clean reactive oxygen species. Mitochondria are involved in the aging process. Their interaction with calcium homeostasis and their important role in reducing oxidative stress lead to the mitochondrial clock theory of aging, also referred to as the membrane hypothesis of aging (Seidman et al., 2004).

366 T.N. ROTH Mitochondria have a high transmembrane gradient that are reduced in ARHL, this suggests that a closely related is vulnerable to oxidative stress. Thus, oxidative stress and interdependent connection meticulously tunes the not only damages the mitochondrial membrane but also electrolyte exchange, particularly sodium, potassium, leads to a disturbed calcium regulation and hence to and calcium (Fig. 20.14) (Goto et al., 1999; Ichimiya et al., altered intracellular signal processes that entail dis2000; Wangemann, 2002; Spicer and Schulte, 2002; turbed cell metabolism and finally lead to cell death Ohlemiller et al., 2006; Mann et al., 2009; Smaili (Smaili et al., 2013). et al., 2013). Mitochondrial pathologies play an important role in Reduced endocochlear potential itself influences both inherited and acquired hearing loss. Genetic mutainner-ear homeostasis by increasing oxidative stress, tion of mitochondria, e.g., the MELAS syndrome (syncausing further cell damage and thereby accelerating drome of mitochondrial encephalopathy, lactic the aging process. This age-related alteration is most acidosis, and stroke-like episodes) presents clinically in apparent in the basal turn of the cochlea, the region with a high percentage with sensorineural hearing loss caused the highest density of mitochondria. Whether the basal mainly by dysfunction of the stria vascularis, which turn has high energy demands or is the most important accounts for the cochlear battery, as mentioned above and powerful region in inner-ear homeostasis is a diffi(Takahashi et al., 2003). cult question to answer. ARHL seems to be caused by mitochondrial dysfuncIn addition to the mitochondrial aging theory or other tion. Several factors cause oxidative stress that leads local cellular factors, strial insufficiency may also be to the accumulation of acquired mitochondrial DNA caused by microvascular pathologies due to systemic mutations. With preponderance of DNA damage, changes, such as hypertension, diabetes mellitus, hypermitochondria are damaged and the cell becomes bioenerlipoproteinemia, hyperlipidemia, or autoimmune disgetically deficient (Fischel-Ghodsian et al., 2004). Prior eases, which all have an impact on ARHL. Correlated to hair cell injury, mitochondria seem to be affected with age and duration of diabetes, significant changes by oxidative stress first. Altered mitochondria were in the cochlea were described: thickening of the vessels found in the afferent nerve endings (Omata and and basilar membrane and atrophy of stria vascularis Scha¨tzle, 1984), and elevation of reactive oxygen species were seen in all turns of the cochlea, while loss of outer was observed after acute noise exposure (Ohlemiller hair cell was found only on the lower basal turn et al., 1999). (Fukushima et al., 2005). Furthermore, mitochondria are providing the energy In a similar manner, acute otitis media with labyrfor the transmembrane ion pumps that maintain the high inthitis shows a decreasing slope in higher frequencies endocochlear potential. in the tone audiogram, similar to Figure 20.1. This is explained by bacterial toxins and inflammatory mediators penetrating through the oval window and leading Endocochlear potential to oxidative stress and consequently to a disturbed Histological changes in ARHL are predominantly in the homeostasis damaging the adjacent structures, i.e., in basal end of the cochlea, progressing to the upper base. the basal turn of the cochlea (Cureoglu et al., 2004). They were investigated with particular interest in the The destruction depends on bacterial virulence and local stria vascularis (Ohlemiller et al., 2008). The stria vascuimmune conditions. laris shows a high density of mitochondria and contains Independently of the pathophysiologic origin of marginal cells, which are characterized by a unique energy loss, it seems conceivable that age-related reduccomplement of potassium channels and pumps respontion of the endocochlear potential will be particularly dissible for maintaining the high endocochlear potential. tinctive in the basal turn due to the high density of The potassium exchange is supported by fibrocytes, mitochondria. This corresponds with the clinical obserwhich exhibit an important function in inner-ear vation that many entities affecting the inner ear, e.g., homeostasis (Garcı´a Berrocal et al., 2008). Typically, inflammation, noise, or infection, lead to a sensory hearARHL is combined with degeneration of the stria vascuing loss (Fig. 20.1). The significant histopathologic laris and reduced endocochlear potential (Fig. 20.13) changes of the cochlea, i.e., decrease in outer and inner (Schuknecht et al., 1974; Ohlemiller, 2009). hair cells and decrease in stria vascularis and the spiral The changes in the stria vascularis are not only ligament in the basal turn, were shown to be induced marked by loss of marginal cells and fibrocytes, but also by chronic otitis media (Cureoglu et al., 2004). Cochlear in reduced density of mitochondria. Both these changes inflammation is supposed to disrupt fibrocyte function lead to reduced endocochlear potential. Given the obserof the spiral ligament; the stimulated fibrocytes produce vation that all these parts of the stria vascularis, i.e., chemoattractant mediators that induce prolonged mitochondria, fibrocytes and endocholear potential, inflammation and consequently lead to structural

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Fig. 20.13. Potassium exchange in the lateral wall of the cochlea. Reprinted from Ohlemiller (2009) and Nin et al. (2008), with permission. Copyright (2008) National Academy of Sciences, U.S.A. Schematic structure of the cochlear duct with the lateral wall. (A) Appropriate ionic composition of the endolymph and the endocochlear potential (EP) require that an ion barrier line scala media, the intrastrial space, and strial capillaries. A nearly continuous cellular network guides K+ from the organ of Corti through finger-like root cells into (primarily) type II and I fibrocytes. Fibrocytes must take up K+ from the extracellular space around root cells. Locations of five major types of fibrocytes are indicated by roman numerals. (B) Schematic enlargement of the boxed area in (A) depicts the cells and components required to generate the EP. Type I fibrocytes, strial basal cells, intermediate cells, as well as capillary pericytes (not shown) are joined by gap junctions composed mostly of connexins 26 and 30. K+ enters the intrastrial space through Kir4.1, then through marginal cells via Na+/K+-ATPase, the NKCC ion exchanger, and KCNQ1/KCNE1 channel complexes. TJ, tight junction. (Reproduced from Ohlemiller, 2009 and Nin et al., 2008.)

changes, as mentioned above (Ichimiya et al., 2000; Moon et al., 2006). The reduced endocochlear potential not only affects the sensory part of the inner ear but also leads to alteration of the supporting structures, e.g., fibrocytes and connective tissue.

Fibrocytes and fibroblast growth factor Fibrocytes are not only important in the embryologic development of the cochlea; they continue to exhibit a crucial function in “backstage work,” providing innerear homeostasis; as mentioned above, they are involved in potassium ion exchange. Five different types of

fibrocytes are present in the spiral ligament, enabling the Corti organ to conduct signal transduction (Suko et al., 2000) (Fig. 20.15). Moreover, fibrocytes are involved in repairing function during acute or chronic inflammation (Ichimiya et al., 2000); their mediating role in inflammation seems to be decreased and inhibited by corticosteroids (Moriyama et al., 2007). Fibrocytes are important contributors to forming and supporting cochlear structures, such as delivering components of microtubules to the hair cells (Szarama et al., 2012). Microtubules of the Corti organ also show agerelated changes and may contribute to the alteration of micromechanical properties in signal transduction (Saha and Slepecky, 2000). Normal ciliar function

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Fig. 20.14. The maintenance of the endocochlear potential demands a high quantity of energy that is supplied by mitochondria. Mitochondria are particularly present in the marginal cells. Marginal cells and fibrocytes are also supporting the high potassium gradient of the inner ear.

depends also on calcium homeostasis (Lumpkin and Hudspeth, 1998). Disturbed function of the cilia in hair cells contributes to altered signal transduction and consequently to hearing difficulties. Age-related altered fibrocytes not only have decreased efficiency in maintaining inner-ear

homeostasis with respect to the demanding endocochlear potential, but probably secrete altered microfilaments and other microstructures, which may influence cochlear dynamics by reducing the mechanical elasticity of the basilar membrane (Spicer and Schulte, 2002). Given these observations, it may be hypothesized that these changes are primarily due to altered function of supporting inner-ear cells, e.g., fibrocytes. It may explain Schuknecht’s difficulties in correlating the audiogram with the variable histopathologic changes leading to the somewhat unclear or unproven classification of indeterminant, mixed, or cochlear-conductive hearing loss. Fibroblast growth factor (FGF) is expressed by neurons in the spiral ganglion and in the cochlear nucleus. FGF is not only responsible for normal fibrocyte differentiation and function, but also exhibits an important role in myelination of the cochlear nerve. Two cell types are involved in myelination: Schwann cells myelinate the peripheral part and oligodendrocytes the central part of the cochlear nerve (Wang et al., 2009). Disturbed function of myelination, independently of central or peripheral origin, leads to reduced signal transmission in the cochlear nerve visible in longer latencies of auditory evoked potentials (Makary et al., 2011). Furthermore, FGF has an important role in hair cell differentiation and repairing function of the inner ear after injury (Jacques et al., 2012). Due to the production of FGF in spiral ganglion cells, it may be hypothesized that spiral ganglion loss results in hypo- or demyelination of the cochlear nerve and has adverse effects on sensory and supporting cells of the cochlea. Loss of spiral ganglion cells was also shown to be a direct result of acoustic overexposure, not just a consequence of hair cell loss (Makary et al., 2011).

Gender and hormones

Fig. 20.15. Schematic showing localization of the spiral ligament fibrocyte types, as classified by Spicer and Schulte. The type II and type V fibrocytes shown here are both considered type II fibrocytes according to the Takahashi and Kimura classification system. (Reproduced from Ichimiya et al., 2000.)

Epidemiologically, men are more affected by ARHL than women. Consequently, hormones, especially estrogen, have to be considered not only in presbyacusis but also in other pathologies. Gender differences have been reported in auditory brainstem response, showing that women have shorter latencies than men. Women with Turner’s syndrome, being biologically estrogendeficient, have longer latencies in auditory brainstem response and show early presbyacusis (Hultcrantz et al., 2006). Hormone replacement therapy was supposed to have a slightly positive effect on hearing thresholds in menopausal women, but contradictory observations exist, reporting that contraceptive medication and hormone replacement therapy are associated with sudden hearing loss (Hanna, 1986; Strachan, 1996). Moreover, the known prothrombotic effect of

AGING OF THE AUDITORY SYSTEM 369 conceptive pills might play a role. Nevertheless, human lobe. These findings open the discussion about a new and studies investigating the effect of sex hormones on hearmore sophisticated concept than the classic model of ing show an influence of estrogen (Horner, 2009). understanding human language and central auditory sysThe estrogen receptors, alpha and beta, are localized tem (Poeppel et al., 2012). where electric impulses are transmitted (inner and outer Despite the controversies concerning the hemispheric hair cells, spiral ganglion) and where inner-ear homeoasymmetry or connectivity and the modulating role of stasis is maintained (stria vascularis, spiral ligament) the frontal lobe, it has been shown that, in elderly (Stenberg et al., 2002); therefore, estrogens seem to have patients, particularly in patients with Alzheimer’s disa role in signal transmission and cochlear homeostasis. ease, the asymmetry in dichotic listening is accentuated (Bouma and Gootjes, 2011). These observations of agerelated and pathologic changes of the brain with progresAGING OF THE CENTRAL AUDITORY sive decline of structural areas and tracts may lead to SYSTEM partial or gradual intrahemispheric and interhemispheric Auditory cortex disconnectivity, due to disturbed signal transmission. Thus, the theory of cortical “disconnection,” i.e., the disSpeech recognition is a frequent complaint of older ruption of subcortical white-matter tracts, has been put adults, particularly in complex and demanding listening forward as a mechanism of age-related cognitive conditions. When differentiated hearing is impaired, the decline. The cortical disconnection seems to involve age-related changes not only involve the abovethe central auditory system and impair speech perception mentioned cellular structures of the cochlea, but also (Gootjes et al., 2007). affect the central nervous system, in particular the auditory cortex and the frontal lobe. The latter seems to be progressively involved with increased age and to exhibit Calcium homeostasis an important role in speech recognition when central Calcium was shown on the one hand to have an imporauditory regions show a declining structural integrity tant function in intracellular processes and cell signaling (Eckert et al., 2008). and on the other hand to be closely involved in genetics ARHL has been described as correlating with ageof aging (Takumida et al., 2009; Smaili et al., 2013). Furrelated changes in the auditory cortex (Eckert et al., thermore, calcium not only provides the synaptic poten2012). A lower gray-matter volume of the auditory cortial that permits a finely tuned signal transmission, but tex has been observed in older adults with mild to modalso has an important impact on neural viability and synerate hearing loss (Husain et al., 2011), but it remains a aptic plasticity (Foster, 2007). question for further research whether these findings As mentioned above, calcium is intimately linked are causatively connected. A study investigated the to the activity of mitochondria that are implicated in gender-related morphologic symmetries of brain structhe clearance of reactive oxygen metabolites. The high tures and described differences in the auditory cortex membrane potential of mitochondria is maintained by volume, which was less in men than in women a calcium gradient that is tightly regulated by spe(Rademacher et al., 2001). Given the epidemiologic cific calcium transport mechanisms. Oxidative stress observation that women are less affected by ARHL than leads to defective mitochondrial membrane proteins men, the question about causality between epidemiology and in turn to a disturbed calcium homeostasis and chanand the structural difference in the auditory cortex arises ged intracellular activity with its pathophysiologic and the role and influence of sex hormones have to be consequences. considered. Contrariwise, age-related reduced calcium regulation alters mitochondrial activity that increases oxidative Theory of cortical disconnection stress, leading to cell damage (Ouda et al., 2012; Before the era of functional imaging the classic model of Smaili et al., 2013). Calcium dysregulation decreases hearing was focused on the Broca’s and Wernicke’s area neural transmission properties and leads to impaired on the left hemisphere. The hemispheric specialization of or disrupted information exchange between the conlanguage was supported for many years by differences nected brain areas in dichotic listening paradigms. But recent studies The connection between mitochondrial activity and using functional neuroimaging revealed that speech intracellular calcium regulation points to the importance recognition is not restricted to the left hemisphere, but of both components in aging. seems to be bilaterally organized (Rogalsky et al., Progressive demyelination of the central nervous sys2008). Furthermore, speech perception is not only contem due to age-related changes in calcium homeostasis fined to the temporal lobe, but also involves the frontal or mitochondrial activity impairs precise and rapid signal

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transmission. Impaired signal transduction reduces the viability of synapses and neurons. As explained in the section above, loss of spiral ganglion cells disturbs the activity of fibrocytes, affecting the endocochlear potential and the highly differentiated microstructures of the Corti organ. Comprehension of these interacting and interconnected mechanisms is important to understand the age-related changes in the clinical examination, discussed in the section below.

DIAGNOSIS AND CLINICAL MANIFESTATION Patients often complain about hearing loss in a nonspecific way, but a detailed history can point out the circumstances or the social environment where hearing poses a problem. Given the above-mentioned age-related changes of the entire auditory pathway from the peripheral organ to the auditory cortex, all parts of the auditory system have to be considered and analyzed separately, but none the less, in relation to the entire auditory system. According to the site of the lesion, patients’ complaints may vary in degree and characteristics. The clinical evaluation of ARHL should not focus only on the cochlea but also pay attention to the central nervous system. Additionally, psychologic aspects have to be considered, together with social personal activities when aiming to provide comprehensive holistic medical care. One of the main characteristics in ARHL is the progressive difficulty in speech recognition, particularly in noisy environment. Some patients note that intelligibility depends on the frequency and phonetic resonance of the speaker’s voice. This complaint may correspond to the above-mentioned age-related changes in the cochlea with its altered structures, mainly in the basal turn of the Corti organ. But diminished speech recognition may also be a sign of affected auditory cortex. It is quite a demanding clinical task to differentiate the involved site of ARHL and to determine whether the peripheral, the central, or both parts are predominantly affected. Several clinical tests are used in the topodiagnostic evaluation of hearing loss. These are complemented by other tests, such as auditory evoked potentials, functional magnetic resonance imaging, and motor evoked potential, which can document slowing of the central nervous system. There are two main components of the central nervous system that are affected by age: cognitive ability and temporal processing. Temporal processing becomes slower and cognitive ability decreases progressively. The latter is mainly influenced by altered central selection mechanisms, consisting of impairment of information transduction. In the aging central nervous system these

modulating mechanisms, apart from being slower and less efficient, are shifted to the frontal cortex and hence, associative or memory function becomes more important in hearing processing and speech recognition. The tone audiogram is the basic test to determine hearing loss (Figs 20.1–20.3). ARHL is typically characterized by symmetric high-frequency loss. This test depends on the patient’s attention and cooperation. The tone audiogram provides quite a good evaluation of peripheral audition, including its mechanical components. A central component is included in speech audiometry, since speech recognition depends on central auditory pathways and requires cognitive abilities. Central auditory testing by dichotic sentence or digit identification is recommended in the evaluation of elderly with hearing impairment (Gates et al., 2008). Otoacoustic emissions play a less important role in the clinical evaluation of ARHL, because they exhibit an individual variability and therefore it is impossible to get a standard reference (Probst et al., 1991). It represents a dynamic exam that only with longitudinal testing can reveal age-related changes of the individually measured cochlear mechanisms. These changes are less prominent compared with threshold level and seem to depend on the decreasing endocochlear potential that is not measurable in clinical routine exam. Auditory evoked potentials give important information about the central component of the auditory system. According to the age-related changes mentioned above, latencies are prolonged and the potential diminished. In the clinical exam they are mainly used to answer the question of whether there is a retrocochlear hearing disturbance. As with otoacoustic emissions, there is no standard reference, for the same reason of individual variability.

REHABILITATION Current hearing rehabilitation is focused on the peripheral auditory part by applying hearing aids. With the continuous development of technical possibilities, the industry tries to improve the fine-tuning of the devices to compensate for age-related deficits. Unfortunately, they show limited success due to the above-mentioned variety of structural changes in the hearing pathway. The more the central auditory pathway and central nervous system are affected by structural changes, the less the success of hearing aids. In contrast, peripheral deficits respond well to the application of hearing aids. In case of profound hearing loss unamenable to standard hearing aids, a cochlear implant (CI) can be evaluated. CIs in the elderly showed satisfying results, even if the difference in hearing improvement was less marked

AGING OF THE AUDITORY SYSTEM than in children. Hence, if the peripheral auditory deficit can be compensated for sufficiently by CI, the central part of auditory deficit seems to be of less importance (Lenarz et al., 2012; Blamey et al., 2013). When age-related changes mainly affect the central components, peripheral efforts will fail and auditory training should be attempted together with psychomotor or general daily activity.

CONSEQUENCES OFARHL Based on the above-mentioned epidemiologic considerations, ARHL is the most common chronic disabling condition in older adults. Hearing loss affects one of the most important human capabilities: verbal communication. The disabling severity of ARHL is shown by a wide range of negative consequences caused by difficulties in understanding. These age-related changes in hearing lead to a reduced quality of life that affects all parts of human activity. Social isolation, emotional frustration, cognitive dysfunction, and behavioral changes may be further consequences of hearing impairment. Moreover, the central nervous system, social activity, or lifestyle and psychologic factors have to be considered when dealing with hearing impairment. Patients with hearing impairment risk being isolated and isolating themselves, and therefore are prone to developing depression. Premature aging of the central nervous system seems to affect the hearing process, on the one hand due to declined psychomotor activity and social interest, and on the other hand because reduced central activity may have a negative impact on auditory processing and possibly also on the peripheral auditory organ. Hearing loss also affects negatively work productivity and has an impact on the economy. In this context, hearing loss seems to entail negative consequences for the social state, health, and survival (Barnett and Franks, 1999). Furthermore, ARHL is estimated to have a considerable economic weight in the public healthcare system. For all these reasons, prevention (for example, through public health campaigns and work legislation on noise exposure), early identification, and appropriate management of AHRL are all important.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 21

Decreased sound tolerance: hyperacusis, misophonia, diplacousis, and polyacousis 1

PAWEL J. JASTREBOFF1* AND MARGARET M. JASTREBOFF2 Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA 2

JHDF, Inc., Ellicott City, MD, USA

INTRODUCTION Decreased sound tolerance, diplacousis, and polyacousis are dysfunctions of auditory perception. Decreased sound tolerance can be subdivided into hyperacusis and misophonia (Jastreboff and Jastreboff, 2002, 2013). While both phenomena are frequently observed in otolaryngologic and audiologic clinics, our knowledge of decreased sound tolerance is very limited and its proposed mechanisms are unproven and speculative. Nevertheless, available information suggests that decreased sound tolerance results from dysfunction of the central auditory pathways and their connections with the central nervous system rather than from dysfunction of the inner ear. There is no consensus on the testing of decreased sound tolerance. Limited information is available regarding normative data for loudness discomfort levels (LDLs), which are typically used to assess the presence of hyperacusis (Sherlock and Formby, 2005). Questionnaires have been proposed to evaluate hyperacusis severity (Khalfa et al., 2002; Dauman and Bouscau-Faure, 2005); however, their validity needs to be confirmed. Moreover, the questionnaires do not address the presence and extent of misophonia. Reported data on the prevalence and epidemiology of hyperacusis are highly diverse. Hyperacusis can occur alone or as an adjunct to complex medical conditions (Jastreboff and Jastreboff, 2009). In spite of all the limitations listed above, the treatment of decreased sound tolerance can be highly successful (Jastreboff and Jastreboff, 2000, 2013; Jastreboff and Hazell, 2004; Formby, 2007; Formby et al., 2007).

Diplacousis was first reported in 1907 by Shambaugh, Sr. (Albers and Wilson, 1968a) and is much less frequently diagnosed than decreased sound tolerance. Diplacousis occurs when a subject who is exposed to a single-frequency tone perceives multiple tones, roughness, and beats (Ward, 1952, 1955; Flottorp, 1953; Zurek, 1981; Bacon and Viemeister, 1985). A characteristic feature of diplacousis is that the distortions are perceived only for low levels of sound. When the intensity of the external tone increases, the distortions disappear and the subject perceives a single pure tone. The mechanism of diplacousis is linked to dysfunction of the inner ear (Knight, 2004), and only single reports link it to dysfunction of the central auditory pathways (Ghosh, 1990). Polyacousis occurs when more than two tones are perceived. This term is seldom used and only one paper on the subject can be found in MedLine (Corliss et al., 1968). An internet search, using various search engines, yielded no hits for polyacousis.

DEFINITIONS A variety of terms (e.g., hyperacousia, auditory hyperesthesia, recruitment, dysacousis, auditory dysesthesia, odynacusis, and auditory allodynia) (Baguley and McFerran, 2010) have been proposed to describe decreased sound tolerance, with the word “hyperacusis” used most frequently (Jastreboff and Jastreboff, 2004). One approach proposes further dividing hyperacusis into loudness hyperacusis, annoyance hyperacusis, and fear hyperacusis (Tyler et al., 2009). Stedman’s Medical Dictionary defines hyperacusis as “Abnormal acuteness of hearing due to increased

*Correspondence to: Pawel J. Jastreboff, Ph.D., Sc.D., Department of Otolaryngology, Emory University School of Medicine, 550 Peachtree St. NE, Medical Office Tower 11th Floor, Suite 1130, Atlanta, GA 30308, USA. Tel: +1-404-778-3388, Fax: +1-404-778-3382, E-mail: [email protected]

376 P.J. JASTREBOFF AND M.M. JASTREBOFF irritability of the sensory neural mechanism. Syn: audithe subject’s previous evaluation of the sound, his/her tory hyperesthesia,” with hyperesthesia defined as belief that the sound is a potential threat or that exposure “Abnormal acuteness of sensitivity to touch, pain, or to it will be harmful, the subject’s psychologic profile, other sensory stimuli” (Anon., 1997). American Heritage and the context in which the sound is presented Dictionary defines hyperacusis as “An abnormal or (Jastreboff and Jastreboff, 2002, 2013; Jastreboff and pathological increase in sensitivity to sensory stimuli, Hazell, 2004). The strength of the reaction is only par[as of the skin to touch or] the ear to sound” tially determined by the sound’s physical characteristics. (Anon., 1994). A specific category of misophonia occurs when fear is The definitions promoted in this chapter are based on the dominant emotion and patients are afraid of the reports from patients and on potential physiologic mechsound (i.e., phonophobia: phobia ¼ fear) (Jastreboff anisms, in which the auditory system (both peripheral and Jastreboff, 2002, 2013; Jastreboff and Hazell, 2004). and central parts) and the limbic and autonomic nervous Neither hyperacusis nor misophonia has any relation systems are the main systems involved. An analysis of to the threshold of hearing, which can be normal or can the negative reactions of subjects who suffer from involve hearing loss. Therefore, the term “recruitment” decreased sound tolerance points to the involvement is not related to decreased sound tolerance. Recruitment of the limbic and autonomic nervous systems in cases refers to an unusually rapid growth of loudness as of clinically significant decreased sound tolerance the level of a tone is increased. It occurs in association (i.e., where a subject’s difficulty with this condition is with hearing loss and is a purely cochlear-based phenomsubstantial enough to seek professional help). A wide enon (Moore, 1995). Recruitment might coexist with spectrum of emotional reactions is observed (e.g., disdecreased sound tolerance, but there is no functional link comfort, dislike, distress, annoyance, anxiety, and fear), between the two conditions (Jastreboff and Jastreboff, as well as a variety of negative sensations (e.g., pain, 2004). Out of 740 patients treated at the Emory Tinnitus physical discomfort, fullness in the ear) and reactions and Hyperacusis Center, during the first visit 497 associated with the overstimulation of the sympathetic patients reported a problem with decreased sound tolerpart of the autonomic nervous system (e.g., anxiety, ance and 73% of patients in this group reported a probpanic, decreased ability to enjoy life activities, sleep lem with hearing as well. A total of 126 patients (17%) problems, problem with digestion) (Jastreboff and had hyperacusis that required specific treatment and Hazell, 2004; Jastreboff and Jastreboff, 2004, 2009, out of that group of patients, 84 (67%) had concurrent 2013; Schroder et al., 2013). problems with hearing. On the other hand, 476 out of Decreased sound tolerance is defined as present when 740 patients (64%) reported a problem with hearing. In a subject exhibits negative reactions when exposed to all, 362 patients (76%) from this group also reported a sound that would not evoke the same response in an problem with decreased sound tolerance and 70 patients average listener (Jastreboff and Jastreboff, 2002, 2013; (15%) required specific treatment for hyperacusis. Jastreboff and Hazell, 2004). These negative reactions There is more than one definition of diplacousis (the can be observed when the subject is exposed to low-, spelling “diplacusis” is also used). One of the older defmoderate-, or high-level sound. The notion that sound initions is that diplacousis is a perception of rough or must be loud, or louder than a certain level, is not a prenoisy sound, or the perception of two or more sounds requisite for, and is not used as a criterion to, diagnose when a subject is exposed to a single pure tone (Ward, decreased sound tolerance. A patient’s negative reac1952). Currently, diplacousis is defined as an “abnormal tions may occur in response to any (including low) level perception of sound either in time or in pitch, such that of sound. It is postulated that decreased sound tolerance one sound is heard as two” (Anon., 1997). The name origconsists of two components: hyperacusis and misophoinates from a combination of two Greek words: diplous, nia, which frequently occur together. meaning double and akousis, meaning hearing. While Hyperacusis is defined as present when negative reacspecific epidemiologic studies are lacking, it is believed tions to a sound depend only on its physical characteristhat diplacousis is present in many people; however, if tics (i.e., its spectrum and intensity). The sound’s the pitch difference is less than a half-tone and the submeaning and the context in which it occurs are irrelevant ject does not have musical training it is not noticed. (Jastreboff and Jastreboff, 2002, 2013; Jastreboff and Diplacousis predominantly affects musicians as they Hazell, 2004). are often trained to distinguish between small pitch Misophonia is defined as an abnormally strong reacdifferences. tion to a sound with a specific pattern and meaning to a A broader definition is that diplacousis is present given subject. The physical characteristics of the sound when exposure to a pure tone results in the perception are secondary. Reactions to the sound depend on the subof several tones in addition to the presented tone ject’s past history and on non-auditory factors such as (Ward, 1955). A tone may be perceived as harmonics

DECREASED SOUND TOLERANCE 377 of a fundamental sound or the subject’s voice (Brookler, running water, wind, and rain are rarely reported as neg2009). Diplacousis depends on the frequency of the ative (Hazell et al., 2002). evoking sound (Brookler, 2009) and on the sound’s Decreased sound tolerance can prevent people from intensity. When the intensity increases, diplacousis working and interacting socially. In extreme cases, decreases (Burns, 1982). patients do not leave their homes, and their lives and their Several subtypes of diplacousis can be distinguished family’s lives revolve around (and are controlled by) the (Bauman, 2013). Diplacousis binauralis occurs when one avoidance of offensive sounds. Misophonia evokes the sound is perceived dissimilarly in each ear and may difsame reactions as hyperacusis and further enhances fer in pitch or in time. Diplacousis dysharmonica occurs the effects of hyperacusis. when the sound is perceived normally in one ear and at a Diplacousis and polyacousis are rare and are infredifferent pitch in the other ear (i.e., an interaural pitch quently reported as causing a problem for subjects difference (IPD)). Diplacousis echoica occurs when who experience them. The exception is some musicians, exposure to a sound results in the perception of the as diplacousis may have an impact on their ability to sound followed by the repetition or echo of the sound. work by decreasing their perception of music (Kaharit Diplacousis monauralis occurs when exposure to a et al., 2003; Jansen et al., 2009). Jansen et al. (2009) persound results in the perception of two different sounds formed a study on 241 professional musicians in a symin one ear. Diplacousis dysharmonica/IPD (dL) is the phony orchestra, aged from 23 to 64 years, and assessed most common type of diplacousis. IPD is defined as their hearing loss and other hearing-related complaints. dL ¼ (fR  fL)/fL ¼ fR/fL  1, where fR/fL denotes the freThey found that musicians often complained about quencies at the left and right ear, obtained by the adjusthyperacusis and tinnitus (79% and 51%, respectively), ment of either frequency to achieve the pitch match while diplacousis diagnosed by the presence of IPD > 1% (Terhardt, 2000). Diplacousis is typically associated with was measured in 44% of musicians, but reported as a hearing loss. A variety of presumed mechanisms for problem for only 7%. Interestingly, 24% of subjects comdiplacousis are associated with its different subtypes plained about the distortion of tones. and are discussed below. Considering that differences in pitch sensation Polyacousis is a specific case of diplacousis that between 1.6% and 2.3% are common in non-musicians occurs when more than two tones are perceived. This (Brink van den, 1970; Burns, 1982), it is notable in this term is rarely used. study of diplacousis that IPD larger than 2% was observed in 18% of subjects and IPD larger than 3% was present in 3% of subjects. Jansen et al. (2009) reported only a few very sensitive DECREASED SOUND TOLERANCE people who experienced diplacousis. This postulate is (HYPERACUSIS AND MISOPHONIA), further corroborated by their finding that, when the subDIPLACOUSIS, AND POLYACOUSIS AS A jective results on diplacousis were compared to the PROBLEM results of diplacousis matching, no significant correlaDecreased sound tolerance can have an extremely strong tion was found for any of the tested frequencies. Conseimpact on patients’ lives. Any sound can become offenquently, even when diplacousis is documented by IPD, it sive and evoke a negative reaction. With hyperacusis, may neither be noticed nor create a problem, even for any sound which is louder than acceptable to a patient musicians. evokes negative reactions. For misophonia, a broad variKaharit et al. (2003) evaluated 139 rock/jazz musiety of sounds have been reported to create problems. cians for hearing disorders (Table 21.1). The presence These sounds can be loud or soft, such as street sounds, of tinnitus, hyperacusis, distortion, or diplacousis was car brakes, lawnmower, vacuum cleaner, garbage disestablished by the subject’s answers on a questionnaire. posal, flushing toilet, cutlery and plates, keys rattling, The authors defined tinnitus, hyperacusis, distortion, hair dryer, school bell, announcements in a metro station and diplacousis in the following non-standard manner: or on a train or airplane, typing on a computer keyboard, Tinnitus was defined as a spontaneous or evoked the sound of a computer, refrigerator, supermarket sensation of sounds, e.g. ringing or buzzing, often freezer, the hum of electricity, a swimming-pool pump, combined with pure tones that occur in the shoveling cement, a husband/wife breathing in bed, snorabsence of an external sound source. The different ing, sounds of eating, one’s own voice, a crying baby, a sounds could be uni- or bilaterally located in the musical instrument, singing, other people’s headphones, ears, or experienced and located somewhere in fetal heart sounds, or the sound of drawing with a feltthe head. Hyperacusis was defined as hypersensitipped pen (Hazell et al., 2002; Jastreboff and Jastreboff, tivity to the loudness of sounds, including a 2004, 2013). On the other hand, sounds such as bird song,

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Table 21.1 Type of hearing disorders reported in 103 affected musicians Groups of single or >1 hearing disorder

Hearing loss n (%)

Tinnitus n (%)

Hyperacusis n (%)

Distortion n (%)

Diplacusis n (%)

Single hearing disorder >1 Hearing disorder

11 (10.7) 57 (55.3)

7 (6.8) 60 (58.3)

9 (8.7) 54 (52.4)

1 (1) 24 (23.3)

0 (0) 4 (3.9)

Data modified from Kaharit et al. (2003).

decreased pure tone and uncomfortable loudness level of specific sounds normally not experienced as loud, uncomfortable or annoying. Distortion was defined as frequencies, overtones and/or harmonics that were not experienced in their true original form but as distorted, unclear, fuzzy and out of tune. Diplacusis was defined as a pathological matching of frequency and pitch that may involve dissonance or a sudden change of pitch when a change in loudness occurs. On the basis of audiometry and the questionnaire, to determine the presence of hearing loss the subjects were first divided into two subgroups: those who were not affected by tinnitus, hyperacusis, distortion, or diplacousis (n ¼ 36 or 26%) and those who were affected by at least one of these disorders (n ¼ 103 or 74%). The latter group was further subdivided into a group that had one of these disorders and a group that had more than one disorder, as shown in Table 21.1. Hearing disorders have been observed in 74% of subjects, with tinnitus, hyperacusis, distortion, and diplacousis reported either as a single or combined disorder (Table 21.1).

DIAGNOSIS Diagnosis of decreased sound tolerance is complex and there is no agreement on how it should be done. For hyperacusis, there is a general agreement that pure-tone LDLs must have decreased values. Low values by themselves, however, do not prove the presence of hyperacusis as these values may be due to misophonia. There is no consensus on how LDLs should be evaluated. Varied results depend on the specific method used to administer LDLs (e.g., stimuli: pure tone, warble tone, noise; presentation: free field, insert earphones, headphones) and the instructions given to patients (Hawkins et al., 1987; Byrne and Dirks, 1996; Ricketts and Bentler, 1996; Cox et al., 1997; Sherlock and Formby, 2005). Several studies indicate LDLs are in the range of 90–110 dB sound pressure level (SPL) in the normal population. The results tend to cluster within

95–110 dB SPL for frequencies from 500 to 8000 Hz, which corresponds to approximately 90–100 dB hearing level (HL) (Hood and Poole, 1966; Stephens and Anderson, 1971; Sherlock and Formby, 2005). A study aimed specifically at this issue showed that the average LDL value for subjects who do not have a sound tolerance problem was 100 dB HL (Sherlock and Formby, 2005). The study has been performed on 59 adults with normal hearing and no problem with sound tolerance. In addition to evaluating LDLs, loudness growth function was measured by categoric scaling judgments on a subgroup of 18 subjects. There were no differences between absolute (LDL) and relative (categoric scaling) judgment of loudness discomfort, intersubject variability, or intrasubject test–retest reliability. The authors concluded that administering LDLs to estimate loudness discomfort is an efficient and valid clinical measure to characterize the “threshold of discomfort.” When hyperacusis is present, LDLs are lower, typically in the 60–85 dB HL range (Jastreboff and Jastreboff, 2002). In cases of pure misophonia, LDL values from 30 to 120 dB HL can be observed. Therefore, LDLs alone are insufficient to diagnose hyperacusis or misophonia, and a specific detailed interview is crucial to diagnose and assess the relative contribution of hyperacusis and misophonia to decreased sound tolerance. Notably, hyperacusis and misophonia frequently occur together. Indeed, misophonia is inevitable in cases of severe hyperacusis. However, misophonia does not induce hyperacusis. When interviewing prospective patients, it is important for the clinician to identify sounds that evoke negative reactions as well as sounds that are well tolerated in order to detect any discrepancies between reactions and the intensity of the sound. While a patient with normal LDLs does not have hyperacusis, decreased sound tolerance can still be present due to misophonia. Consequently, diagnosis of decreased sound tolerance is subjective and based predominantly on the patient’s report. To decrease the impact of misophonia on LDLs, we promote a modification of the standard procedure for administering LDLs (Hood and Poole, 1966) so that the results are dominated by hyperacusis and the effects

DECREASED SOUND TOLERANCE of the misophonic component of decreased sound tolerance are kept to a minimum. To achieve this, patients are provided full control during testing and given the power to stop it at any time (Jastreboff et al., 1996; Jastreboff and Jastreboff, 2004). There are no established and validated questionnaires to determine the severity of decreased sound tolerance. Two questionnaires have been proposed to assess the extent of hyperacusis – the Hyperacusis Questionnaire (Table 21.2) (Khalfa et al., 2002) and the MultipleActivity Scale for Hyperacusis (MASH) (Table 21.3) Table 21.2 Khalfa’s Hyperacusis Questionnaire Surname, first name: Sex: Age: Profession or studies: Place (town or area) of residence: Telephone: Are you or have you been exposed to noise? Do you tolerate noise less well as compared to a few years ago? Have you ever had hearing problems? If so, of what kind? In the following questionnaire, put a cross in the box corresponding to the answer which best applies to you: No; Yes, a little; Yes, quite a lot; Yes, a lot 1. Do you ever use earplugs or earmuffs to reduce your noise perception (do not consider the use of hearing protection during abnormally high noise exposure situations)? 2. Do you find it harder to ignore sounds around you in everyday situations? 3. Do you have trouble reading in a noisy or loud environment? 4. Do you have trouble concentrating in noisy surroundings? 5. Do you have difficulty listening to conversations in noisy places? 6. Has anyone you know ever told you that you tolerate noise or certain kinds of sound badly? 7. Are you particularly sensitive to or bothered by street noise? 8. Do you find the noise unpleasant in certain social situations (e.g., night clubs, pubs or bars, concerts, firework displays, cocktail receptions)? 9. When someone suggests doing something (going out, to the cinema, to a concert, etc.), do you immediately think about the noise you are going to have to put up with? 10. Do you ever turn down an invitation or not go out because of the noise you would have to face? 11. Do noises or particular sounds bother you more in a quiet place than in a slightly noisy room? 12. Do stress and tiredness reduce your ability to concentrate in noise? 13. Are you less able to concentrate in noise towards the end of the day? 14. Do noise and certain sounds cause you stress and irritation?

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(Dauman and Bouscau-Faure, 2005) – but their specificity and selectivity need to be further evaluated. The Hyperacusis Questionnaire was created by testing that was performed only on the general population of subjects who did not complain of hyperacusis. The questionnaire focuses on the psychologic and social aspects of hearing rather than on an indication of hyperacusis. Only four of 14 questions (rated on a scale from 1 to 4) are related to hyperacusis while the remaining questions appear to be related to other aspects, including hearing loss (“5. Do you have difficulty listening to conversations in noisy places?”) (Khalfa et al., 2002). MASH consists of a list of 14 activities, and patients are asked to indicate their level of annoyance related to a given activity on a scale from 0 to 10 (Dauman and Bouscau-Faure, 2005). Both questionnaires have been reported to be effective in the evaluation of hyperacusis, but interestingly, there was no correlation of their scores with audiologic measurements of discomfort levels (i.e., LDL and speech discomfort level) (Dauman and Bouscau-Faure, 2005). Notably, neither of these questionnaires differentiates between hyperacusis and misophonia. There is no validated questionnaire for misophonia. Diagnosis of diplacousis and polyacousis is based on an interview with the patient and on pitch matching of Table 21.3 The Multiple-Activity Scale for Hyperacusis (MASH) Concert Shopping center Cinema/TV Work Restaurant Driving a car Sport Church Housework Children Social activities Pottering about Gardening Others For each individual activity the patient was asked to provide a score from 0 to 10 to indicate the level of annoyance caused. If the subject did not attend concerts, because of a dislike of or lack of interest in live music, his/her reaction to loud music was taken into consideration. When the scores for cinema and TV differed, the highest was selected. When the patient felt unable to indicate a score for a given item, the item was deleted, even though the activity may have been relevant to him/her. The most frequently mentioned “other” noises (open-set) were small motorcycles and emergency vehicle sirens. The mean MASH score was calculated by dividing the total score by the number of relevant activities.

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the perceived tone in both ears (Kaharit et al., 2003; Ogura et al., 2003; Jansen et al., 2009). For example, Jansen et al. (2009) used an adaptive procedure to compare the pitch of pure tones presented alternatively to the right and left ear by headphones using three different frequencies: 1, 2, and 4 kHz. Specifically, in the first step, subjects were asked to match the loudness of a tone in the left ear to a 60-dB HL tone presented in the right ear using increments of 1 dB. Subjects were then asked to match the pitch of the tone in the left ear to that in the right ear using increments of 1 Hz. The procedure was repeated by alternating ears and changing the frequency of the test tone. The result of diplacousis matching was determined by the deviation between the ears and was expressed as a percentage of the measured frequency (Jansen et al., 2009). There are no reported methods to assess the severity and impact of diplacousis and polyacousis on a patient’s life; severity is judged only on the basis of the patient’s report.

PREVALENCE AND EPIDEMIOLOGY The lack of an objective method to determine the presence of decreased sound tolerance and the variety of epidemiologically oriented questionnaires used to do so yield limited data on the prevalence of decreased sound tolerance in the general population. Notably, the data obtained from 10 349 randomly selected subjects showed that 15.3% reported hyperacusis (Fabijanska et al., 1999). Diagnosis of hyperacusis is made even more complex because LDL measurements are not part of a routine audiologic evaluation. Moreover, a careful inspection of the reports revealed that, in some cases, misophonia rather than hyperacusis was present (e.g., reports on Williams syndrome) (Klein et al., 1990; Blomberg et al., 2006). An estimation of the prevalence of decreased sound tolerance can be obtained by analyzing its co-appearance with tinnitus, and more detailed and extensive data are available in that regard. Approximately 60% of tinnitus patients have significant decreased sound tolerance. Of these, about 30% of patients suffer from hyperacusis and require treatment for it (Jastreboff et al., 1999; Jastreboff and Jastreboff, 2002; Jastreboff and Hazell, 2004). Since, on average, the prevalence of bothersome tinnitus reported in the literature is about 4% (Hoffman and Reed, 2004), it is possible to estimate that 1.2% of the general population has tinnitus and hyperacusis. On the other hand, it has been reported that 86% of patients with hyperacusis suffer from tinnitus (Anari et al., 1999). It is therefore possible to calculate that 14% of subjects with hyperacusis (i.e., 0.56% of the general population) do not have tinnitus. Taking the above information into account, it is possible to estimate that clinically

significant hyperacusis exists in approximately 1.75% of the general population. As the data indicate that about half the patients with decreased sound tolerance have hyperacusis, the prevalence of decreased sound tolerance in the general population can be estimated at 3.5%. Limited data exist on the prevalence of diplacousis and polyacousis. A wide variety of ototoxic factors have been linked to diplacousis, with noise exposure being the most common (Albers and Wilson, 1968b). Nevertheless, clinical observations indicate that diplacousis is reported infrequently, and mainly by musicians or people to whom the accurate perception of music is crucial for their work. To date, only a couple of studies in the literature report on the epidemiology of diplacousis and both studies analyze the population of musicians. In the first study, performed on 139 rock/jazz musicians and described earlier in this chapter, 4 subjects (2.9%) reported diplacousis (Kaharit et al., 2003). A more recent study of diplacousis prevalence amongst 241 symphony orchestra musicians revealed that diplacousis was generally not reported as a problem and affected only 7% of subjects (Jansen et al., 2009). Subjects in this study mainly complained about tinnitus and hyperacusis. A total of 79% of the musicians complained about hyperacusis, 51% complained about tinnitus, and 24% complained about tone distortion (Jansen et al., 2009). Interestingly, while only 7% of the musicians perceived an interaural difference in pitch perception as a problem, the results of diplacousis matching revealed that 18% experienced an IPD of more than 2%. Notably, the subjective perception of diplacousis did not correlate with the extent of differences in pitch matching and there was no difference between males and females with regard to the subjective rating of diplacousis (Jansen et al., 2009).

MECHANISMS The mechanisms of hyperacusis are speculative. The lack of an animal model of hyperacusis makes it difficult to prove the validity of any postulated mechanisms responsible for this condition. Existing theories suggest a potential involvement of both peripheral and/or central mechanisms (Wrinch, 1909; Jastreboff and Jastreboff, 2004; Baguley and Andersson, 2007; Niu et al., 2013). At the peripheral level, the abnormal enhancement of cochlear basilar membrane vibration by the outer hair cells (OHCs) might result in the overstimulation of the inner hair cells, and therefore result in hyperacusis (Jastreboff, 1990; Jastreboff and Hazell, 2004). Indeed, in rare cases, it is possible to observe high-amplitude distortion product otoacoustic emissions and distortion products evoked by low-level primaries (Jastreboff and Mattox, 1998). The presence of asymmetric

DECREASED SOUND TOLERANCE 381 hyperacusis would indicate a peripheral mechanism supports the proposed hypothesis by showing an because the involvement of central mechanisms would improvement in hyperacusis, difficulty understanding more likely act similarly on both sides. However, in speech, withdrawn depression, lethargy, and hypersensinearly all cases decreased sound tolerance is symmetric, tivity to touch, pressure, and light after following treatwhich argues against the dominant role of the peripheral ment with selective serotonin reuptake inhibitors (Gopal mechanisms (Jastreboff et al., 1999). et al., 2000). Substantial data support the presence of central A high prevalence of decreased sound tolerance in mechanisms in hyperacusis. Animal research has shown people with Williams syndrome (over 80%) suggests a that damage to the cochlea or a decrease in auditory genetic basis of decreased sound tolerance in those subinput results in a decrease of the response threshold in jects (Nigam and Samuel, 1994; Gothelf et al., 2006). a significant proportion of neurons in the ventral The mechanisms of misophonia could involve the cochlear nucleus and inferior colliculus (Boettcher and enhancement of the functional links between the auditory Salvi, 1993). Studies on evoked potentials indicate an and limbic systems at both the cognitive and subconscious abnormal increase of gain in the auditory pathways after levels (Jastreboff, 1990; Jastreboff and Hazell, 2004). such manipulations are applied (Gerken, 1993). The Alternatively, a tonic high level of activation of the limbic notion of increased gain within the central part of the and autonomic nervous systems may result in strong auditory pathways has been discussed and promoted in behavioral reactions to moderate sounds (Jastreboff and recent approaches to the mechanisms of tinnitus and Hazell, 2004). A recent study supported the proposed hyperacusis (Norena and Farley, 2013). mechanisms of misophonia by showing the enhanced autoA number of medical conditions have been linked to nomic reactivity to a sound, but not to other sensory stimuli decreased sound tolerance (e.g., tinnitus, Williams synin misophonic patients (Edelstein et al., 2013). In January drome, Bell’s palsy, Lyme disease, Ramsay Hunt syn2013, Schroder et al. redefined misophonia based on their drome, poststapedectomy, perilymphatic fistula, head work in a psychiatric center and proposed to classify the injury, migraine, depression, withdrawal from benzodicondition as a new psychiatric disorder. In our opinion, azepines, cerebrospinal fluid high pressure, Addison’s Schroder et al. studied a population of psychiatric patients disease, translabyrinthine excision of a vestibular who happened to have misophonia as well. In our clinical schwannoma) (Adour and Wingerd, 1974; Klein et al., work, we have seen 318 misophonic patients (compared to 1990; Wayman et al., 1990; Lader, 1994; Nields et al., 42 cases reported by Schroder et al.), all evaluated by phy1999; Gopal et al., 2000; Jastreboff and Hazell, 2004; sicians, and in only 7 cases (2.2%) did patients exhibit psyBlomberg et al., 2006). These conditions can be linked chiatric problems. Moreover, our misophonic patients to the central processing of signals and to the modificashowed significant improvement when treated with a comtion of the level of neuromodulators as possible factors bination of counseling and a specific version of sound that induce or enhance hyperacusis. Moreover, serotherapy (described below), without any need for psychiattonin has been implicated in hyperacusis on the basis ric intervention. of indirect reasoning that some conditions occur with The mechanisms of diplacousis are hypothetic. hyperacusis as a symptom (e.g., migraine, depression, Nearly all the proposed mechanisms of diplacousis pyridoxine deficiency, benzodiazepine dependence, involve the cochlea, and only one paper describes diplaand postviral fatigue syndrome) and involve a disturcousis of (presumably) central origin linked to a lesion in bance in serotonin activity (Marriage and Barnes, the posterior thalamus (Ghosh, 1990). The first class of 1995). These authors speculated that, as serotonin is proposed mechanisms links diplacousis to hearing loss considered to have an inhibitory role in sensory modulaand OHC damage in the cochlea. OHCs work as a tion at a central level, a reduction in forebrain serotonin mechanical amplifier within the cochlea and are responactivity is therefore the most likely underlying pathology sible for sharp tuning of the traveling wave in the that causes central hyperacusis. The authors have not cochlea. Notably, the OHCs amplify sounds of lower proposed any more specific mechanisms of serotonin intensities only – below 60 dB SPL – which corresponds involvement, and have stated that the increase or roughly to half the dynamic range of hearing. OHCs prodecrease of serotonin may be linked to hyperacusis. vide gradually less amplification when the level of a Additionally, they labeled decreased sound tolerance sound increases and become inactive for sound intensias hyperacusis, with stress on phonophobia, which may ties higher than 60 dB SPL. have different mechanisms than hyperacusis, and is The mechanism for diplacousis linked to hearing loss inconsistent with current classifications (Jastreboff is discussed below. The hypothesis is based on basic sciand Jastreboff, 2002, 2013; Tyler et al., 2009). ence regarding the functioning of the cochlea and the Serotonin involvement in hyperacusis has not been mechanisms of pitch perception. There is a strict relaconfirmed. There is only one case presentation which tionship between a given place on the cochlea’s basilar

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membrane and the frequency of tone that evokes it. Neuronal activity in the auditory nerve is correlated with the phase of the incoming pure tone only for frequencies below 1000 Hz. For higher frequencies, the place on the basilar membrane where the maximal amplitude of the traveling wave develops determines the perceived pitch (Moore, 1995). When a group of OHCs is damaged, the tuning curve becomes broader and its peak shifts in frequency. When compared to an ear with undamaged OHCs for this specific frequency region, the shift in place occurs where maximal stimulation of the basilar membrane occurs. Consequently, the subject perceives a different pitch in one ear than in the other ear. Note that, as OHCs do not function for sound intensities higher than 60 dB SPL, diplacousis based on this mechanism decreases with the increase of a sound’s intensity and disappears when the intensity exceeds 60 dB SPL. Diplacousis may or may not appear depending on the difference in the damage of OHC systems in one ear versus the other ear for a given frequency range. This theory explains the clinical observation that diplacousis is particularly linked to unilateral/asymmetric hearing loss, the intensity of a sound to which a subject is exposed, and the relation of the affected pitch to the regions of hearing loss. The theory also explains instances of temporal or permanent diplacousis evoked by a loud noise, as reported in the literature (Knight, 2004; Jansen et al., 2009). The temporal dysfunction of OHCs occurs following exposure to a loud noise (i.e., the cilia of the OHC becomes disorganized, making a cell temporarily dysfunctional). Depending on the asymmetry of damage and pre-existing damage of the OHC system, diplacousis may temporarily appear. If the exposure to a sound results in permanent damage to a group of OHCs, permanent diplacousis emerges. Local damage of OHCs causes a loss of sharp tuning of stimulation of IHCs and a shift of frequency where maximal stimulation occurs. This results in the perception of a different frequency than the one to which the subject is exposed (Fig. 21.1). Broadening of the curve may result in the perception of a fuzzy sound. A question arises regarding the mechanisms of diplacousis in subjects without hearing loss. First, a normal audiogram can be seen in subjects who lost up to 30% of their OHCs (Harding and Bohne, 2007, 2009; Chen et al., 2008), and yet for these subjects the proposed mechanisms described above are still applicable. An evaluation of the functional status of OHCs by highfrequency resolution distortion product otoacoustic emissions (DPOAE) measurement is needed to determine whether groups of OHCs are damaged. A study of a sudden hearing loss case supports the proposed mechanisms: while there was no clear relation of diplacousis with hearing threshold and transient otoacoustic

Fig. 21.1. Potential mechanisms of diplacousis as a result of outer hair cell (OHC) dysfunction or loss. Damage of OHC results in a broadening response curve and shifting frequency where maximal stimulation occurs. Horizontal axis, frequency; vertical axis, threshold of stimulation of inner hair cell (IHC); solid line, intact OHC; dashed line, OHC are dysfunctional or damaged in an area on the basilar membrane; fn perceived frequency in normal cochlea; fd perceived diplacousis frequency in cochlear with dysfunctional OHC; Df diplacousis frequency shift.

emissions, the observed frequency shifts in the DPAOE fine structure were in close agreement with the changes in diplacousis (Knight, 2004). Another mechanism may be involved in subjects with diplacousis who have normal hearing. This mechanism may also explain the presence of monaural diplacousis. An indication for this mechanism arises from two observations: (1) in diplacousis related to hearing loss, the pitch shift is pronounced and exists in a broad frequency range, while in subjects with normal hearing the shift is typically only 2% and is distributed in a random manner with a mean shift close to zero; (2) spontaneous otoacoustic emissions (SPOAE) are commonly observed in people with normal hearing; these emissions consist of a number of pure-tone/very narrow noise bands and may have relatively high intensity. If a person with SPOAE is exposed to a low-level tone, then due to the non-linear properties of the cochlea, the tone will interact with SPOAE idiotones and create a number of distortions with frequencies that follow the equation fd ¼  mfet  nfSPi, where f denotes the frequency, subscript d denotes distortion, et refers to an

DECREASED SOUND TOLERANCE external tone, SPi is an “i” component of SPOAE, and n and m are natural numbers (i.e., 1, 2, 3, etc.). The condition fd > 0 has to be fulfilled. As SPOAE may contain many frequencies, the resulting perception of a sound can be complex. Reported properties of diplacousis support this hypothesis, while pointing to the complex nature of the proposed interactions (Formby and Gjerdingen, 1981; Long, 1998).

THE NEUROPHYSIOLOGICAL MODEL OF DECREASED SOUND TOLERANCE The neurophysiologic model of tinnitus, decreased sound tolerance, and the treatment approach based on the model, known as tinnitus retraining therapy (TRT), were introduced in 1990 (Jastreboff, 2000, 2007b, 2010; Jastreboff and Jastreboff, 2001, 2006). An analysis of negative reactions experienced by patients led to the proposition that the auditory system plays a secondary role in clinically significant decreased sound tolerance, and that other systems in the brain are dominant. While a number of systems in the brain are important (e.g., prefrontal cortex, attention networks, systems involved in memory), the limbic and autonomic nervous systems seem to be crucial. The block diagram of the neurophysiological model of tinnitus as applied to decreased sound tolerance has been described in detail elsewhere (Jastreboff, 2004; Jastreboff and Hazell, 2004; Jastreboff and Jastreboff, 2004). The model can be used to discuss the potential mechanisms of hyperacusis and misophonia. First, the reactions experienced by patients are the same in both hyperacusis and misophonia. This supports the postulate that the same systems in the brain are responsible for these reactions. In turn, the type of negative reactions supports the notion that the limbic and autonomic nervous systems are dominant in the emergence of these reactions. The activation of these systems in the brain occurs in a different manner for hyperacusis than it does

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for misophonia. With hyperacusis, the presumed mechanism is an abnormally high amplification occurring within the auditory pathways (predominantly at the subconscious level) that yields a strong neuronal activation evoked by moderate or weak sound. Similar activation is evoked in a normal subject following exposure to a high level of sound. The limbic and autonomic nervous systems are activated as a consequence of the high level of auditory system activation. Thus, patients with hyperacusis experience the same problems while exposed to moderate or weak sound that a person without hyperacusis does when subjected to a very high level of sound (Fig. 21.2A) (Jastreboff and Jastreboff, 2004). Proposed mechanisms of misophonia involve a high level of activation of the limbic and autonomic nervous systems due to enhanced functional connections between the auditory system and other systems in the brain (mainly the limbic and autonomic nervous systems for specific patterns of a sound only) (Jastreboff and Jastreboff, 2009, 2013). At the same time, the auditory system functions normally (Fig. 21.2B). Note that the presumed neurophysiological mechanisms are distinctively dissimilar for hyperacusis and misophonia, and consequently the treatments are different as well. Therefore, it is important to assess the presence and extent of both phenomena in a patient as each condition needs to be treated using different approaches. Audiologic evaluation provides only partial help in this regard and therefore a detailed interview is crucial.

TREATMENTS Treatment for hyperacusis has taken two opposite directions. The most common approach is to advise patients to avoid sounds and use ear protection. This is based on the reasoning that, because patients became sensitive to a sound, they are supposedly more susceptible to sound exposure and consequently need extra protection. Patients easily embrace this reasoning and begin to

Fig. 21.2. Block diagram of potential mechanisms responsible for decreased sound tolerance. (A) Block diagram of potential mechanisms responsible for hyperacusis. Hyperacusis results from an abnormal amplification of sound-evoked activity occurring within the auditory pathways (marked by black lines). (B) Block diagram of potential mechanisms responsible for misophonia. Misophonia results from enhanced functional connections between the auditory and the limbic and autonomic nervous systems for a specific pattern of sound-evoked activity (marked by black lines). Note the overamplification of the limbic and autonomic system occurring in both conditions and marked by cross pattern. (Modified from Jastreboff and Jastreboff, 2004.)

384 P.J. JASTREBOFF AND M.M. JASTREBOFF protect their ears, even to the extent of using earplugs in for the treatment of hyperacusis and have shown that quiet environments. Unfortunately, this well-intended the desensitization approach used in TRT has a statistiapproach makes the auditory system even more sensitive cally and clinically significant impact on hyperacusis to sound and further exacerbates hyperacusis (Vernon (Formby, 2007; Formby et al., 2007, 2013). Therefore, and Press, 1998; Formby et al., 2003, 2007, 2013; for hyperacusis patients, avoiding silence and being conHawley et al., 2007). tinually exposed to sound are crucially important. The The opposite approach to treating hyperacusis sound level should be well controlled during treatment involves desensitization, wherein patients are exposed and should never induce discomfort or annoyance. to a variety of sounds. The desensitization approach Ear-level, wearable sound generators, which facilitate has been promoted for some time with a number of prokeeping the sound at a constant, well-controlled level, tocols and types of sounds used. For example, sounds are often employed. with certain frequencies removed, short exposure to Unfortunately, patients with decreased sound tolermoderately loud sound, or prolonged exposure to relaance (particularly misophonia) tend to set the sound level tively low-level sounds have been used (Vernon and of their devices close to or at the threshold of hearing, Press, 1998; Jastreboff and Jastreboff, 2000). “Pink and this is considerably less efficient for tinnitus and noise therapy,” as proposed by Vernon and Press hyperacusis treatment. The use of real-ear measure(1998), has gained some recognition. In this approach, ments as a guide in setting and checking the sound level patients were advised to stop ear overprotection and to for all patients who use instrumentation to treat listen to pink noise through headphones set to the highest decreased sound tolerance is very helpful to patients comfortable level for 2 hours a day. A group of patients and should be performed during their initial and were provided with pink-noise cassette tapes and quesfollow-up visits with the TRT clinician. The recomtionnaires were mailed to 30 participants. Out of mended range of sound is from 6 to 16 dB sensation 20 patients who responded, 13 reported using these tapes level (SL). in a systematic manner and 7 (54%) reported improveDesensitization works on the auditory system. Therement in their hyperacusis (Vernon and Press, 1998). fore, this approach will not affect misophonia, which A version of pink-noise therapy has also recently been needs to be addressed via the active extinction of condiproposed for tinnitus and hyperacusis by Johnson tioned reflexes between the auditory system and the lim(2014). The protocol combines the use of pink noise with bic and autonomic nervous systems. This can be a 16-week cognitive exercise program divided into secachieved by specific counseling and protocols for worktions devoted to different topics, such as recognition ing with sound (Jastreboff, 2007a; Jastreboff and and relief. To date, no results have been published in Jastreboff, 2002, 2004, 2013). In particular, patients the peer-reviewed literature regarding the effectiveness are advised to systematically engage in pleasant activiof this approach. ties they enjoy where sounds play an indispensable role, There are no published treatments for diplacousis and such as listening actively to one’s favorite music or to polyacousis. In one patient’s case, the use of aspirin audiobooks following a specific protocol (Jastreboff resulted in a reduction of SPOAE into the noise floor and Jastreboff, 2002). Other activities include shopping and eliminated monaural diplacousis (Long, 1998). in a mall, going to parties, dining in restaurants, and attending movies. The main idea is to create an association of a given sound with a pleasant situation (impleTinnitus retraining therapy (TRT) for menting the active extinction of conditioned reflexes). decreased sound tolerance There are four classes of protocols for misophonia. TRT can help patients with tinnitus and hyperacusis. The The specific protocol used is tailored to the individual presence of hyperacusis is one of the key factors in the patient. Frequently, more than one protocol is used to categorization of TRT patients and in determining the treat misophonia. Each protocol is geared to create a posprotocol for treatment (Jastreboff, 1999, 2010; itive association with a sound, but the protocols differ Jastreboff and Hazell, 2004). It is recommended that with respect to the extent of control the patient has over if hyperacusis is present it must be treated first. For some the sound environment and, in the case of protocol catpatients with decreased sound tolerance, it is possible to egory 4, employ the use of sounds with a positive assocompletely remove hyperacusis and misophonia and to ciation together with bothersome sounds which evoke effectively provide a cure for these conditions negative reactions (Jastreboff and Jastreboff, 2013). (Jastreboff and Jastreboff, 2001, 2013). Protocol category 1 provides the patient with full conAccording to the principles of the neurophysiological trol over the selection of sound, its level, and duration. model of tinnitus, prolonged exposure to relatively As such, it can be used even in cases of coexisting signiflow-level sound is recommended and is used as a part icant hyperacusis and can be implemented from the start of TRT. Independent results support the use of TRT of treatment.

DECREASED SOUND TOLERANCE Protocol category 2 affords the patient full control over the type of sound, but only partial, indirect control over the sound level, by yielding control to someone close to the patient who is instructed to set the sound volume to a level he or she thinks the patient will accept. After a listening session, the patient should provide feedback as to whether the sound level was too high, too low, or just fine. Protocol category 3 enables the patient to select the type of sound, but the sound level is fully out of the patient’s control. This protocol can be used only when significant hyperacusis is absent or has been eliminated by treatment. Therefore, the introduction of this protocol is frequently delayed. Protocol category 4 uses the concept of complex conditioned stimuli and combines the exposure to sounds which evoke negative reactions with the simultaneous exposure to sound the patient regards as highly positive and enjoyable. The ratio of sound levels of positive-tonegative sound is gradually decreased. The environment where this protocol is used is taken into account, as many patients react differently depending on where they are exposed to a bothersome sound (i.e., home, school, a public place, a restaurant, a friend’s home). The multisensory aspect of stimuli is also taken into account, as some patients react even to seeing someone produce offensive sounds (e.g., eating). An analysis was made of 201 consecutive patients diagnosed with decreased sound tolerance and treated with TRT at Emory Tinnitus and Hyperacusis Center. A total of 184 patients (92%) had misophonia; 17 patients (8%) had hyperacusis alone, and 56 patients (28%) had hyperacusis and misophonia concurrently. The proportion of patients with significant hyperacusis (with or without misophonia) who required specific treatment is similar to the 25–30% reported in the literature (Jastreboff et al., 1999; Hazell et al., 2002; Herraiz et al., 2003, 2006; Jastreboff and Jastreboff, 2004) and to the 26% we have reported previously (Jastreboff and Jastreboff, 2002). Improvement in hyperacusis was judged on the basis of changes in LDLs combined with responses obtained during the structured interviews, while improvement in misophonia was solely based on the interviews. This decision was based on the observation that, in cases of misophonia, any LDL values could be seen and the values were not correlated with patients’ judgment of the problems due to decreased sound tolerance. Of 201 patients with decreased sound tolerance, 165 patients (82%) showed significant improvement. For 56 patients with hyperacusis (with or without misophonia), 45 patients (80%) showed significant improvement. The effectiveness of treatment for misophonia with or without hyperacusis was identical (152 of 184 patients with misophonia accompanied by hyperacusis, or 83%,

385

and 139 of 167 patients with misophonia alone, or 83%). As noted earlier, in some cases it is possible to achieve a cure for misophonia as well as for hyperacusis (Jastreboff and Jastreboff, 2001, 2013). Furthermore, our clinical observations demonstrated that treatment of misophonia is crucial to achieving a successful outcome for tinnitus treatment (Jastreboff and Jastreboff, 2012).

CONCLUSIONS Decreased sound tolerance (hyperacusis and misophonia) remains a challenging topic to study and to treat. Many questions are unanswered. The mechanisms are speculative and unproven. Even less is known about diplacousis and polyacousis. The neurophysiological model of tinnitus and TRT provide an approach that helps patients and may ultimately result in a better understanding of decreased sound tolerance. There is a need to investigate the potential mechanisms of diplacousis and polyacousis as our knowledge of these phenomena is severely limited and effective treatments for these problems have not been established.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 22

Auditory synesthesias PEGAH AFRA* Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA

INTRODUCTION The term synesthesia is composed of two parts, syn ¼ together and aesthesia ¼ sensation, literally meaning “experiencing together” (Baron-Cohen et al., 1987). It denotes that sensory stimulation of one sensory modality (the inducer) will elicit an involuntary or automatic sensation (the concurrent). The sensory experience of concurrent can be in a different aspect of the same sensory modality as inducer or in another sensory modality. The inducer does not normally elicit the concurrent in normal subjects and the perception of concurrent does not represent the events in the external world. For example, in auditory-visual synesthesia, hearing music or environmental sounds can trigger color experience, or in auditory-gustatory synesthesia, hearing spoken words may trigger taste. As mentioned above, the concurrent can be in the same modality as inducer (for example, in grapheme-color synesthesia, the letter “A” can be seen as “red” regardless of its ink color), or the inducer and concurrent can be in two different modalities (for example, in auditory-visual synesthesia). The terminology of synesthesia was rather ambiguous until 2001, when Grossenbacher and Lovelace introduced the terms inducer and concurrent. They suggested the inducer–concurrent pairing to be used as standard terminology for synesthesia (i.e., instead of earlier terms of “colored-hearing” synesthesia, the term “soundcolor” or “auditory-visual” synesthesia should be used). Regarding the inducer phenomenology, synesthetic perception occurs when the concurrent is induced by perceiving particular sensory stimuli, while synesthetic conception is when the concurrent is induced by thinking about a particular concept (Grossenbacher and Lovelace, 2001). In regard to concurrent phenomenology, associator (internal) synesthetes perceive the concurrent by the “mind’s eye” while projector (external)

synesthetes perceive the concurrent in the external space (Dixon et al., 2004).

TYPES OF SYNESTHESIA Three types of synesthesia – developmental, acquired, and induced – have been recognized (Grossenbacher and Lovelace, 2001; Sinke et al., 2012). Developmental synesthesias are lifelong experiences and subjects remember them back to their childhood. Acquired synesthesias usually happen subsequent to sensory deafferentation or pathologic insult to the brain (although a single idiopathic case has been described). They persist for a variable duration of time, from days to months or even years. Induced synesthesias are transient phenomena and are experienced temporarily in the setting of sensory deprivation or acute intoxication. Sinke et al. (2012) have reviewed the phenomenologic differences between the different types of synesthesia. Some of these are discussed below.

Consistency The developmental synesthesias are highly consistent experiences throughout one’s life, i.e., the same inducer will always induce the same concurrent in the same individual (low intraindividual variability). They are also highly idiosyncratic experiences, i.e., the same inducer can elicit different concurrents in different individuals (high interindividual variability). Consistency has not been studied in acquired forms. Drug-induced synesthesias are highly variable experiences both inter- and intraindividually.

Automaticity Developmental synesthesias are highly automatic processes. As soon as the subject recognizes the inducer,

*Correspondence to: Pegah Afra, M.D., Department of Neurology, University of Utah, 175 N. Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA. E-mail: [email protected]

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the concurrent is involuntarily experienced. Acquired synesthesias are less automatic in that synesthetic experience can depend on the state of the subject, i.e., synesthesia is usually experienced during drowsiness, calm, and still states (Lessell and Cohen, 1979; Jacobs et al., 1981). Drug-induced synesthesias are not automatic and are highly dependent on the emotional state of the subject.

Dynamicity In developmental synesthesias the dynamicity of the concurrent mimics the inducer. Specifically, when the inducer is music, then both the inducer and concurrent are quite dynamic. Acquired synesthesias are not dynamic. Drug-induced synesthesias are highly dynamic and complex, with different inducers eliciting the same concurrent and constantly changing concurrents.

Affectivity In developmental and acquired synesthesias the subject’s emotional state does not influence the synesthetic experience. Developmental synesthetes find their experience enjoyable and aesthetically appealing and synesthetic artists use their synesthesia as inspiration for their artwork. The synesthesias in acquired form can be disturbing to the subject. In drug-induced synesthesia affectivity plays a central role. The three types of auditory synesthesia are summarized in Table 22.1 and discussed below.

Table 22.1 Auditory synesthesias that have been scientifically reported Types of auditory synesthesia Developmental auditory synesthesia Unidirectional auditory synesthesia Auditory synesthesia with auditory stimuli as inducer Auditory-visual synesthesia Auditory-olfactory synesthesia Auditory-gustatory synesthesia Auditory synesthesia with auditory concurrent “Hearing-motion” synesthesia Bidirectional auditory synesthesia Auditory-visual and visual-auditory synesthesia Acquired auditory synesthesia Lesional Pathological affection of anterior optic pathways (i.e., visual deafferentation) Pathological affection of the central nervous system with intact visual pathways Non-lesional Associated with epilepsy Associated with migraines Idiopathic Induced auditory synesthesia Induced by sensory deprivation Drug-induced

AUDITORY SYNESTHESIA WITH AUDITORY STIMULI (TABLES 22.2 AND 22.3)

AS INDUCER

Auditory-visual synesthesia

Developmental auditory synesthesias The developmental synesthesias are not a neurologic disorder but rather a different way of experiencing one’s environment. These are involuntary and highly consistent experiences throughout one’s life and the subjects remember them back to their childhood (Rich and Mattingley, 2002). Several types of developmental auditory synesthesia have been studied scientifically and are discussed in this chapter (Rich and Mattingley, 2002; Rich et al., 2005; Novich et al., 2011). These are summarized in Table 22.1. Additionally, many more types have been self-reported to The Synesthesia List, an international e-mail forum for synesthetes and those researching or interested in synesthesia (Day, 2005). These are summarized in Tables 22.2–22.4. The wide variation in presentation of synesthesia is due to the presence of multiple types of auditory stimuli triggering a variety of concurrents (Tables 22.2 and 22.3) and multiple types of inducer that can trigger auditory synesthetic perception (Table 22.4).

Auditory-visual synesthesia is the most common type of developmental auditory synesthesia and is reported to make up 18% of a large self-referral sample of synesthetes (Day, 2005). It occurs when auditory stimuli elicit a definite and reliable visual experience. A variety of auditory stimuli have been reported as inducers. These could be classified as lexical-phoneme (i.e., spoken words) and non-lexical auditory stimuli (i.e., noise and sound stimuli, including clicking sounds, environmental sounds, vowels, voices, musical sounds, notes, chords, intervals, and timbre). Different characteristics of the auditory stimuli have been associated with different characteristics of visual concurrent. The pitch of the auditory stimuli has been associated with luminance of visual concurrent (higher-pitch sounds are lighter, while lower-pitch sounds are darker), vertical position or spatial coordinate (higher-pitch sounds are higher in space, while lower-pitch sounds are lower in space), shape (higher-pitch sounds are angular, while lower-pitch sounds are more rounded), and size (higher-pitch sounds are smaller, while lower-pitch sounds are larger)

Table 22.2 Reported inducer–concurrent couplings in developmental auditory synesthesias with auditory inducer and visual concurrent Auditory inducer

Visual concurrent

Color Noise Sound (pitch or loudness) Musical sounds, notes, or chords Music interval Timbre Genre of music Vowels Lexicon-phoneme Voice

Color and texture

x

Authors Size or shape

Luminescence

x x

x

x

x

x

x x x x x x

x x x

x x

x

Spatial coordinate

Movement

Number x x

x

x

x

Jackson and Sandramouli, 2012 Marks, 1975; Day, 2005; Jackson and Sandramouli, 2012 Marks, 1975; Mills et al., 2003; Beeli et al., 2005; Day, 2005; Rich et al., 2005; Novich et al., 2011 Mills et al., 2003 Marks, 1975; Mills et al., 2003; Novich et al., 2011 Marks, 1975; Mills et al., 2003 Marks, 1975 Day, 2005 Rich et al., 2005; Jackson and Sandramouli, 2012

Table 22.3 Reported inducer–concurrent couplings in developmental auditory synesthesias with auditory inducer and non-visual concurrent Auditory inducer

Non-visual concurrent Olfactory

Gustatory

Smell

Taste

Authors Somatosensory Food quality

Tactile/ touch

Noise

x

Sound (pitch or loudness)

x

x

x

x

Musical sounds, notes, or chords

x

x

x

x

Music interval

Temperature

x

x

Emotional

Pain

Kinetic

Emotion

x x

Pierce, 1907; Cytowic, 2002; Jackson and Sandramouli, 2012 x

Day, 2005; Day website; Jackson and Sandramouli, 2012; Pierce, 1907; Novich et al., 2011; Richer et al., 2011 x

Pierce, 1907; Day website; Rich et al., 2005; Richer et al., 2011 Beeli et al., 2005

Timbre Genre of music Vowels

x

Lexicon-phoneme

x

Voice Day website: types of synesthesia.

x

Pierce, 1907

x

Pierce, 1907; Richer et al., 2011

x

Rich et al., 2005; Richer et al., 2011

AUDITORY SYNESTHESIAS

393

Table 22.4 Reported inducer–concurrent couplings in developmental auditory synesthesias with auditory concurrent Inducers

Auditory concurrent

Author(s)

Noise Sound Music Phoneme Voice Olfactory Smell

x

Day, 2005; Day website; Rich et al., 2005

Gustatory Taste/flavor

x

Day, 2005; Day website; Rich et al., 2005

x x

Day, 2005; Day website; Rich et al., 2005; Novich et al., 2011 Saenz and Koch, 2008 Rich et al., 2005

Visual Vision Flash/motion Complex/painting

x

Somatosensory Tactile, touch Temperature Pain Kinetic

x x x x

Day, 2005; Day website Day, 2005; Day website Rich et al., 2005 Day website

Time unit

x

Day website

Emotion

x

Day website

Day website: types of synesthesia.

(Karowski et al., 1942; Ward et al., 2006; Chiou et al., 2012; Fernay et al., 2012). Timbre has been associated with color saturation or richness of colors (Ward et al., 2006). The visual concurrents are usually colors or geometric shapes, although movement and texture have also been reported (Mills et al., 2003). Color is the most common visual concurrent, and its properties can depend on the acoustic properties of the inducing stimuli, as described above. However, when spoken words are the inducing stimuli, then color can depend on the linguistic properties of the auditory stimuli (Paulesu et al., 1995). In such cases the term lexical-color synesthesia is suggested (Rich et al., 2005), pointing to the fact that color concurrent can be induced by the graphemic (i.e., visual) or phonemic (i.e., auditory) component of the words. Colors can be either within the visible spectrum or non-real “Martian colors” (Ramachandran and Hubbard, 2001; Sinke et al., 2012). When within the visible spectrum, synesthetes can have difficulty explaining their concurrent synesthetic color. In case of non-real “Martian colors” they claim that they have never seen their concurrent synesthetic color in reality (Sinke et al., 2012). When music is the inducer, the colors can be accompanied by form and structure that can move and change with the music (i.e., the concurrent mimics the inducer in its dynamics). Auditory-visual synesthesia can occur in combination with other types of synesthesia. These are discussed below.

Auditory-olfactory and auditory-gustatory synesthesia A case of auditory-visual synesthesia coexisting with auditory-olfactory synesthesia has been reported (Jackson and Sandramouli, 2012). In this case, the auditory-visual component consisted of voices causing shapes with different locations in the visual field, and other sounds (like clicking sounds, treading on grass or gravel, ripping paper, or untuned television) causing numbers, shapes, or colors. For the auditory-olfactory component noises and certain sounds elicited different smells (for example, the sound of a drill smelled like bleach, vacuum cleaner like vomit, and music like food). The synesthetic smell could be overpowering (i.e., the smell of bleach could cause vomiting). A unique case of a musician with auditory-visual and auditorygustatory (music interval-taste) synesthesia who made use of the synesthetic sensation in the complex task of tone-interval identification has also been reported (Beeli et al., 2005). In the auditory-visual component, the inducers were tones and concurrent synesthetic perceptions were colors (for example, C is red and F-sharp is violet). In regard to the auditory-gustatory component, the inducers were musical-tone intervals and the concurrent synesthetic perceptions were tastes (for example, minor second is sour and major third is sweet). Historically the earliest cases of auditory-gustatory synesthesia were reported in the early 20th century. Pierce (1907) reported a case of auditory-gustatory

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synesthesia in an anosmic subject with partial deafness. The inducers were reported to be a wide range of auditory stimuli, including spoken words, phonemes, vocal sounds (in the form of nonsense syllables) and non-vocal sounds (in the form of musical notes, tuning-fork vibrations, as well as noises). The concurrents were the four basic tastes, and food characteristics like temperature, texture, consistency, and pressure. Auditory-gustatory synesthesia had also been reported in two Italian speakers with intact olfaction with and without associated auditory-olfactory synesthesia (Ferrari, 1907, 1910). In recent years, the term lexical-gustatory synesthesia has been suggested to replace auditory-gustatory synesthesia. This term denotes that the linguistic inducer of the taste can be auditory (i.e., spoken words and phonemes) or visual (i.e., written words and graphemes), although in nearly all studied cases of lexical-gustatory synesthesia the inducers are auditory i.e., phonemes (Ward et al., 2005; Simner et al., 2006). The concurrent gustatory experiences are complex and detailed. As with the cases discussed above, they include not only taste but also food characteristics such as texture and temperature. Multiple other developmental auditory synesthesias are summarized in Table 22.3. These were self-reported to The Synesthesia List (Day, 2005).

AUDITORY SYNESTHESIA WITH AUDITORY CONCURRENT (TABLE 22.4) A unique case series of 4 subjects in whom visual motion (i.e., inducer) elicited sounds (i.e., concurrent) were reported and called by authors as “hearing-motion synesthesia.” Almost all other cases of auditory synesthetic perception have been self-reported to The Synesthesia List (Day, 2005), with a variety of inducer–concurrent pairings, as summarized in Table 22.4.

BIDIRECTIONAL AUDITORY SYNESTHESIA Bidirectional synesthesias are rare and bidirectional auditory synesthesias have been occasionally reported. These include reports of 2 subjects who have concomitant auditory-visual and visual-auditory synesthesia (Goller et al., 2009), and a very unusual case of bidirectional lexical-gustatory synesthesia (Richer et al., 2011).

PREVALENCE AND GENETICS OF DEVELOPMENTAL SYNESTHESIAS

The reported prevalence of developmental synesthesias varies from 1 in 10 to 1 in 100 000 depending on the definitional criteria of the particular study (Simner et al., 2006). On one self-referral-based study the prevalence of synesthesia is reported to be 1 in 2000

(Baron-Cohen et al., 1996). In another study the prevalence of synesthesia was found to be 1.1–4.4% (Simner et al., 2006). In this latter study the definition of synesthesia was more liberal, large samples of the population were screened, and synesthesia was verified with objective measures of consistency. The reported prevalence of synesthesia within synesthetic families is 16% (Ward and Simner, 2005). Additionally, about 36–44% of synesthetes report at least one other family member with synesthesia (Rich et al., 2005; Ward and Simner, 2005). The female-to-male ratio is also variable across different studies, ranging from 6:1 to 1:1 (Baron-Cohen et al., 1996; Rich et al., 2005; Simner et al., 2006; Barnett et al., 2008; Ward, 2013). Earlier studies had shown a higher female-to-male ratio and familial segregation, therefore at one time synesthesia was thought to be an X-linked dominant trait with lethality in males (Ward and Simner, 2005). Subsequent studies did not show the female preponderance and the earlier-reported female bias is thought to be due to sex differences in self-disclosure (Simner et al., 2006). There is continued evidence for strong genetic predisposition with complex modes of inheritance. Whole-genome linkage studies in auditory-visual synesthesia suggested an oligogenic disorder subject to multiple modes of inheritance and locus heterogeneity with linkage to chromosomes 5q33, 6p12, and 12p12 (Asher et al., 2009).

NEUROBIOLOGIC INVESTIGATION OF DEVELOPMENTAL AUDITORY SYNESTHESIAS

The neurobiologic investigations of developmental auditory synesthesias can be divided into three groups: structural studies, functional studies, and neurophysiologic studies. These are discussed below. Structural studies There is a single study (Hanggi et al., 2008) investigating the neuroanatomic basis of interval-taste and tone-color synesthesia in a synesthetic musician in comparison to 20 controls and 17 non-synesthetic musicians (10 with absolute pitch and 7 with relative pitch). In the synesthetic subject with interval-taste and tone-color synesthesia, anatomic differences were found in the inducer auditory area for both tone and musical interval (i.e., Heschl’s gyrus/planum temporale) and the concurrent areas for taste (insular cortex) and color (occipital cortex). In comparison with 20 controls and 17 nonsynesthetic musicians, there was an increase in whitematter volumes in the right Heschl’s gyrus/planum temporale and a decrease in gray-matter volumes in left superior temporal gyrus (i.e., the inducer area for both tone and musical interval). Additionally there was a decrease in gray-matter volume in left insula

AUDITORY SYNESTHESIAS (i.e., concurrent areas for taste) and an increase in graymatter volume in occipital areas (i.e., the concurrent area in tone-color synesthesia). Fractional anisotropy revealed evidence of hyperconnectivity in bilateral perisylvian-insular regions (i.e., between inducer and concurrent areas involved in the interval-taste synesthesia) in the synesthetic subject compared to 10 nonsynesthetic musicians with absolute pitch.

Functional studies Using the spatial resolution of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), these studies aid in functional localization of auditory synesthesias, by identifying the anatomic areas that are functionally different in synesthetes compared to controls. There is a single fMRI study of auditory-visual synesthesia with 14 synesthetic subjects and 14 controls (Neufeld et al., 2012). This study used six different classes of auditory tone (i.e., not spoken words) and found stronger connectivity of the left inferior parietal cortex with left primary auditory cortex and right primary visual cortex in synesthetic subjects compared to controls (Fig. 22.1). Several functional studies investigate lexical-color synesthesia (i.e., experience of color triggered by spoken words). Overall there are reports of activation of primary visual areas (V1), color areas (V4/V8), visual association cortices (posterior inferior temporal (PIT) cortex, and parieto-occipital junction). Due to some inconsistencies between the different studies, they are described individually below.

395

In a PET study, six synesthetes were compared with six controls in the task of listening to spoken words (Paulesu et al., 1995). These synesthetes had color sensation elicited only during listening to spoken words and not to tones, suggesting lexical-color synesthesia. The inducer brain areas (i.e., perisylvian regions) were activated in both synesthetes and controls, while the visual association cortices (i.e., PIT and parieto-occipital junction) were activated only in synesthetes. In this study there was no activation of the primary visual areas (V1 and V2) or the color area (V4). The fMRI studies have higher spatial resolution and sensitivity compared to PET studies. In two fMRI studies the task of passively listening to spoken words was used, pointing to the fact that their synesthetic subjects had lexical-color synesthesia in response to spoken words. One of the studies (Aleman et al., 2001) reported activation of V1 in addition to PIT in a single synesthetic subject. The other study (Nunn et al., 2002) reported activation of left-hemispheric color areas (V4/V8) in 13 synesthetes compared to controls in the condition of listening to spoken words versus pure tones. However, no activation was found in V1 (Fig. 22.2). The reason for the inconsistencies is unknown, but may be related to the baseline condition of listening to pure tones in the latter study.

Neurophysiologic studies With their higher temporal resolution, these studies evaluate the neurophysiologic basis of auditory synesthesias and the timing of synesthetic perception. Table 22.5 summarizes the results of these studies.

Fig. 22.1. Significant group differences in functional connectivity of the inferior parietal cortex (IPC). The connectivity analysis revealed two brain areas exhibiting significantly more connectivity to the IPC in synesthetes compared to controls: (A) a cluster in the left temporal cortex (center of mass at MNI coordinates xyz ¼  40, 26, 8), identified as the primary auditory cortex (Brodmann area (BA) 41) and (B) a cluster in the left occipital cortex (center of mass at MNI coordinates xyz ¼ 12, 94, 6), identified as the primary visual cortex (Brodmann area 17). p, posterior; a, anterior; r, right; l, left; color bars indicate the strength of activation. (Reproduced from Neufeld et al., 2012.)

Fig. 22.2. Yellow: Activation maps in the condition of listening to spoken words versus baseline test of listening to pure tones (words minus tones) in synesthetes (top row) versus controls (bottom row). Blue: Color activation maps in normal non-synesthetic subjects (top and bottom row). Red: cluster common to both conditions. Note activation of language areas (i.e., bilateral superior temporal gyrus (STG) and left inferior frontal gyrus (IFG)) in both synesthetes and controls. Left-hemispheric colored areas were activated only in synesthetes. (Reproduced from Nunn et al., 2002.)

Table 22.5 Summary of neurophysiologic studies in developmental auditory synesthesia Authors

Number of subjects

Modality/stimulus

Results

Rizzo and Eslinger, 1989

1 auditory-visual synesthesia

BAEP/clicks LLAEP/clicks

Goller et al., 2009

8 auditory-visual synesthesia 2 auditory-visual synesthesia + visual-auditory synesthesia 10 controls 13 auditory-visual synesthesia 13 controls

LLAEP/tones

Normal BAEP (wave I–V) Normal LLAEPs No evidence of auditory evoked visual potential (in O1, O2, and Oz) No report on BAEPs Lower amplitude of N1 in long-latency AEPs No evidence of auditory evoked visual potential No evidence of late negative deflections (i.e., slow wave around 400–800 ms)

Beeli et al., 2008

LLAEP/words, pseudowords and letters LORETA

Jancke et al., 2012

11 auditory-visual synesthesia 11 controls

Averaged activation over 2000 ms (simulating time resolution of fMRI) Preattentive MMN /tones LORETA

No report on BAEPs Lower amplitude and longer latency of N1 and P2 in LLAEPs N1 (at 122 ms): enhanced activation in left PIT P2 (at 218 ms): (a) Enhanced activation in ventromedial OFC and PIT (for words) (b) Enhanced activation left SFG, left PC, right IPS (for letters) Left V4, mesial and left lateral orbitofrontal areas

Increased MMN amplitude in response to deviant tones Higher P3a amplitudes Increased intracerebral current densities from auditory cortex, parietal cortex, and ventral visual areas

BAEP, brainstem auditory evoked potentials; LLAEP, long-latency auditory evoked potentials; LORETA, low-resolution brain electromagnetic tomography; MMN, mismatch negativity; OFC, orbitofrontal cortex; PIT, posterior inferior temporal; SFG, superior frontal gyrus; PC, precuneus; IPS, intraparietal sulcus; fMRI, functional magnetic resonance imaging.

AUDITORY SYNESTHESIAS 397 To sum up their results, brainstem auditory evoked neurophysiologic and imaging investigations of synespotentials (BAEPs) were normal (Rizzo and Eslinger, thesia. Some of the models have been used to explain 1989). The results of long-latency auditory evoked potenauditory synesthesias (Ward et al., 2006) and are tials (LLAEPs) have been variable. When auditory clicks discussed below. were used, the LLAEPs were normal (Rizzo and The cross-activation model (Fig. 22.3A and B) proEslinger, 1989), when tones were used as stimulus, the vides the best explanation for the neural basis of synesN1 component of the LLAEPs had longer latency thesias in which inducer and concurrent brain areas are (Goller et al., 2009), and when words and letters were lisadjacent to each other, although the adjacency is not nectened to, there was lower amplitude and longer latency essary (Hubbard et al., 2011). This model proposes that: of the N1 and P2 component of LLAEPs (Beeli (1) the neural representations of inducer and concurrent et al., 2008). should lie in densely interconnected regions; (2) activaRegardless of the type of stimulus used, there was no tion should pass directly from neurons that code for evidence of auditory induced visual evoked potentials the inducer to the neurons that code for the concurrent; (i.e., no occipital activation was seen). The intracerebral and (3) genetic factors lead to a decrease in pruning and source of the N1 and P2 components was estimated with the resulting anatomic differences are responsible for low-resolution brain electromagnetic tomography. This synesthetic experience (Ramachandran and Hubbard, revealed that in synesthetes there was stronger activation 2001; Rich and Mattingley, 2002; Hubbard and in the left PIT at 122 ms (i.e., N1 component) for both Ramachandran, 2005; Bargary and Mitchell, 2008). This words and letters, and in the orbitofrontal cortex and theory was originally developed to explain the neural left PIT for words, and in left superior frontal gyrus, basis of grapheme-color synesthesia (a non-auditory left precuneus, and right intraparietal sulcus for letters. synesthesia that at the time was thought to be the most This indicates that the timecourse of processing of the common form of synesthesia). Grapheme-color synessynesthetic colors in the brain is early and similar to visuthesia could be considered a form of lexical-color alized colors. When the activation was averaged over synesthesia that occurs in response to graphemes. Music 2000 ms to simulate resolution time of fMRI, local maxinterval-taste synesthesia is a rare example of auditory ima of averaged activation were seen in left V4 and synesthesia in which there is adjacency between inducer left mesial and lateral orbitofrontal areas for both words and concurrent areas, and using fractional anisotropy, and letters. hyperconnectivity in bilateral perisylvian-insular regions One study used mismatch negativity (MMN), a preat(i.e., between inducer and concurrent areas) has been tentive component of event-related potentials, in the task reported (Hanggi et al., 2008). of passive listening to the standard tones that were rarely The re-entrant feedback model (Fig. 22.3C and D) interspersed with deviant tones (Jancke et al., 2012). In suggests cross-talk between the inducer and concurrent synesthetes, the deviant tones induced a change in color brain areas mediated via feedback from a multisensory perception of the standard tone. This caused an increase nexus area (Grossenbacher and Lovelace, 2001; Smilek in MMN amplitude between 100 and 150 ms after stimet al., 2001; Bargary and Mitchell, 2008). ulus onset in synesthetes compared to controls. This indiThe disinhibited feedback model (Fig. 22.3E and F) cates that the tones and concurrent color perception are suggests that synesthesia results from failure of mechaprocessed early and automatically in the processing nisms that normally inhibit cross-talk between the stream (i.e., preattentively, at 100–150 ms after tone inducer and concurrent brain areas mediated via feedpresentation). back from a multisensory nexus area. This theory Additionally, a resting-state electroencephalograph differs from other theories in that it suggests synesthesia (EEG) study in auditory-visual synesthesia has shown is due to already existing connections in the brain strong hub regions (i.e., brain regions with strong inter(Grossenbacher and Lovelace, 2001; Ward et al., connections) in the right-sided auditory cortex and the 2006), i.e., not due to atypical anatomic connections left-sided parietal area (Jancke and Langer, 2011). not found in non-synesthetes. There are several observations in support of this model (Sagiv and Ward, 2006), particularly for the developmental auditory-visual NEURAL MODELS OF DEVELOPMENTAL SYNESTHESIAS synesthesias. Synesthesia is an umbrella term that encompasses sevThere is evidence of auditory-visual connections in eral distinct groups with different underlying mechahuman infants. In the first month of life auditory evoked nisms (Novich et al., 2011). Therefore different potentials (in response to spoken language) are recorded neuropsychologic models have been proposed to explain not only over the temporal cortex but also over the occipthe neural basis of synesthesia. These models have ital areas (Maurer, 1993). These auditory evoked visual been developed based on behavioral observation and/or potentials persist until 6 months of age. After 6 months

398

P. AFRA

Fig. 22.3. (A and B) Oversimplified schematic drawing of the cross-activation model. (A) Neural representation of inducer and concurrent pathways in a normal non-synesthetic individual. (B) Neural representation of inducer and concurrent pathways in a synesthetic individual, demonstrating the presence of direct cross-activation from inducer to concurrent area, resulting in concurrent perception. (C and D) Oversimplified schematic drawing of the re-entrant feedback model. (C) Neural representation of inducer and concurrent pathways in normal non-synesthetic individual. (D) Neural representation of inducer and concurrent pathways in synesthetic individual, demonstrating cross-talk between the inducer and concurrent brain areas mediated via feedback from a multimodal nexus area. (E and F) Oversimplified schematic drawing of the disinhibited feedback model. (E) Neural representation of inducer and concurrent pathways in normal non-synesthetic individual. (F) Neural representation of inducer and concurrent pathways in synesthetic individual, demonstrating cross-talk between the inducer and concurrent brain areas mediated via disinhibited feedback from a multimodal nexus area. (Modified from Bargary and Mitchell, 2008.)

of age the auditory evoked responses over the visual areas gradually decrease until they disappear at 36 months (Neville, 1995). These observations have led to development of a neonatal synesthesia hypothesis which suggests that human infants are born with intercortical connections between sensory areas and synesthesia resulting from failure of normal pruning processes that eliminate these connections (BaronCohen, 1996). There is observational evidence of the persistence of auditory-visual connections in adult humans with intact visual pathways that could be unmasked chemically with hallucinogenic drugs (Hollister, 1968) or with acute visual deprivation due to experimental or surgical blindfolding (Lessell and Cohen, 1979; Merabet et al., 2004), resulting in emergent auditory-visual synesthesia. There is neurophysiologic and functional neuroimaging evidence of the persistence of these auditory-visual connections in the late blinds, when auditory evoked potentials are recorded over the occipital areas (Rao et al., 2007), or when there is functional evidence of auditory processing by fMRI in the occipital cortex (Gougoux et al., 2005; Fig. 22.4). Neurophysiologic studies in normal human adults have shown the sound-induced illusory flash effect, i.e., when a single visual flash is accompanied by multiple auditory beeps, the single flash is perceived as multiple flashes. The brain evoked potentials recorded from occipital electrodes (O1, O2, and Oz) were similar for a physical flash and illusory flash (Shams et al., 2001). Comparison between synesthetes and nonsynesthetes has shown shared cross-modal audiovisual associations (between pitch and lightness, or timbre and saturation). However, the synesthetic experience is automatic, precise, conscious, and explicit, while the non-synesthetic associations are not (Ward et al., 2006). Despite all the above, neurophysiologic studies to date have not shown auditory-induced visual evoked potentials in developmental auditory-visual synesthesias, although auditory-induced visual evoked potentials have been reported in neonates, in individuals who become blind late in life, and in acquired synesthesia (Maurer, 1993; Rao et al., 2007; Afra et al., 2012). Therefore it is quite possible that the neurophysiologic basis of developmental auditory-visual synesthesias is different from the synesthesia in neonates, individuals who become blind late in life, or any other form of acquired synesthesia. This topic is subject to future research. The hyperbinding model suggests that synesthesia arises due to anomalous binding of information from inducer and concurrent brain regions and results from overactivation of parietal binding mechanisms (Robertson, 2003; Hubbard, 2007). Because the binding mechanisms require a feature upon which to act, a

AUDITORY SYNESTHESIAS

399

Fig. 22.4. Functional evidence of auditory processing by functional magnetic resonance imaging in occipital cortex during monaural sound localization in 12 early blind subjects versus 7 healthy sighted subjects. These data show the correlational analysis between performance (mean absolute error) in a pointing task to monaurally presented sounds and cerebral blood flow (CBF) in a group of blind subjects. The two columns of brain images (left image series, sagittal sections; right image series, coronal sections) illustrate the statistical parametric map of the correlation, which is maximal in the ventral extrastriate cortex (A) but also significant in dorsal extrastriate (B) and striate (C) cortices. The red arrows in the coronal slices indicate the focus selected for the respective sagittal slices. The scattergram shows the individual values extracted from each of these regions; closed circles indicate blind subjects; open circles indicate the sighted control group. (Reproduced from Gougoux et al., 2005.)

two-stage cross-activation/hyperbinding model is suggested (Hubbard, 2007; Jancke et al., 2012). A number of functional and neurophysiologic studies are supportive of this theory, including PET and fMRI studies in which activation of PIT is seen (Paulesu et al., 1995; Aleman et al., 2001), and resting-state EEG study showing left-sided parietal area as a strong hub region (Jancke and Langer, 2011). The limbic mediation hypothesis (Cytowic, 2002) suggests that synesthesia is mediated by the hippocampus and the limbic system.

Acquired auditory synesthesias The acquired auditory synesthesias are symptoms of neurologic disease; they usually emerge subsequent to neuropathologic insult to the brain. Cases of acquired auditory-visual and auditory-tactile synesthesias have been described in the neurologic literature and auditory-gustatory synesthesia has been described in the psychiatric literature.

ACQUIRED AUDITORY-VISUAL SYNESTHESIA The acquired auditory-visual synesthesias have been reported in the presence as well as absence of a recognizable neuropathologic lesion, with the most commonly

reported cases being in the setting of visual deafferentation. Therefore the reported cases of acquired auditoryvisual synesthesia are discussed below in two categories of lesional and non-lesional (Table 22.1). In the lesional category the reported cases could be further divided depending on the presence or absence of visual deafferentation (i.e., pathological affection of anterior optic pathways versus pathological affection of the central nervous system with intact visual pathways (Table 22.1). In the non-lesional category the auditory-visual synesthesias have been reported in association with epilepsy and migraine, as well as in a single idiopathic case (Table 22.1).

Lesional acquired auditory-visual synesthesia Lesional acquired auditory-visual synesthesia with pathological affection of anterior optic pathways (i.e., visual deafferentation). There have been about 19 reported cases across different case series and reports (Bender, 1977; Lessell and Cohen, 1979; Jacobs et al., 1981; Page et al., 1982; Kim et al., 2006; Rao et al., 2007), making this the most common type of acquired auditory synesthesia. In these cases the auditory stimuli are experienced ectopically in the deafferented visual system. Concomitant positive visual phenomena

400

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that were not sound-induced and were not perceived concomitant with synesthesia have been reported in some cases (Jacobs et al., 1981; Page et al., 1982). Table 22.6 summarizes the clinical characteristics of the 19 reported cases of acquired auditory-visual synesthesia (Afra et al., 2009). The neuropathologic abnormalities involve the anterior optic pathways (i.e., optic nerve, chiasm, or both) and consist of demyelination, ischemia, or tumors as well as posttraumatic total ocular blindness, with the most commonly reported neuropathology being optic neuritis followed by ischemic optic neuropathy. The degree of deafferentation has been variable across different reported cases, ranging from mild to severe partial deafferentation as well as near-complete and complete blindness (Afra et al., 2009). There seems to be no relationship between the onset of synesthesia and the underlying neuropathology. The onset of synesthetic visual sensations in relation to the clinical onset of the visual symptoms (due to deafferentation) has been variable, ranging from acute (1–3 days), and subacute (1–4 weeks) to chronic (months). There has been a single reported case of synesthetic visual sensations preceding the clinical onset of the visual symptoms (Page et al., 1982). The reported synesthetic visual sensations are not well formed and rather simple, like light flashes, kaleidoscope, and color (Afra et al., 2009). Eight of the 19 reported cases have commented on the ambient light during experience of synesthesia: five were reported to experience their synesthesia in dark, two in light, and one in both light and dark. Eighteen of the 19 reported cases commented on the state of the patient: nine

experienced their synesthesia in a drowsy state, seven in a relaxed state, one in an awake state and two when they were still (Lessell and Cohen, 1979; Jacobs et al., 1981; Page et al., 1982; Kim et al., 2006; Rao et al., 2007; Afra et al., 2009). The induced visual sensations are usually ipsilateral to the side of the perceived auditory stimuli and, regardless of laterality, they are perceived in the deafferented eye, and at times in the area of scotoma itself (Jacobs et al., 1981). In one case the induced visual phenomena were reported to occur in front of the eye (Page et al., 1982). The duration of synesthesia was reported in 16/19 of cases. It ranged from 2 to 49 months in 7/19 of the reported cases, to being persistent in 9/19 of the cases (Jacobs et al., 1981; Page et al., 1982; Kim et al., 2006; Rao et al., 2007; Afra et al., 2009). Neurophysiologic investigations. A variety of neurophysiologic studies have been used in the assessment of acquired auditory visual synesthesia. 1.

2. 3.

Visual evoked potentials show abnormalities of anterior optic pathways as expected (Jacobs et al., 1981; Page et al., 1982; Rao et al., 2007). Electroretinogram (ERG) has not shown any ERG activation after sound stimuli (Page et al., 1982). BAEPs have shown intact auditory pathways (Jacobs et al., 1981; Page et al., 1982). Rao et al. (2007) reported occipital activation (i.e., auditory evoked visual potentials) 40–80 ms (P1 component) and 100–120 ms (N1 component) following auditory stimulation.

Table 22.6 Summary of reported cases of acquired auditory-visual synesthesia due to deafferentation Pathology

No

Deafferentation

Onset

Laterality

Author(s)

Vascular occlusive disease Temporal arteritis Chiasmal tumor Optic neuritis

1

Partial

Acute

Ipsilateral

Jacobs et al., 1981

2 2 6

Near complete Partial 5 Partial, 1 near complete

Acute Acute Acute/ subacute

Ipsilateral Ipsi/bilateral 4 Ipsilateral; 2 not reported

ION

3

Partial

Not reported

Arteritic ION Neurilemoma Melanocytoma PSA PT TOB/B

1 1 1 1 1

Partial Partial Partial Complete Complete

Preceding/ subacute Subacute Chronic Chronic Chronic Chronic

Jacobs et al., 1981 Jacobs et al., 1981 Bender, 1977; Lessell and Cohen, 1979; Jacobs et al., 1981; Page et al., 1982 Page et al., 1982

Not reported Ipsilateral Not reported Ipsilateral Ipsi/bilateral

Page et al., 1982 Lessell and Cohen, 1979 Kim et al., 2006 Jacobs et al., 1981 Rao et al., 2007

No, number of reported patients; ION, ischemic optic neuropathy; PSA, postsurgical amaurosis; PT TOB, posttraumatic total ocular blindness; Ipsi, ipsilateral; B, bilateral.

AUDITORY SYNESTHESIAS Lesional auditory-visual synesthesia associated with pathological affection of the central nervous system with intact visual pathways. Two cases of lesional acquired auditory-visual synesthesia with pathologic effect on the central nervous system with intact visual pathways have been reported. In one case (Vike et al., 1984) a gliotic mass involved the left temporal area and adjacent midbrain. The synesthesia was reported to be experienced bilaterally but more on the left (ipsilateral side). BAEPs and visual evoked potentials were normal with no commentary about auditory evoked visual potentials (i.e., occipital activation following auditory stimulation). Synesthesia was aborted after the removal of tumor. In the second case (Fornazzari et al., 2012) a hemorrhagic stroke involving the left lateral posterior nucleus of the thalamus was reported. The stroke initially caused right hemiparesis, hemisensory deficit, hemianopsia, slurred speech with normal comprehension, and a transient alien-limb phenomenon. The synesthesia developed 9 months after the stroke, at which time the patient had residual right hemiparetic gait, hemisensory deficits, and full visual fields. The synestheisa was multimodal with auditory-visual, auditory-tactile, and graphemegustatory components as well as conceptual synesthesia. The auditory-visual component consisted of the appearance of light blue colors in the left halves of both visual fields when listening to high-tone sounds such as Hindi, Inuit, or Chinese music. The auditory-tactile component is discussed further below (under acquired auditorytactile synesthesia). Non-lesional auditory-visual synesthesia Non-lesional auditory-visual synesthesia associated with epilepsy. Synesthesia-like symptoms, called “internal synesthesia,” were reported in a single case of left temporal-lobe epilepsy (Jacome and Gumnit, 1979). During his aura the patient experienced sudden onset of pain on the right side of his face, and simultaneously heard the word “five” in both ears and saw the number “5” or “five” on a gray background before his eyes. Non-lesional auditory-visual synesthesia associated with migraines. There have been two reported cases of auditory-visual synesthesia occurring in the aural phase of migraine and one reported case in the headache phase. In one case (Sacks, 1992), the patient had experienced “synesthetic equivalence between auditory stimuli and visual images,” i.e., in the midst of migraine aura (with migratory paresthesias, sense of timelessness, and déjà vu), the subject experienced the hum of crickets translated into the hum of color when eyes were closed. In the second case (Alstadhaug and Benjaminsen, 2010), multimodal synesthesia was

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reported in the aural phase of migraine headache. Interestingly, the patient distinguished the aural component from the synesthesia component: “the flickering is present all along and seems to come from within,” but “the other is caused by external stimuli and may be avoided.” In regard to multimodal synesthesia, the auditory-visual component (audio-induced central scotoma) was intermixed with a visual-gustatory component (staring at bright light induced intense taste of lemon with flow from the salivary glands). What is unusual and unique about this case of multimodal synesthesia is the simultaneous presence of negative visual phenomena in the auditory-visual component with positive phenomena in the visual-gustatory component. In a third case, the patient had dual diagnosis of basilar migraines and migraine aura without headache (Podoll and Robinson, 2002). The auditory-visual synesthesia occurred in the headache phase on three separate occasions: when the patient had been woken up by the alarm clock experiencing migraine headache and a “colored optical pattern” pulsating in correspondence to the alarm sound in the center of her visual field. Idiopathic non-lesional auditory-visual synesthesia. A single case of adult-onset acquired auditory-visual synesthesia has been reported for which no cause could be identified despite extensive workup (Afra et al., 2012). Neurophysiologic investigation included magnetoencephalography. Auditory stimuli (700 Hz, 50 ms duration, 0.5 second interstimulus interval) were presented binaurally at 60 dB above the hearing threshold in a dark room. The patient had bilateral symmetric auditory evoked neuromagnetic responses in the auditory cortices followed by an occipital evoked field 16.3 ms later (Figs 22.5 and 22.6). It was suggested that activation of occipital cortex following auditory stimuli may represent recruitment of existing crossmodal sensory pathways.

MECHANISMS OF ACQUIRED AUDITORY-VISUAL SYNESTHESIA

The pathophysiologic basis of acquired auditory-visual synesthesia is not known. The anatomic, imaging, and neurophysiologic evidence for the presence of early cross-modal interactions may explain potential mechanisms and is discussed briefly. There is anatomic evidence of the presence of connections between auditory and primary visual areas in primates by tracer injection studies (Falchier et al., 2002; Rockland and Ojima, 2003). It is not known if the same connections exist in humans. As discussed above, there is neurophysiologic evidence of the existence of these connections in human neonates, when auditory evoked responses extend over the occipital areas in the first

402

P. AFRA

Fig. 22.5. Topographic magnetoencephalography channel plot of averaged auditory evoked fields (–50 ms to 400 ms). The encircled selections (red) represent the different activated areas: left and right auditory cortices as well as midline occipital cortex. Data of 204 planar gradiometer are displayed. A, anterior; P, posterior; L, left; R, right. (Reproduced from Afra et al., 2012.)

6 months of life (Maurer, 1993), followed by a gradual decrease until disappearance at 36 months (Neville, 1995). In normal human adults there is functional evidence of the persistence of these auditory-visual connections with the presence of bilateral blood oxygen level-dependent responses in the primary visual cortices subsequent to auditory stimuli (Martuzzi et al., 2007). In individuals who were blind early in life, there is functional evidence of auditory processing by fMRI in the occipital cortex (Gougoux et al., 2005). Also in an individual who became blind late in life with posttraumatic total ocular blindness, auditory evoked potentials have been recorded over the occipital areas, providing neurophysiologic evidence of the persistence of these connections (Rao et al., 2007). An additional piece of neurophysiologic evidence is the presence of a soundinduced illusory flash effect in normal humans (Shams et al., 2001). When synesthesia occurs as a result of neuropathologic insult to the anterior optic pathways, the region of the primary visual cortex corresponding to the affected axons will be deafferented. The imbalance between excitation and inhibition will result in increased excitability in and surrounding the deafferented area (Eysel et al., 1999). There will be reorganization and

Fig. 22.6. Auditory evoked magnetic responses, magnetic field maps, and source localizations. Left: Right, left, and midline occipital auditory evoked magnetic fields (AEFs) in response to binaural stimulation at 60 dB above hearing threshold (auditory tone of 700 Hz, 50 ms in duration at a rate of 2 Hz). Center: AEF maps over the expected right and left temporal areas as well as the occipital region. Right: Magnetic source localizations of the AEFs spatially aligned with magnetic resonance imaging. (Reproduced from Afra et al., 2012.)

AUDITORY SYNESTHESIAS change in weight of synaptic neurons before recovery. It has been shown that recovery from optic neuritis to normal or near-normal vision is associated with a change in the distribution of cerebral response to visual stimulation in fMRI (Werring et al., 2000). There is extensive extrastriate activation that may be evidence of long-term changes in the networks involved in neuronal processing of visual stimuli. The onset of synesthesia is variable across different patients, with some patients developing it preceding or acutely after visual symptoms (in the subclinical or clinical denervation supersensitivity period), while others develop it subacutely to chronically during or after recovery (i.e., during or after any cortical reorganization or plasticity). Also the degree of deafferentation is variable, with some patients experiencing synesthesia with mild degrees of deafferentation and some with severe degrees of deafferentation, and some never experiencing it at all. The reason for this variability in presentation is unknown but may be due to interindividual differences between patients and their central sensory synapses. The temporal lobe harbors the primary auditory cortex and auditory association areas in the Heschl’s and superior temporal gyri as well as higher-order association areas in the lateral temporal lobe. In the case of temporal-lobe epilepsy, these areas could be easily recruited by seizures of temporal-lobe origin. In the case of temporal-lobe space-occupying lesions, synesthesia could have been due to a mass effect on these areas, as it disappeared after removal of the lesion. It is interesting that synesthesias associated with migraine headaches have been reported in both aural and headache phases. The mechanisms of these synesthesias are not understood but may be due to alterations of cross-modal networks by cortical spreading depression (Alstadhaug and Benjaminsen, 2010) or the neurovascular changes of the headaches phase.

ACQUIRED AUDITORY-TACTILE SYNESTHESIA The two reported cases of auditory-tactile synesthesia are in association with thalamic stroke. In one case, there was hemorrhagic stroke affecting the left lateral posterior nucleus of the thalamus (Fornazzari et al., 2012). In this case the auditory-tactile synesthesia emerged as a component of multimodal synesthesia 9 months after the stroke (as described above, under lesional auditory-visual synesthesia). The auditory-tactile component was reported as extracorporeal sensations of “riding the music, surfing the music or flying on the top of the music.” In another case a lacunar infarct affected the right ventrolateral nucleus of the thalamus, resulting in

403

residual multisensory neglect for vision and touch and tactile and visual antiextinction at 1 year poststroke (Ro et al., 2007). Auditory-tactile synesthesia, contralateral to the thalamic lesion, was experienced at 3 years poststroke. The neural basis of synesthesia was suggested to be abnormal connectivity from right ventrolateral to the cortex in the form of disorganized and fewer fiber bundles originating from the right thalamus.

ACQUIRED AUDITORY-GUSTATORY SYNESTHESIA A case of auditory-gustatory synesthesia in combination with olfactory-gustatory synesthesia has been reported in a patient with postpartum depression. The synesthesia was considered part of a perceptual disorder associated with depression and was resistant to tricyclic antidepressants and electroconvulsive therapy, but was treated successfully with phenelzine (McKane and Hughes, 1988).

Induced synesthesias Induced auditory synesthesias are emergent phenomenon that have been reported in the setting of sensory deprivation (i.e., physical deafferentaion) as well as recreational drug use (i.e., chemical deafferentation).

AUDITORY SYNESTHESIA INDUCED BY SENSORY DEPRIVATION

Auditory-visual synesthesias have been reported in the context of visual deprivation in a single case of postsurgical blindfolding for keratoconus surgery (Lessell and Cohen, 1979) and two of 13 subjects in visual deprivation experiments (Merabet et al., 2004). In all three cases the reported synesthesia was of acute onset and emergent. The triggering auditory stimuli in the postsurgical case were unexpected auditory sounds and noises and in the visual deprivation experiments were TV and Mozart’s Requiem. The duration of synesthesia in the postsurgical case was 1 week, despite blindfolding for several weeks.

DRUG-INDUCED AUDITORY SYNESTHESIA (USE OF HALLUCINOGENS AND PSYCHEDELICS) Drug-induced synethesias are highly variable experiences with no consistent inducer–concurrent couplings. The experienced synesthesias are not automatic, i.e., the same stimulus may induce synesthetic perception in one occasion but not another. In the majority of druginduced cases the inducers are auditory (music and sound), although any sensory input (haptic, visual, gustatory, olfactory, pain, or emotional stimuli) can act as inducer (Shanon, 2002; Sinke et al., 2012). The concurrents are almost always visual, although a single case of drug-induced synesthesia with auditory concurrent

404

P. AFRA

has been reported. In this reported case of visualauditory synesthesia due to methamphetamine abuse, the subject was reported to hear voices of colors that he saw in the carpet (Ahmadi et al., 2011). Auditory-visual synesthesias have been reported with a variety of drugs, including LSD (Hollister, 1968), ayahuasca (Shanon, 2002), mescaline (Simpson and McKellar, 1955), hashish (Marks, 1975), and a psychotropic mint called Salvia divinorum (Babu et al., 2008). Additionally auditory-tactile synesthesia as well as auditory-algesic synesthesia in association with auditory-visual synesthesia has been reported with mescaline (Simpson and McKellar, 1955). The synesthetic experience with hallucinogenic drugs happens as an accompaniment to other symptoms of intensified sensory perception, including illusions, pseudohallucinations, and true hallucinations (Leuner, 1962), all of which can be well formed and complex (Hollister, 1968). Salvia divinorum also produces visual hallucinations in addition to synesthesia (Babu et al., 2008). The experienced drug-induced synesthesias are highly dependent on the state of the subject and can be experienced with both closed and open eyes (Sinke et al., 2012). With closed eyes it is experienced in any kind of inner screen while with open eyes it is in the form of synesthetic illusion (i.e., superimposed over real things in the outer world). The synesthetic experience can be well formed and complex (Hollister, 1968), as well as very intense and dynamic with emotional involvement (Sinke et al., 2012). They occur in a dream-like state of consciousness, although the subject is aware of the synesthetic experience (Sinke et al., 2012).

MECHANISM OF INDUCED AUDITORY SYNESTHESIAS Acute visual deprivation (by blindfolding) causes cortical excitability, evidenced by decreased phosphene threshold to transcranial magnetic stimulation in the occipital regions and enhanced activation of visual cortex to incoming input, as measured by fMRI (Boroojerdi et al., 2000). In synesthesia secondary to surgical or experimental blindfolding, there is complete and sudden deafferentation with no neuronal injury. In these cases the onset of synesthesia is acute (Lessell and Cohen, 1979; Merabet et al., 2004), pointing to the presence of some existing auditory-visual pathways that could be unmasked due to hyperexcitability of the cortex deprived of visual stimuli. A variety of mechanisms have been proposed as the basis of drug-induced synesthesias. The cause of hallucinogenic drug-induced auditory-visual synesthesia is thought to be chemical deafferentation of the lateral geniculate body, which deprives the occipital cortex of visual stimuli (Hollister, 1968).

Brang and Ramachandran (2008) hypothesized that serotonin 2a receptors are the “synesthesia receptor.” LSD is known to selectively activate serotonin 2a receptor. Additionally mescaline and ayahuasca are serotonin 2a agonists. Ayahuasca contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and betacarboline, a monoamine oxidase inhibitor (Riba et al., 2003). DMT is a partial agonist of serotonin 2a receptors and beta-carboline inhibits the visceral metabolism of DMT, increasing its systemic levels. Salvinorin A, the active ingredient of Salvia divinorum, is a selective kappa-opioid receptor agonist (Babu et al., 2008), and hence points to a different mechanism of action compared to serotonin 2a receptor agonists. Delta-9-tetrahydrocannabinol, the active component of hashish, exerts its central effects through the CB1 cannabinoid receptor (Iversen, 2003).

EFFECT OF DRUGS ON DEVELOPMENTAL SYNESTHESIA LSD has been reported to cause a new type of synesthesia. A subject with developmental grapheme-color synesthesia was reported to have experienced a new type of synesthesia in the form of auditory-visual synesthesia under LSD (Sinke et al., 2012). LSD and cannabis have also been reported to alter or overpower inducer–concurrent pairings, causing “false synesthesia.” Following their use a subject with auditory-visual synesthesia was reported to experience musical tones in the wrong color (Sinke et al., 2012). Cannabis has been reported to intensify pre-existing auditory-visual synesthesia (Mayer-Gross, 1931) and mescaline has been reported to augment the vividness of synesthetic experience in two patients, one with auditory-visual and the other with auditory-tactile synesthesia (Simpson and McKellar, 1955).

AUDITORY SYNESTHESIA: HISTORYAND ART Synesthesia has been an old accompaniment to the human race and reports of synesthesia date back to ancient China and Persia. An ancient Persian scheme provides correspondence between musical tones and colors: D violet, C blue-black, G bright blue, A green, E yellow, B rose, F black (Day’s synesthesia website: History). Reports of auditory-visual synesthesia date back to Pythagoras, sixth century BC and Aristotle,fourth century BC, and a steady and continuous stream of reported cases from the 16th century up to today (Marks, 1975). The very first known scientifically reported case of synesthesia, published by Dr. G.T.L. Sachs in 1812 in Latin (Ione and Tyler, 2004), was a medical dissertation on two albinos with synesthesia (the author himself and

AUDITORY SYNESTHESIAS his sister). The author refers to his colored sensations evoked by vowels, consonants, musical notes, sounds of instruments, numbers, dates, days of the week, periods of history, and stages of human life (Ione and Tyler, 2004). Another well-known early scientific report of synesthesia is an essay by Galton in 1883. In this essay he referred to published earlier cases, including ones by Bleuler and Lehman in 1881. The famous writer, Vladimir Nabakov, and several famous musicians/composers have been reported to have had auditory-visual synesthesia. These include Jean Sibelius, Franz Liszt, and Tony DeCaprio (Pearce, 2007). A full account of famous artists and writers can be found in Day’s synesthesia website (please see under web references).

CONCLUSION Auditory synesthesias are anomalous perceptual experiences induced by auditory stimulation or due to auditory synesthetic perception. The history of these synesthetic perceptual experiences dates back to ancient times. Auditory synesthesias can be lifelong and normal variations of human perceptual and cognitive function. Alternatively, they can be emergent and a symptom of neurologic or psychiatric disease, or the result of recreational drug intake. Neural mechanisms of developmental synesthesias provide a window into human cognitive processes and are the subject of research in the field of human neuropsychology, while the acquired forms of synesthesias represent an unusual symptom of neurologic and psychiatric disease and warrant neurophysiologic and neuroimaging investigation.

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Maurer D (1993). Neonatal synesthesia: implications for the processing of speech and faces. In: B de Boysson-Bardies, S de Schonen, P Jusczyk et al. (Eds.), Developmental neurocognition: speech and face processing in the first year of life, Kluwer, Dordrecht, pp. 109–124. Mayer-Gross W (1931). Uber Synasthesien im Meskalinrausch. In: G Anschutz (Ed.), Ferbe-ton-forschungen, vol. III. Psychologischasthetische Forchungsgesellschaft, Hamburg, pp. 266–277. McKane JP, Hughes AM (1988). Synaesthesia and major affective disorder. Acta Psychiatr Scand 77 (4): 493–494. Merabet LB, Maquire D, Warde A et al. (2004). Visual hallucinations during prolonged blindfolding in sighted subjects. J Neuroophthalmol 24 (2): 109–113. Mills CB, Boteler EH, Larcombe GK (2003). “Seeing things in my head”: a synesthete’s images for music and notes. Perception 32 (11): 1359–1376. Neufeld J, Sinke C, Zedler M et al. (2012). Disinhibited feedback as a cause of synesthesia: evidence from a functional connectivity study on auditory-visual synesthetes. Neuropsychologia 50 (7): 1471–1477. Neville HJ (1995). Developmental specificity in neurocognitive development on humans. In: M Gazzaniga (Ed.), The Cognitive Neurosciences, MIT Press, Cambridge, pp. 219–231. Novich S, Cheng S, Eagleman DM (2011). Is synaesthesia one condition or many? A large scale analysis reveals subgroups. J Neuropsychol 5 (2): 353–371. Nunn JA, Gregory LJ, Brammer M et al. (2002). Functional magnetic resonance imaging of synesthesia: activation of V4/V8 by spoken words. Nature Neurosci 5 (4): 371–375. Page NG, Bolger JP, Sanders MD (1982). Auditory evoked phosphenes in optic nerve disease. J Neurol Neurosurg Psychiatry 45 (1): 7–12. Paulesu E, Harrison J, Baron-Cohen S et al. (1995). The physiology of coloured hearing. A PET activation study of colour–word synaesthesia. Brain 118: 661–676. Pearce JMS (2007). Synaesthesia. Eur Neurol 57 (2): 120–124. Pierce AH (1907). Gustatory audition: a hitherto undescribed variety of synaesthesia. Am J Psychol 18 (3): 341–352. Podoll K, Robinson D (2002). Auditory-visual synesthesia in a patient with basilar migraine. J Neurol 249 (4): 476–477. Ramachandran VS, Hubbard EM (2001). Psychophysical investigation into the neural basis of synesthesia. Proc Biol Sci 268 (1470): 979–998. Rao A, Nobre AC, Alexander I et al. (2007). Auditory evoked visual awareness following sudden ocular blindness: an EEG and TMS investigation. Exp Brain Res 176 (2): 288–298. Riba J, Valle M, Urbano G et al. (2003). Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther 306 (1): 73–83. Rich AN, Mattingley JB (2002). Anomalous perception in synaesthesia: a cognitive neuroscience perspective. Nat Rev Neurosci 3 (1): 43–52. Rich AN, Bradshaw JL, Mattingley JB (2005). A systematic, large-scale study of synaesthesia: implications for the role of early experience in lexical-colour associations. Cognition 98 (1): 53–84.

AUDITORY SYNESTHESIAS Richer F, Beaufils GA, Poirier S (2011). Bidirectional lexicalgustatory synesthesia. Conscious Cogn 20 (4): 1738–1743. Rizzo M, Eslinger PJ (1989). Colored hearing synesthesia: an investigation of neural factors. Neurology 39 (6): 781–784. Ro T, Farne A, Johnson RM et al. (2007). Feeling sounds after a thalamic lesion. Ann Neurol 62 (5): 433–441. Robertson LC (2003). Binding, spatial attention and perceptual awareness. Nat Rev Neurosci 4 (2): 93–102. Rockland KS, Ojima H (2003). Multisensory convergence in calcarine visual cortex. Int J Psychophysiol 50 (1–2): 19–26. Sacks OW (1992). Migraine: Revised and expanded, University of California Press, Berkeley, pp. 86–87. Saenz M, Koch C (2008). The sound of change: visuallyinduced auditory synesthesia. Curr Biol 18 (15): R650–R651. Sagiv N, Ward J (2006). Crossmodal interactions: lessons from synesthesia. Prog Brain Res 155: 259–271. Shams L, Kamitani Y, Thompson S et al. (2001). Sound alters visual evoked potentials in humans. Neuroreport 12 (17): 3849–3852. Shanon B (2002). The antipodes of the mind: Charting the phenomenology of Ayahuasca Experience, Oxford University Press, Oxford. Simner J, Mulvenna C, Sagive N et al. (2006). Synesthesia: the prevalence of atypical cross –modal experience. Perception 35 (8): 1024–1033. Simpson L, McKellar P (1955). Types of synaesthesia. J Ment Sci 101: 141–147. Sinke C, Halpern JH, Zedler M et al. (2012). Genuine and drug induced synesthesia: a comparison. Conscious Cogn 21 (3): 1419–1434.

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Smilek D, Dixon MJ, Cudahy C et al. (2001). Synaesthetic photism influence visual perception. J Cogn Neursci 13 (7): 930–936. Vike J, Jabbari B, Maitland CG (1984). Auditory-visual synesthesia. Report of a case with intact visual pathways. Arch Neurol 41 (6): 680–681. Ward J (2013). Synesthesia. Annu Rev Psychol 64: 49–75. Ward J, Simner J (2005). Is synaesthesia an X-linked dominant trait with lethality in males? Perception 34 (5): 611–623. Ward J, Simner J, Auyeung V (2005). A comparison of lexicalgustatory and grapheme-colour synesthesia. Cogn Neuropsychol 22 (1): 28–41. Ward J, Huckstep B, Tsakanikos E (2006). Sound-color synesthesia: to what extent does it use cross-modal mechanisms common to us all? Cortex 42 (2): 264–280. Werring DJ, Bullmore ET, Toosy AT et al. (2000). Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: a functional magnetic resonance imaging study. J Neurol Neurosurg Psychiatry 68 (4): 441–449.

WEB REFERENCES http://www.daysyn.com/Types-of-Syn.html (last accessed 06/30/2013). http://www.daysyn.com/History.html (last accessed 06/30/ 2013). http://www.daysyn.com/Famous-synesthetes.html (last accessed 06/30/2013).

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 23

Tinnitus ROBERT A. LEVINE1* AND YAHAV ORON2 Department of Ear, Nose and Throat and Head and Neck Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

1

2

Department of Otolaryngology, Head and Neck Surgery, E. Wolfson Medical Centre, Holon, Israel

INTRODUCTION Tinnitus, the perception of sound in the absence of an external sound, usually results from a disorder of: (1) the auditory system (peripheral/central); (2) the somatosensory system (head and neck); or (3) a combination of the two. The purpose of this chapter is twofold: (1) to describe an approach for determining its cause using the presenting complaint; and (2) to present the major features of its pathophysiology.

DETERMINING TINNITUS ETIOLOGY The history must pay close attention to not only hearing issues, but also cervical, dental, and head issues, including their relationship to the tinnitus onset, such as new neck stress from altering an exercise program. The most important features of the percept that must be ascertained are: (1) its quality, particularly whether or not it is ever pulsatile or has a clicking component, even if very minor; (2) its location, whether it is heard on one side or not; (3) its variability, whether it is constant, fluctuating, or intermittent; (4) whether it is predominantly low- or high-pitched; and (5) whether the patient can do something to modulate it. The physical exam should include inspection of the teeth for evidence of wear, listening around the ear and neck for sounds similar to their tinnitus, palpation of the craniocervical musculature for trigger points (discrete regions with increased muscle tension and tenderness) with special attention to asymmetries, and probing whether the tinnitus percept can be modulated with “somatic testing”: maximal isometric contraction of the head and neck muscles or strong pressure upon these same muscles and the auricle. All subjects should have a recent audiogram.

The tinnitus characteristics will help in determining its etiology (Table 23.1), as described below.

Specific quality Some types of tinnitus have such characteristic features that the description alone is the major determinant of the direction of the diagnostic approach. These types of tinnitus can be strictly in one ear (lateralized) or nonlateralized. Patients use a variety of expressions to describe non-lateralized tinnitus, such as: “both ears about equally,” “both ears but worse in one ear,” “in the head but not strongly toward either side,” or “in the head toward one side.” Tinnitus with a characteristic quality includes sudden, brief, unilateral, tapering tinnitus (SBUTTs), hallucinations (musical or auditory), exploding-head syndrome (auditory sleep starts), staccato irregular unilateral tinnitus (“typewriter tinnitus”), and “somatosounds” – physical sounds generated by the body and heard by one or both ears.

SPECIFIC AND ALWAYS LATERALIZED Sudden, brief, unilateral, tapering tinnitus (SBUTT) About 75% of adults have experienced the sudden onset of a tone or noise in one ear that begins abruptly and fades away within seconds with no definite trigger. It is sometimes associated with a fullness, pressure, blocking, or hearing loss of the same ear. Once it begins, it remains at a constant loudness for several seconds then wanes until it is no longer perceived. All the while, the quality of the tinnitus otherwise remains unchanged. Typically it lasts less than a minute with no permanent hearing change. Their frequency of occurrence ranges

*Correspondence to: Robert Aaron Levine, M.D., Department of Ear, Nose and Throat and Head and Neck Surgery, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Tel: 617-383-4955, Fax: 617-963-7130, E-mail: [email protected]

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Table 23.1 Tinnitus characteristics Tinnitus with specific quality Lateralized Sudden, brief, unilateral, tapering tinnitus (SBUTT) Coarse intermittent sounds coincident with jaw or head movements Fluttering Non-lateralized Exploding-head syndrome Sometimes, but not always, unilateral Autophony (echoing of the voice), or blowing tinnitus Hallucinations (non-verbal, stereotyped, repetitive) Clicking Non-lateralized Lateralized Unilateral staccato irregular intermittent (typewriter tinnitus) Pulsatile (cardiac synchronous) Non-lateralized Lateralized Auditory nerve vascular compression Lateralized or Non-lateralized: Somatosensory pulsatile tinnitus syndrome Tinnitus with non-specific quality Non-lateralized Chronic progressive symmetric hearing loss (chronic acoustic trauma, presbycusis, hereditary hearing loss) Autoimmune inner-ear disease Central nervous system disorder – rostral to trapezoid body Medication-related (including withdrawal syndromes) Lateralized Never with vestibular symptoms Conductive hearing loss Otoacoustic emissions Auditory nerve compression (usually vascular) May be with vestibular symptoms Me´nie`re’s syndrome Perilymphatic fistula Semicircular canal dehiscence (SSCD) Herpes zoster oticus (Ramsay-Hunt syndrome) Cerebellopontine angle tumors Central nervous system disorder – caudal to trapezoid body Sudden idiopathic hearing loss May be lateralized or non-lateralized Acute acoustic trauma Somatic (head or upper cervical) Head trauma Postinfectious Idiopathic

from less than one a year to more than twice a week. They never occur simultaneously in both ears; the right is more common. In the majority they are always in

the same ear, but for some the ear can vary. SBUTTs are benign. They are not associated with the development of hearing loss or chronic tinnitus (Oron et al., 2011). Coarse intermittent sounds coincident with jaw or head movements This is typical of a foreign body such as cerumen, hair, or a liquid (usually water) resting against the tympanic membrane. Fluttering Stapedius muscle contractions tend to be described as a fluttering. If the fluttering is associated with facial movements, then stapedial contraction is highly likely to be causing the fluttering sound. This is most commonly seen after recovery from Bell’s palsy, unilateral facial paralysis. When the affected side of the face contracts, the ipsilateral stapedius muscle also contracts (synkinesis) due to aberrant facial nerve regeneration. Abnormalities in the pattern of the stapedial reflex or acoustic impedance measurements corresponding to the characteristics of the patient’s tinnitus can occur (Marchiando et al., 1983). The normal stapedius reflex occurs only for high-intensity sounds (>85 dB hearing loss (HL)). Fluttering that is evoked by high-intensity sounds is usually due to stapedius reflex dysfunction and can be treated by releasing the stapedius tendon.

SPECIFIC AND ALWAYS NON-LATERALIZED Exploding-head syndrome Typically subjects report that as they are dropping off to sleep they hear a brief loud sound (e.g., “bang,” “explosion,” “shotgun,” “cymbals”) throughout their head. By the time the subject is wide awake it stops. Most commonly it occurs with initiation of sleep, but it can also happen during the night or even with napping. One sleep study found it occurring during the transition from non-rapid-eye movement stage 1 sleep to wake (Palikh and Vaughn, 2010). It can occur in any age group, including childhood. Often the condition remits for prolonged intervals, even several months (Pearce, 1989). Reassurance is usually sufficient. If not, benefit from clonazepam, clomipramine, nifedipine, and topiramate has been suggested from isolated case reports.

SPECIFIC AND SOMETIMES, BUT NOT ALWAYS, UNILATERAL

Autophony (echoing of the voice), or blowing tinnitus The characteristics of this type of tinnitus are so unique that the history alone virtually makes the diagnosis,

TINNITUS namely a patulous (freely open) eustachian tube. Patients describe blowing sound with respiration and an echoing quality to their own voice. The condition can be unilateral or bilateral. Confirmatory features include (1) disappearance of their complaints when their head is dependent and (2) abnormally large changes in the tympanic membrane acoustic impedance with respirations (Poe, 2007). Hallucinations (non-verbal, stereotyped repetitive) Unlike the hallucinations associated with psychoses, these patients have no associated thought disorder, and the hallucinations do not have personally relevant content. Rather the hallucinations are either “musical,” in which patients report hearing one or a series of familiar tunes incessantly, or “auditory,” in which a variety of different sounds are described (Baurier and Tuca, 1996). Typically the strictly musical hallucinations occur in elderly patients (more commonly in women) with a longstanding progressive moderate to severe bilateral hearing loss (see Chapter 24). The tunes can be vocal and/or instrumental. While they are usually bilateral, they can be unilateral even with a bilateral hearing loss. Occasionally they can be precipitated by a new medication, and the hallucinations resolve when the medication is stopped. If the presentation is typical, no brain imaging is necessary. Auditory hallucinations differ from musical hallucinations in several respects. They are usually abrupt in onset and associated with focal neurologic findings due to a brainstem stroke or space-occupying lesion. There usually is no major pre-existing chronic hearing loss and the hallucinations are usually not only musical, but may have a variety of other sounds such as bells or a waterfall. They often are transient (Baurier and Tuca, 1996). Brain imaging is required.

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eustachian tube muscles, which can be observed or heard by the examiner. Sometimes acoustic impedance measurements have abnormalities that correspond to this type of tinnitus or visualization of the tympanic membrane can reveal movements coincident with the clicking. Unilateral staccato irregular intermittent (typewriter tinnitus). Probably the most common type of unilateral clicking is “typewriter” tinnitus, characterized by unilateral staccato irregular intermittent clicking. Besides “typewriter,” other terms that patients have used are “popcorn,” “Morse code,” “nail clipper,” “tapping,” “snapping,” “crackling,” and “machine gun.” In some the clicking can be triggered by a specific class of external sounds (e.g., running water). Most have no associated unilateral hearing loss. The irregular clicking can occur with no other symptoms, including no other tinnitus and no hearing loss. It always responds to carbamazepine usually at low dose; it can also respond to other trigeminal neuralgia medications but less predictably (Levine, 2006; Brantberg, 2010). Like the other unilateral staccato irregular intermittent cranial nerve syndromes (trigeminal and glossopharyngeal neuralgia, hemifacial spasm, and vestibular paroxysmia), typewriter tinnitus typically occurs in people above the age of 50, probably because it is most commonly due to vascular compression of the VIIIth nerve (Fig. 23.1); however, any condition that distorts the VIIIth nerve can cause typewriter tinnitus, probably because the VIIIth nerve becomes hyperexcitable (Nam et al., 2010). Variants of pure typewriter tinnitus occur. There may be another tinnitus: ipsilateral constant hissing usually

Clicking Non-lateralized. Very few conditions cause synchronous clicking, i.e., both ears at the same time. Palatal myoclonus is the only consideration. Often the clicking can be heard by the examiner listening at the patient’s ear or with use of stethoscope or recording with a microphone in the external auditory canal. Inspection of the palate will usually reveal the problem. Occasionally nasal endoscopy will be necessary. Medications that have been reported to improve palatal myoclonus include clonazepam, lamotrigine, piracetam, and valproate. Botox injections provide temporary relief (4–12 months) (Krause et al., 2006). Lateralized. Unilateral clicking tinnitus can have two etiologies. It may be a unilateral form of palatal myoclonus due to contractions of tensor tympani or the

Fig. 23.1. Vascular compression of right VIIIth nerve. Magnetic resonance imaging scan from a 60-year-old whose right cardiac synchronous tinnitus alternated between loud pulsatile “whooshing” and quieter pulsatile “clicking.” The point of contact between right anterior inferior cerebellar artery (AICA) and right VIIIth nerve (curved arrow) results in deviation of the VIIIth nerve from the normal straight path, as can be seen for the contralateral VIIIth nerve. CSF, cerebrospinal fluid.

412 R.A. LEVINE AND Y. ORON associated with a sensorineural hearing loss; it can even or head pains suggests a carotid dissection. A change be pulsatile. An example is shown in Figure 23.1; this in tinnitus intensity with head turning suggests a patient had definite vascular compression ipsilateral to venous source for the tinnitus, from a source ipsilateral her pulsatile tinnitus that alternated between typewriter to the direction that decreases the tinnitus. This can be (“clicking”) and non-typewriter (“whooshing”). In genconfirmed with jugular compression. If the patient can eral, the typewriter tinnitus can begin at the same time, obliterate the tinnitus with mild localized pressure in precede, or follow the constant tinnitus by months or the periauricular region then an emissary vein is probyears. Only the typewriter tinnitus component responds ably accounting for the tinnitus. to carbamazepine (Levine, 2006). Another variant is The physical exam can be revealing. Abolishing the bursts of typewriter tinnitus occurring with vertigo (vestinnitus with ipsilateral jugular compression points to a tibular paroxysmia) (Russell and Baloh, 2009). venous source. A crescentic purple coloration to the tympanic membrane is diagnostic of a glomus jugulare tumor. A red mass behind the tympanic membrane is eviPulsatile (cardiac synchronous) dence for an aberrant carotid artery, dehiscent jugular The first step is to determine whether the pulsations bulb, or a vascular tumor. A unilateral conductive hearare cardiac synchronous. This can be evaluated by coming loss in association with ipsilateral pulsatile tinnitus paring the examiner’s silent count of the cardiac pulse and an otherwise normal exam suggests otosclerosis, with the patient’s silent count of the tinnitus pulsations. as does Schwartze’s sign (a red hue behind the tympanic If the two counts are discordant then the tinnitus is not membrane on otoscopy). Detection of an ipsilateral bruit cardiac-related. Once it has been established that the pulsuggests the tinnitus is from the source of the bruit. satile tinnitus is cardiac synchronous, then the next propA bruit in the region of the carotid artery bifurcation erty that needs to be established is where the percept is suggests fibromuscular dysplasia, carotid stenosis, or perceived. carotid dissection; ipsilateral Horner’s syndrome suggests a carotid dissection. Non-lateralized. If it is “heard” throughout the head, If the bruit is more widely distributed, such as then very few conditions can cause it. Two different unithroughout the periauricular region or even more widelateral sources, one from each side, can be easily spread, a dural arteriovenous fistula becomes likely. If excluded because their onset will have been at different heard over the globe, a carotid-cavernous sinus fistula times. A high cardiac output state such as anemia or is suspected, particularly if there is proptosis. If venous hyperthyroidism can be checked with a complete blood pulsations are seen within at least one of the optic count and thyroid profile. A central somatosound is fundi, then cerebrospinal fluid pressure is normal another possibility, such as from a carotid-cavernous fisand raised intracranial pressure can be ruled out. If tula or aortic stenosis. Once these uncommon possibili“somatic testing” eliminates the pulsations or the tinnities are excluded, then somatosensory pulsatile tinnitus tus then the somatosensory pulsatile tinnitus syndrome syndrome becomes most likely. becomes the working diagnosis, particularly if all diagnostic testing including imaging is negative (see Lateralized or Non-lateralized: Somatosensory above under non-lateralized pulsatile tinnitus). If pulsatile tinnitus syndrome. Its percept is cardiac somatic testing does not stop the pulsations, then synchronous, usually high-pitched, and can be either VIIIth-nerve vascular compression is likely (see below lateralized or non-lateralized. Its defining feature is that and Fig. 23.1). the pulsations and/or the tinnitus can be momentarily The diagnostic studies following the initial visit will abolished by somatic testing: a strong muscle contraction be guided by the findings of the clinical evaluation of the head or neck or a strong pressure applied to these and laboratory studies (Fig. 23.2). Because high-cardiacsame muscles (Levine et al., 2008; Levine, 2013). Usually output states such as anemia or hyperthyroidism can the tinnitus is constant but in some it is intermittent. Concause pulsatile tinnitus (usually bilateral), all patients tinuous auricular stimulation with electric pulses can should have a thyroid profile and a hematocrit. If a quiet the tinnitus of many who have this syndrome carotid lesion is suspected then either a duplex ultra(Cardarelli et al., 2010). sound study of the carotid, computed tomography Lateralized. The patient’s history can give clues to the (CT) angiography, or magnetic resonance angiography source of the pulsatile tinnitus (Sismanis, 2011). An (MRA) should be performed. If a retrotympanic mass association with headaches, blurring of vision, and is suspected, then a high-resolution contrast-enhanced menstrual irregularities in an obese young woman is CT scan of the temporal bones should be obtained. suspicious for benign intracranial hypertension (pseuOtherwise a contrast-enhanced magnetic resonance dotumor cerebri). Abrupt onset with unilateral neck imaging (MRI) scan of the temporal bone and cranium

TINNITUS

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Unilateral Pulsatile Tinnitus ----------------------Clinical and Laboratory Evaluation Including Somatic Testing

Abnormal

Normal

Attenuated by Jugular Compression

Suspected Carotid Disease

Suspected Middle-Ear Mass

Contrast MRI / MRV

Duplex Ultrasound

Contrast CT

Abnormal

Normal

Abnormal

Fundoscopy of Retina Venous Pulsations

NoVenous Pulsations Lumbar Puncture

Abnormal

Normal

MRA

Normal

Contrast MRI / MRA

Abnormal

Normal

Non-Contrast CT

Abnormal

Angiogram

Normal

Angiogram

Abnormal

Vascular Compression

Fig. 23.2. Pulsatile tinnitus: diagnostic algorithm. Somatic testing and laboratory studies (hematocrit and thyroid profile) should be done before imaging. If somatic testing does not suppress pulsations and diagnostic testing reveals no abnormality, then vascular compression of the auditory nerve is very likely. MRI, magnetic resonance imaging; MRA/MRV, magnetic resonance arteriography/venography of cervical and intracranial vasculature; CT, thin-section computed tomography of temporal bone.

should be obtained. The MRI scan may not detect anomalous arterial patterns such as a persistent stapedial artery, so a non-contrast high-resolution CT scan of the temporal bone is performed if the MRI scan is normal. If still no etiology is apparent and neither papilledema nor retinal venous pulsations were observed (by the examiner and/or a neuroophthalmologic consultant) then cerebrospinal fluid pressure should be measured via a lumbar puncture. If all the above non-invasive imaging studies have been unremarkable and raised intracranial pressure has been ruled out, then cerebral angiography, which can have rare but significant morbidity, should be considered, because a dural arteriovenous malformation can sometimes go undetected by any other diagnostic study, even though there may or may not be a thrill or bruit on physical examination (Madani and Connor, 2009). Eighth-nerve vascular compression. That VIIIthnerve vascular compression can cause unilateral tinnitus which in some cases is pulsatile has been well established by Ryu and colleagues. They made their observations in subjects whose primary complaint was hemifacial spasm, not tinnitus. From surgically decompressing the facial nerve in the cerebellopontine angle, it was observed that 100% of those with preoperative ipsilateral tinnitus (half of whom were pulsatile) had VIIIth-nerve compression, and in those without tinnitus, only 6% had VIIIth-nerve compression. Furthermore, with decompression 70% of those with tinnitus had their tinnitus

abolished and another 10% were markedly improved. Eighty percent of those with pulsatile tinnitus had their tinnitus resolved (Ryu et al., 1998). Hence, vascular compression of the auditory nerve can cause unilateral tinnitus, including pulsatile tinnitus. With rare exceptions (Fig. 23.1), determining with certainty that an individual’s unilateral tinnitus, whether pulsatile or non-pulsatile, is from VIIIth-nerve vascular compression has not yet been possible. A comprehensive study of vascular decompression surgery using very conservative auditory brainstem response (ABR) and MRI criteria (“VIII neurovascular conflict defined by an orthogonal contact between the nerve and the blood vessel which provoked a nerve’s pathway distortion,” such as in Fig. 23.1) found that, after more than 5 years of postoperative follow-up, 3 of 5 patients with vertebral artery vascular compression had no tinnitus. In contrast, none with anterior or posterior inferior cerebellar artery compression were abolished; but 40% were improved (Guevara et al., 2008). From analogy with trigeminal neuralgia and with some supporting imaging data we have suggested previously that typewriter tinnitus is also due to VIIIth-nerve vascular compression. The symptoms of the patient, whose MRI (Fig. 23.1) revealed clear-cut right auditory nerve vascular compression, provide more supporting evidence for: (1) pulsatile tinnitus and (2) clicking tinnitus being related to VIIIth-nerve vascular compression, since (1) her tinnitus was always pulsatile and (2) when quieter it was clicking pulsatile. When louder it was

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whooshing pulsatile. She never heard clicking and whooshing together.

Non-specific quality Included in this category are a variety of descriptors of tinnitus, such as buzzing, tonal, hissing, humming, ringing, roaring, rushing, whistling and whooshing, cicadas, and crickets. None of these descriptors points to a specific diagnosis. Roaring while non-specific, when unilateral, is often associated with Me´nie`re’s syndrome. Since the quality of the tinnitus is non-specific, aids in making a diagnosis must come from sources other than the tinnitus quality. Associated symptoms, ameliorating and exacerbating factors, as well as circumstances surrounding the tinnitus onset, are some of the pointers to the tinnitus etiology. In attempting to arrive at a diagnosis for tinnitus in which the characteristics of tinnitus are non-specific, there are several important considerations that must be kept in mind (Table 23.2). The first is that tinnitus is very common in the general population. Many people have tinnitus but have never complained of it or sought medical attention for it. The landmark 1953 study found such tinnitus in 94% of people (Heller and Bergman, 1953). More recent studies of normal-hearing subjects have also found large percentages (52–92%) reporting such tinnitus (Levine et al., 2003; Tucker et al., 2005; Del Bo et al., 2008; Knobel and Sanchez, 2008). In our study in which normal subjects were placed in a low-noise room, 20% had previously been aware that they had tinnitus in the quiet. Another 35% for the first time noticed that they had tinnitus in the quiet (Levine et al., 2003). Seventy-five percent of our subjects reported having experienced SBUTTs, another type of “normal” tinnitus; namely, unilateral tonal/noise tinnitus typically lasting less than a minute (Oron et al., 2011). Another type of transient tinnitus, which is common, follows exposure to loud sound. About 50% of our study subjects recalled such tinnitus, lasting from a few minutes to several hours or even days (Abel and Levine, 2004). In fact, patients have occasionally presented to our clinic complaining of one of these types of “normal” tinnitus. Table 23.2 Non-specific tinnitus: why problematic to establish a definitive etiology? 1. Tinnitus is common in the general population 2. For any disease, not all subjects will develop tinnitus 3. The coexistence of tinnitus and a disease does not imply that the two are related 4. Tinnitus can be multifactorial

A second important consideration is that with any pathologic process associated with tinnitus, not all subjects will develop tinnitus. In surveys of profoundly deaf subjects, about 80% will have tinnitus, but 20% will not (Levine, 1999); similarly for idiopathic sudden sensorineural hearing loss (Huy and Sauvaget, 2005). Hence, the presence of tinnitus and a pathologic process by itself does not imply that the two are related. Because there is no obligatory association between the pathologic process and tinnitus, it is possible that, even though a tinnitus patient has a chronic condition associated with tinnitus, the tinnitus may not be related to the chronic condition; rather the tinnitus and the pathologic process could coexist, but be unrelated (Levine et al., 2007). Because tinnitus is common in the general population (35% of whom are unaware of it), a third consideration is that the pathologic process only draws the patient’s attention to the pre-existing tinnitus. Furthermore, if the disease in and of itself did not cause the tinnitus but hearing loss is part of the disease, the hearing loss could be “unmasking” the pre-existing tinnitus. Just as bringing a normal subject into a low-noise environment can make subjects aware of tinnitus they had not appreciated previously, so could a hearing loss unmask tinnitus (Levine et al., 2003). Therefore, the question always remains in any patient with non-specific tinnitus: was the tinnitus pre-existing and unmasked because of loss of hearing, or because the patient’s attention was drawn to his or her hearing? A striking example was a young adult with no hearing complaints (including tinnitus) who awoke with new onset of distressing tinnitus the day after learning that she had a bilateral major high-frequency sensorineural hearing loss (60 dB loss at 2 kHz and above) (Levine, 2013). Casual attention to tinnitus of which people were previously unaware does not appear to be associated with the development of disturbing tinnitus, since following the Heller and Bergman type of studies no subjects developed troublesome tinnitus. Clinical anecdotes suggest that, when attention to tinnitus, of which they were previously unaware, is emotionally charged, then the tinnitus can become troublesome (Levine, 2013). Since on the one hand non-specific tinnitus can be physiologic, and on the other hand non-specific tinnitus is not obligatorily associated with any pathologic process, when a condition is very slowly progressive (e.g., presbycusis), establishing the etiology of non-specific tinnitus is more problematic than for most medical symptoms. In general, there is a level of confidence associated with any diagnosis that might account for a symptom. For tinnitus some relationships increase this confidence. The first is a temporal association between the tinnitus

TINNITUS 415 and the diagnostic consideration. For example, in hearing loss, their non-lateralized tinnitus will begin, if Me´nie`re’s syndrome, if the tinnitus fluctuates with the ever, since 20% of such people will never develop tinnihearing loss and vertigo, then this strengthens the confitus despite a profound hearing loss. If: (1) the audiogram dence of the association between the tinnitus and is asymmetric; (2) the tinnitus begins first in one ear and Me´nie`re’s syndrome. Another way the confidence of only later in the other ear; or (3) the tinnitus is lateralized, the diagnosis is strengthened is if the pitch of the tinnitus then one or more other factors, such as acoustic neucorresponds to the audiometric hearing loss pattern. roma, must be sought to account for the asymmetry. Considering again Me´nie`re’s syndrome, where early in The establishment of a causal relationship between the illness low-frequency hearing loss often predomichronic progressive hearing loss and tinnitus is problemnates, if the tinnitus is described as roaring and/or the atic, because there is no perceptible change in the hearing pitch match is a low-frequency one, then the confidence or audiogram associated with the onset of the tinnitus. of the relationship between the Me´nie`re’s syndrome and What has been well established is that the prevalence the tinnitus is strengthened. Likewise, changes in the tinand reported loudness of tinnitus increase with increasnitus percept that are closely coupled to changes in physing hearing loss (Chung et al., 1984). However, for any ical findings strengthen the association between the two. patient with chronic progressive symmetric hearing loss Another important consideration in establishing the and recent onset of non-lateralized tinnitus, a triggering tinnitus etiology is that its cause may be multifactorial. factor or other cause for the tinnitus must be sought, Tinnitus can be considered a threshold phenomenon (see even though the yield has been low in the authors’ expesection “Tinnitus is a threshold phenomenon”, below), rience. The association between tinnitus and chronic prosuch that, while any one factor such as chronic progresgressive hearing loss must be considered tenuous. sive hearing loss may not be sufficient to elicit a tinnitus complaint, two or more factors may synergistically lead Autoimmune inner-ear disease to the tinnitus becoming symptomatic (Levine This condition is like chronic progressive hearing loss, et al., 2007). except the progression of the bilateral hearing loss is Closely related to the threshold idea is the concept of measured in weeks or months rather than years. It can “triggering factors” that can lead to symptomatic fluctuate and be asymmetric. Due to its more rapid time chronic tinnitus (Fowler, 1943; Coles, 1996). Such factors course, the association of tinnitus with the disease is include psychosocial stress (see young adult case more compelling. Positive blood tests for general autodescribed above in this section), viral infection or the immune disease or inner-ear antibodies support the postviral state, medications or withdrawal from medicadiagnosis. tions, and head and neck somatic factors (e.g., whiplash, temporomandibular joint syndrome, ear syringing, Central nervous system disorder – rostral trauma not involving the head). Clinical experience sugto trapezoid body gests that the clinical problem of tinnitus can be precipitated by one (or more) of these triggering factors. While The evidence available indicates that, for central nervous a triggering factor may appear to be responsible for inisystem lesions rostral to the trapezoid body (such as tiating the tinnitus, sometimes the tinnitus will persist involving the inferior colliculus), tinnitus is usually trandespite resolution of the triggering factor. sient and bilateral (see section The tinnitus pathway rosWith these considerations in mind, we next consider tral to DCN, below) (Hausler and Levine, 2000). diagnostic entities that appear to be associated with non-specific tinnitus. Medication-related (including withdrawal syndromes) ALWAYS NON-LATERALIZED The temporal association of the onset of the tinnitus with Chronic progressive symmetric hearing loss exposure to a toxin establishes the diagnosis particularly (presbycusis, chronic acoustic trauma, hereditary if the tinnitus resolves when the toxin is withdrawn. An hearing loss) association is less clear when tinnitus begins just after a These three conditions can be considered together, since new medication was begun but does not remit when disthey affect only hearing, generally have a symmetric continued. Such instances raise the possibility that the hearing loss, and are slowly progressive, albeit at differnew medication acted as a trigger factor for the tinnitus. ent rates. They are the most common type of tinnitus Cisplatin, aminoglycoside antibotics, and loop diuretics encountered in a tinnitus clinic. When their tinnitus can cause permanent hearing loss and tinnitus. Highbegins, it is non-lateralized. Presently it cannot be predose aspirin and quinine can cause a reversible hearing dicted when, during the course of their progressive impairment and tinnitus. Transient or, rarely, long-

416 R.A. LEVINE AND Y. ORON lasting tinnitus can be a part of a sedative withdrawal blown picture consists of episodic attacks of intense versyndrome (Ashton, 1991) which, in the case of benzoditigo persisting hours, fluctuating unilateral hearing loss azepines, can be precipitated by fluoroquinolones, typically involving the lower frequencies (in the early because these antibiotics cause a pharmacologic withstages), ear fullness, and a roaring low-frequency tinnidrawal. Despite no change in the daily benzodiazepine tus. Early in its course there may be no persistent sympconsumption, they compete directly with benzodiazetomatology; however, with recurrent episodes any or the pines for the benzodiazepine receptor site, displacing entire symptoms can persist and cumulatively progress benzodiazepines and thereby precipitating a pharmacowith each recurrence. While the tinnitus is often logic benzodiazepine withdrawal (McConnell, 2008). described as roaring early in the illness, with more advanced stages of the syndrome, the tinnitus tends to ALWAYS LATERALIZED become more variable in its description. There are no definitive tests to establish the diagnosis; however, elecNever with vestibular symptoms trocochleography can be supportive of the diagnosis, if Conductive hearing loss. Any type of unilateral conthere is a large ratio of summating potential to action ductive hearing loss, such as cerumen impaction, ossicpotential amplitudes. Documentation of the fluctuation ular discontinuity, or otosclerosis, can be associated with in hearing with serial audiograms is supportive of the tinnitus of that ear. The tinnitus may be related at least in diagnosis. The fluorescent treponemal antibody absorppart to an unmasking of a “normal” underlying tinnitus, tion (FTA-Abs) test can sometimes be positive in this as discussed above. Otosclerosis may sometimes be syndrome. associated with inner-ear involvement, which could be Formes frustes of this syndrome may occur. In particcontributing to the tinnitus as well. ular, episodic low-frequency fluctuating hearing loss with a contemporaneous roaring tinnitus and aural fullOtoacoustic emissions. While spontaneous otoacousness may occur without vertigo. tic emissions are common (75% of females and 45% of males with normal or near-normal ears), tinnitus due to Perilymphatic fistula spontaneous otoacoustic emissions is uncommon. It is Like Me´nie`re’s syndrome, perilymphatic fistula can said to be accounting for the tinnitus of 1–2% of the cause hearing loss, vertigo, and tinnitus. However, the patients of one British tinnitus clinic, but in our experitinnitus and hearing loss tend to be high-frequency (hisence it has been much less frequent (Penner, 1992). The sing, crickets, etc.) with no recovery. The fistula consists diagnosis is made by measuring an emission and showof a communication between the perilymph of the innering that its suppression abolishes the tinnitus. The emisear fluids and the middle ear through a round or oval sion can be suppressed in one of two ways: presentation window defect or sometimes a defect of the bony labyof a low-level tone near the emission frequency or the rinth. The defect can be caused by barotrauma (e.g., airuse of aspirin (Penner and Coles, 1992). plane descent or scuba ascent), head trauma, Valsalva Eighth-nerve compression (usually vascular). As maneuver, erosion of the bony labyrinth due to an discussed earlier, the tinnitus of VIIIth-nerve compresinflammatory or neoplastic process, or following sion is unilateral, rarely associated with vestibular sympmiddle-ear surgery such as stapedectomy. The diagnosis toms, and can take three forms: (1) non-specific (hissing, can be suggested by the “fistula test” – the induction of buzzing, etc.); (2) pulsatile; and (3) staccato, irregular nystagmus by positive or negative pressure applied to the intermittent clicking (typewriter). All those with unilatexternal auditory canal. If symptoms persist and the eral non-specific tinnitus should be questioned closely findings are suggestive then the middle ear can be about whether there ever is a clicking or pulsating explored for a fistula with patching of the round and oval component to their non-specific tinnitus, even if very windows. Generally the hearing loss and tinnitus are not rarely. If so, then the possibility of VIIIth-nerve improved by patching the oval and round windows compression becomes more likely and should be investiwhether or not a leak is found at surgery. gated using a heavily T2-weighted MRI (constructive interference in steady state (CISS) or fast imaging Superior semicircular canal dehiscence (SSCD) employing steady-state acquisition (FIESTA)) of the SSCD is closely related to perilymphatic fistula. Whereas cerebellopontine angle. the perilymphatic fistula is a defect of the otic capsule into the middle ear, SSCD is a defect of the otic capsule May be with vestibular symptoms into the floor of the middle cranial fossa. While vestibMe´nie`re’s syndrome. As a syndrome this condition ular symptoms from loud sounds or straining are more has tinnitus as one of its defining features. The fullcommonly the presenting SSCD symptom, in one series

TINNITUS 35% of patients reported unilateral high-pitched tinnitus as one feature of their presentation (Yuen et al., 2009). Other auditory symptoms include monaural heightened bodily sounds (eye movements, heartbeat, footsteps, or voice). The diagnosis is suspected from an air–bone gap with bone thresholds exceptionally good, intact acoustic reflexes, and ipsilateral low thresholds of their vestibular evoked myogenic potential. CT scan can demonstrate the dehiscence. Much rarer are dehiscences involving the posterior or lateral semicircular canals. A variety of surgically induced dehiscences can also occur. Herpes zoster oticus (Ramsay Hunt syndrome) Intense ear pain followed by ipsilateral tinnitus, hearing loss, vertigo, and facial paralysis will be recognized as due to herpes zoster once vesicles appear on the pinna, external auditory canal, or tympanic membrane. Cerebellopontine angle tumors The most common presentation of such tumors is a gradual unilateral sensorineural hearing loss with minimal, if any, vestibular complaints. Dizziness and facial weakness, in general, are either non-existent or very minor accompaniments of acoustic neuromas at any time. The audiometric pattern is variable. They are more likely to have poor speech discrimination, acoustic reflex decay, and pure-tone decay. Other presentations do occur, including unilateral tinnitus only or sudden hearing loss with or without subsequent recovery. Any unilateral tinnitus with or without unilateral sensorineural hearing loss must be considered suspect for a cerebellopontine angle tumor, even though only about 3% of all patients with acoustic neuromas first present complaining of unilateral tinnitus only (Dornhoffer et al., 1994; Morrison and Sterkers, 1996). Therefore, should every such patient have a contrast-enhanced or high-resolution T2-weighted MRI scan to exclude the diagnosis, since such imaging has a sensitivity “approaching, if not reaching 100%” (Curtin, 1997; Fortnum et al., 2009)? In 25 years of evaluating all patients with unilateral tinnitus for a cerebellopontine angle lesion, we have detected just two lesions of the cerebellopontine angle. Dawes and Basiouny (1999) have reported a similar experience: one acoustic neuroma was detected in 174 patients with unilateral tinnitus Alternatives to obtaining the “gold standard” contrastenhanced MRI scan immediately are using the shortlatency brainstem auditory evoked potentials (especially stacked ABR: Don et al., 2012), a good but imperfect test, to decide whether or not to proceed to the MRI scan, or following the patient with revisits and repeat audiograms at 6-month intervals, looking for development

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of an ipsilateral hearing loss before going to the MRI scan. The issue ultimately becomes one of costeffectiveness and availability of MRI scanning, since there is virtually no morbidity associated with the MRI scan. Central nervous system disorder – caudal to trapezoid body The hallmark of tinnitus due to a disorder of the central nervous system is other neurologic system involvement. If the central auditory nervous system involvement occurs between the ear and the trapezoid body (where the auditory inputs from the two sides intermix and cross) then there may be an associated ipsilateral hearing loss with unilateral tinnitus. The type of associated neurologic involvement will depend crucially upon the precise location of the lesion. With unilateral tinnitus it can include dizziness, diplopia, limb ataxia, ipsilateral facial weakness, ipsilateral facial paresthesias, but contralateral-limb paresthesias. The tinnitus is often transient. Stroke, intrinsic or extrinsic neoplasms, demyelinating disease, inflammatory diseases, and meningitides can all lead to unilateral tinnitus and hearing loss. The diagnosis will be established by the pattern of neurologic system involvement, the temporal profile of the illness, and the results of ancillary diagnostic studies such as MRI scanning, cerebrospinal fluid examination, or arteriography. Sudden idiopathic hearing loss Patients can present with an abrupt unilateral tinnitus as their only complaint and upon evaluation are found to have a corresponding unilateral hearing loss of which they may have been unaware. More typically they complain of both the hearing loss and tinnitus or hearing loss alone. The hearing loss and tinnitus are abrupt in onset and always unilateral. The quality of the tinnitus usually is closely related to the pattern of the pure-tone audiogram. Vestibular symptoms, should they occur, are usually not prominent. Once other rare but identifiable causes have been considered, such as Me´nie`re’s syndrome, cerebellopontine angle tumor, cochlear ischemia, syphilis, or herpes zoster, then the diagnosis of sudden idiopathic hearing loss is secure.

MAY OR MAY NOT BE LATERALIZED Acute acoustic trauma There is no difficulty establishing the diagnosis of tinnitus due to acoustic trauma when the history is one of immediate development of hearing loss and tinnitus following an intense sound exposure with partial or complete recovery of hearing (temporary threshold shift)

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over a few days. On the other hand, if the audiogram is normal or the tinnitus does not immediately follow a unilateral intense sound exposure, then other causes for the tinnitus must be sought.

Somatic (head or upper cervical) Observations abound supporting the notion that head and neck somatic events can be associated with tinnitus (Biesinger, 1997). The patient is not aware of any hearing loss with its onset, but there may or may not be a preexisting hearing loss. Prior to their first visit, about 20% of patients in our clinic have noticed that they can modulate their tinnitus somatically, such as by clenching the teeth or pushing on various places on the head (Levine, 2004). For 2 years we systematically examined our patients with a battery of isometric head and neck contractions. More than 75% of patients could modulate their tinnitus. A variety of changes can occur. Most frequently the tinnitus gets louder (72%), but less often the tinnitus becomes quieter (25%) (Levine et al., 2003; Abel and Levine, 2004). In 18% the tinnitus became quieter for some maneuvers and louder for others (Levine et al., 2008). Less frequently, patients describe pitch or location changes. Tinnitus is generally included amongst the features associated with pain in the temporal or preauricular region that goes by various names, such as Costen’s syndrome, craniomandibular disorder, and temporomandibular joint syndrome. Well-designed studies have shown a higher incidence of tinnitus in normal-hearing subjects with temporomandibular joint syndrome than in controls (Chole and Parker, 1992). The same is true for whiplash (Tjell et al., 1999; Tranter and Graham, 2009). From multiple other observations and case reports, the concept of tinnitus associated with whiplash and temporomandibular joint syndrome can be generalized to include tinnitus associated with any disorder of the upper cervical region or head, including dental pain. The tinnitus temporally associated with unilateral somatic disorders is localized to the ipsilateral ear (Levine, 1999; Reisshauer et al., 2006). Hence unilateral tinnitus with no associated auditory or vestibular symptoms such as hearing loss must be suspect for an ipsilateral head or neck somatic disorder. The physical examination should include: (1) inspection of the teeth for wear as evidence of bruxism; (2) palpation of the head and neck musculature for tender muscles with increased tension (trigger points) (Teachey et al., 2012); and (3) assessment of the effects upon the patient’s tinnitus from “somatic testing”: forceful systematic isometric contraction of muscle groups of the

head and neck and deep palpation of these same muscles and the auricle. At least four factors have been associated with changes in tinnitus attributes: somatic modulation (SM), stress, exposure to loud sound, and use of benzodiazepines. As described above, it is clear that to formal systematic testing most subjects can somatically modulate their tinnitus. It may be that in day-to-day activities everyone can somatically modulate their tinnitus. Patients consistently describe that they are more bothered by their tinnitus when stressed. Whether this is due to the patient focusing attention upon the tinnitus or actual changes in the tinnitus loudness usually cannot be distinguished by the patient. In fact, it is very possible that stress acts through SM to increase tinnitus loudness, since there is a very well-recognized association between stress and oral parafunctional behavior such as tooth grinding, jaw clenching, fingernail biting, and pencil chewing, as well as furrowing the brow, or grimacing. Hence one way by which stress may lead to increased tinnitus loudness is through increasing head and neck muscle contractions which in turn lead to louder tinnitus by the somatic mechanism. Some subjects clearly associate an increase in their tinnitus loudness with exposure to loud sound, and in some the louder tinnitus can persist for hours after the exposure has discontinued. Finally use of benzodiazepines can cause fluctuations in tinnitus since they are commonly used for insomnia and anxiety, both of which are often associated with tinnitus, and benzodiazepines quieten tinnitus to some degree in the majority of people (Johnson et al., 1993; Vernon and Meikle, 2003; Jalali et al., 2009; Han et al., 2012). Thus, if a patient reports that tinnitus is intermittent or has wide fluctuations in loudness or other qualities, and there is no exposure to intense sound, evidence for stress, or use of benzodiazepines, then the SM mechanism must be suspected. A history of variations in tinnitus loudness then raises the suspicion for a somatic factor modulating the percept’s loudness (Table 23.3). At an extreme are patients who describe that they have periods when their tinnitus cannot be heard, even in the quiet while focusing on their hearing. Others report wide variations in the loudness of their tinnitus. For still others, their tinnitus is unilateral when it is relatively quiet but becomes non-lateralized when the tinnitus is louder. Such Table 23.3 Tinnitus properties suggesting a somatic component 1. Large fluctuations in loudness, including intermittent tinnitus, and diurnal tinnitus 2. Variability of location 3. No hearing loss but head or neck disorder

TINNITUS 419 phenomena suggest that there are ongoing somatically not uncommon, chance association of the two is to be mediated factors modulating the tinnitus percept. expected. Diurnal fluctuations in the tinnitus percept also suggest that SM is operative. Patients who describe their tinIdiopathic nitus as louder upon awakening raise the possibility that Sometimes, despite an exhaustive evaluation of nonsomatic factors (such as bruxism, or grinding of the specific tinnitus, no specific diagnosis can be made with teeth) are active during sleep and are causing an increase any high degree of confidence. Hence, the diagnosis of in tinnitus loudness. Others describe that their tinnitus “idiopathic” is tentatively made. has usually vanished by the time they awaken and then returns a few hours into the day; this scenario suggests TREATMENT OF TINNITUS that during the day they are reactivating their tinnitus through somatic mechanisms, such as the tonic muscle Once the etiology of the tinnitus is tentatively identified contractions required to support the head in an upright then treating the underlying cause of the tinnitus can position or oral parafunctional activities related to the lead to its resolution. A preliminary study using a stress of daily activities. Finally, others describe that somatic approach to tinnitus treatment by needling head and neck myofascial trigger points resulted in complete their tinnitus is louder after awakening from a nap in cessation of tinnitus for 25% of patients and decided a chair; this may relate to somatic factors such as stretching of the neck muscles when their head passively falls improvement in another 25% (Teachey et al., 2012). forward while dozing in a sitting position. If the pathologic process for the tinnitus cannot be In our experience, while a somatic factor on its own reversed, then suppression of the tinnitus acoustically, can cause tinnitus, much more frequently somatic facpharmacologically, or electrically can be attempted. tors combine with other factors (such as chronic hearing For people with hearing loss, hearing aids can often loss) to act as trigger factors or modulators (Levine act as maskers of their tinnitus. Additionally, when hearing is improved, patients no longer perceive the tinnitus et al., 2007). as interfering with their hearing. Consequently they pay less attention to their tinnitus once their ability to hear Head trauma external sounds is improved. The contemporaneous association between head trauma, With programmable digital hearing aids, it has been hearing loss, and tinnitus makes the diagnosis straightreported that there was a more than 50% tinnitus forward. The association with trauma becomes less cerimprovement in 65% of subjects who received one heartain when some of these elements are missing, such as a ing aid and in 80% of subjects who received bilateral delay between the trauma and the onset of the tinnitus. hearing aids (Trotter and Donaldson, 2008). With hearThe longer the delay, the less is the confidence of any ing aids that incorporate linear octave frequency transassociation between the two. Tinnitus but no hearing loss position, a recent study reported a large number of following trauma, likewise, makes the association more subjects who completely suppressed their tinnitus; these tenuous and raises the possibility that trauma is causing same subjects were said to have had no benefit from tinnitus through a brainstem mechanism or indirectly hearing aids using classic amplification or non-linear such as through a somatic mechanism. Abnormalities frequency compression (Peltier et al., 2012). of otoacoustic emissions, including those involving the Anecdotal tinnitus suppression has been reported for brainstem (the contralateral suppression of otoacoustic a large number of medications (fluoxetine, sertraline, emissions), have been found in subjects with tinnitus paroxetine, risperidone, ginkgo, scopolamine patch, and head injury, including some with normal audiograms, famotidine, and gabapentin). Only benzodiazepines raising the likelihood that a brainstem mechanism is have been shown to significantly quieten tinnitus in mulaccounting for the tinnitus associated with head trauma tiple well-designed studies. All three benzodiazepine (Ceranic et al., 1998; Attias et al., 2005). Hyperbaric oxystudies report that in about 75% of subjects the benzodigen has recently been reported to provide major benefit to azepine quietens tinnitus to some degree (Johnson et al., some patients with tinnitus following mild traumatic brain 1993; Vernon and Meikle, 2003; Han et al., 2012). injury (Shlamkovitch, 2012; Boussi-Gross et al., 2013). A fourth study found a “significant improvement in VAS [visual analog scale] score in the benzodiazepine Postinfectious group compared with the placebo group (P < 0.001)” Occasionally patients report the onset of tinnitus follow(Jalali et al., 2009). In our clonazepam study using a ing an upper respiratory infection. Whether this is cause strict protocol, 7% had their tinnitus completely supand effect has never been established. Since upper respipressed. It is likely that in clinical practice the percentratory infections are common, and idiopathic tinnitus ages who suppress their tinnitus completely will be

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much higher, because the dose can be individualized and other benzodiazepines can be tried. Acamprosate was shown to quieten tinnitus in two well-designed studies (Azevedo and Figueiredo, 2005; Sharma et al., 2012) but was said not to be effective in a third as yet unpublished study (Martin, 2011). One of the studies found that at 90 days the tinnitus was not heard in more than 10% of subjects (Sharma et al., 2012). The medications for trigeminal neuralgia, especially carbamazepine, suppress completely staccato irregular unilateral tinnitus (“typewriter tinnitus”). Auditory nerve electric stimulation, whether by a cochlear implant or from the middle-ear promontory, has been repeatedly shown to suppress tinnitus in many subjects, but no promontory stimulation device is currently commercially available (Matsushima et al., 1997a; Van de Heyning et al., 2008). If the tinnitus cannot be quietened satisfactorily, then behavioral methods or antidepressants can improve the subject’s tinnitus tolerance by shifting the subject’s attention away from the tinnitus and/or improving the associated depression (Sullivan et al., 1993). While a review of randomized controlled trials concluded that “only studies examining cognitive behavioral therapy were numerous and similar enough to perform metaanalysis, from which the efficacy of cognitive behavioral therapy (moderate effect size) appears to be reasonably established,” in the hands of a proficient practitioner the behavioral methods may all be about equally effective (Hoare et al., 2011). Some of the other behavioral techniques include tinnitus retraining therapy, neuromonics, mindfulness, binaural beats, and self-hypnosis (Attias et al., 1993; Caffier et al., 2006; Davis et al., 2008; David et al., 2010; Hesser et al., 2011; Kreuzer et al., 2012).

HYPERACUSIS Hyperacusis refers to reduced sound tolerance (see Chapter 21). People with hyperacusis report that they find sound intensities considered comfortable by most people to be unbearably loud (Baguley, 2003). There is a close relationship between hyperacusis and tinnitus; about 40% of patients with tinnitus report some degree of hyperacusis. Furthermore, while less than 10% of people in the general population have hyperacusis, more than 80% of those with hyperacusis report coexisting tinnitus. In a small number of individuals hyperacusis is their prime concern; tinnitus is of secondary importance. There is evidence supporting the notion that sound avoidance as a reaction to new-onset tinnitus creates a negative-feedback situation leading to hyperacusis. It has been shown in short-term experiments with people wearing ear plugs that this form of sound avoidance

leads to decreased sound tolerance (Florentine, 1976; Formby et al., 2003; Blaesing and Kroener-Herwig, 2012). The negative feedback then is as follows: sound avoidance because of tinnitus leads to more sound intolerance, which in turn leads to more sound avoidance. Further support for this concept has come from the success in treating hyperacusis with desensitization programs (Vernon, 1987; Jastreboff and Jastreboff, 2003; Andersson et al., 2005; Norena and Chery-Croze, 2007). These desensitization programs all have in common the gradual introduction of sounds within a supportive environment that had been previously poorly tolerated, thereby breaking the vicious cycle of negative feedback.

THE NEUROLOGY OF TINNITUS Over the last 45 years, based upon interactions between clinical observations and animal models, a comprehensive understanding of the neurology of tinnitus has emerged. Since tinnitus may have several different etiologies, so too there are different ways that the tinnitus percept may develop in the central nervous system. Presently the most compelling evidence for the most common types of tinnitus is the DCN hypothesis, which will be presented in detail.

Hearing loss and somatic tinnitus: the unilateral dorsal cochlear nucleus hypothesis HEARING LOSS The first insights into the neurology of hearing-loss tinnitus came from auditory nerve fiber recordings in experimental sensorineural hearing loss. In these cases auditory nerve fibers lost all spontaneous activity (normally spontaneous activity ranges between 1 and 100 per second) and became unresponsive to acoustic stimulation (Kiang et al., 1970). Over 25 years later it was shown that, with a cochlear hearing loss, the DCN develops elevated multiunit spontaneous activity limited to the region of the DCN tonotopically corresponding to the damaged region of the cochlea (Kaltenbach and McCaslin, 1996). Subsequent studies demonstrated this finding in multiple species, including animals with behavioral evidence of “tinnitus” (Brozoski et al., 2002; Kaltenbach et al., 2005; Dehmel et al., 2012) and found that it is the fusiform cell which has elevated spontaneous activity (Brozoski et al., 2002; Finlayson and Kaltenbach, 2009). More recently it has been shown that (1) elevated spontaneous activity involves only one type of fusiform cell, those that respond to tone bursts with a “buildup” response pattern (Dehmel et al., 2012) and (2) only the subpopulation of DCN neurons that can be

TINNITUS 421 excited by the somatosensory system show increased projections from the C2 and C3 dorsal nerve roots to spontaneous rates following hearing loss. the cochlear nuclei (Biesinger, 1997). This DCN subpopulation also developed increased Unaware of Biesinger’s work, Levine (1999) came to sensitivity to trigeminal electrical stimulation and a the same conclusion, but went further. Using existing change in their response pattern to sounds interacting anatomic and physiologic evidence combined with the with trigeminal electric stimulation (Koehler and properties of either the somatic tinnitus syndrome alone Shore, 2013). This increased sensitivity finding is consisor SM of tinnitus alone, he elaborated and detailed how tent with functional imaging findings in tinnitus both somatic aspects of tinnitus lead to the conclusion patients. It was observed that the only significant differthat the ipsilateral DCN is the likely site of somatic– ence between tinnitus and non-tinnitus subjects to auditory interaction and the initiating site of somatic tinsomatosensory activation (jaw motion) was increased nitus (Fig. 23.3). The details of the arguments that led to responsiveness in the brainstem nuclei (cochlear nucleus these conclusions can be found in the 1999 paper and inferior colliculus) of tinnitus patients (Lanting (Levine, 1999). et al., 2010). In summary, consideration of the clinical features of This change in the response pattern to sounds when the somatic tinnitus syndrome as well as the properties interacting with trigeminal electric stimulation follows of SM of tinnitus, along with experimental neuroanatupon in vitro studies of the DCN (Tzounopoulos, omy and electrophysiology, has led to the hypothesis that 2008). The changes occurred only in the animals with SM of tinnitus and the somatic tinnitus syndrome occur “tinnitus.” Despite being exposed to the same tinnitusthrough modulation of the pathway from somatosensory inducing stimulus, the animals that did not develop nucleus of the medulla to the ipsilateral DCN (Fig. 23.3). “tinnitus” from the tinnitus-inducing stimulus also did If increased activity in the fusiform cells, the primary not show a change in their auditory–somatosensory output cells of the DCN, is associated with tinnitus, as interaction pattern. This latter finding is highly signifihas been suggested for hearing loss tinnitus, then the cant because it opens the way to providing insights into speculation can be taken a step further to suggest that why some people with the same disorder, whether somatoinhibition of this pathway (somatosensory nucleus of sensory or auditory, develop tinnitus and others do not. the medulla to ipsilateral DCN) could lead to tinnitus These findings are consistent with clinical observations through disinhibition of the DCN fusiform cells and support the notion that alteration in the auditory– (Brozoski et al., 2002; Finlayson and Kaltenbach, 2009). somatosensory interaction at the level of the DCN fusiBased upon clinical observations Levine et al. conform cell is a fundamental mechanism of tinnitus. cluded that the somatosensory inputs appear to originate In support of the DCN hypothesis, lesions interruptfrom motor afferents (Golgi tendon organs and muscle ing rostral DCN output prevented the development of spindles) of the proprioceptive system and almost exclu“tinnitus” if they occurred prior to the “tinnitus” inducer sively from the ipsilateral upper cervical and head (high-level noise) and were bilateral (Brozoski et al., regions (Levine et al., 2003). Two more recent cases have 2012). On the other hand the full story appears to be more provided unequivocal support for SM being mediated by complex. If such lesions were unilateral, they did not prethe posterior column-medial lemniscus exclusively vent “tinnitus,” whether ipsilateral or contralateral to the (Table 23.4). Both subjects had unilateral tinnitus and noise exposure. When contralateral the experimental anisymmetric audiograms. Both could modulate their tinnimal’s tinnitus behavior was exacerbated. Also if bilateral tus with standard somatic testing (strong muscle conlesions were made after “tinnitus” onset there was no tractions of the head and neck), but in addition both effect upon the “tinnitus” (Brozoski and Bauer, 2005). had roughly the same area of their scalp in which their tinnitus could be modulated. The very circumscribed region was located in their temporal scalp above and just THE SOMATOSENSORY SYSTEM rostral to the pinna, as shown in Table 23.4. Within this After hearing loss, tinnitus from a somatic disorder of region their tinnitus loudness could be raised by stimuli the head and neck is the other major cause of tinnitus from the posterior column-medial lemniscus class of (Levine, 2004). That it can cause tinnitus is now beyond stimuli (deep pressure and vibration), could not be moddoubt, as previously discussed. In 1997 Biesinger (in the ified by stimuli from other somatosensory classes (light German literature) raised the possibility that “dizziness, touch, temperature, pain), and could not be modified by tinnitus, sudden hearing loss, otalgia, globus pharyngeus any of these stimuli when applied outside the outlined and cephalgia” may originate from the cervical spine and temporal regions. that manual treatment of the upper cervical spine (C2 Soon after Levine’s 1999 paper more support for and C3) could treat these conditions. He postulated a this hypothesis of disinhibition of the ipsilateral DCN neurologic basis for the tinnitus that was related to through the muscle and joint receptors of the posterior

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Fig. 23.3. Schematic depiction of the anatomic basis for the dorsal cochlear nucleus (DCN) hypothesis: both somatic and otic (ear) tinnitus occur owing to net disinhibition of the DCN. In both cases, tinnitus is due to increased activity in the output of the DCN, which projects to the higher centers and eventually leads to activation of the auditory perceptual machinery responsible for tinnitus. For somatic tinnitus ipsilateral sensory inputs from (1) the face via the trigeminal (V) nerve in the spinal trigeminal tract; (2) the external and middle ears via the common spinal tract of the facial (VII), glossopharyngeal (IX), and vagus (X) cranial nerves; and (3) the neck via the C2 dorsal spinal root converge to a common region of the lower part of the medulla, the somatosensory nucleus of the medulla, from which fibers project to the ipsilateral DCN. Modulation of activity in the somatosensory nucleus of the medulla to DCN pathway results in net disinhibition of the DCN. For otic tinnitus, loss of input (spontaneous activity) from the auditory (VIII) nerve leads to net disinhibition of the dorsal cochlear nucleus. Table 23.4 Changes in tinnitus loudness (visual analog scale) for 2 subjects with similar temporal regions of sensitivity (outlined by triangles) ipsilateral to their unilateral tinnitus

Baseline visual analog scale loudness (0–10) System Modality Cutaneous Light touch Pulling hair Stretch skin Spinothalamic Cooling Pinprick Posterior column Vibration Deep pressure

Subject AR

Subject AM

6R/0L

0R/6L

NC NC NC NC NC 10 R / 0 L 10 R / 0 L

NC NC NC NC NC 0R/8L 0R/8L

R, right; L, left; NC, no change.

column-medial lemniscus system came from an in vivo animal physiologic study (Kanold and Young, 2001). Kanold and Young (Fig. 23.4) showed that stimulation of the pinna with modalities subserved by the posterior

column-medial lemniscus system and not stimuli from other sensory systems modulates ipsilateral DCN single cell activity. Just as in clinical observations regarding SM of tinnitus and somatic tinnitus they reported that “only

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DCN Recordings 140

Spikes/s

140

0

0 0

A

50 Seconds

B

100

0

50 Seconds

100

C

Fig. 23.4. Responses of dorsal cochlear nucleus (DCN) fusiform cells to stretch of cat pinna muscles. (B and C) The responses of two different neurons to manual pressure (indicated by the bars above the plots) applied to the ipsilateral pinna, as shown in (A). The effect of the pinna pressure was continuous inhibition, maintained as long as the pressure was applied. The effect of pinna pressure is mediated through the following neural pathway: C2 spinal nerve to fasciculus cuneatus to the somatosensory nucleus of the medulla to ipsilateral dorsal cochlear nucleus (Fig. 23.3). Muscle stretch or vibration was the most potent modulator of DCN activity. Cutaneous stimulation (light touch, brushing of hairs, or stretching of skin) had no effect. (Reproduced from Kanold and Young, 2001.)

stimuli that activate . . . muscle receptors, such as stretch or vibration of the muscles connected to the pinna, were effective in driving DCN units, whereas cutaneous stimuli such as light touch, brushing of hairs, and stretching of skin were ineffective” (Kanold and Young, 2001). A more recent brain slice study provides evidence that it is a decrease in gamma-aminobutyric acid (GABA)mediated inhibition that is accounting for the tinnitusrelated DCN disinhibition (Middleton et al., 2011). Levine’s group went on to show that SM of auditory perception: (1) was not a phenomenon restricted to people with clinical tinnitus but was just as prevalent in people whose tinnitus was not a clinical problem; (2) was present in about 60% of people who did not have tinnitus; and (3) was present in people with non-functioning ears whether or not they had tinnitus (Table 23.5) (Levine et al., 2003). This result in the profoundly deaf made the neurologic model iron-clad. Later confirmatory support for these findings came from a functional imaging study, which found that somatosensory input enhances activity throughout the auditory pathway in all subjects whether or not they had tinnitus (Lanting et al., 2010). Consistent with the unilateral DCN hypothesis regarding hearing loss and somatic tinnitus is a report of (a) a significant correlation between ipsilateral tinnitus and unilaterally diminished cervical rotation and (b) abolishment of unilateral tinnitus with blocking the ipsilateral C2–3 facet joint (Reisshauer et al., 2006; Gritsenko et al., 2014). Besides changes in auditory perception as related to strong muscle contractions, evidence for auditory– posterior column-medial lemniscus interaction in humans has been coming from other very different

approaches. As previously mentioned, a functional imaging study has reported somatosensory enhancement of the auditory pathway, including the cochlear nucleus, but also Lewald and colleagues have shown how auditory spatial perception in the horizontal plane could be altered by neck vibration, a potent posterior column-medial lemniscus stimulus (Lewald et al., 1999; Lanting et al., 2010). Consistent with these studies is a study reporting poorer sound lateralization performance in people with tinnitus, especially on the side with unilateral tinnitus (An et al., 2012).

WHY DOES THE SOMATOSENSORY SYSTEM COMMUNICATE WITH THE DCN? The answer to this question relates to the general principle that the DCN, as a cerebellar-like structure, is a pattern recognizer (Bell et al., 1997; Steuber et al., 2007).

Neck proprioception The DCN is highly involved in auditory spatial perception in the vertical plane (i.e., front–back and up–down). By using modifications in the acoustic spectra produced by the interactions of sound with the pinna, the DCN can determine the sound location with respect to the ear (Oertel and Young, 2004). In order to know the position of the sound in space, the DCN also needs to know where the ears are located – in other words, the head’s position. The position of the head (ears) is provided by the cervical posterior column-medial lemniscus system (proprioceptive input coming from the joints, muscles, and tendons of the upper neck). By integrating the auditory

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and proprioceptive information the central nervous system can infer from where in space a sound originates. Jaw proprioception This sound location argument easily accounts for why the neck somatosensory system projects to DCN, but does not account for the jaw proprioceptive inputs. (This involves a more involved argument that again involves the unitary principle that the DCN is a pattern recognizer.) The DCN cytoarchitectonics (the cellular structure and the arrangement of its cells) is similar to that of another sensory nucleus, the electrosensory nucleus of the mormyrid electric fish. The argument then is as follows: similar structure implies similar function. If the function of the electrosensory nucleus for electric stimuli is known, then by analogy the function of the DCN will be something similar but for acoustic stimuli. There is strong evidence that the function of this fish’s electrosensory nucleus is to perform a “sensory subtraction.” The self-generated electric signals (such as from its muscles, including its heart) are subtracted from the total signal in the electrosensory nucleus to obtain the environmental electric signals (Bell et al., 1997). This leads to the hypothesis that the DCN functions as a “sensory subtractor” for acoustic signals. The self-generated auditory signals are subtracted from the total signal in the DCN to obtain the environmental auditory signals. And what are the self-generated auditory signals? They are sounds generated from our breathing, chewing, vocalizations, and heart beats (Haenggeli et al., 2005; Shore, 2005). The generation of many of these sounds involves the neck and jaw muscles and therefore to optimize their subtraction the DCN uses the proprioceptive input from the neck and jaw muscles. Recall that the hallmark of the somatosensory pulsatile tinnitus syndrome is that somatic testing suppresses pulsations (heart beats). This feature suggests that this type of pulsatile tinnitus may be due to a failure of the DCN to suppress the normal self-generated sound of our heart beats. Suppression of pulsatile tinnitus with somatosensory activation from somatic testing may represent a temporary correction of this malfunction (Levine et al., 2008).

THE DORSAL COCHLEAR NUCLEUS HYPOTHESIS AND NON-LATERALIZED TINNITUS Support for DCN involvement in non-lateralized tinnitus is less compelling; however, the giant cells in the deep layers of the DCN do project to the contralateral dorsal, anteroventral, and posteroventral cochlear nucleus

(Cant and Gaston, 1982; Doucet et al., 2009; Brown et al., 2012). Hence these direct synaptic connections from one cochlear nucleus to the other could play a significant role in non-lateralized tinnitus. These commissural connections between the cochlear nuclei of the two sides, as well as the connections between the different divisions of each cochlear nucleus, raise numerous possibilities besides the simple DCN model described above. Bringing home this point is a recent demonstration that in human subjects the auditory nerve compound action potential is reduced in tinnitus subjects (Gu et al., 2012). This commissural pathway could also account for the unusual property of the tinnitus of some people deafened from acoustic neuroma surgery. While they are deaf and have tinnitus on the side from which the tumor was removed, sound presented to their contralateral normal functioning ear transiently intensifies their deaf ear’s tinnitus and the intensification can persist for hours.

IMPLICATIONS OF THE DCN HYPOTHESIS The hypothesis can account for why, with any degree of hearing loss, some people develop tinnitus and others do not. A schematic diagram of the fusiform cell of the DCN along with its inputs is shown in Figure 23.5A. While it is a complex picture, it can be simplified by segregating the inputs to the fusiform cell by whether they are via the apical or basal dendrite (Fig. 23.5B) and whether they are excitatory or inhibitory (Fig. 23.5C). The output of the DCN is principally via the fusiform cell axon, which projects to the contralateral inferior colliculus (Fig. 23.5B and C). The apical dendrites receive no direct inputs from outside the DCN. Their inputs are from the parallel fibers of the “granule cell domain,” whose inputs are multiple. They include type II auditory nerve fibers from cochlear outer hair cells, the head and neck posterior column-medial lemniscus system, auditory cortex, vestibular system, and pontine nuclei. In contrast, the basal dendrite receives direct inputs from the type I auditory nerve fibers from cochlear inner hair cells and its inhibitory interneuron, the vertical cell. By rearranging the diagram into excitatory and inhibitory inputs to the fusiform cell, it can be appreciated that tinnitus results when excitation outweighs inhibition at the level of the DCN fusiform cell. By the same token, there will be no tinnitus when inhibition outweighs excitation. This framework can account then for a fundamental unanswered question regarding tinnitus and hearing loss, namely, with any degree of hearing loss, why do some people develop tinnitus and others do not (Chung et al., 1984), and likewise with animal models (Brozoski et al., 2010; Dehmel et al., 2012; Bauer et al.,

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Fig. 23.5. (A) A schematic representation of a dorsal cochlear nucleus fusiform cell with its inputs. (Reproduced from Kaltenbach et al., 2005.) (B) Block diagram of (A) based upon whether the input is to the apical or basal dendrite. (C) Rearrangement of the inputs to the fusiform cell according to whether they are excitatory or inhibitory. ANF, auditory nerve fiber; IHC, inner hair cell; OHC, outer hair cell; MOCB, medial olivocochlear bundle; MSN, somatosensory nucleus of medulla; TG, trigeminal ganglion; + indicates an excitatory synapse; – indicates an inhibitatory synapse.

2013; Koehler and Shore, 2013)? While the prevalence of tinnitus increases with increasing hearing loss, it never exceeds 80% (e.g., sensorineural hearing loss (Table 23.5), including sudden idiopathic hearing loss (Levine, 1999; Huy and Sauvaget, 2005)). From transection of the auditory nerve some (50–75%) but not all subjects get relief of their unilateral tinnitus (Perry and Gantz, 2000). Whether or not any individual will develop tinnitus from a tinnitus-inducing insult, then, will depend upon the insult’s net effect upon the fusiform cell (Fig. 23.5C) as well as a second related factor, the individual’s “tinnitus threshold” (see section Tinnitus is a threshold phenomenon, below).

Table 23.5 Effect of somatic testing on the auditory perception of profoundly deaf subjects Subject type

With tinnitus Without tinnitus Totals

Totals

11 3 14

Modulate? Yes

No

6 (54%) 2 (67%) 8 (57%)

5 (45%) 1 (33%) 6 (43%)

The hypothesis can account for why potentiators of GABA quieten tinnitus. As can be appreciated from Figure 23.5C, anything that promotes inhibition of the fusiform cell or reduces its excitation will diminish the output of the fusiform cell and thereby tinnitus. This can explain why GABAergic drugs quieten tinnitus, as has been shown in both human and animal studies. The synapse between the stellate cell and the fusiform cell (Fig. 23.5A) is mediated by the inhibitory neurotransmitter, GABA. Hence, medications that enhance this synapse will reduce fusiform cell activity and thereby quieten tinnitus. In fact, four well-designed studies have shown that the GABA potentiators, the benzodiazepines, quieten tinnitus in about 75% of people (Johnson et al., 1993; Vernon and Meikle, 2003; Jalali et al., 2009; Han et al., 2012) and suppress tinnitus completely in 7% of people (Han et al., 2012). Two other GABA-potentiating drugs, primidone (Mysoline) and ethanol, have also been shown to quieten tinnitus in humans, albeit in less rigorous studies (Shea and Emmett, 1981). In animals vigabatrin, a GABA potentiator, reversibly abolishes “tinnitus” (Brozoski et al., 2007). The hypothesis can account for why cochlear electric stimulation can quieten tinnitus. Multiple human studies have demonstrated that electric stimulation of the cochlea quietens tinnitus (Matsushima et al., 1997b; Rubinstein et al., 2003; Van de Heyning et al.,

426 R.A. LEVINE AND Y. ORON 2008). According to the DCN hypothesis, this can occur Tinnitus is a threshold phenomenon in multiple ways, such as: (1) activation of inhibition Evidence that tinnitus is a threshold phenomenon has (vertical, cartwheel, or stellate cells); (2) reduction in emerged from observations of differences between subexcitation of the fusiform cell (type I auditory nerve jects with and without chronic tinnitus regarding the fiber or parallel fibers); or (3) some combination of three ways transient tinnitus commonly occurs: (1) from the two. SM, strong pressure on or contraction of the muscles of the head and neck; (2) from loud sounds (LS); and (3) The tinnitus pathway rostral to DCN SBUTTs. For all three phenomena there is evidence that a change in auditory perception is more frequent for The tinnitus pathway rostral to DCN is likely very compeople with chronic tinnitus as opposed to those without. plex. For example, a recent report implicates involveThis contrasts with Lanting’s functional imaging data ment of the paraflocculus of the cerebellum in a rat which revealed “a remarkable result . . . for the majority model of tinnitus. Established “tinnitus” could be elimof auditory brain areas, the response to jaw protrusion is inated by paraflocculus inactivation; however, its ablasimilar between” tinnitus and non-tinnitus subjects tion prior to “tinnitus” induction did not eliminate the (Lanting et al., 2010). The Lanting result is very different rats’ “tinnitus” (Bauer et al., 2013). than the result for SM and LS, where a significant differThe primary output of the DCN is from the fusiform ence between tinnitus and non-tinnitus subjects was cell, whose axon projects via the dorsal acoustic stria to found for both. In tinnitus subjects about 80% can modthe contralateral inferior colliculus (Fig. 23.5) (Osen, ulate their auditory perception with SM as opposed 1972; Romand and Avan, 1997; Alibardi, 2000). Inferior to 60% in non-tinnitus subjects. For LS the comparable colliculus recordings contralateral to the traumatized ear percentages were 63% vs 32% (Abel and Levine, in animals with “tinnitus” have found an increased num2004). A similar trend was found for SBUTTs (Oron ber of neurons with bursting (epochs of very regular 1/ms et al., 2011). neuronal discharges) (Bauer et al., 2008). Elevated sponThe reason these findings are evidence for a tinnitus taneous activity and increased cross-fiber synchrony threshold will be explained from the SM data, since it were found in the inferior colliculus for some, but not was not dependent upon the subject’s memory. With all, types of experimental hearing loss. SM tinnitus can become louder (SM(+)) or quieter In human observations a 2-cm infarction involving (SM(–)) and/or change its quality. If there were not a the left caudate, putamen, and neighboring deep white threshold, then it would be predicted that, for SM, the matter totally eliminated the tinnitus of a 63-year-old occurrence of a change in auditory perception with otolaryngologist with 40 years of bilateral high-pitched SM(+) would be the same whether or not people had tinnitus. Similarly, a discrete infarction involving the ongoing tinnitus, as was found with Lanting’s functional junction of the head and body of the left caudate nucleus imaging. Since this is not the case, a straightforward of a 56-year-old woman with refractory Parkinson’s disinterpretation is that neural activity must exceed a neural ease resulted in bilateral tinnitus suppression (total for threshold in order to be perceived as a sound (Fig. 23.6). the ipsilateral ear, partial for the contralateral ear) Following the Lanting result, the hypothesis is that for (Larson and Cheung, 2013). Electric stimulation in this SM(+) the strong muscle pressure or contraction prosame locus can modulate (usually decrease) tinnitus duces an elevation in neural activity within the auditory loudness bilaterally (Cheung and Larson, 2010). With pathway (Fig. 23.6A). For any degree of elevated neural electric stimulation of the ventralis intermedius nucleus activity, the tinnitus subject would be more likely than of the thalamus, 2 of 4 subjects reported a transient the non-tinnitus subject to detect the change in neural decrease in their tinnitus loudness for 15–20 minutes activity, since it will be manifested as an increase in tin(Shi et al., 2009). nitus loudness. On the other hand, the non-tinnitus subChronic electric stimulation of primary or secondary ject will sometimes not detect the change in neural auditory cortex can suppress tinnitus to some degree in activity, because the overall rise in neural activity with about two-thirds of subjects, selected by their response strong muscle contraction will not be sufficient to cross to transcranial magnetic stimulation (TMS). However the non-tinnitus subject’s neural threshold for auditory not only does TMS not predict who will respond to such perception. All other things being equal, then, the prevchronic electric stimulation, but no other predictors have alence of a change in auditory perception with SM(+) been identified (Langguth et al., 2012). TMS has tranwill be higher in the tinnitus subject than in the nonsiently suppressed tinnitus in some subjects from a varitinnitus subject. For SM there is another factor at play ety of skull locations, including the ipsilateral and as well, namely SM(–), that is, quieting of tinnitus with contralateral temporoparietal region and frontal region strong muscle contraction (Fig. 23.6B). Presumably (dorsolateral prefrontal lobe).

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Fig. 23.6. How the threshold concept for tinnitus accounts for higher incidence of somatic modulation of tinnitus in people with than without ongoing tinnitus. The dashed line represents the neural threshold for tinnitus perception, i.e., tinnitus is perceived when neural activity exceeds this threshold. People with tinnitus are represented by the curve whose neural activity prior to a strong muscle contraction is above the dashed line and those without tinnitus are below the dashed line. Part (A) considers the case where somatic testing results in a net increase in neural activity. For the same degree of increase in neural activity the change will always be detected by the ongoing tinnitus subjects, but not all the non-tinnitus subjects, if the degree of change is insufficient to exceed the neural threshold. Likewise, in (B) for somatic testing that results in a net decrease in neural activity, no change in auditory perception will occur for any non-tinnitus subject since, unlike the tinnitus subjects with a strong muscle contraction, their neural activity remains below the neural threshold for tinnitus.

SM(–) corresponds to a decrease in neural activity within the auditory pathway. Since a non-tinnitus subject has no ongoing auditory perception, a decrease in neural activity within the auditory pathway will not be perceived as a change in auditory perception. Hence, because of the threshold effect and no detection for SM(–), the subject without ongoing tinnitus has a lower incidence of transient tinnitus from SM than does the tinnitus subject.

Typewriter tinnitus: cross-talk between auditory nerve fibers To understand how typewriter tinnitus likely occurs requires an understanding of how we hear faint sounds. In a healthy ear, all 30 000 auditory nerve fibers have “spontaneous activity.” In the absence of sound they are continuously transmitting nerve impulses from the inner ear to the cochlear nuclei (at a rate of 1–100/second) (Liberman, 1978). Sound is not perceived because the spontaneous activity is random and the nerve fibers discharge their spikes independently of each other (Johnson and Kiang, 1976). The spike-firing pattern of one auditory nerve fiber is different from the spikefiring pattern of all other auditory nerve fibers. There is no synchrony between the discharge patterns of any of the auditory nerve fibers. When a faint sound is heard there is no change in the firing rate of the individual nerve fibers, but they become

synchronized to the faint sound and thereby to each other. Faint sounds are heard because of neural synchrony. Typewriter tinnitus appears to be caused by distortion of the auditory nerve, most commonly from vascular compression of the VIIIth nerve (Fig. 23.1), probably because the insulating myelin sheath of the auditory nerve fibers becomes thinned. This leads to ephaptic transmission or “cross-talk” between adjacent single auditory nerve fibers. At the points where the myelin has been critically thinned, an original spike in one nerve will cause a new synchronous spike in its neighbor. Since auditory nerve fiber synchrony is responsible for auditory perception, this synchrony due to cross-talk will be perceived as a click. This cross-talk hypothesis explains not only why the clicks of typewriter tinnitus can occur spontaneously (ergo “tinnitus”) but also why sometimes clicking can be elicited by an external sound. External sounds generate auditory nerve activity and this auditory nerve activity leads to cross-talk which causes nerve fiber synchrony that then causes the perception of a click. Medications that suppress typewriter tinnitus, such as carbamazepine, do so by decreasing nerve excitability, which reduces the likelihood of cross-talk, and thereby reduces the clicking.

CONCLUSIONS In some surveys about 10% of adults report having chronic tinnitus and one out of 20 of them feels the

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tinnitus interferes with the ability to lead a normal life. On the other hand, in dead silence somewhere between 50 and 90% of adults report experiencing an auditory percept. About 75% of adults have experienced sudden brief unilateral tapering tinnitus, typically lasting about a minute or less. About 50% of adults have experienced transient tinnitus following loud noise exposure. A wide range of disorders can cause tinnitus. Many involve a disturbance of the peripheral auditory system, including various types of hearing loss. However one of the major, but underappreciated, causes of tinnitus has no involvement with the ear but causes tinnitus through its connections to the auditory system within the central nervous system. Myofascial disorders of the head and neck cause tinnitus by modulating the activity of the somatosensory system which projects to the central auditory system at multiple levels, including the DCN and inferior colliculus. While myofascial disorders or hearing loss alone can cause tinnitus, they also can combine to cause tinnitus. For this reason all tinnitus patients should have an audiogram and be questioned and examined for a myofascial disorder of the head and neck. Specifically the history must cover the topics of headache, bruxism, dental disorders, neck and facial pain, trauma, and changes in physical activities such as a new or altered exercise program. The physical exam must include an examination of the head and neck for myofascial disorders and for evidence of tinnitus modulation from activation of the head and neck muscles. If there is evidence that the tinnitus is related to a myofascial disorder of the head and neck, then a welldesigned treatment program directed toward the myofascial disorder can result in a major improvement of the tinnitus in about half of such individuals. Two features of tinnitus must be specifically questioned, since they are often very minor and so not spontaneously described by the patient, yet they can have important diagnostic significance. If unilateral clicking is present even if very infrequent and not troubling, the possibility of auditory nerve compression must be considered. Likewise, it must be ascertained whether the tinnitus sometimes has a cardiac-synchronous (pulsatile) character. If bilateral and sometimes but not always pulsatile, then a myofascial etiology is very likely; if unilateral and intermittent then, besides myofascial, auditory nerve vascular compression must also be considered. An interaction between findings in the experimental animal and clinical observations has led to the DCN hypothesis as the most compelling model that can account for the major features of the common tinnitus syndromes. The DCN hypothesis proposes that

increased activity from the major output cell of the DCN can cause tinnitus when a threshold is exceeded due to changes in the auditory inputs to the DCN, the somatosensory inputs to the DCN, or a combination of the two. Unilateral staccato irregular intermittent clicking (typewriter tinnitus), like other vascular compression syndromes, appears to be related to ephaptic transmission between adjacent single auditory nerve fibers and, like the other vascular compression syndromes, is usually suppressed by membrane-stabilizing drugs such as carbamazepine.

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TINNITUS Middleton JW, Kiritani T, Pedersen C et al. (2011). Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proc Natl Acad Sci U S A 108 (18): 7601–7606. Morrison GA, Sterkers JM (1996). Unusual presentations of acoustic tumours. Clin Otolaryngol Allied Sci 21 (1): 80–83. Nam EC, Handzel O, Levine RA (2010). Carbamazepine responsive typewriter tinnitus from basilar invagination. J Neurol Neurosurg Psychiatry 81 (4): 456–458. Norena AJ, Chery-Croze S (2007). Enriched acoustic environment rescales auditory sensitivity. Neuroreport 18 (12): 1251–1255. Oertel D, Young ED (2004). What’s a cerebellar circuit doing in the auditory system? Trends Neurosci 27 (2): 104–110. Oron Y, Roth Y, Levine RA (2011). Sudden brief unilateral tapering tinnitus: prevalence and properties. Otol Neurotol 32 (9): 1409–1414. Osen KK (1972). Projection of the cochlear nuclei on the inferior colliculus in the cat. J Comp Neurol 144 (3): 355–372. Palikh GM, Vaughn BV (2010). Topiramate responsive exploding head syndrome. J Clin Sleep Med 6 (4): 382–383. Pearce JM (1989). Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry 52 (7): 907–910. Peltier E, Peltier C, Tahar S et al. (2012). Long-term tinnitus suppression with linear octave frequency transposition hearing AIDS. PLoS One 7 (12): e51915. Penner MJ (1992). Linking spontaneous otoacoustic emissions and tinnitus. Br J Audiol 26 (2): 115–123. Penner MJ, Coles RR (1992). Indications for aspirin as a palliative for tinnitus caused by SOAEs: a case study. Br J Audiol 26 (2): 91–96. Perry BP, Gantz BJ (2000). Medical and surgical evaluation and management of tinnitus. In: R Tyler (Ed.), Tinnitus Handbook, Singular, San Diego, pp. 221–242. Poe DS (2007). Diagnosis and management of the patulous eustachian tube. Otol Neurotol 28 (5): 668–677. Reisshauer A, Mathiske-Schmidt K, Kuchler I et al. (2006). Functional disturbances of the cervical spine in tinnitus. HNO 54 (2): 125–131. Romand R, Avan P (1997). Anatomical and functional aspect of the cochlear nucleus. In: G Ehret, R Romand (Eds.), The central auditory system, Oxford, New York, pp. 97–191. Rubinstein JT, Tyler RS, Johnson A et al. (2003). Electrical suppression of tinnitus with high-rate pulse trains. Otol Neurotol 24 (3): 478–485. Russell D, Baloh RW (2009). Gabapentin responsive audiovestibular paroxysmia. J Neurol Sci 281 (1–2): 99–100. Ryu H, Yamamoto S, Sugiyama K et al. (1998). Neurovascular decompression of the eighth cranial nerve in patients with hemifacial spasm and incidental tinnitus: an alternative way to study tinnitus. J Neurosurg 88 (2): 232–236.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 24

Auditory hallucinations JAN DIRK BLOM* Parnassia Psychiatric Institute, The Hague and University of Groningen, Groningen, The Netherlands

INTRODUCTION Our knowledge of the variegated group of phenomena that fall under the term auditory hallucinations has rapidly expanded over the past two decades. This is mainly due to the possibility of measuring and visualizing hallucinatory activity in the brain with the aid of functional imaging techniques, and to insights derived from the philosophy of science which radically altered the way we conceptualize the auditory hallucinatory experience as well as the hearing of actual sounds. The two phenomena are now considered products of gamma-band oscillations of approximately 40 Hz resonating within the thalamocortical network, and hence as closed, intrinsic functional brain states which only differ as regards the degree of restraint exerted by information from the inner ear. The brain areas responsible for the mediation of those percepts, as traditionally conjectured on the basis of lesion studies, neuropsychologic experiments, and clinical reasoning, have by and large been empirically confirmed with the aid of functional and structural neuroimaging. While recently many other brain areas have been added to the traditional list, we ceased to conceptualize those areas in terms of – relatively isolated – modules, and instead started granting them, in conformity with the principles of network science, the role of hubs in the structural and functional networks responsible for mediating the auditory hallucinatory experience. It is thus that functional neuroimaging, the philosophy of science, and network science have revolutionized hallucinations research, and in their wake fueled studies on more traditional aspects, such as the phenomenology, epidemiology, neuroanatomy, neurophysiology, and neuropsychiatry of auditory hallucinations. Due to the intensification of empiric research throughout the past two decades, a rather detailed body of knowledge on auditory hallucinations is now

available. In fact our understanding of those phenomena now surpasses that of the other types of hallucinations, perhaps even including that of the visual hallucinations. The sobering and rather pragmatic reason for this head start is that auditory hallucinations are often experienced in the form of discrete epochs of activity with “silent” episodes in between, both with a duration in the order of minutes, which makes them particularly well suited for research with the aid of functional neuroimaging techniques. As the success of such hallucinatory state studies stands and falls with the presence of a sufficiently contrasting change of signal during the time of scanning, other types of hallucination – which are mostly experienced either sporadically or for prolonged periods of time – tend to defy a similar approach. On the theoretic side, various explanatory models have been devised for specific types of auditory hallucinations, and network science has been heralded as the prime candidate for a truly unifying model. The present chapter will summarize the current state of affairs in this rapidly expanding area, and propose various directions for future research. As we shall see, the source material is rich, voluminous, and revealing. However, throughout the present chapter it should be borne in mind that the area is still very much in flux. Despite all the new insights, auditory hallucinations go on to constitute an elusive group of phenomena with many challenging aspects yet to be fathomed, and novel treatment paradigms yet to come to fruition.

DEFINITION, CONCEPTUALIZATION, AND CLASSIFICATION Definition Auditory hallucinations are also known as acoustic hallucinations, aural hallucinations, hallucinations of

*Correspondence to: Jan Dirk Blom, M.D., Ph.D., Parnassia Academy, Kiwistraat 43, 2552 DH The Hague, The Netherlands. Tel: 0031-88-3570322, E-mail: [email protected]

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hearing, and voices. They are traditionally defined as sounds experienced by a waking individual in the absence of a corresponding stimulus from the external world. Sometimes the alternative term auditory hallucinosis is used. Since its introduction by Wernicke (1900, p. 270), hallucinosis has variously been defined as: (1) a mental state characterized by continual hallucinations; (2) an abnormal condition characterized by hallucinations; (3) a psychiatric disorder involving hallucinations; (4) a syndrome, usually of organic origin, characterized by more or less persistent hallucinations; (5) a transient hallucinatory state accompanied by a clear sensorium and/or proper insight into its nature; and (6) a delusional state triggered by hallucinations (Blom, 2010, p. 229). Especially in clinical neurology, the term is sometimes used to denote hallucinations with an organic origin, but because of its multiple connotations, psychiatrists and hallucinations researchers do not employ it or, for that matter, the related term auditory hallucinosic syndrome. For the sake of continuity with the mainstream literature on the subject, the present chapter will also refrain from using those terms and stick to the more common term, auditory hallucination.

Classification The classification of auditory hallucinations has yielded numerous types and subtypes (for an overview, see Blom and Sommer, 2010). From a taxonomic point of view it is debatable whether also various closely related phenomena should be included, such as echo of reading, Gedankenlautwerden, polyacousis (Chapter 21), certain forms of auditory synesthesia (Chapter 22), tinnitus (Chapter 23), and palinacousis (Chapter 25). As all those auditory phenomena involve the hearing of sounds which are not – or no longer – objectively present, they would seem to fit in well with the class of auditory hallucinations. Alternatively, they are sometimes conceptualized as lying on a continuum of endogenously mediated auditory percepts, i.e., a continuum which also encompasses the auditory hallucination. Irrespective of whether we adhere to a broad or a narrow definition, the class of auditory hallucinations constitutes a patchwork of interrelated phenomena which for various reasons have been singled out as clinically and/or scientifically meaningful. Proceeding from a broad definition, Table 24.1 offers an overview of those types of hallucination. In addition, it indicates their occurrence in the context of various clinical and nonclinical conditions.

Conceptualization and demarcation Auditory hallucinations are traditionally conceptualized as percepts – i.e., auditory percepts – experienced during the waking state. As such they are distinguished from auditory percepts experienced during the dream state, auditory percepts experienced while falling asleep or waking up (i.e., hypnagogia), auditory imagery (i.e., sounds imagined or remembered), and auditory pareidolia (also known as auditory illusion, i.e., the hearing of actual sounds which are either misperceived or misinterpreted). Although proper differentiation may not always be feasible in clinical practice, they are also distinguished from non-perceptual phenomena such as thought insertions and obsessive thoughts. Alternatively, auditory hallucinations have occasionally been conceptualized as “reported auditory sensations” (Myers and Murphy, 1960). Or, as Berrios (2005) puts it, a class of utterances reporting subjective experiences “putatively perceptual in nature” which occur in the absence of an adequate external stimulus. Although our access to other people’s hallucinations does indeed depend on third-hand verbal self-reports, in clinical practice it is customary to take for granted that those reports refer to actual perceptual phenomena. Therefore the present chapter will also designate auditory hallucinations as percepts rather than as reports of percepts.

PHENOMENOLOGIC CHARACTERISTICS Perceived location Auditory hallucinations are perceived as originating in the extracorporeal world (i.e., external auditory hallucinations), inside the head, or from an indefinite location. In the latter two cases, they are known as internal auditory hallucinations (Copolov et al., 2004). External auditory hallucinations are usually perceived on both sides, in which case they are called bilateral hallucinations, and occasionally from one side alone, when they are called unilateral hallucinations. But they may also be perceived as stemming from aberrant locations such as the belly, the knee, the nose, or the shoe, in the sense that they are described as being heard by the belly, the knee, the nose, or the shoe respectively, as if the voice hearer’s ear were located in those places. Such bizarre percepts are appropriately called extracampine hallucinations (i.e., hallucinations occurring outside the regular field of perception; Bleuler, 1903). In a study by McCarthy-Jones et al. (2014) among 199 psychotic individuals experiencing auditory hallucinations, 47% reported internal hallucinations, 38% external ones, and 15% internal as well as external ones. A study by Kingdon et al. (2010) and one by Slotema et al. (2012) among a total number of 148 patients diagnosed with

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Table 24.1 Types of auditory hallucination in relation to various conditions

Auditory sleep start Auditory synesthesia Bilateral hallucination Command hallucination Echo of reading External hallucination Extracampine hallucination Functional hallucination Gedankenlautwerden Hypnagogic hallucination Hypnopompic hallucination Indirect Gedankenlautwerden Internal hallucination Musical hallucination Musical tinnitus Non-verbal auditory hallucination Palinacousis Psychomotor verbal hallucination (i.e., subvocalization) Pulsatile tinnitus Tinnitus Unilateral hallucination Verbal auditory hallucination

Psychotic disorder

Mood disorder

Hearing loss

+ + + + + +

+ + +

+

+

+

+ +

+

+

Substanceinduced

Alcoholic hallucinosis

Hypnagogic state

Normal wakefulness

+ + + + + +

+ + + +

+ + + + +

+ +

+ +

+ + + +

+

+

+ +

+ +

+

+

+ + + +

+

+

+ +

+ +

+

+

+ +

+ +

+

+ + +

+

+

+ + + +

+

+

+ + + +

+ indicates that this type of hallucination is known to occur in the context of the condition listed. Adapted from Blom and Sommer (2010).

psychotic disorder and/or borderline personality disorder found roughly comparable rates for internal and external hallucinations, with internal auditory hallucinations being reported by slightly more than 50% of the patients in both groups (Slotema and Kingdon, 2012). Although clinicians have long believed that voices experienced by individuals diagnosed with borderline personality disorder tend to be of the internal type – or even that they constitute some sort of imagery, designated sometimes as “pseudohallucination” or “quasi-hallucination” – those two studies indicate that their phenomenologic characteristics are similar to those experienced by psychotic individuals, and that the percepts at hand therefore fully deserve the predicate of hallucinations proper. Extracampine hallucinations have been described almost exclusively in the context of psychosis.

Their prevalence is unknown, but they are believed to be extremely rare (Sato and Berrios, 2003). The same holds true for unilateral auditory hallucinations, which, due to their clinical association with ipsilateral ear lesions and contralateral brain lesions, always require careful neurologic as well as auxiliary examination (Almeida et al., 1993; Takebayashi et al., 2002).

VERBAL AUDITORY HALLUCINATIONS As regards their content, auditory hallucinations are traditionally divided into verbal and non-verbal ones. Verbal auditory hallucinations are also known as auditory verbal hallucinations, voice hallucinations, phonemes, hallucinated speech, and voices. They consist of hallucinated sounds which feature a linguistic content.

436 J.D. BLOM That content may vary from hearing one’s name called experienced more than one type of non-verbal auditory out (a phenomenon usually designated as a simple mishallucination. The substantial prevalence of musical halperception, due to its relatively low complexity) to comlucinations in that study is remarkable, especially if we plete sentences or even choruses of multiple voices consider that those phenomena have traditionally been which may or may not be continually present. Some speregarded as relatively rare. However, it also confirms cial types of verbal auditory hallucination are command the clinical impression that they may well be more prevhallucinations (which convey an incentive or command; alent than the literature has until recently suggested Erkwoh and Willmes, 2002), functional hallucinations (Berrios, 1990; Sacks and Blom, 2012). (which are triggered by a shift of attention towards an Non-verbal auditory hallucinations occupy the end of actual stimulus such as running water or the hissing of the spectrum closest to the vicinity of tinnitus. As tinnisteam pipes; Jaspers, 1997, p. 66), Gedankenlautwerden tus involves the hearing of amorphous sounds not actu(hallucinated sounds which are either recognized as ally present, one might argue that it too belongs to the one’s own thoughts or literally echo one’s conscious class of auditory hallucinations (Blom and Sommer, thoughts; Sommer et al., 2009), echo of reading (a con2010). But even when conceptualized as a separate phedition in which the reading of words or sentences is nomenon, there are many instances in which proper accompanied by a hallucinated echo of the same linguisdemarcation may prove a challenging task. For instance, tic content; Morel, 1933), and psychomotor verbal halluwhen a noise-type tinnitus or a tonal tinnitus gradually cinations (also known as motor hallucinations, motor takes on a musical quality, it is referred to as musical tinverbal hallucinations, muscular verbal hallucinations, nitus, even though phenomenologically it is then indistinand subvocalization), in which verbal auditory hallucinaguishable from a musical hallucination. Likewise, there tions may co-occur with subtle instances of motor are many instances of non-verbal sounds which can be activity within the larynx and/or vocal cords (Green classified at once as non-verbal auditory hallucinations and Preston, 1981). Among psychotic individuals who or as tinnitus. This may perhaps strike one as a somewhat experience auditory hallucinations, command hallucinaacademic classificatory issue, but in clinical practice it tions have been reported by 67% of the patients may have consequences for the treatment of choice. (McCarthy-Jones et al., 2014). Functional hallucinations, A notable exception to the rule of thumb that auditory Gedankenlautwerden, echo of reading, and indirect hallucinations are experienced during wakefulness is the Gedankenlautwerden (a type of illusion in which actual, auditory sleep start or exploding-head syndrome, a rare but often unintelligible, sounds are experienced as conphenomenon typically experienced within an hour or two veying one’s own thoughts) would seem to be much of falling asleep (Pearce, 1988). It consists of a loud rarer, but their prevalence has never been assessed sysbang, explosion, roar, or ringing noise which appears tematically. When psychomotor verbal hallucinations to originate from a place deep inside the head. It is typwere first described it was hoped that the laryngeal activically accompanied by a flash of light, called the visual ity typical of those phenomena might hold the key to sleep start. The cause of either phenomenon is unknown. understanding all types of auditory hallucination, but Pearce (1988) was the first to describe this phenomenon, later studies indicated that they constitute a relatively and in his paper he speculated that “a momentary rare subgroup of the class as a whole. (almost ictal) disinhibition of the cochlea or its central connections in the temporal lobes, or a sudden involuntary movement of the tympanum or tensor tympani, NON-VERBAL AUDITORY HALLUCINATIONS might be the explanation.” But with empiric studies in Non-verbal auditory hallucinations are also known as this area yet to be initiated, other possible causes cannot acoasms, acousmata, non-verbal hallucinations, and be ruled out. non-vocal auditory hallucinations. They lack the linguistic content characteristic of verbal auditory hallucinaMusical hallucinations tions, consisting instead of sounds ranging from ticking, clicking, or humming to the barking of dogs, Musical hallucinations consist of songs, tunes, melodies, the drone of airplane engines or all-out classic symphoharmonics, rhythms, and/or timbres which are perceived nies. In their study among psychotic individuals in the absence of any actual music. Individuals experiencing auditory hallucinations, McCarthy-Jones experiencing those phenomena initially tend to believe et al. (2014) found that non-verbal auditory hallucinathat there is a band or a radio playing nearby, and they tions were reported in 32% of cases. Forty-six percent often go around asking whether someone could turn of those cases involved musical hallucinations, 43% ringdown the volume. After that initial phase of surprise ing, 29% animal sounds, 27% clicks, 24% humming, and disbelief, most people come to accept within a cou10% water, and 56% other sounds; some individuals ple of days that the music originates in their head. But

AUDITORY HALLUCINATIONS out of fear for being perceived as “crazy” or demented, most of them keep the experience to themselves. This may partly explain why the reported prevalence of musical hallucinations has historically been so low (another explanation being that only few clinicians have the habit of systematically assessing their presence). Musical hallucinations differ from “earworms” (Sacks, 2006), or tunes that go round in the head – familiar to us all, by their unmistakable perceptual quality. Moreover, they tend to resist termination or alteration by force of will. They are often continuously present, and although their content does not tend to be threatening or frightening in nature, they may interfere significantly with one’s daily functioning. They can be heard inside the head, but more often they are described as if coming from outside the head. When they are repetitive and stereotyped in nature they are called stable musical hallucinations, as opposed to the group of complex musical hallucinations which are more elaborate and more prone to change. Thus various types of musical hallucination can be discerned. Table 24.2 provides an overview of those types, as well as an overview of related phenomena which involve the hearing of music.

ETIOLOGY Auditory hallucinations are experienced in the context of various psychiatric and neurologic conditions, but also in the context of various intoxications, withdrawal syndromes, metabolic conditions, and even in the absence of any demonstrable pathology. Table 24.3 provides a schematic overview of those various conditions. It might

437

be tempting to designate those conditions as etiologic factors, but the etiology of auditory hallucinations is a rather complex issue that is all but fully understood. As auditory hallucinations can be experienced in the context of numerous clinical and non-clinical conditions, their occurrence in the context of any given condition does not necessarily imply that that condition can de facto be considered the agent responsible for initiating them. For example, a verbal auditory hallucination experienced by a patient diagnosed with schizophrenia may be mediated by the hyperactive dopaminergic signal transduction considered characteristic of that condition, but it may also be triggered by the smoking of marijuana, prolonged social isolation, or the recent death of a parent. Moreover, as auditory hallucinations are also experienced by otherwise healthy individuals, it may be that there are etiologic mechanisms at play which have nothing to do whatsoever with the clinical condition (or conditions) diagnosed in this particular patient. In addition, it should be noted that auditory hallucinations tend to show little respect for the boundaries we draw between various clinical conditions. As a consequence, it is not always clear whether known associations with clinical conditions are fully deserving of the predicate “etiologies.” With that important restriction in mind, the following can be said about the etiology of auditory hallucinations. Auditory hallucinations, notably those of the verbal type, tend to be associated primarily with psychosis. And yet, although it is true that some 70% of all individuals diagnosed with schizophrenia report verbal auditory hallucinations (Mueser et al., 1990), they may also be

Table 24.2 Glossary of musical hallucinations and related phenomena Phenomenon

Characterization

Musical hallucination (musical hallucinosis, musical-ear syndrome) Auditory Charles Bonnet syndrome

An auditory hallucination characterized by songs, tunes, melodies, harmonics, rhythms, and/or timbres A musical hallucination in the presence of severe deafness and in the absence of other pathology A musical hallucination occurring in the absence of any type of associated pathology other than hearing loss A musical hallucination occurring in the presence of any type of associated pathology other than hearing loss An auditory percept resulting from a misrepresentation or misinterpretation of random auditory stimuli, which may or may not have a musical quality A paradoxic auditory illusion created with the aid of actual musical sounds A musical hallucination with evolution from “ringing in the ears” The continued perception or reperception of an actual piece of music An imagined or remembered piece of music, having no perceptual characteristics A tune going round in the head, having no perceptual characteristics

Idiopathic musical hallucination Symptomatic musical hallucination Auditory illusion (auditory pareidolia) Musical illusion Musical tinnitus Musical palinacousis Musical imagery Earworm After Sacks and Blom (2012).

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Table 24.3 Schematic overview of various clinical and non-clinical conditions in the context of which auditory hallucinations are experienced

Systemic disease

Substance intoxication and/or withdrawal

Physiologic

Presbycusis

Neurosyphilis

Alcohol

Idiopathic

Delirium tremens

Tinnitus

AIDS

Cannabis

Hypnagogia

Dementia

Severe deafness

Thyrotoxicity

Cocaine

Bereavement

Parkinson’s disease

Cushing’s disease

Amphetamines

Brain tumors

Hyperhomocysteinuria

Hallucinogens

Social and/or sensory isolation Intensive meditation

Paraneoplastic neurologic syndromes Limbic encephalitis

22q11.1 deletion syndrome

Antidepressants

Posthypnotic

Sarcoidosis

Anticholinergics

Sleep deprivation Aging

Psychiatric disorders

Neurologic disorders

Otologic disorders

Psychotic disorders Bipolar disorder Depressive disorder Dissociative disorder

Delirium

Borderline personality disorder

Prion disease Intracerebral arteriovenous malformations Epilepsy Exploding-head syndrome

Antibiotics

AIDS, acquired immunodeficiency syndrome.

experienced in the context of unipolar depressive disorder, bipolar disorder, dementia, dissociative disorder, borderline personality disorder, and occasionally other psychiatric disorders (Larøi et al., 2012). In addition, they may be experienced in the context of bereavement, sensory or social isolation, sleep deprivation, intensive meditation, psychotic disorder due to alcohol abuse, alcohol withdrawal, delirium, delirium tremens, the use of cannabis or other illicit substances, and as a side-effect of antidepressants, anticholinergics, and numerous other pharmaceuticals (Larøi et al., 2012; Sommer et al., 2012a). Auditory hallucinations may also be experienced in the context of systemic somatic disease (i.e., organic psychosis, a condition which constitutes 3% of all the psychoses; Falkai, 1996). Some examples of those systemic somatic diseases are neurosyphilis, human immunodeficiency virus (HIV) infection, thyrotoxicity, and Cushing’s disease. Other associations with somatic conditions include brain tumors, paraneoplastic neurologic syndromes, limbic encephalitis, prion disease, hyperhomocysteinuria, 22q11.1 deletion syndrome,

sarcoidosis, and intracerebral arteriovenous malformations (Sommer et al., 2012a). Hallucinations occurring in the context of Parkinson’s disease tend to be visual in nature, but auditory ones are reported in no less than 20% of cases (Fe´nelon and Alves, 2010). In the context of epilepsy they tend to occur more often, either in the form of an aura preceding an epileptic seizure or in the context of post- or interictal psychosis (see Chapter 26 for additional details). In most of those cases they take the form of non-verbal auditory hallucinations, but verbal auditory hallucinations have also been reported (Kasper et al., 2010). Most of them are simple and repetitive in nature, and yet more extensive linguistic utterances have also been described, as well as musical hallucinations (Sacks and Blom, 2012).

Occurrence in the absence of pathology Auditory hallucinations primarily evoke associations with psychiatric and, to a lesser extent, neurologic and otologic disease, but they are also experienced by

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Table 24.4 Prevalence rates of hallucinations in the general population, as found in 10 cross-sectional studies Study

Number of participants

Prevalence of hallucinations

United Kingdom: SPR (Sidgwick et al., 1894)* France (Marillier, 1894)* United States: ASPR (James, 1894)* Germany (Von Schrenck-Notzing, 1894)* United States: ECA Program baseline (Tien, 1991) United States: ECA Program follow-up (Tien, 1991) United Kingdom/Germany/Italy (Ohayon, 2000) United States (Olfson et al., 2002) United Kingdom (Johns et al., 2004) The Netherlands: NEMESIS (Van Os et al., 2005)

17 000 3393 6311 625 18 572 15 258 13 057 1005 8580 7076

9.9% 20.01% 13.5% 8.16% 13.0% 11.1% 21.2% 13.0% 4.2% 6.1%

*

Summarized in Parish (1897). For full details of the references listed in this table, see Blom (2012). Reproduced from Blom (2012).

10–15% of all individuals in the general population, i.e., in the absence of any demonstrable pathology (Beavan et al., 2011). That lifetime prevalence rate has been quite consistent throughout the past 120 years, during which time 10 large epidemiologic surveys of hallucinations were carried out in the general population of various western countries (Table 24.4). The frequency of auditory hallucinations in healthy voice hearers tends to be low, but they may also be experienced throughout the day and for years on end (Daalman et al., 2011). In either case the majority of those phenomena are appraised as benevolent in nature. By comparing 111 healthy voice hearers with 118 voice hearers diagnosed with a schizophrenia spectrum disorder, Daalman et al. (2011) found that healthy voice hearers have a higher degree of control over their voices, and that they tend to experience them from a significantly younger age onwards. The authors also found that a younger age of debut, a higher degree of control over the voices, a relatively low frequency, and a benevolent appraisal of their content can in 92% of the cases accurately predict the absence of psychotic disorder (i.e., in terms of the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders: American Psychiatric Association, 2013), while benevolent appraisal alone can do so in 88% of cases (Daalman et al., 2011). Other phenomenologic characteristics of auditory hallucinations such as loudness, the number of voices, and perceived location were quite similar among healthy and psychotic voice hearers, and proved to be of little aid in predicting the presence or absence of psychotic disorder. A group of phenomena experienced by an even larger number of individuals in the healthy population are hypnagogic and hypnopompic hallucinations, collectively known as hypnagogia. Hypnagogic hallucinations, i.e.,

perceptual phenomena experienced during the transitional phase from wakefulness to sleep, have reported incidence rates of 75% and higher in the general population (Mavromatis, 1987, p. 5). They tend to consist of elevator feelings, geometric visual hallucinations, and facial hallucinations (hence the synonym “faces in the dark”) but they may also feature non-verbal and even verbal auditory phenomena, such as replays of recent conversations, hearing one’s name called out, the sound of one’s child calling or crying, sentences as if read from a book, and indistinct talking. Occasionally musical hallucinations have also been described. Hypnopompic hallucinations, on the other hand, which occur during the transitional phase from sleep to wakefulness, would seem to be less prevalent, and to consist mainly of dream images that linger on during the first seconds or minutes of wakefulness. It appears to be quite rare for them to consist of auditory percepts, although hypnopompic musical hallucinations have also been described. Because of their association with sleep, neither hypnagogic nor hypnopompic hallucinations tend to be counted as hallucinations proper, and in the absence of any additional indicators of parasomnia their clinical relevance is considered negligible.

PATHOPHYSIOLOGY As one might expect with such a variegated group of phenomena, the pathophysiology of auditory hallucinations is far from straightforward. And yet, regardless of all the variation, a central role in their mediation is attributed to the auditory nervous system. It has long been suspected that many parts – if not any part – of that system may be involved in the mediation of auditory hallucinations, and hence historically various explanatory models

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Table 24.5 Historic hypotheses regarding the mediation of auditory hallucinations (AHs) Hypothesis

Characterization

Reference

Centripetal model

Suggests that AHs may arise from any part of the auditory system, and emphasizes the possible involvement of the peripheral auditory system Conceptualizes AHs as reperceptions of previously experienced auditory percepts; emphasizes the involvement of memory function and limbic structures Conceptualizes AHs as a variant of peduncular hallucinosis; emphasizes the involvement of the pedunculus cerebri, midbrain, pons, or diencephalon Attributes AHs to spontaneous activity within deafferentiated cortical areas, notably in conjunction with hearing loss; also known as the auditory Charles Bonnet syndrome Attributes AHs occurring in the context of migraine or epilepsy to paroxysmal neuronal activity affecting the superior temporal gyrus Conceptualizes AHs in terms of a misattribution of one’s own thoughts to an external source; emphasizes the involvement of Wernicke’s and Broca’s areas Basically a variant of the inner-speech model; attributes the mediation of AHs to a default in the corollary discharge signal from frontal speech production areas towards speech reception areas Attributes AHs to a disinhibition of non-dominant speech areas, notably within the right hemisphere, due to aberrant cerebral lateralization

Braun et al. (2003) Copolov et al. (2003)

Reperception model

Brainstem auditory hallucinosis model Deafferentiation model

Aura model Inner-speech model Corollary discharge model Lateralization model

Cascino and Adams (1986) Cole et al. (2002)

Kechid et al. (2008) Mechelli et al. (2007) Ford et al. (2001)

Sommer et al. (2008)

Adapted from Blom and Sommer (2010).

(Table 24.5) have been competing for first place, notably the perceptual release theory, the reperception model, the deafferentiation hypothesis, the cortical excitation hypothesis, the inner-speech hypothesis, and the lateralization hypothesis (Blom and Sommer, 2010; McCarthyJones, 2012). Throughout the next section it should be held in mind that the majority of the findings to be presented stem from studies among voice hearers diagnosed with psychotic disorder, and that it is as yet unclear whether those findings allow for proper generalization to other patient groups and/or types of auditory hallucination. Moreover, it should be noted that the pathophysiology of musical hallucinations has not been studied very extensively, and that the literature on other non-verbal auditory hallucinations largely overlaps with that on tinnitus (Chapter 23).

Evidence for a functional auditory network The brain network responsible for the mediation of verbal auditory hallucinations comprises the classic and non-classic ascending pathways, the descending systems, as well as a number of anatomic structures connected with the non-classic pathways. As summarized by Jardri et al. (2011) in their meta-analysis of functional neuroimaging findings, the areas involved include Broca’s area and its contralateral homolog, the anterior insula, the frontal operculum, the precentral gyrus, the

middle temporal gyrus, the superior temporal gyrus (i.e., Wernicke’s area) and its contralateral homolog, the bilateral inferior parietal lobule, and the hippocampal and parahippocampal regions. Figure 24.1 provides a graphic overview of those regions, based on a modelbased analysis of functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signals obtained from individuals who were diagnosed with psychotic disorder, and who experienced intermittent verbal auditory hallucinations (Looijestijn et al., 2013). Figure 24.2 provides a somewhat similar overview, but one that is based on a model-free analysis of those same fMRI data (Looijestijn et al., submitted). The two activation maps show a significant overlap, but due to its increased number of degrees of freedom, the model-free analysis yields a larger number of structures involved. The significance of this will be discussed below. In terms of the network science paradigm, the networks outlined in Figures 24.1 and 24.2 are designated as functional networks. The fMRI BOLD signal reflects local increases in cerebral oxygen consumption, and the neurovascular-coupling hypothesis stipulates that such increases are indicative of changes in brain function (Villringer, 1997). When those changes co-occur with reported verbal auditory hallucinations (in this case, signaled with the aid of balloon presses by the subjects inside the scanner, indicating the onset as well as the

AUDITORY HALLUCINATIONS

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Fig. 24.1. Brain regions active during the conscious experience of verbal auditory hallucinations, as derived from a model-based analysis of functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signals during within-scanner reporting of hallucinations with the aid of balloon presses. The purple-yellow color coding indicates hallucinatory activity, with the lighter color referring towards Zmax. Multiple brain regions were found to be involved, including bilateral inferior and middle frontal areas (1), bilateral insula (2), anterior cingulate gyrus (3), and predominantly left-sided superior temporal gyrus (4), as well as a motor network which included left motor cortex (5) and the right cerebellum (6), the latter most likely corresponding with the balloon presses. (Courtesy of Dr. Jasper Looijestijn, Parnassia Psychiatric Institute, The Hague, the Netherlands, based on fMRI scans obtained at the University Medical Center Utrecht, Utrecht, the Netherlands.)

cessation of hallucinatory epochs), they are taken as reliable indicators of hallucinatory activity. Given the prominent role of the auditory cerebral cortex in the conscious perception of sounds, it is perhaps unsurprising to find that that bilateral structure also plays a significant role in the perception of hallucinated sounds. With the aid of fMRI recordings, Dierks et al.

(1999) demonstrated activity in the primary auditory cortex concurring with verbal auditory hallucinations, and Shergill et al. (2000) in the bilateral temporal cortices. However, Copolov et al. (2003) were unable to confirm those results in their positron emission tomography (PET) study, and instead found activity in the parahippocampal gyri. Diederen et al. (2010) also found significant

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Fig. 24.2. Brain regions active during the conscious experience of verbal auditory hallucinations, as derived from a model-free analysis of functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) signals during within-scanner reporting of hallucinations with the aid of balloon presses. The method employed was a data-driven independent-component analysis (ICA). It indicates the presence of four functional networks associated with the mediation of verbal auditory hallucinations, derived from post hoc linkage of group ICA, functional networks with hallucination timings, and psychometrics. The purpleyellow color coding indicates hallucinatory activity, with the lighter color referring towards Zmax. Component I consists of predominantly left-sided superior temporal gyrus (1), and a strongly right-oriented medial temporal (2), insula, putamen, thalamus (3), and inferior frontal network (4). Component II consists of left-sided (para)hippocampal regions (1), and bilateral superior temporal regions (2). Component III consists of anterior cingulate cortex (1) and bilateral Broca’s area (2). Component IV consists of leftoriented dorsolateral prefrontal cortex (1), widespread parietal cortex (2), middle temporal regions (3), and inferior frontal gyrus (4). Components I and III show large overlap with the activation patterns in Figure 24.1. (Courtesy of Dr. Jasper Looijestijn, Parnassia Psychiatric Institute, The Hague, the Netherlands, based on fMRI scans obtained at the University Medical Center Utrecht, Utrecht, the Netherlands.)

activity in the parahippocampal gyrus, but that activity typically preceded the conscious experience of verbal auditory hallucinations. Careful reconstructions of the time series of fMRI findings in their patients indicated that deactivation of the parahippocampal gyri takes place some 6 seconds prior to the conscious experience of verbal auditory hallucinations, and that the signal then spreads into the direction of the language areas and, notably, their contralateral homologs (Diederen et al., 2010). Part of those findings confirmed the prior results of a single-photon emission computed tomography (SPECT) study by McGuire et al. (1993), which found increased activity in Broca’s area, the anterior cingulate, and left temporal cortex, an fMRI study by Hoffman et al. (2007), which indicated that the conscious perception of verbal auditory hallucinations coincides with bilateral activity in frontal and temporal areas, and a study by Sommer et al. (2008), which found marked activity in the right inferior frontal area and the right superior temporal gyrus. By comparing the fMRI findings of 21 healthy voice hearers with those of 21 voice hearers diagnosed with psychotic disorder (who were matched for the frequency and duration of hallucinatory epochs), Diederen et al. (2011) found similar patterns of activity in the language areas and their contralateral homologs, thus indicating that the verbal auditory hallucinations experienced by healthy voice hearers are physiologically similar to those of patients diagnosed with psychotic disorder, and, more specifically, that the mediation of verbal auditory hallucinations would seem to depend on the very resources involved in the normal processing of linguistic information.

The speech perception and speech production areas, usually located on the left in right-handed individuals, are held responsible for providing the linguistic content of verbal auditory hallucinations. The same holds true for their contralateral homologs, even though the latter presumably have relatively limited capacities for linguistic processing, and in spite of the fact that their activity normally tends to be inhibited by the language areas via reciprocal callosal connections (Bloom and Hynd, 2005) during the execution of language functions such as reading, speaking, and listening to speech. As proposed by Sommer et al. (2008), the involvement of the non-dominant language areas may well hint at an insufficient inhibition by the dominant language areas, and perhaps also at a structural problem of language lateralization. The ensuing lateralization hypothesis serves to explain why many voice hearers diagnosed with psychotic disorder experience relatively simple and stereotyped propositions (being mediated by the right hemisphere with its limited linguistic capacities), especially during the advanced stages of their illness, and also why engaging in conversation or listening to music – activities that promote a competitive use of auditory areas – may aid to suppress those hallucinated voices. The involvement of the parahippocampal gyrus, on the other hand, would seem to indicate that memory, and presumably also emotion, are important factors during the preparatory phase of verbal auditory hallucinations in individuals diagnosed with psychotic disorder. The role of memory in the mediation of hallucinatory activity complies with the reperception model as

AUDITORY HALLUCINATIONS 443 proposed by classic authorities such as Kahlbaum (1886) middle planum temporale and the right-sided middle and Penfield (1975). And yet the majority of functional frontal gyrus. Although the left planum temporale is also imaging findings would seem to be in line with known for its role in phonologic processing, its role in Hughlings-Jackson’s Darwinian thesis that normal activprojecting hallucinated voices outwards into auditory ity of the brain’s “lower” (i.e., evolutionary “older”) censpace – and thus in lending them the perceptual quality ters may present in the form of positive symptoms when of externally mediated sounds – is in conformity with the “higher” (i.e., evolutionary “younger”) structures cease structure’s previously established function in the cateto exert their inhibitory function (Hughlings-Jackson, goric analysis of auditory signals. 1888). Devoid of its Darwinian connotations, that model was reintroduced by West (1962), and given the name Evidence for a structural auditory network perceptual release theory (also known as dream intrusion, dual-input model, and seepage theory) to designate The functional auditory network presented above curhallucinations as release phenomena originating from rently constitutes our most reliable indicator of the brain aberrant activity in the limbic system, the diencephalon, network involved in the mediation of verbal auditory haland other subcortical centers. As indicated above, espelucinations. The involvement of that network has been largely corroborated by structural imaging studies, in cially the work by Diederen et al. (2010) on the preparathe sense that they also show up on scans obtained with tory deactivation of the parahippocampal gyri can be interpreted as an empiric corroboration of that hypothethe aid of techniques such as MRI and diffusion tensor sis. In a similar vein, Hoffman et al. (2008) found prehalimaging. It might be tempting to infer from those findlucination activity in the left anterior insula and the right ings that the functional aberrations involved in the medimiddle temporal gyrus, as well as deactivation of the ation of verbal auditory hallucinations are therefore anterior cingulate and parahippocampal gyri, whereas caused by structural aberrations in the neural networks Shergill et al. (2004) failed to find any such deactivation, themselves, but to draw that conclusion would be premature at this stage. A review of studies on postlesion halbut instead found increased activity 6–9 seconds prior lucinations by Braun et al. (2003) indicates that the to the onset of verbal auditory hallucinations in the left frontal and right middle temporal gyri, which the lesions causing hallucinations tend to be located in the authors interpreted as an indication of inner speech pathways of the sensory modality involved (i.e., lesions being generated prior to the conscious experience of verin the auditory pathways in the case of auditory hallucibal auditory hallucinations. Other subcortical structures, nations, and so on), and the authors suggest that the including the thalamus, were found to be involved by damaged tissue must therefore originally have had an Silbersweig et al. (1995) and others. inhibitory function that prevented the pathway from engaging in the mediation of hallucinatory activity. Although the results from studies such as these are But structural imaging studies of individual voice not unequivocal, they do indicate that the mediation of verbal auditory hallucinations may well be equally hearers do not tend to show any signs of such structural dependent on the temporal course of prehallucinatory pathology. As a consequence, the mapping of structural activity as on the activity registered in cortical areas durabnormalities associated with auditory hallucinations ing hallucination epochs. More research is needed to has mainly been a matter of comparing brain scans of establish which time courses play a role under which cirgroups of individuals with and without auditory hallucicumstances, but the very notion of time courses would nations (Allen and Modinos, 2012). The findings thus obtained in groups of psychotic individuals experiencing seem to be paramount to our understanding of halluciverbal auditory hallucinations include volumetric natory activity. The components of the auditory hallucination netdecreases in the superior temporal sulcus and other senwork identified with the aid of neuroimaging studies sory areas, in non-sensory areas such as prefrontal corlargely overlap with the modular components targeted tex, insula, amygdala, anterior cingulate cortex, and the as candidate regions in classic models. And yet neuroimparahippocampal gyri, as well as an enhanced structural aging studies have added various novel components to integrity of white-matter tracts (as deduced from the classic canon, including the insula (Sommer et al., enhanced fractional anisotropy found in diffusion tensor imaging studies) such as the arcuate fasciculus 2008), the inner-speech network (Vercammen et al., and inferior longitudinal fasciculus, which both play a 2011), and the auditory “where” pathway, which comprises the left planum temporale and prefrontal regions. role in language processing (Allen and Modinos, As indicated by Looijestijn et al. (2013), in an fMRI study 2012). By and large, those findings are consistent with among 52 right-handed, psychotic voice hearers, the the functional networks outlined in the previous section. exteriorization of verbal auditory hallucinations would They would seem to justify hypotheses involving a seem to depend on increased activity of the left-sided reduced connectivity between frontal and temporal

444 J.D. BLOM regions, notably the auditory cortical areas, languageareas involved in speech reception, thus failing to tag related areas, and areas that have a function in memory those signals as self-generated (van Lutterveld and retrieval (Clos et al., 2014). But as most of the structural Ford, 2012). That failure of the corollary discharge signal studies carried out so far involve region-of-interest studhas been interpreted as supportive of the inner-speech ies, structural aberrations located outside those regions model, which suggests that verbal auditory hallucinamay well have been systematically neglected. As a contions may result from an inability to recognize one’s sequence, the structural network responsible for the own thoughts as inner speech. Unfortunately, however, mediation of auditory hallucinations may well be larger it is as yet unclear in how far those findings can be genthan we currently believe it to be, although at present it eralized to other types of auditory hallucination and to would seem to comply roughly with the functional netdifferent population groups. work identified so far.

Pathophysiology of musical hallucinations Pathophysiologic processes It would seem that pathophysiologic models of auditory hallucinatory activity as formulated throughout the history of the neurosciences all deserve a role in the current auditory hallucination paradigm. As a corollary, perceptual release, reperception, deafferentiation, cortical excitation, inner speech, and default lateralization are no longer envisaged as competing doctrines or mutually exclusive mechanisms, but rather as mechanisms applicable to certain patients and to certain types of auditory hallucination. As regards the pathophysiologic processes that govern those mechanisms, relatively little is certain as yet. Cortical excitation is by definition a matter of aberrant electrophysiologic activity, but the other mechanisms may well be indebted to a variety of processes. As suggested by the dopamine hypothesis of schizophrenia, hallucinations occurring in the context of psychosis may well be mediated by hyperactive dopaminergic signal transduction, notably in the mesolimbic regions (Carlsson and Carlsson, 1990). Although there is a voluminous body of work on the role of dopamine and its various receptor subtypes in hallucinations and other psychotic symptoms (Madras, 2013), and although the efficacy of phenothiazines and other substances marketed as antipsychotics would seem to suggest that this neuromodulator does indeed play a role in their mediation, the evidence for this is indirect and in need of further research. Likewise, the role of other neurotransmitters and neuromodulators is in need of further research. The same holds true for the involvement of default corollary discharge signals. As originally suggested by Feinberg (1978), a default functioning of the corollary discharge mechanism may well play a role in the mediation of auditory hallucinations. Ford et al. (2001, 2010), among others, studied this basic feedforward system with the aid of electroencephalographs and magnetoencephalography in patients diagnosed with psychotic disorder, and noted that those experiencing verbal auditory hallucinations show disruptions in the signal sent from frontal areas involved in thought generation to temporal

The pathophysiology of musical hallucinations has not been studied on a scale comparable to that of verbal auditory hallucinations. This is mainly due to the fact that musical hallucinations have a significantly lower prevalence, and that it is therefore more difficult to find large-enough groups of patients for functional neuroimaging studies. That said, the few functional imaging studies carried out so far with the aid of PET and fMRI indicate that musical hallucinations, not unlike actual musical perception, co-occur with activity in an extensive network of brain areas which includes auditory areas, motor cortex, visual areas, basal ganglia, brainstem, pons, tegmentum, cerebellum, hippocampi, amygdala, and perhaps even the peripheral auditory system (Gordon, 1999; Sacks and Blom, 2012). Apparently the network as a whole – which may well include many additional brain areas not yet identified as relevant – is capable of promoting and/or mediating musical hallucinations (Stewart et al., 2006). The factors that precede and promote musical hallucinations may not be as diverse as those in verbal auditory hallucinations, but nevertheless they show considerable variation. In temporal-lobe epilepsy, for example, the musical network is stimulated directly by an irritable focus. Especially instances of repetitive, stereotyped musical hallucination tend to be attributed to that mechanism. But what seems to occur in most cases of musical hallucination is a release of activity in the musical network when normal mechanisms of inhibition or constraint are weakened (Keshavan et al., 1992). In this sense the pathophysiologic mechanism underlying the majority of musical hallucinations is considered more or less similar to that underlying many types of verbal auditory hallucination. In either case, however, we should take heed not to draw any premature conclusions, and acknowledge that future research may well shed a different light on the alleged role of those mechanisms. Contrary to the situation in verbal auditory hallucinations, the most prevalent clinical condition associated with musical hallucinations is auditory deprivation or

AUDITORY HALLUCINATIONS 445 deafness. Thus the musical hallucinations of – notably conventional treatment options for auditory hallucinathe elderly – deaf are considered analogous to the visual tions will be summarized. As we shall see, most of those hallucinations of the visually handicapped, also known treatment methods are known for their effects on psyas Charles Bonnet syndrome. In both cases, it is as if chotic symptoms in general, and only few of them have the networks normally employed in musical or visual been assessed in double-blind, randomized controlled perception escape into a spontaneous and autonomous trials aimed at establishing their efficacy on auditory halactivity of their own if there is no longer adequate perlucinations per se. ception to constrain them. In that sense, most (although certainly not all) instances of musical hallucination Pharmacotherapy would seem to fulfill the criteria of deafferentiation phenomena. The method of choice for the symptomatic treatment of auditory hallucinations is antipsychotic medication, especially when the hallucinations at hand are experiTREATMENT enced in the context of psychotic disorder, mood disorAuditory hallucinations do not always require treatder, or delirium. Although clinical trials that compare the ment. They are experienced by a substantial number efficacy of various antipsychotic drugs for the sole and of individuals who lack any demonstrable pathology, specific indication of auditory hallucinations are lackand many of those individuals value their hallucinations ing, results from the European First Episode Schizophreas positive or at least find that the burden caused by nia Trial (EUFEST) allow for comparison of the effects them does not outweigh the risks and side-effects of of five antipsychotic agents on the severity of hallucinatreatment (Sommer et al., 2010). As a consequence, a tions experienced by patients diagnosed with psychotic first step should always be to carefully assess the need disorder (Kahn et al., 2008). As suggested by the EUFfor treatment (Sommer and Blom, 2012). When there is EST data, which were obtained from 498 individuals with no such need, it may suffice to offer reassurance and a first psychotic episode, there are no significant differsome basic psychoeducation aimed at normalization, ences in efficacy between haloperidol, olanzapine, zipraacceptance, and awareness of any circumstances sidone, quetiapine, and amisulpride in their potential to that should prompt the voice hearer to apply for reduce the frequency or severity of hallucinations. They re-evaluation. In addition, it may be helpful to provide all yield a strong reduction in symptom severity during some information on neurobiologic models of hearing the first month, with further reductions taking place durvoices, on their occurrence in the general population, ing the first 12 months of treatment. It should be noted, and on the numerous ways in which others have however, that haloperidol was found to yield a slightly succeeded in coping with them (see, for example, less pronounced effect than the other antipsychotic Romme et al., 2009). As advocated by the Hearing agents (Sommer et al., 2012b). Regarding their sideVoices Movement (see section on non-pharmacologic effects, antipsychotics roughly fall into two groups, treatment methods, below), there are even ways to help i.e., those predominantly inducing weight gain, metapeople find peace with their auditory hallucinations bolic syndrome, and sedation (i.e., quetiapine, olanzawithout necessarily attempting to diminish their frepine, and clozapine), and those primarily associated quency or intensity. with extrapyramidal symptoms, such as acathisia, dystoHowever, if there is a need – and/or a medical necesnia, and parkinsonism (i.e., haloperidol and ziprasidone). sity or legal obligation – to treat auditory hallucinations, As a consequence, the choice for a specific type of antithe method of choice is determined primarily by the clinpsychotic is determined more often on the basis of ical disorder or syndrome in the context of which they potential side-effects than on any alleged differences are experienced. When they occur in the context of intoxin therapeutic efficacy. ications or neurologic or other somatic conditions, treatIf the drug of first choice fails to yield a significant ment will primarily be targeted at alleviating those decrease in symptom severity during the first 2–3 weeks, conditions. Thus hallucinations co-occurring with epia switch is recommended. Traditionally such a switch is lepsy are treated differently from those co-occurring advocated 4–6 weeks into treatment, but relatively with cannabis use, AIDS, Parkinson’s disease, or Lewy recent studies indicate that antipsychotics start to exert body disease. But even in such cases symptomatic treattheir efficacy during the first hours to days rather than ment may be required as an augmentation strategy. Curweeks, and that prolonged periods without switching do rently various methods are being explored for the not tend to yield any additional results (Agid et al., 2007). symptomatic treatment of auditory hallucinations in If necessary, a different antipsychotic agent tends to be their own right, notably repetitive transcranial magnetic chosen from a group with a different receptor profile, stimulation. In what follows, however, the various even though there is no direct evidence that that strategy

446 J.D. BLOM will lead to superior results (Buchanan et al., 2010). Non-pharmacologic treatment methods When the second antipsychotic also fails to yield any sigNon-pharmacologic treatment methods for auditory halnificant results, a switch to clozapine is warranted. Apart lucinations include psychotherapy, various protocols from the risk of sedation and metabolic syndrome as aimed at teaching patients to cope with their voices, side-effects, significant drawbacks of the use of clozaself-help groups, and electroconvulsive therapy (ECT). pine are an increased risk of leukocytopenia and agranSome academic institutions also offer treatments with ulocytosis (which in case of infectious diseases may lead the aid of repetitive transcranial magnetic stimulation, to unnecessary and even fatal complications) and heart but transcranial magnetic stimulation treatment paradisease (notably pericarditis, myocarditis, and cardiomydigms are still under development and currently the opathy). Therefore treatment with the aid of clozapine is method has only been registered in a limited number only considered safe when blood tests are run during the of countries for the treatment of depressive disorder full course of treatment, and when patients are being (Slotema et al., 2011). Usually non-pharmacologic treatmonitored for any signs of clozapine-induced heart disment methods are offered in combination with pharmaease, especially during the first 15 days of treatment cotherapy, but in milder cases it is sometimes possible to (Layland et al., 2009). In those cases where hallucinastart with psychotherapy alone, or with a coping-withtions prove to be resistant even to clozapine at adequate voices course or participation in the meetings of a therapeutic blood levels for a prolonged period of time, self-help group. clinicians tend to advocate various pharmacologic augAs regards psychotherapy, the method of choice mentation strategies with the aid of therapeutics ranging tends to be cognitive-behavioral therapy. Starting from from selective serotonin reuptake inhibitors to lithium, the premise that the impact of auditory hallucinations sodium valproate, lamotrigine, benzodiazepines, risperdepends primarily on the way they are appraised and idone, haloperidol, quetiapine, and aripiprazole. Case dealt with psychologically, cognitive-behavioral therapy reports and randomized controlled trials among modest targets five specific aspects of the hallucinatory experinumbers of patients suggest a superior result of such ence: (1) the voices’ often compellingly realistic nature; combinations. A recent meta-analysis which quantita(2) the personal meaning of their content; (3) the more tively summarized 29 randomized controlled trials or less fixed identity of the voices; (4) the voice hearer’s involving the pharmacologic augmentation of clozapine relationship with them; and (5) the impact of the voices among a total number of 1066 patients indicates a modon the voice hearer’s life (Beavan, 2011). The cognitive est improvement of total symptom severity for augmenstrand of cognitive-behavioral therapy involves putting tation with lamotrigine, sulpiride, citalopram, and the those appraisals in perspective and offering alternative glutamatergic agonist CX516 (Sommer et al., 2011). explanations for their origin and meaning. The behavOn the basis of the results of that study we must ioral strand involves the testing of novel ways to deal conclude, however, that pharmacologic augmentation with situations where the voices play a negative role, in clozapine therapy is not yet supported by much as well as relabeling their emotional appraisal convincing evidence from the literature (Sommer and (Sommer et al., 2012b). As soon as the first signs of Blom, 2012). doubt begin to show regarding the alleged reality and Cases of tinnitus (mostly experienced in the absence power of the voices, patients are encouraged to limit of any signs of psychosis) are treated differently (see the time they give them their attention, to pick up the rouChapter 23), and the same holds true for musical hallutines of their daily lives, and to reclaim meaningful social cinations. In cases of musical hallucination, any underroles. In addition, they are encouraged to diminish any lying pathology, if present, should be treated first. In safety routines they may have developed, such as the the absence of any identifiable pathology, the symptomavoidance of social contacts, sports, education, or labor atic treatment of musical hallucinations tends to involve out of a fearful anticipation of possible disastrous the prescription of anticonvulsant, antidepressant, or consequences. antipsychotic drugs. In the literature a few case reports Cognitive-behavioral therapy has been developed for can be found on successful treatments with the aid of the voice hearers in general, but also for specific subgroups anticonvulsants gabapentin, carbamazepine, and valsuch as those suffering from command hallucinations, proic acid, respectively, as well as with the antideprescritical voices, humiliating voices, or reperceptive hallusant clomipramine. However, none of those drugs cinations. Effect sizes for those treatment programs has yet shown a broad usefulness, and the majority of range from 0.64 to 1.16 (Sommer et al., 2012b). the cases of musical hallucination appear to be quite Coping-with-voices protocols can either be offered in refractory to current treatment methods (Sacks and the context of cognitive-behavioral therapy programs or Blom, 2012).

AUDITORY HALLUCINATIONS 447 as separate treatment methods (van Gastel and Daalman, be learned from philosophers. A classic epistemologic 2012). The same holds true for the meetings offered by conundrum is whether hallucinations differ qualitatively any of the self-help groups which have been founded in from so-called veridical perceptions. From what was said the majority of western countries throughout the past so far, the differences between the two may appear self25 years, the most renowned one being the international evident, but there are many critical reflections on this Hearing Voices Movement (Romme and Escher, 2012). issue to be found in the philosophical literature, ranging Those groups tend to proceed from a set of principles from Sextus Empiricus (c. 160–210 AD) to Nelson Goodman (1906–1988) and beyond. Especially those aimed at toning down the medicalization of auditory halconcerned with the nature of existence (ontology) and lucinations, at destigmatizing and normalizing the expethe nature of knowledge (epistemology) consider the rience per se, and at exploring and validating possible hallucinatory experience a fertile test case for paradigms links with prior traumatic experiences. By focusing on ranging from naı¨ve realism to idealism, skepticism, and acceptance, emancipation, and coping skills rather than constructionism (de Haan, 2009). In addition, there are medical diagnosis and treatment, they tend to encourage various empiric findings that invite us to examine the empowerment rather than symptom reduction per se. conceptualization of hallucinations as percepts-withoutA final non-pharmacologic treatment method availan-external-source in some more detail, and it is to able for – especially medication-resistant – auditory halthose that we shall now turn. lucinations is ECT. Although the efficacy of ECT has In the first place, the phenomenologic characteristics never been studied for the exclusive purpose of treating of sensory and hallucinatory percepts appear to be quite auditory hallucinations, and consensus on its usefulness similar. Voice hearers tell us that their verbal auditory in such cases is lacking, in clinical practice ECT tends to hallucinations tend to sound like actual voices, and indibe used mainly when hallucinations occur in association viduals experiencing musical hallucinations that they with psychotic depression or catatonia, i.e., the two stansound like actual music. The hallucinations at hand dard indications for ECT (Sommer and Blom, 2012). In a may not invariably possess all the phenomenologic charsystematic meta-analysis of double-blind, randomized acteristics of so-called veridical perceptions (as in the studies comparing ECT and antipsychotic medication case of internal auditory hallucinations and unilateral with sham and medication, Tharyan and Adams (2005) types), but they certainly can, and frequently they do. included 10 randomized controlled trials carried out What is more, especially external auditory hallucinations among a total number of 392 patients, and concluded tend to blend in seamlessly with environmental sounds, that the relative risk for clinical improvement was 0.78 and thus constitute an integral part of the voice hearer’s in favor of ECT. Although a significant finding, the auditory landscape. studies on which the meta-analysis was based failed to Secondly, we may ask ourselves what we mean reveal anything specific about the reaction of auditory exactly when we use the term veridical perception. As hallucinations to ECT. we all know, regular sense perception involves something more than a straightforward representation of METATHEORETIC CONSIDERATIONS stimuli we assume present in the external world. WhatStructural and especially functional neuroimaging findever we may think of the ontologic status of those stimings have revolutionized our understanding of auditory uli, as soon as we accept that they constitute the basis of hallucinations by linking them to an extensive network of our sense perceptions, we also accept that sense percepbrain areas involved in their mediation. In that sense, our tion is not a purely linear process, and acknowledge insights into their nature and origin have increased siginstead that it leaves us some room for manufacturing nificantly over the past 20 years. Meanwhile the concepour own idiosyncratic version of that which we call realtualization of auditory hallucinations – as well as ity. In the case of audition, we tend to rely on contextuhallucinations in general – has silently undergone a revalization and the “filling in” of unheard and ambiguous olution of its own, partly due to those neuroimaging sounds to arrive at meaningful phrases which may or findings, and partly due to ideas that stem from the phimay not correspond with what was spoken. Meanwhile losophy of science and from network science. Those conpreoccupations, attentional biases, wishes, fears, and ceptual developments and their theoretical implications many other psychologic factors exert a considerable will now be summarized. influence on all that we (think that we) are hearing. So we may ask ourselves how “veridical” our veridical perInsights from the philosophy of science cepts actually are. In the third place, it is as yet uncertain whether there As regards hallucinations and so-called veridical percepare any neurophysiologic differences between sensory tions – and any differences between the two – much is to

448 J.D. BLOM and hallucinatory percepts. As suggested by the neuro40 Hz resonating in the thalamocortical system (Llina´s imaging findings discussed above, auditory hallucinaand Ribary, 1994). Although the exact mechanism is still tions and actual sounds appear to depend on common in need of further elucidation, those oscillations are held brain networks for their mediation. Apparently the netresponsible for engaging widely disseminated parts of works at hand are capable of mediating auditory perthe thalamocortical system in synchronous electrophyscepts on their own, irrespective of the presence or iologic activity, thus ensuring their collective contribuabsence of external auditory stimuli. As a consequence, tion to the mediation of percepts. Judging by the it may not always be clear to us whether that which we continuous presence of those gamma-band oscillations, perceive has an ontologic substrate in the extracorporeal it would seem that the mediation of percepts is an ongoworld or not. ing process. Apparently many – if not most – of the ensuTaken together, those findings beg the ancient philoing percepts never breach the threshold of our sophic question of whether a reliable distinction can be consciousness, but when we dream, daydream, or expemade between hallucinations and that which we call rience microsleeps we are able to catch glimpses of them. veridical perceptions. According to Descartes (1637), As soon as we are fully awake, however, and start optiwe are fundamentally unable to make that distinction mizing the use of our sense organs, those oscillations are (unless we acknowledge that it is God who tells us which modulated in such a way that they provide us with signifis which). Kant (1781) likewise stated that we are unable icantly more information about what is going on in the to gain access to the world itself, the Ding an sich, and outside world than during sleep or other states of lowsaid that all we ever experience are our own internally ered consciousness. The information originating from mediated percepts. Descartes and Kant lived centuries the sense organs is therefore believed to temporarily ago, but the epistemologic issues they raised never lost restrict the thalamocortical system’s potential, in the any of their significance. Ironically, perhaps, similar sense that it limits its ability to create percepts the way issues are now being raised by empiric scientists such it does in its natural, more or less freewheeling, state as hallucinations researchers and those working in the (Behrendt and Young, 2004; Collerton et al., 2005). As field of perceptual neuroscience. regards the auditory modality, this means that the numFish (2009), in a scholarly defense of realism, offers us ber of degrees of freedom of the thalamocortical system the following solution to the question of how hallucinais being curtailed by information provided by the inner tions differ from veridical perceptions. According to ear, thus forcing it to refrain from mediating its auditory him, the perception of objects or events in the outside percepts more or less at random, and instead forcing it to world involves our becoming acquainted with them, thus modulate them in such a way that they show certain parrendering the experience a phenomenal character, whereas allels with the external auditory stimuli to which the syshallucinations are mistakenly supposed to possess such a tem is exposed. phenomenal character whilst in fact they lack them. On the basis of this line of thought it has been sugAmong philosophers that solution is known as disjunctigested that auditory perception – like all perception – vism, a term coined by Hinton (1973). As proposed by comes down to a closed, intrinsic functional brain state Hinton, the qualities of perceived objects are instantiated (Llina´s and Ribary, 1994), irrespective of whether it is in cases of genuine sense perception, whereas in cases of experienced during a dream, in a hallucinatory state, hallucinatory perception they are merely represented. or in an unclouded state of wakeful consciousness. FolWith their disjunctivist approach, authors such as lowing through this line of thought, actual sounds can Hinton and Fish would seem to voice the traditional point then be characterized as products of the thalamocortical of view that hallucinations can be distinguished from system which are restrained by information from the sense perceptions because of our knowledge of what inner ear, whereas auditory hallucinations can be characis actually going on in the external world. Their oppoterized as similar products which are unrestrained by nents, however, notably those who adhere to the qualia information from the inner ear, and auditory pareidolias theory, stress the Kantian point of view that our attempts (i.e., illusions) as similar products which are underresto gain access to the external world through the senses trained by information from the inner ear. If anything, are ultimately in vain, and that the qualitative properties this account does justice to the role of neurophysiologic of the ensuing percepts are indistinguishable from those and psychologic factors in audition, and hence downof hallucinations (see, for example, Crane, 2006). They plays the notion that voice hearers might be the only ones offer a somewhat different solution, but one that has sigexposed to endogenous modulation of their percepts. nificant implications for the conceptualization of both In addition, it would seem to make sense in terms of phenomena. the brain’s economic use of resources. However, what During the 1980s it was suggested that all perception this account sacrifices is the clear – albeit somewhat depends on gamma-band oscillations of approximately naı¨ve – distinction between sensory and hallucinatory

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percepts we are acquainted with. Whether that is a sacrifice worth making is up to the reader to decide.

Insights from network science A further development that has fundamentally altered the way we think about hallucinatory activity stems from the relatively young field of network science. Having emerged from earlier mathematic disciplines such as graph theory, cybernetics, and probabilistic theory, network science is a means of analyzing complex relational data which is applicable, due to its scale-free nature, to any aspect of the universe, and hence also to brain structures and the way they are interrelated at a structural as well as a functional level. Because of the huge number of factors involved in the mediation of hallucinations, until recently it has appeared nigh impossible to develop a global view of their mediation, let alone indicate which factors stand in causal relations to others, and to determine the weight and importance of each factor under varying circumstances. The sections above have indicated that we are still far removed from realizing such a global view of hallucinatory activity, but network science counts as a serious candidate for bringing that goal within our reach during the years to come. As explained by Goekoop and Looijestijn (2012) in their scholarly introduction to the subject (upon which most of the present section is based), network science starts from the deceptively simple premise that interactions between agents existing separately in space can be studied with the aid of graphic representations called network graphs (for an example of such a network graph, see Fig. 24.3). Those network graphs consist of nodes, and of links interconnecting those nodes. Together, the nodes and links constitute the network’s structure. Information traveling from one node to another along the links represents the network’s function. Like all biologic systems, cerebral networks are conceptualized as possessing a small-world structure, which means that they are believed to consist of many nodes which possess relatively few connections, and relatively few nodes which possess a large number of connections (Meunier et al., 2010). The richly connected nodes are called hubs, and those hubs are connected to other hubs in such a manner that information traveling from one side of the brain to the other can take place in a maximum of six steps, irrespective of location and function. It is believed that the brain’s small-world topology thus serves to maximize the efficiency of information transfer, and that it does so in the most economic way, i.e., by using the smallest possible number of links in its network. As regards the study of hallucinations, network science offers the possibility to examine physiologic as well

Fig. 24.3. Network graph showing an example of a “smallworld” network structure. Hubs (i.e., high-degree nodes) connect clusters of lesser-degree nodes into superclusters (marked by circles), and so on. This hierarchic network structure is called scale-free or fractal-like, since a similar structure can be found in nature at all spatial-scale levels of organization, including networks of genes, proteins, metabolites, organelles, neurons, brain areas, social networks, and markets. (Reproduced from Goekoop and Looijestijn, 2012, with permission.)

as pathologic changes in neural network structure and function with the aid of computer models of neural networks, in which have been incorporated data deriving from anatomic, physiologic, electrophysiologic, biochemical, molecular genetic, or neuroimaging studies, or in fact any other type of empiric data relevant to the subject. Because of the method’s scale-free character, the ensuing network graphs can even be linked to networks graphs representing phenomenologic, psychologic, and social as well as other environmental factors, thus allowing for weighted analyses at levels of conceptualization that extend beyond the brain itself. Some of the models currently used for that purpose are attractor network models (Brunel and Wang, 2001). An attractor network comprises a network of neurons (such as pyramidal cells in the primary auditory cortex) which receives exogenous dendritic input (originating from the inner ear, for example) which it modulates in such a way that it can serve as an output signal for axons that connect the network to another attractor network (such as the auditory association cortex). Neurons located within each attractor network have excitatory collaterals which feed back to their dendritic connections (serving to produce collateral excitation) and to inhibitory interneurons which, on average, suppress the activity in networks lying outside the attractor

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network (serving to produce collateral inhibition) (Brunel and Wang, 2001). In this way the excitatory and inhibitory collaterals constitute positive- and negative-feedback loops, which are believed to operate via N-methyl-D-aspartic-acid (NMDA) and gammaaminobutyric-acid (GABA) receptors, respectively (Goekoop and Looijestijn, 2012). That basic layout can be used to explain how the auditory network is able to mediate all types of auditory perception, irrespective of whether the ensuing percepts originate from signals in the environment or from within the brain itself. In terms of the network science paradigm, auditory hallucinations are conceptualized as attractor states (i.e., active or passive states) which are produced – and often sustained – in the absence of an external source. As proposed by Goekoop and Looijestijn (2012), such false-positive attractor states can be produced in a normal brain under certain extreme circumstances (such as sensory or social deprivation, deafness, extreme anxiety, or substance abuse), as well as under normal circumstances in a sensitive brain. As the authors explain, in sensory deprivation the lack of external stimuli may force attractor networks to enter their resting states, and to prevent collateral inhibition from suppressing any “noise” deriving from within the brain itself. Meanwhile the low stimulus intensities may lead to neural adaptation, thus further reducing the number of GABAergic inhibitory currents, and decreasing the firing thresholds of neurons within the attractor network (Goekoop and Looijestijn, 2012). As a result, the attractor network at hand will become extremely sensitive, and require only little energy to assume a false-positive state. In terms of energy landscapes, the attractor state thus constitutes a local minimum or “hole” from which trajectories of network activity cannot easily escape. As a consequence, the aberrant neurophysiologic activity has a tendency to persist, and, when altered, to return time and again to its aberrant state. In the case of a sensitive brain, the network attractor model aids to explain the mediation of auditory hallucinations under normal circumstances. It does so by describing pathologic differences in the structure and/or function of the attractor network itself. Such differences may involve any level of excitation, inhibition, and/or neuromodulation governing the activity of the attractor network, notably those regarding the NMDA receptor, deficits in GABAergic inhibition, and elevated ratios of D2 versus D1 dopamine receptors (Goekoop and Looijestijn, 2012). As noted by Jardri and Dene`ve (2013), the attractor network model is a means of investigating the functional stability of networks, and, more specifically, to study how at the synaptic level alterations in ion channels

and neurotransmitters may affect spiking activity within such networks. In addition, it offers an unprecedented opportunity to study the mediation of auditory hallucinations by examining the interrelationships between networks and biochemical agents, structural and functional connectivity, phenomenologic characteristics of hallucinations, psychologic factors, and the social – as well as wider environmental – context. Figure 24.4 offers a graphic representation of the ensuing coupled network graphs. With network attractor models becoming increasingly sophisticated, it is expected that computer simulations will soon be able to aid in identifying brain areas to be targeted for the purpose of symptom reduction. Functional neuroimaging studies, meanwhile, may aid in identifying the networks and hub regions to be studied in network attractor models. Traditionally the results of such neuroimaging studies are based on model-based analyses (see, for example, van Lutterveld et al., 2014), which means that the brain areas are selected with a preconceived set of notions in mind regarding their possible involvement. An alternative approach is model-free analysis, a type of analysis which refrains from using any such preconceived ideas. Modelfree analyses tend to yield a substantially larger number of brain areas potentially involved in the mediation of hallucinations. Some of those areas may turn out to be false-positive findings, whereas others may constitute valuable additions to the hallucination network previously overlooked in model-based analyses. Because of the overwhelmingly large number of data to be analyzed in model-free analyses of whole-brain scans, it used to be hard – if not technically impossible – to attempt such analyses. But with the aid of network science such analyses have now become feasible, and various studies using this technique are currently underway.

CONCLUSION With the above outline of network science as a method potentially useful for the study of auditory hallucinations, we have gradually moved from discussing rather robust empiric findings to what, strictly speaking, deserves little more than the status of a “future development.” Summing up, the present chapter demonstrated that our knowledge of auditory hallucinations has transcended the rich phenomenology and taxonomy inherited from classic neuroscientific discourses to encompass the even richer harvest of neuroimaging findings obtained during the past two decades, thus making it possible to gain an impression of a structural as well as a functional auditory network in the brain, and to relate various aspects of the auditory hallucinatory experience to

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Fig. 24.4. Coupled network graphs of functional connectivity in relation to a network structure of symptoms of patients who experience verbal auditory hallucinations (Looijestijn et al., data in preparation). Measured data are shown in color. Functional connectivity: network of neurophysiologic data (independent components of functional magnetic resonance signal). Phenotype: subjective symptoms as rated with the aid of a questionnaire (PSYRATS) and registered hallucination timings during magnetic resonance imaging. Hypothetic additional levels of organization are shown in gray, and can be added to the model at later stages. Based on knowledge of the relationships between the various factors that relate to the origin and phenomenologic expression of hallucinations, therapeutic intervention foci can be predicted at each level of network organization (i.e., medication, transcranial magnetic stimulation, psychotherapy, work). (Reproduced from Goekoop and Looijestijn, 2012, with permission.)

important nodes and hubs located in those networks. In the case of verbal auditory hallucinations experienced in the context of psychosis, subcortical structures such as the parahippocampal gyri and the insula were thus found to play a dominant role in the initiation of preparatory hallucinatory activity, the language centers, and their contralateral homologs in furnishing them with a linguistic content, the auditory cortices in promoting awareness of the percepts involved, and the auditory “where” pathway in lending them the phenomenologic quality of either an internal or external percept. Although admittedly a crude simplification of what must actually be going on in the brain before and during the conscious experience of a verbal auditory hallucination, that characterization allowed us to catch a glimpse of the temporal sequences leading up to that hallucinatory experience, and of the widely disseminated brain areas involved in their mediation.

In addition, the present chapter indicated that recent developments such as network science and model-free analysis hold the promise of a further – and possibly exponential – growth of knowledge in this already rapidly expanding area of research. Meanwhile insights derived from the philosophy of science compelled us to adjust our conceptualization of auditory hallucinations – as well as that of the hearing of actual sounds – in such a way that they do justice to our empiric findings. As a consequence, we now conceive of auditory hallucinations as closed, intrinsic functional brain states produced by the thalamocortical system in such a way that they are unrestrained by information from the inner ear; of auditory illusions as similar brain states underrestrained by information from the inner ear; and of actual sounds as similar brain states restrained by information from the inner ear. Thus the three types of auditory percept are conceptualized in conformity with the qualia

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theory as being qualitatively similar, which also makes sense from the point of view that they are all indebted to the same auditory network for their mediation. In a word, the previous sections indicated that our knowledge of the auditory hallucinatory experience has increased considerably since the advent of functional neuroimaging research. On the downside, we saw that our knowledge of the neurophysiologic basis of auditory hallucinations is almost exclusively restricted to the subgroup of verbal auditory hallucinations. The various other subgroups – largely neglected from the 1950s onwards by major psychiatric classifications – are now back in the center of scientific attention, but it will probably take some time before they will be investigated as extensively as the subgroup of hallucinated voices. Another significant limitation of our current knowledge is that it has so far failed to yield any new, successful therapeutic strategies. There are various novel treatment methods on the horizon, including asenapine and other drugs marketed as antipsychotics, as well as cannabidiol – a non-psychoactive compound of cannabis – but on the basis of our current insights into the role of specific hubs in the auditory network it should become possible in the near future to target those areas more precisely, for example with the aid of direct-current stimulation, deep-brain stimulation or transcranial magnetic stimulation. Transcranial magnetic stimulation has been researched extensively for its potential to target relatively circumscript cortical – and sometimes even subcortical – areas involved in the mediation of auditory hallucinations without yielding any significant sideeffects, but treatment paradigms in this area are still in need of further development for the method to become applicable in clinical practice (Aleman and Larøi, 2011; Sommer et al., 2012c).

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In: JD Blom, IEC Sommer (Eds.), Hallucinations, Research and Practice. Springer, New York, NY, pp. 125–132. Slotema CW, Blom JD, de Weijer AD et al. (2011). Can lowfrequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial. Biol Psychiatry 69: 450–456. Slotema CW, Daalman K, Blom JD et al. (2012). Auditory verbal hallucinations in patients with borderline personality disorder are similar to those in schizophrenia. Psychol Med 42: 1873–1878. Sommer IEC, Blom JD (2012). Classical somatic treatments: Pharmacotherapy and ECT. In: JD Blom, IEC Sommer (Eds.), Hallucinations, Research and Practice. Springer, New York, NY, pp. 331–348. Sommer IEC, Diederen KMJ, Blom J-D et al. (2008). Auditory verbal hallucinations predominantly activate the right inferior frontal area. Brain 131: 3169–3177. Sommer IEC, Diederen KMJ, Selten J-P et al. (2009). Dissecting auditory verbal hallucinations into two components: audibility (Gedankenlautwerden) and alienation (thought insertion). Psychopathology 43: 137–140. Sommer IEC, Daalman K, Rietkerk T et al. (2010). Healthy individuals with auditory verbal hallucinations; who are they? Psychiatric assessments of a selected sample of 103 subjects. Schizophr Bull 36: 633–641. Sommer IEC, Begemann MJ, Temmerman A et al. (2011). Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: A quantitative literature review. Schizophr Bull 38: 1003–1011. Sommer IEC, Koops S, Blom JD (2012a). Comparison of auditory hallucinations across different disorders and syndromes. Neuropsychiatry 2: 57–68. Sommer IEC, Slotema CW, Daskalakis ZJ et al. (2012b). The treatment of hallucinations in schizophrenia spectrum disorders. Schizophr Bull 38: 704–714. Sommer IEC, Aleman A, Slotema CW et al. (2012c). Transcranial stimulation for psychosis: the relationship between effect size and published findings. Am J Psychiatry 169: 1211. Stewart L, von Kriegstein K, Warren JD et al. (2006). Music and the brain: disorders of musical listening. Brain 129: 2533–2553. Takebayashi H, Takei N, Mori N et al. (2002). Unilateral auditory hallucinations in schizophrenia after damage to the right hippocampus. Schizophr Res 58: 329–331. Tharyan P, Adams CE (2005). Electroconvulsive therapy for schizophrenia. Cochrane Database Syst Rev 18, CD000076. Van Gastel WA, Daalman K (2012). Groundwork for the treatment of voices: Introducing the Coping-With-Voices Protocol. In: JD Blom, IEC Sommer (Eds.), Hallucinations. Research and Practice. Springer, New York, NY, pp. 375–384. Van Lutterveld R, Ford JM (2012). Neurophysiological research: EEG and MEG. In: JD Blom, IEC Sommer

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 25

Palinacousis MADELINE C. FIELDS* AND LARA V. MARCUSE Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA

INTRODUCTION Palinacousis is derived from the Greek words palin, which means again or anew, and acousis, meaning hearing. It was first described by Jacobs et al. (1971), who defined the phenomenon as “an auditory illusion of perseveration or persistence of sound impressions for seconds, minutes, or hours after the cessation of auditory stimulation.” One of the salient features of palinacousis is that it does not occur spontaneously but is triggered by something in the environment. The first published case of auditory perseveration can be found as early as the 1930s in a boy after a right temporal lobectomy (Rylander, 1939). In the 1950s, Mullen and Penfield (1959) were able to reproducibly elicit auditory perseveration by direct electric stimulation of the temporal lobe. In the 1970s, Jacobs et al. described the first 7 cases of “palinacousis,” most of whom had recent seizures and lesions of the temporal lobe. However, over the last 75 years there have been only a limited number of case reports in the literature. From the time of its original description, palinacousis has been associated with seizure phenomena (Jacobs et al., 1971). Electroencephalographic (EEG) recordings from patients with palinacousis have often shown the brain region to be hyperexcitable but frank electrographic seizures during palinacousis have not been captured. Despite even more modern technologies like magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) scans, deciphering the etiology of palinacousis remains somewhat of a diagnostic conundrum.

DEFINING CHARACTERISTICS Perseveration The definition of perseveration is “the continuation or recurrence of an experience or activity without the

appropriate stimulus” (MacNalty, 1961; Dorland, 1965). The term perseveration was first coined by Neisser in 1895. Goldstein (1948) described perseveration as an inability to inhibit a previous thought. When Jasper (1931) helped to define perseveration he wrote that the cause of this phenomenon is “the tendency of a set of neurons, once excited, to persist in the state of excitement autonomously, showing resistance to any change in this state.” Allison (1966) went on to describe perseveration as “the continuance or recurrence of a purposeful response which is more appropriate to a preceding stimulus than to the succeeding one which has just been given, and which is essential to provoke it.” Perseveration is involuntary. By definition it does not occur without previous stimulation and is not a spontaneous phenomenon (Allison, 1966). Perseveration can occur in a variety of conditions, including epilepsy, psychoses, dementia, Parkinson’s disease, traumatic brain injury, and stroke. Perseveration of movements, thoughts, and speech have all been well described. In Alzheimer’s disease perseveration worsens as the disease progresses (Pekkala et al., 2007). Perseveration of thought is seen in patients with psychosis or obsessive-compulsive disorder and perseveration of speech can be seen in aphasic patients after a stroke. Palinacousis is a sound or phrase from the environment that replays in the person’s head – auditory perseveration. Palinacousis can result in perseveration of speech. The perseveration of speech occurs because the individual is responding to an auditory perseveration as if it were real.

Illusion Palinacousis is a form of illusion. Our senses of hearing, touch, sight, smell, and taste provide the brain with primary sensory data that the brain integrates, creating a perception that is experienced. An illusion is a

*Correspondence to: Madeline C. Fields, MD, Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY 10029, USA. E-mail: [email protected]

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misperception of real external stimuli. Illusions are not rare in human experience. A common example is our perception of three-dimensional space while looking at a two-dimensional picture of a road that travels off into the distance. Warren and Warren (1970) investigated the presence of auditory illusions in normal subjects in the 1970s. In their experiments, a phoneme or speech sound was deleted from an audiotape and replaced by another sound or cough of the same duration. Subjects heard the missing speech sound as clearly as any of the phonemes that were actually present. Additionally, after being told that a sound was missing, subjects could not distinguish the illusionary sound from the real one. If the phoneme was replaced by a period or silence rather than a cough the deletion became obvious. Misperceptions of sound can occur in normal healthy subjects, as just described. In palinacousis these misperceptions are recurring auditory phenomena when in fact none exists. Illusions are different than either hallucinations or delusions. A hallucination is a false sensory perception experienced without real external stimuli. For example, a schizophrenic person may perceive voices talking or hear a voice speaking his/her thoughts when in fact none exists. However, these voices occur spontaneously, not in response to an environmental stimulus. Alternatively, delusions are fixed, false beliefs (not perceptions) that cannot be corrected by logic. Palinacousis is an auditory illusion. It is the persistence or repetition of a sound or phrase (auditory perseveration) when in fact the original sound or phrase no longer exists.

HISTORY In the late 1800s Hughlings Jackson recognized that auditory hallucinations occur during epileptic attacks and could be localized to the “temporosphenodial” lobe. In 1939 Rylander described a boy’s status post partial right temporal lobectomy. “Sometimes he [the patient] repeated the same sentence. . .in a way typical of an epileptic person.” When given psychologic tests “the patient sometimes repeated the answer to the question directly preceding the one put to him.” It was thought that the boy repeated the answer to the question because he heard the question again. This is in fact the first recorded description of palinacousis. In one of the cases of electric stimulation performed by Mahl et al. in 1964, the experimenter said “findings” as part of a sentence seconds prior to electric stimulation. During temporal-lobe stimulation the patient heard the word “findings” over and over. In the 1950s and 1960s electric stimulation of the brain in epileptic patients helped to elucidate the anatomy and physiology of the brain as well as characterize epileptic

Fig. 25.1. Superior temporal gyrus. (Courtesy of Nora Patrone.)

seizures. Penfield and Perot (1963) found that auditory illusions were triggered by stimulating either cerebral hemisphere, primarily in the first temporal convolution, which is now more commonly referred to as the superior temporal gyrus (Fig. 25.1). Penfield describes “flashbacks” or “experiential responses” as those induced by electric stimulation of the cortex via implanted electrodes. These experiences were elicited in 40 of 520 patients whose temporal lobes were electrically stimulated. Over 60% of these patients experienced a sound and the accompanying emotions of a time period identified by the patient as coming from his/her past (Penfield and Perot, 1963). In case 66, the “operator’s voice echoed.” In other cases the quality of the operator’s voice was altered. During electric stimulation, auditory sensations were most often referable to the ear contralateral to the temporal lobe being stimulated (Penfield and Rasmussen, 1958).

ANATOMY For a detailed explanation of the auditory pathway, please see Chapters 1 and 2. In the literature there is a single illustrative case of palinacousis caused by a lesion in the medial geniculate body (MGB). The MGB is the primary sensory input to the auditory cortex. The MBG has subsequently been considered the auditory relay nucleus and receives both auditory and somatosensory inputs. The MGB may be involved with sound pattern recognition, auditory memory and localization of sound in space (Pandya, 1995). In 1998 Fukutake and Hattori described a 49-year-old male with untreated hypertension who was also an 80-pack-year smoker. The patient was watching a gunshot scene on television when suddenly the sounds appeared louder and began to echo, predominantly on the right side. He shut the television off but then yelled at his wife to again shut the television off because he

PALINACOUSIS continued to hear sounds coming from the television. These illusionary sounds lasted for 10 minutes. Additionally, he was noted to have transient slurred speech, left mouth numbness, and hypesthesia in the left thigh. A computed tomography (CT) scan of the head showed a low-density lesion in the right posterior inferior thalamus and an MRI showed a hemorrhagic infarction in the right posterior inferior thalamus, including the MGB. This case describes auditory illusions caused by a relatively discrete lesion involving the MGB. The primary auditory cortex (PAC) (Brodmann area 41) can be identified along the mediolateral axis of Heschl gyrus (HG), which is located in the superior temporal gyrus (Fig. 25.2A). Penfield and Perot (1963) found that stimulation of HG produced alterations in interpretation of sounds being heard. The PAC occupies most of HG (Fig. 25.2B). PAC is tonotopically organized with low-frequency stimuli more lateral and high-frequency stimuli more medial. There is still an ongoing argument as to the lateralization or asymmetries following acoustic stimulation (Meyer, 2011). Brodmann area 42, which is inferior to area 41, is also involved in the detection and recognition of speech. Brodmann areas 21 and 22 are the auditory association areas. Dysfunction of the temporal-lobe association areas have been implicated in some cases as the cause of palinacousis (Auzou et al., 1995, 1997). These areas are referred to as Wernicke’s area and deficits in the region can result in Wernicke’s aphasia or fluent aphasia. Individuals suffering from Wernicke’s aphasia speak fluently but they do not make sense. They are not able to repeat simple phrases and they are most often unaware of their deficit. They have great difficulty naming objects. Furthermore, they cannot make

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sense of auditory commands and will not follow commands well. The deficit in Wernicke’s aphasia centers around the comprehension of speech and language and is more closely linked to audition than a Broca’s aphasia. Broca’s aphasia is the result of lesions in the frontal lobe. These individuals can understand language but they cannot produce it well and they are highly frustrated. In 11 out of the 24 cases of palinacousis described in the literature, aphasia or a language disturbance is a part of the presenting complaint. This is likely due to the fact that the areas involved in auditory processing, comprehension, and memory are all centered within a limited area of the temporal lobe. Typically in patients experiencing palinacousis, once the aphasia improves or resolves they are able to describe auditory perseveration. For example, in 2007 Kim et al. described a 67-year-old woman with hypertension who suddenly developed a Wernicke-type aphasia. Three days after admission, when her symptoms were improving she “occasionally heard voices repeatedly when they actually were no longer produced.” For example, when the physician-in-charge said, “Your symptoms are much improved,” she heard “much improved” repeatedly afterward. This patient typically heard fragments of the latter part of the sentence. Sometimes, the repetitious sounds occurred a few hours after the actual conversation. When her symptoms first started she replied to the voice because she thought that somebody nearby actually talked to her. She soon realized that she was experiencing an illusion. MRI revealed an intracerebral hemorrhage in the left middle temporal gyrus. These authors concluded that, because the lesion itself did not directly involve the superior temporal gyrus

Fig. 25.2. (A) Transverse temporal gyri of Heschl. (B) Primary auditory cortex. (Courtesy of Nora Patrone.)

460 M.C. FIELDS AND L.V. MARCUSE (Wernicke area or HG), there was a rapid improvement thought “I am going to bed” and heard “going to bed” in the Wernicke aphasia and palinacousis. Additionally, repeated about 100 times. hyperemia in the area surrounding the intracerebral hemSingle words or phrases seem to perseverate. Most orrhage may have resulted in either hyperexcitation of often a fragment of the original sentence is heard repeatsurrounding auditory pathways or transient loss of inhibedly (Jacobs et al., 1973; Auzou et al., 1995, 1997; itory fibers to the auditory system. Mohamed et al., 2012). Non-verbal stimuli can also recur, including ringing of a doorbell, a telephone, sirens, whispering, grinding of subway wheels, toilet flushing, gunAUDITORY MEMORY shots from a television, and pages of a book turning (Jacobs et al, 1971; Fukutake and Hattori, 1998; Comprehension of noise or discourse depends upon Wustmann and Gutmann, 2007). Another feature of auditory short-term memory. Auditory short-term mempalinacousis is that the content of the voice/sound is neuory involves the posterior superior temporal gyrus and tral and not disturbing. This fact is important when difsulcus (Penhune et al., 1996; Leff et al., 2009) and the ferentiating palinacousis from the persecutory voices of inferior parietal lobe (Becker et al., 1999; Buchsbaum psychotic illness. et al., 2001). Based on a recent study looking at patients with brain lesions it has been proposed that verbal shortterm memory is mediated by a left-hemisphere inferior Quality frontal/posterior temporal circuit and that manipulation The perseverated sound/sentence may seem louder or or rearrangement of information within short-term softer. It may have a muffled quality. A few of the memory recruits posterior parietal cortices. Additionpatients described by Jacobs et al. in 1973 mentioned feelally, there is evidence that verbal short-term memory ing a “clogged ear” prior to experiencing palinacousis as and language processing share overlapping neural subwell as during palinacousis. Often times the utterance strates (Koenigs et al., 2011). sounds distorted to the patient. By far the most common The temporal lobe is responsible for recalling past quality described by patients with palinacousis is that of experiences as well as interpreting present experiences. an “echo.” For example, in one of the cases described by A seizure in the temporal lobe can therefore trigger preDiDio et al. (2007), a 72-year-old woman with a history viously stored auditory experiences (Jacobs et al., 1973). of a left temporal meningioma suffered from recurrent During seizures or electric stimulation in the operating aphasic seizures. On one occasion she presented with room, as described above, a patient may hear a familiar global aphasia on exam and was found to be perseverasound/voice. This auditory precept is thought to be tive. This patient “complained of hearing people’s voices stored and retrieved from one’s memory. In palinacousis echoing in the room emanating from over her right the brain registers and stores an auditory memory, which shoulder.” During this time the patient could be found then misfires. Jacobs et al. (1973) suggest that the turning and looking to the right after a presented retrieval of stored auditory sounds by abnormal electric auditory stimulus. She was noted to perseverate on a prestimulation of the brain is similar to electric excitation of vious action or command. The patient was ultimately the temporal region which may revive stored thoughts/ able to say that she heard the examiners’ voices echo emotions which then appear as reality. phrases over and over again, from beyond her right side. The repetitious sound typically blocks out other CLINICAL CHARACTERISTICS OF sounds. This results in the repetitious sound having the PALINACOUSIS same impact as the original sounds. Very often the perseverated sound seems so real that the patient responds Content by behaviorally searching for the source in the environHuman voices tend to be the most frequent source of ment (Jacobs et al., 1973; Auzou et al., 1995; DiDio perseverated auditory stimuli. Typically the voice is et al., 2007). one of someone nearby. For example, a 16-year-old girl In a single case, covering the ear suppressed the perdescribed by Jacobs et al. (1971) heard the word severated sound (Jacobs et al., 1973). In this case the “Eisenhower” in a discussion of government policies. patient was listening to the television and could not The girl continued to hear “Eisenhower” repetitively understand what was occurring because he heard “the over the next 10 minutes. The perceived sound almost sound repetitively bouncing off the wall on his right.” always originates from the external environment. There When he put his hand over his right ear he could decipher is only one case where a woman heard her own thoughts the voices on the television with the left ear. Other perseverated and was thought to suffer from palinacouattempts at covering the ear to eliminate the palinacousis sis (Terao and Matsunaga, 1999). In this case the patient have not been reproducible (Patterson et al., 1988;

PALINACOUSIS Prueter et al., 2002; Bega et al., 2014). In the example by Patterson a previously healthy 50 year-old woman presented with complaints of a headache 2 days prior to admission as well as nausea, vomiting, and pain in her right thigh. In the emergency room she was confused with global aphasia. Shortly thereafter she had two tonic-clonic seizures. A day later she was more alert but with a fluent aphasia (Wernicke’s aphasia). On the third day she complained of “echoing voices” in her right ear. “These did not arise spontaneously, but represented recurring words or fragments of sentences that the patient had heard during the preceding minutes.” Sounds other than speech also “echoed” in her right ear. The sounds were not altered by occlusion of either or both ears. The patient was found to have a large contrastenhancing lesion in the left temporoparietal region with mass effect by CT scan.

Latency The perseverated sound typically occurs immediately following the original stimulus. For example, if the physician asks “How are you?” the patient will hear “How are you? How are you? How are you?” immediately after the question is asked. In other patients the perseverated sound is triggered by another sound. Rarely, palinacousis appears with a latency of minutes, hours, or days after the original stimulus (Jacobs et al., 1971; Kim et al., 2007; Mohamed et al., 2012). In one case described by Jacobs et al. (1973), the patient heard the perseverated sound 24 hours after the original stimulus. This sound would then recur periodically thereafter for a period of 4 days. This certainly makes the diagnosis much more difficult.

Lateralization of sound In 11 cases (46%) in the literature, the auditory illusion is heard in the opposite auditory space or in the opposite ear to the cerebral lesion (Jacobs et al., 1973; Patterson et al., 1988; Auzou et al., 1995, 1997; Prueter et al., 2002; DiDio et al., 2007; Mohamed et al., 2012) (Table 25.1). In 2 (8%) documented cases the perseverated stimulus was heard ipsilateral to the lesion (Jacobs et al, 1973; Fukutake and Hattori, 1998). In the remaining cases no lesion was found, the patients could not lateralize/localize the sound, or it seemed to perseverate from the initial stimulus location (Jacobs et al., 1971; Bekeny and Peter, 1972; Malone and Leiman, 1983; Masson et al., 1993; Freudenreich and McEvoy, 1996; Terao and Matsunaga, 1999; DiDio et al., 2007; Kim et al., 2007; Wustmann et al., 2010; Bega et al., 2014). DiDio et al. (2007) described a 49-year-old woman with a history of depression, anxiety, and known left parietal cavernous angioma. She presented a number

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of times to the hospital with recurrent episodes of aphasia. While the patient was aphasic she retrospectively was able to describe experiencing an echo in her head immediately after a stimulus was presented. This original stimulus would echo numerous times, sometimes lasting for more than 10 minutes. This echoing remained at a constant intensity. As her aphasia resolved she perceived a more complex echoing phenomenon: she perceived a short-lived echo localized in space to a subsequently presented auditory stimulus. The echo was heard only when a second auditory stimulus was presented. For example, she heard the first sentence presented by the doctor echo only after the doctor uttered a second sentence. The second auditory stimulus was extinguished by the resurgence of the first stimulus, in the form of an echo. At times this echoing phenomenon was even more complicated. If three auditory stimuli were presented one after another, the third stimulus would be extinguished by the first two stimuli echoing simultaneously. Additionally, this patient heard her own voice echoing from the mouth of the doctor as he answered her questions. This echoing would last for seconds.

Lesion location In 12 cases (50%) the lesion was on the left side. In 5 cases (21%) the lesion was on the right side. The remainder of the cases either had bilateral lesions or no lesions (Table 25.1). The most common location for a cerebral lesion is the temporal lobe (Jacobs et al., 1973; Patterson et al., 1988; Auzou et al., 1995, 1997; DiDio et al., 2007; Kim et al., 2007; Bega et al., 2014) (Table 25.1). Other areas of the brain that can produce palinacousis include the MGB (Fukutake and Hattori, 1998), and parietal lobe (Masson et al., 1993; DiDio et al., 2007; Mohamed et al., 2012; Bega et al., 2014). All brain areas documented to produce palinacousis are known to process auditory stimuli.

DIFFERENTIAL DIAGNOSIS Auditory hallucinations of psychotic illness One of the important distinctions to make is between palinacousis and auditory hallucinations caused by an underlying psychiatric condition (see Chapter 24). Auditory hallucinations are the most common form of hallucination, often occurring in schizophrenia and in bipolar disorders (Andreasen, 1997). In fact, up to 75% of schizophrenic patients experience auditory hallucinations (Nayani and David, 1996). Thought echoing, also known as Schneider’s symptoms, is characteristic of schizophrenia. Both palinacousis and auditory hallucinations are false perceptions of sound. However, there are

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Table 25.1 List of patients with palinacousis

Case

Author

1

Jacobs et al. (1971)

F40

Temporal

R

L

2

F16

L

R

Yes

3

UK

R

L

Yes

4 5 6 7

UK M60 UK M64

Temporalparietaloccipital Temporaloccipital Temporal Temporal Indefinite Temporaloccipital Frontaltemporal None

L L R

R R L/R R

Meningioma

Yes Yes Yes No

L

None

Cystercercosis

Yes

None

None

None

Yes

L

R

Yes

R

None

Grade IV astrocytoma ICH

Yes

L

R

GBM

Yes

None

None

None

No

8 9 10 11 12 13 14 15 16

17 18

19 20 21 22 23 24

Bekeny and Peter (1972) Malone and Leiman (1983) Patterson et al. (1988) Masson et al. (1993) Auzou et al. (1995) Freudenreich and McEvoy (1996) Auzou et al. (1997) Fukutake and Hattori (1998) Terao and Matsunaga (1999) Prueter et al. (2002) Wustmann and Gutmann (2007) Kim et al. (2007) DiDio et al. (2007)

Wustmann et al. (2010) Mohamed et al. (2012) Bega et al. (2014)

F38 F75 F50 M60 M78 M32 F51

Lesion lobe

Lesion laterality

Auditory space

Lesion etiology Schwannoma resected

Recent seizure and/or abnormal EEG

Sex and age

Temporalparietal Temporalparietal Temporalparietal None

L

R

GBM

Yes

M49

Temporalparietal MGB

R

R

N/a

F75

None

None

None

Hemorrhagic stroke None

No

F20

Temporal

L

R

None

Yes

M49

None

None

L

None

No

F67 F49

Temporal Parietal

L L

None *

Yes Yes

F72 M18

Temporal None

L None

R None

ICH Cavernous angioma Meningioma None

Yes No

W68

Parietal

L

R

Metastases

Yes

M61

Temporalparietal/ temporal

R/L

None

Metastases

Yes

EEG, electroencephalogram; M, male; F, female; L, left; R, right; GBM, glioblastoma multiforme; ICH, intracerebral hemorrhage; MGB, Medial geniculate body; N/a, not applicable; UK, unknown. * Localized to subsequently presented auditory stimuli.

PALINACOUSIS Table 25.2 Palinacousis vs auditory hallucinations of psychotic illness

Palinacousis Neutral content Replicas or fragments of original environmental sounds No other psychotic symptoms Triggered by external stimuli

Auditory hallucinations of psychotic Illness Persecutory Highly personalized

One in a constellation of psychotic symptoms No external stimuli

a number of differences between palinacousis and auditory hallucinations of psychotic illness (Table 25.2). Auditory hallucinations tend to be persecutory and personalized, and are typically found in patients with other psychotic symptoms. Auditory hallucinations occur without an external stimulus, whereas palinacousis is neutral in content, environmentally provoked, and usually seen in the absence of psychotic symptoms. There have been 4 cases described in the literature where patients with schizophrenia concomitantly suffered from palinacousis (Malone and Leiman, 1983; Freudenreich and McEvoy, 1996; Prueter et al., 2002; Wustmann et al., 2010). The first case of palinacousis in a patient with schizophrenia was described in 1983 by Malone and Leiman. A 75-year-old woman who 15 years earlier had been diagnosed with schizophrenia began to complain of repeatedly hearing her own voice, voices of people around her, and noises from the television or radio. She described these voices/noises repeating to her exactly as she heard them the first time. The voice/noise would repeat until another external sound occurred, at which point the new sound would be repeated. Seven months after these symptoms started she presented to the hospital. A head CT showed degenerative changes without any focal lesion. An EEG showed generalized slowing with sharp waves in the left temporal regions, which is not an expected finding in schizophrenia. Seven days after starting phenytoin her palinacousis ceased. A repeat EEG 5 days later showed only disorganization, no left temporal irritability. The palinacousis was thought to be related to ongoing perhaps subclinical seizures. In 1996 Freudenreich and McEvoy described a 32-year-old male with a 10-year history of schizophrenia with new-onset palinacousis. In this patient there was a history of traumatic brain injury and suspected seizure disorder previously treated with phenytoin. At the time of his palinacousis he described “an echo; you hear something, and it repeats the same thing several times

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until it goes away.” These symptoms were seen in conjunction with auras of bad smells as well as sensory and visual hallucinations. This patient had two normal EEGs, one of which was sleep-deprived (not clearly performed at the time of an actual event). He also had a normal MRI. Despite the normal EEG, the clinicians suspected seizures and carbamazepine was initiated. The palinacousis then resolved. (Note that a normal EEG does not rule out the presence of seizures.) In 2002 Prueter et al. reported a 20-year-old woman with a 1-year history of schizophrenia who described “echoing voices” in her right ear. Her echoes consisted of words other people said or even words she herself had said. Head CT, MRI, and fluorodeoxyglucose (FDG)-PET were normal. EEGs showed a normal background with slowing over the left temporal region. Dipole modeling of the brain waves demonstrated a left mesiotemporal focus. Four weeks after starting carbamazepine the palinacousis resolved. Lastly, in a patient with newly diagnosed schizophrenia the withdrawal of risperdone triggered palinacousis as well as music hallucinations (Wustmann et al., 2010). This patient described hearing contents of conversations after they had ended. Both EEG and MRI were normal. After 6 weeks (the last 2 of which he was treated with the maximum dose of an antipsychotic (sertindole)), the patient’s palinacousis and musical hallucinations resolved.

Postictal psychosis Auditory hallucinations have been known to occur in epileptics either as part of their ictal phenomenon or as part of a postictal psychosis (PIP). PIP consists of a lucid interval following a seizure prior to the appearance of psychotic symptoms (Kanemoto et al., 2010). The lucid interval after a seizure may last from 12 hours to 6 days. Psychosis typically occurs within a week of normal functioning after a seizure. The psychosis may last from a day to more than 3 months (Logsdail and Toone, 1988). Auditory hallucinations have been described in people with PIP (Slater and Bread, 1963; Logsdail and Toone, 1988; Kanemoto et al., 1996). However these auditory hallucinations have a more menacing quality (Slater and Bread, 1963).

Echolalia Echolalia is derived from Greek echo, “to repeat,” and laliá, meaning “speech” or “talk.” Echolalia is the meaningless repetition of words or phrases immediately after their occurrence. This phenomenon is seen normally in children and pathologically in conditions such as Tourette’s and autism. This behavior is automatic and unintentional. Echolalia and palinacousis are similar in that there is a repetition of heard environmental

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stimulation. They are different in that echolalia is a motor event with speech repetition and palinacousis involves auditory perseveration. Furthermore, in echolalia, the patient will most often repeat the most recent phrase. In palinacousis the patient typically hears the original presenting sound/phrase over and over again. Palinacousis occurs after environmental auditory stimulation; however, it tends to be less changeable, and people often perceive the same sound over and over again despite new sounds in the environment.

Palilalia Palilalia is derived from the Greek word pálin, meaning “again,” and laliá, meaning “speech” or “to talk.” Palilalia was originally described in 1908 by AlexandreAchille Souques. He found this condition in a patient with a right brain stroke leading to left-sided hemiplegia. In palilalia the patient repeats the last one or two words of a sentence, often with increasing rapidity and decreasing volume. Palilalia is often seen in stroke patients, especially with pseudobulbar palsy and in postencephalitic parkinsonism. Palilalia occurs as readily in response to the first as to the second stimulus.

Tinnitus Tinnitus is a peripheral auditory phenomenon. There is typically an intense or prolonged antecedent acoustic exposure (acoustic trauma). For example, many people have experienced a temporary ringing in the ears after a loud rock concert. Unlike palinacousis, the sound is usually stereotyped, with no resemblance in quality to the actual stimulus. Additionally, the sound is usually experienced in the head or bilateral ears, unlike palinacousis, which is experienced as coming from the external environment, often on one particular side (Jacobs et al., 1973). There is a single case of tinnitus occurring with palinacousis (Bega et al., 2014). In this patient the palinacousis was distinguishable from the tinnitus.

PATHOPHYSIOLOGY OF PALINACOUSIS The pathophysiology of palinacousis remains unclear, but it does seem to typically occur in the setting of seizures. The debate continues as to whether palinacousis is a direct symptom of an ongoing seizure (ictal) or a kind of release phenomenon of postictal brain tissue.

Ictal The original reports by Penfield and Perot in 1963 found that auditory inputs could be pathologically retrieved from memory by electric stimulation. A number of authors have suggested that palinacousis is an ictal (abnormal electric) phenomenon (Jacobs et al., 1973;

Malone and Leiman, 1983; Patterson et al., 1988; Auzou et al., 1997; Prueter et al., 2002; DiDio et al., 2007). This conclusion is based on a number of characteristics, including, first, its close temporal relationship to seizures. In 6 out of 7 patients seen by Jacobs et al. (1973), palinacousis appeared just prior to a convulsion or minutes to hours following a seizure. Auzou et al. (1995) described a patient with recurrent partial seizures over 4 days who experienced palinacousis during the same time period but at different moments. Auzou et al. (1997) described another patient with a glioblastoma multiforme who developed partial status epilepticus after a brain biopsy and shortly thereafter developed palinacousis. Patterson et al. (1988) had a patient with palinacousis after a generalized tonic-clonic seizure. Additionally, DiDio et al. (2007) observed palinacousis in 2 patients after aphasic seizures. Second, in a number of the cases reported in the literature there was a positive response to antiseizure medications (Malone and Leiman, 1983; Patterson et al., 1988; Freudenreich and McEvoy, 1996; Prueter et al., 2002). Lastly, although not always performed exactly at the time patients were experiencing palinacousis, EEG data often revealed an abnormal focus (Jacobs et al., 1971; Bekeny and Peter, 1972; Malone and Leiman, 1983; Patterson et al., 1988; Masson et al., 1993; Auzou et al., 1995, 1997; Prueter et al., 2002; DiDio et al., 2007; Kim et al., 2007; Mohamed et al., 2012; Bega et al., 2014) (Table 25.1). This abnormal focus consisted of focal slowing, spikes, or sharp waves. Focal slowing is indicative of underlying cerebral dysfunction and sometimes can be seen in patients with structural abnormalities. Spikes and sharp waves are seen in patients with seizure disorders or in those who are predisposed to seizures. In the article by DiDio et al. (2007), periodic spikes and/or sharp waves (lateralized periodic discharges (LPD), previously known as periodic lateralized epileptiform discharges) were seen in both patients described (Figs 25.3 and 25.4). LPD can be seen in a variety of conditions, including stroke, tumors, and meningioencephalitis. Although considered an interictal pattern, they are associated with epileptic seizures and even status epilepticus (Baykan et al., 2000). Although no electrographic seizures up to this point have been recorded during an episode of palinacousis, there are a number of possibilities to explain this lack of sensitivity. As previously mentioned, the EEG was not always performed while the patients were experiencing palinacousis. Most of the EEGs were routine recordings (20–40-minute studies) and may not have been sufficient to capture a seizure. The epileptic focus may have been too small to be detected by scalp electrodes. An epileptic focus has to involve at least 6 cm2 to be seen with scalp electrodes.

PALINACOUSIS

Fig. 25.3. Electroencephalograph showing short runs of spikes and sharp waves in the left temporal region. (Reproduced from DiDio et al., 2007.)

Fig. 25.4. Electroencephalograph showing lateralized periodic discharges seen maximally in the left posterior temporal lobe. (Reproduced from DiDio et al., 2007.)

Postictal Alternatively, some authors have suggested that palinacousis is a postictal or interictal phenomenon. Below is a case with an extremely detailed workup supporting this hypothesis. Mohamed et al. (2012) described a 68-year-old woman who presented to medical attention due to a change in mental status and unintelligible speech. On exam she was found to have components of expressive and receptive aphasia as well as fluent speech with paraphasic errors. The remainder of her neurologic examination was normal. A brain MRI demonstrated a 10-mm enhancing mass in the left inferior parietal lobe as well as increased T2 signal and diffusion restriction in the left hippocampus, pulvinar, and insular cortex without enhancement. A chest CT revealed a mass in the left upper lung, which turned out to be an invasive non-

465

Fig. 25.5. Selective images of fluorodeoxyglucose positron emission tomography (FDG-PET) scan obtained during events of palinacousis. (A) Hypometabolism in bilateral medial temporal lobes, left (white arrow) worse than right (black arrow). (B) Hypermetabolism in the left parietal mass (black arrow). (Reproduced from Mohamed et al., 2012.)

small-cell carcinoma on biopsy. Her brain lesion was felt most likely to be a metastatic lesion. A routine EEG showed LPD in the left temporocentral region. She was given intravenous levetiracetam. The following day her aphasia resolved but she complained of palinacousis. She heard words or phrases from the end of a sentence or command lasting for minutes to hours arising from her right ear. She would also repeatedly hear music from the television played the previous night or conversations between people. After she mentioned this phenomenon to her physicians she was connected to a continuous EEG monitor. She experienced palinacousis while on the EEG, which showed left temporal slowing but no seizures or epileptiform waves. Her dose of levetiracetam was increased without any benefit. Additionally, the patient underwent FDG-PET during an episode of palinacousis, which revealed hypometabolism of the bilateral medial temporal cortices which was worse on the left. The metastatic lesion showed increased tracer uptake (Fig. 25.5). A repeat MRI showed decrease in the T2 hyperintensities in the left temporal cortex and near-complete resolution of the diffusion restriction. The authors concluded that palinacousis is a postictal phenomenon because it started after levetiracetam was administered and did not improve when this medication was increased. Her reversible MRI findings were thought to be secondary to status epilepticus. The EEG performed during the patient’s episode of palinacousis only showed left temporal slowing. Additionally, there was decreased FDG uptake on PET scan consistent with postictal hypometabolism. Below is an e-mail recently received by one of the author’s patients. This note was written by a woman who is status post resection of a right temporal

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M.C. FIELDS AND L.V. MARCUSE

arteriovenous malformation and had suffered from a recent seizure with left-arm numbness and a left-sided dense hemianopsia. I’m a little concerned I am not only hearing sounds in my left ear but more worrying I hear an echo of people talking around me for 20 minutes to longer even after when it is quiet around. It is hard to ignore. I know I am not crazy but it started in the airplane the day after the seizure. I am in Vegas now and in the plane on the way in I started hearing sounds and echos. Is this a phenomenon that shall pass?

characterized by perceiving music without an external source. In Terao’s case a 75-year-old woman heard old Japanese songs repeatedly as well as the voice of conversations exactly as if they were being repeated over and over. She had no clear seizure history. Her EEG was unremarkable. Her MRI showed possible age-related changes. She did have a SPECT scan of the brain, which showed hypoperfusion in the bilateral thalamus and basal ganglia. This woman was found to have syphilis (not neurosyphilis, as lumbar puncture was negative). Carbamazepine caused itching and anorexia and was subsequently discontinued. She was treated with penicillin and her symptoms gradually improved.

ETIOLOGY Various types of lesions have been noted to cause palinacousis. These include vascular malformations, intracerebral hemorrhages, primary brain tumors, including meningiomas, astrocytomas, and glioblastomas, metastatic tumors, stroke, traumatic brain injury, and meningioencephalitis caused by cystercercosis (Bekeny and Peter, 1972; Jacobs et al., 1973; Patterson et al., 1988; Masson et al., 1993; Freudenreich and McEvoy, 1996; Fukutake and Hattori, 1998; DiDio et al., 2007; Kim et al., 2007; Mohamed et al., 2012; Bega et al., 2014). As noted by Mohamed et al. (2012), various types of lesions result in a similar phenomenology and therefore it is more likely the location rather than the etiology that results in palinacousis. Additionally, there are a number of cases where no lesion was identified yet palinacousis was attributed to alcohol withdrawal (Wustmann and Gutmann, 2007), seizures themselves, or antipsychotic medication withdrawal (Wustmann et al., 2010).

ASSOCIATED PHENOMENA Palinopsia Palinopsia is derived from the Greek word palin, for “again,” and opsia, for “seeing.” Palinopsia is a perceptual illusion in which images persist or recur after the viewed object has been removed (Critchley, 1951). In both palinacousis and palinopsia typically only a segment of the original perceptual event is perseverated. Both of these phenomena occur around the time of seizures. There have been a number of cases where palinacousis was seen in conjunction with palinopsia (Jacobs et al., 1973; Auzou et al., 1997). Palinopsia is thought to be the visual equivalent of palinacousis.

Music hallucinations There are 2 cases of palinacousis occurring in conjunction with music hallucinations (Terao and Matsunaga, 1999; Wustmann et al., 2010). Music hallucinations are

CONCLUSIONS Palinacousis is a rare phenomenon but likely more common than is currently recognized and reported. Verbal perseveration may be a clinical sign that a patient is experiencing palinacousis as a patient may respond to the auditory stimulation as if it were real. Palinacousis typically is perceived from the side of space opposite the brain lesion and is less commonly seen ipsilateral or from the source of the environmental trigger. The brain lesion or dysfunction most often localizes to the temporal lobe, and it appears to be more common with left-sided lesions. This may be because language function is most often on the left, and perhaps the left brain is more vulnerable to auditory perseveration. While the underlying mechanism of palinacousis is still not clear, it nearly always occurs in the clinical setting of recent or ongoing seizures.

REFERENCES Allison RS (1966). Perseveration as a sign of diffuse and focal brain damage. I. Br Med J 2: 1027–1032. Andreasen NC (1997). Linking mind and brain in the study of mental illness: a project for a scientific psychopathology. Science 275: 1586–1593. Auzou P, Hannequin D, Cochin JP et al. (1995). Palinacousie avec he´mianacouse par le´sion temporale gauche. Rev Neurol 151: 129–131. Auzou P, Parain D, Ozsancak C et al. (1997). Enregistrements EEG contemporains d’e´pisodes de palinacousie et de palinopsie. Rev Neurol 153: 687–689. Baykan B, Kinay D, Gokyigit A et al. (2000). Periodic lateralized epileptiform discharges: association with seizures. Seizure 9: 402–406. Becker JT, MacAndrew DK, Fiez JA (1999). A comment on the functional localization of the phonological storage substystem of working memory. Brain Cogn 41: 27–38. Bega D, Wang N, Klein J (2014). Reversible palinacousis from intracranial metastases. Neurohospitalist 4: 22–26. Bekeny G, Peter A (1972). Cysticercus meningoencephalitis hallasi perseveratioval. Orv Hetil 113: 3083–3086.

PALINACOUSIS Buchsbaum BR, Hickok G, Humphries C (2001). Role of left superior temporal gyrus in phonological processing for speech perception and production. Cogn Sci 26: 663–378. Critchley M (1951). Types of visual perseveration; “palinopsia” and illusory visual spread. Brain 74: 267–299. DiDio AS, Fields MC, Rowan AJ (2007). Palinacousis – auditory perseveration: two cases and a review of the literature. Epilepsia 48: 1801–1806. Dorland J (1965). Dorland’s Illustrated Medical Dictionary, 24th edn. Saunders, London. Freudenreich O, McEvoy JP (1996). Palincousis after closehead injury in a patient with schizophrenia. J Clin Psychopharmacol 16: 94. Fukutake T, Hattori T (1998). Auditory illusions caused by a small lesion in the right medical geniculate body. Neurology 51: 1469–1471. Goldstein K (1948). Language and Language Disturbances; aphasic symptom complexes and their significance for medicine and theory of language, Grune & Stratton, New York. Jacobs L, Feldman M, Bender M (1971). Palinacousis or persistent auditory sensations. Trans Amer Neurol Assoc 96: 123–126. Jacobs L, Feldman M, Diamond SP et al. (1973). Palincousis: persistent or recurring auditory sensations. Cortex 9: 275–287. Jasper HH (1931). Is perseveration a functional unit participating in all behavior processes? J Soc Psychol 2: 28–50. Kanemoto K, Kawasaki J, Kawai I (1996). Postictal psychosis: a comparison with acute interictal and chronic psychoses. Epilepsia 37: 551–556. Kanemoto K, Tadokoro Y, Oshima T (2010). Violence and postictal psychosis: a comparison of postictal psychosis, interictal psychosis, and postictal confusion. Epilepsy Behav 19: 162–166. Kim J, Kwon M, Jung J (2007). Palinacousis in temporal lobe intracerebral hemorrhage. Neurology 68: 1321–1322. Koenigs M, Acheson DJ, Barbey AK et al. (2011). Areas of left perisylvian cortex mediate auditory-verbal short-term memory. Neuropsychologia 49: 3621–3619. Leff AP, Schofield TM, Crinion JT et al. (2009). The left superior temporal gyrus is a shared substrate for auditory shortterm memory and speech comprehension: evidence from 210 patients with stroke. Brain 132: 3401–3410. Logsdail S, Toone BK (1988). Post-ictal psychosis. A clinical and phenomenological description. Br J Psychiatry 152: 246–262. MacNalty AS (1961). The British Medical Dictionary, Caxton, London. Mahl GF, Rothenberg A, Delgado JM et al. (1964). Psychological responses in the human to intracerebral electrical stimulation. Psychosom Med 26: 337–368. Malone GL, Leiman HI (1983). Differential diagnosis of palinacousis in a psychiatric patient. Am J Psychiatry 140: 1067–1068.

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Masson C, Sztern A, Cambier J et al. (1993). Palinacousie en relation avec une he´morrhagie temporo-parie´tale droite. Presse Med 22: 12. Meyer K (2011). Primary sensory cortices, top-down projections and conscious experience. Prog Neurobiol 94: 408–417. Mohamed W, Ahuja N, Shah A (2012). Palinacousis – evidence to suggest a post-ictal phenomenon. J Neurol Sci 31: 6–12. Mullen S, Penfield W (1959). Illusions of comparative interpretation and emotion. Production by epileptic discharge and by electrical stimulation in the temporal cortex. Arch Neurol Psychiatry 81: 269–284. Nayani TH, David AS (1996). The auditory hallucination: a phenomenologic survey. Psychol Med 26: 177–189. Neisser A (1895). Krankenvorstellung (Fall von ‘Asymbolie’). Allgemeine Zeitschrift F€ ur Psychiatrie 51: 1061–1021. Pandya DN (1995). Anatomy of the auditory cortex. Rev Neurol (Paris) 151: 486–494. Patterson MC, Tomlinson FH, Stuart GC (1988). Palinacousis: a Case Report. Neurosurgery 22: 1088–1090. Pekkala S, Albert ML, Spiro 3rd A, et al. (2007). Perseveration in Alzheimer’s disease. Dement Geriatr Cogn Disord 26: 109–114. Penfield W, Perot P (1963). The brain’s record of auditory and visual experience. A final summary and discussion. Brain 86: 595–696. Penfield W, Rasmussen T (1958). Cortical stimulation, psychical responses. The excitable cortex in conscious man, MacMillan, New York. Penhune VP, Zatorre RJ, MacDonald JD et al. (1996). Interhemispheric anatomical differences in human primary auditory cortex: probabilistic mapping and volume measurement form magnetic resonance scans. Cereb Cortex 6: 661–672. Prueter C, Waberski TD, Norra C et al. (2002). Palinacousis leading to the diagnosis of temporal lobe seizures in a patient with schizophrenia. Seizure 11: 198–200. Rylander G (1939). Personality Changes after Operations on Frontal Lobes, Oxford University Press, London. Slater E, Bread W (1963). Postictal psychosis typically occurs with a lucid interval, after seizures or a cluster of seizures and is characterized by mild confusion and subsequent amnesia. Br J Psychiatry 109: 95–112. Souques A (1908). Palilalie. Rev Neurol 16: 340–342. Terao T, Matsunaga K (1999). Musical hallucinations and palinacousis. Psychopathology 32: 57–59. Warren RM, Warren RP (1970). Auditory illusions and confusions. Sci Am 223: 30–36. Wustmann T, Gutmann P (2007). Palinakusis bei Alkoholhalluzinose. Psychiat Prax 34: 302–304. Wustmann T, Roettig S, Marneros A (2010). Palinacousis as discontinuation symptom after antipsychotic treatment in a patient with first-episode schizophrenia. Psychopathology 43: 248–249.

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 26

Musicogenic epilepsy JOHN STERN* Department of Neurology, Geffen School of Medicine, University of California, Los Angeles, CA, USA

SEIZURES AND REFLEX EPILEPSIES Musicogenic epilepsy is a form of reflex epilepsy, that is, an epilepsy with seizures that are consistently triggered by a specific stimulus. For musicogenic epilepsy, the stimulus is music, but the seizures are epileptic seizures with the other features typical of epileptic seizures. As a whole, epileptic seizures are episodes of cerebral dysfunction due to transiently abnormal neuronal synchronization and excitation, and this dysfunction produces a behavioral change that may be subjective or objective. Subjective experiences during a seizure can include hallucinations (see Chapter 24), and paramnestic phenomena such as déjá vu, but a large number of specific experiences occur. Objective experiences may be a loss of responsiveness with surroundings or a generalized convulsion with bilateral stiffening, falling, and uncontrolled movements. How the seizure manifests depends on where the seizure starts and where the epileptic abnormality then propagates within the brain. Seizures that originate focally within one cerebral hemisphere may produce a subjective experience and such seizures also can propagate to produce a generalized convulsion. These are termed focal-onset seizures and contrast with generalized-onset seizures, which originate with a bihemispheric distribution on scalp electroencephalogram (EEG). Epilepsies are divided into syndromes that each characterize a clinical condition comprising the seizures, other neurologic features, natural history, and treatment options. Reflex epilepsies are one group of epilepsy syndromes, and this group includes both epilepsies with focal-onset seizures and epilepsies with generalizedonset seizures. Moreover, reflex seizures can occur in epilepsies that are due to diffuse brain dysfunction with accompanying intellectual disability and also epilepsies without significant abnormality other than seizures. As

such, reflex epilepsies include a broad range of epilepsy syndromes and are distinct only because of the association of seizure occurrences with particular triggers. These triggers are almost always either a sensory stimulus or a cognitive state. Epilepsies that are not considered reflex epilepsies also may demonstrate sensitivity to triggers, but the triggers are ones that impact more global aspects of brain function. Examples of non-specific triggers are sleep deprivation, fever, and sedative withdrawal (Engel, 2001, 2006). The fact that these non-specific factors, when sufficiently extreme, can produce seizures in people without epilepsy is one justification for considering them non-specific triggers and therefore not a reflex epilepsy trigger. Another reason is that a majority of people with epilepsy will identify a non-specific factor as a seizure trigger and these individuals encompass the full range of epilepsy syndromes. As such, the non-specific triggers may be affecting the seizure threshold and are not a component of a particular seizure onset or epilepsy type. However, some overlap exists between reflex epilepsies and non-reflex epilepsies with provoked seizures (Illingworth and Ring, 2013). Approximately 6.5% of people with epilepsy have exclusively reflex seizures, as was found in a series of 1000 consecutive patients (Symonds, 1959). The recognized precipitating stimuli for reflex seizures include visual stimuli, somatosensory stimuli, hot-water immersion, arithmetic, reading, other specific cognitive tasks or states, and music. Among the reflex epilepsies in this series, approximately 80% are syndromes with sensitivity to a visual trigger (Symonds, 1959; Kasteleijn-Nolst Trenite, 2012). The visual triggers may be simple or complex stimuli, and this is also true for non-visual triggers. Flickering light is an example of a simple visual stimulus, and a specific scene or image with multiple features is an example of a complex visual stimulus. For an individual

*Correspondence to: John Stern, MD, Department of Neurology, Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Tel: +1-310-825-5745, E-mail: [email protected]

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with reflex epilepsy, the response to a trigger is affected by idiosyncratic sensitivity, duration of exposure, and whether a seizure recently occurred. A refractory period of insensitivity commonly follows a reflex seizure, and this period may be as short as seconds but it more often lasts minutes to hours (Forster et al., 1963). One important aspect of the clinical burden of epilepsy is the unpredictable timing of seizures. For the vast majority of people with epilepsy, seizures occur at apparently random times and much of the risk of injury or death from seizures relates to the lack of adequate opportunity to maximize safety. The risk of an unexpected seizure is far less for individuals with reflex epilepsy if avoidance of the seizure trigger is possible. Avoidance of the trigger is routinely sought, and avoidance may have a great impact on daily life, depending on what is being avoided. This possibility of avoidance produces a different clinical burden for people with reflex epilepsies compared to other epilepsies. People with epilepsy often have to restrict their lives to minimize risks if a seizure occurs, but those with reflex epilepsies also typically restrict their lives to avoid exposures to what are innocuous situations to others, including those with non-reflex epilepsies. This can produce considerable compromise to the breadth of daily activities. For example, an individual with medication-resistant non-reflex epilepsy will not drive a car or engage in recreational activities that would pose a risk if a seizure occurred. However, an individual with reflex epilepsy will not allow exposure to the particular trigger, which may mean avoiding situations with flashing lights, such as at a dance club, or situations with particular forms of music, such as the ambient music in stores or the sound track to some television commercials.

CLINICAL ASPECTS OF MUSICOGENIC SEIZURES Musicogenic epilepsy is especially rare and has a prevalence in the general population as low as 1 in 10 million (Critchley, 1977). Nevertheless, it has been well described and clearly defined. Musicogenic seizures are distinguished from simple stimulus audiogenic seizures by clinical features of the epilepsy and by the complexity of the auditory trigger. Musicogenic epilepsy typically first develops later in life than epilepsy with audiogenic seizures, and the average onset age for musicogenic epilepsy is 28 years. Instances of childhood- and even infant-onset musicogenic epilepsy are known to occur, but they are not the norm. Onset in youth is more common for audiogenic epilepsy (Wieser et al., 1997; Lin et al., 2003; Tayah et al., 2006). Audiogenic seizures are less specific to a type of sound and most commonly are triggered by sudden sounds and occur with a short

latency between the sound and the seizure onset. In contrast, musicogenic seizures are associated with sounds that are in melodic or harmonic combination with complex features that make specific sound triggers for each individual. Musicogenic seizures also typically occur with a longer latency, that can be several minutes of stimulation (Shaw and Hill, 1947; Zifkin and Zatorre, 1998). The musical complexity of the sound and the longer latency indicate a cognitive or emotional aspect to the musicogenic trigger, which differs from the more primary response when random sounds or noise are a trigger (Kaplan, 2003). For most individuals with musicogenic epilepsy, the trigger is a specific piece or type of music and 14 of a case series of 83 patients (17%) had seizures only when triggered by music (Wieser et al., 1997). That is, this 17% are consistently seizure-free when not exposed to music. Although the musicogenic trigger is specific for the affected individual, triggers vary broadly across individuals with musicogenic epilepsy. Triggers can be a sequence of simple tones, voices of particular singers, the complex non-musical sound of a vacuum cleaner, background music that is minimally heard, only music that is actively heard, musical pieces when heard or imagined, and only when performing a specific piece of music, that is, hearing the piece or silently pretending to perform the piece is not a trigger (Critchley, 1937; Poskanzer et al., 1962; Sutherling et al., 1980; Brust, 2001; Carlson and St. Louis, 2004).

DIAGNOSTIC EVALUATION OF MUSICOGENIC SEIZURES Musicogenic epilepsy is a syndrome with focal-onset seizures and a temporal-lobe epileptogenic region is present in about 56 of 71 (79%) (Wieser et al., 1997) (Table 26.1). Lateralization to the right occurs in about 60%. The precise localization of musicogenic seizures has varied across the reported patients, which may be due to both the differences in localization techniques and the heterogeneity of the patients. Localizing the epileptogenic region is impacted by the complexity of the normal neural response to music. This response, which has been theorized to include the limbic circuits beyond the regions of acoustic perception in Heschl’s gyrus, may be the reason for varied localizations and the delay from stimulus to seizure onset. Musicogenic seizure localization usually depends upon functional tests because most patients do not have a structural lesion (Kaplan, 2003). Interictal EEG has been reported to demonstrate abnormal temporal slowing or sharp waves that evolve with an increase in frequency during seizure occurrence (Daly and Barry, 1957; Kaplan, 2003). Source localization of interictal

MUSICOGENIC EPILEPSY Table 26.1 Reported localization of musicogenic seizures for 71 patients Localization

Total

Temporal

Extratemporal

Unilateral focal Right focal Left focal Uncertain Independent Right and left Bilateral R>L L>R Uncertain Generalized

50 34 12 3 1

29 9 3 1

5 3

19 4 8 7 2

4 5 5

3 2

Data from Wieser et al. (1997), Nakano et al. (1998), Genc et al. (2001), Gelisse et al. (2003), Lin et al. (2003), Morocz et al. (2003), Shibata et al. (2006), Tayah et al. (2006), Stern et al. (2006), Cho et al. (2007), Pittau et al. (2008), Marrosu et al. (2009), Mehta et al. (2009), Duanyu et al. (2009).

anterior and midtemporal spikes identified equivalent current dipoles in the posterior transverse temporal gyrus (Shibata et al., 2006). Three patients have been reported to have undergone intracranial EEG monitoring of musicogenic seizures, and the findings are similar to the described patient (Tayah et al., 2006). All three had subdural grids or strips placed across the mesial and lateral temporal lobes with varying additional coverage of the frontal or posterior temporal regions. The electrographic ictal onset for each seizure preceded the behavioral onset and was found to be right mesial temporal for 1 patient, right lateral temporal for 1 patient, and independent right and left mesial temporal for the third patient. Reports include description of the surgical treatment of 3 patients with musicogenic epilepsy in addition to the described patient. All 3 reported patients underwent a temporal-lobe resection with 2 who had an anteriormesial resection (similar to the one described above) and 1 who had a posterior neocortical resection (Tayah et al., 2006; Duanyu et al., 2009). Although all 4 patients eventually became seizure-free, the patient who had a neocortical resection had early postoperative seizures.

ILLUSTRATIVE CASE A 46-year-old right-handed woman had the onset of seizures when she was 21 years old. She had no epilepsy risk factors, including a negative family history for epilepsy or seizures, and no history of head injury. For the first few years after the onset, the seizures were triggered by hearing singing. Over the subsequent few years, the

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triggers became a broader range of other specific triggers that included, at different times, electronic music, heavy-metal rock music, flute music, or what the patient described as “squeaky” high-pitched music. During this time, which spanned approximately 10 years, classical music could be used to abort a seizure and headphones playing classical music were routinely worn while in public as a means of protection from seizures that would be triggered by music that happened to be playing in the immediate environment. Classical music in headphones ceased to be protective about 10 years ago prior to her presentation, when classical music became another trigger. At the time of presentation, all forms of music could be a trigger; however, not all forms were equally likely to provoke a seizure and the music of the performer Madonna was the trigger most likely to produce a seizure. Overall, seizure frequency depended entirely on whether there was exposure to music because most exposures triggered a seizure. A refractory period with minimal seizure risk was present for about an hour after a seizure. The seizures always followed an aura of palpitations, followed by an indescribable feeling in the head, and then an auditory illusion of the triggering music repeating in a loop. The seizure behavior was a loss of awareness with right-hand purposeless movements (automatisms) and sometimes falling due to loss of postural tone. Generalization, with progression into a tonicclonic convulsion, never occurred. The patient’s EEG between seizures (interictal) had intermittent abnormal slowing across the right temporal region and occasional right anterior and midtemporal epileptiform discharges, which indicates dysfunction in the temporal region with an increased predisposition for focal seizures within the temporal lobe. Four seizures were recorded with simultaneous video and EEG and these were stereotyped in behavior and EEG pattern. The behavior matched what was previously described and the ictal EEG demonstrated increased right anterior temporal spike discharge occurrences followed by broad right-sided slowing that evolved into a focal rhythm of up to 5 Hz over the right anterior temporal lobe. Interictal magnetoencephalography (MEG) identified right inferior frontal and midtemporal epileptiform dipoles that corresponded to the scalp EEG’s anterior and midtemporal epileptiform discharges. Ictal MEG identified a right temporal onset with spread to the right frontal region. Structural magnetic resonance imaging (MRI) and fluorodeoxyglucose (FDG) positron emission tomography (PET) were normal. Neuropsychologic testing found strength in verbal memory and severe impairment of the non-verbal domains of memory, problem solving, conceptualization, and organization, which indicated

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right-sided dysfunction based on her right-hand dominance. Overall, this non-invasive evaluation indicated a high likelihood for right temporal-lobe epilepsy, but the extent of the epileptogenic zone and its overlap with auditory function regions were not known. To continue with the evaluation for treatment with resective epilepsy surgery, subdural grid electrodes were placed across the right lateral temporal region with extension of the electrodes into the right mesial temporal and inferior parietal and frontal regions (Fig. 26.1). Recording with these intracranial electrodes identified an increase in interictal epileptiform discharge frequency across the mesial and superior temporal regions when listening to music. Seizures occurred when the music exposure was greater, and the seizure onset zone

Fig. 26.1. X-ray of subdural electrode placement.

co-localized to this region. After a resection of the mesial temporal structures and the anterior 6 cm of the lateral temporal lobe, music did not induce epileptiform discharges. The histopathologic evaluation did not identify abnormality; however, the patient has been seizure-free for the approximately 21 months since surgery.

FUNCTIONAL IMAGING OF MUSICOGENIC SEIZURES Functional imaging research techniques have been used to identify the region of seizure onset in musicogenic epilepsy, and the patient described in the illustrative case had a seizure during functional MRI (fMRI) prior to resective epilepsy surgery. Scalp EEG was recorded during the fMRI using 64 electrodes that covered the full scalp along with ocular and cardiac regions. Subtraction of fMRI artifact on the EEG was performed using techniques that have been described (Goldman et al., 2000; Stern et al., 2006). Music identified by the patient to likely trigger a seizure was played through headphones at the beginning of functional imaging. The first EEG evidence of a seizure occurred approximately 3 minutes into the recording and was the development of rhythmic 2–3-Hz activity across the right hemisphere (Fig. 26.2). This activity evolved with increasing amplitude as the co-localized background activity diminished. Approximately 2 minutes later, the patient reported an aura and then manifested unresponsiveness with her typical ictal automatisms. fMRI was terminated at this time. Because the patient was motionless through the initial 2 minutes of the seizure, the EEG and fMRI onsets were recorded without movement artifact.

Fig. 26.2. Electroencephalogram during functional magnetic resonance imaging demonstrating ictal rhythm across the right temporal region.

MUSICOGENIC EPILEPSY Image analysis was performed using FEAT (fMRI Expert Analysis Tool) version 5.1 as part of FSL (fMRIB’s Software Library, Oxford, UK) version 3.2 (Forman et al., 1995; Woolrich et al., 2001). Statistical analysis included a canonic hemodynamic response function and a cluster threshold determined by a minimum z score of 1.6 and cluster significance of P ¼ 0.05. Analyses were performed using the entire image file, which was 307.5 seconds. The seizure recording with simultaneous EEG and fMRI lasted 132.5 seconds and ended about 15 seconds after the aura occurred and around the time of loss of awareness. Ictal fMRI analysis that used the EEG onset time as the seizure’s beginning and included the entire recorded seizure in the analysis localized the seizure to bilateral, anterior frontal lobes and cerebellum. The ictal fMRI results differed when the seizure onset time was moved to 10 seconds prior to EEG onset based on the recognition that the true seizure onset precedes the scalp EEG onset when scalp EEG is compared to intracranial EEG. Scalp EEG is not as sensitive to the earliest changes as intracranial EEG. The addition of 10 seconds prior to EEG onset resulted in a seizure localization within the right frontal and temporal lobes (Fig. 26.3). Subsequent analyses divided the seizure into 10-second periods with the intention to observe the seizure propagation. This produced a sequence of localizations. The first period began 20 seconds before EEG onset (–20 to 10 seconds) and did not have a significant

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fMRI finding. The next period (–10 to 0 seconds) identified a localization across a large region in the mid and posterior right temporal lobe, the left cerebellar hemisphere, and bilateral inferior parietal/perisylvian regions. During the first 10 seconds after EEG onset (0–10 seconds), localization was within the right anterior and midtemporal lobe and the right perisylvian region immediately superior to the temporal-lobe activity (Fig. 26.4). At the time of the aura, which was a 30-second period at the end of the imaging, fMRI localization was bilateral frontal lobes, bilateral cerebellum, and the right temporal lobe. The onset localization identified with fMRI for the illustrative case patient is consistent with most of the published reports using ictal single-photon emission computed tomography (SPECT). Of the six ictal SPECTs reported, four were right temporal, one was left temporal, and one did not identify a region of hyperperfusion (Wieser et al., 1997; Nakano et al., 1998; Genc et al., 2001; Lin et al., 2003; Gelisse et al., 2003; Cho et al., 2007). Two reports of the right temporal hyperperfusion also included description of mesial temporal hyperperfusion. The one description of left temporal hyperperfusion was of an infant with musicogenic seizures, so the atypical age of the patient raises a question of the differences due to brain development. In one instance, the trigger was found to be unilateral, with a seizure occurring only when monoauricular stimulation was given to the left ear, which was contralateral to the ictal onset on SPECT

Fig. 26.3. Ictal functional magnetic resonance imaging with seizure defined as starting 10 seconds before onset on electroencephalogram and lasting until imaging ended due to seizure-related movements. Threshold set to z  1.6.

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Fig. 26.4. Ictal functional magnetic resonance imaging of first 10 seconds after seizure onset on electroencephalogram. Threshold set to z  1.6.

(Gelisse et al., 2003). Interictal FDG-PET has identified right temporal hypometabolism in musicogenic epilepsy (Wieser et al., 1997; Cho et al., 2007). Reports of simultaneous EEG and fMRI during a musical trigger for musicogenic seizures have identified signal change within the bilateral frontal and right temporal lobes (Morocz et al., 2003; Pittau et al., 2008; Marrosu et al., 2009). The frontal regions included parts of the insula, middle cingulate cortex, orbitofrontal cortex, accumbens, and frontal pole with the right frontal lobe containing larger regions of signal change than the left. The imaging methodology included alternating music stimulus and no stimulus until a seizure occurred, with image results that combined seizure onset and spread. Overall, musicogenic epilepsy has a mostly consistent lateralization and localization with early functional imaging changes in the posterior temporal lobe and subsequent spread through the limbic system and anterior frontal regions.

RELEVANCE OF MUSICOGENIC EPILEPSY TO EPILEPSYAND MUSIC Reflex epilepsies provide opportunities to elucidate the mechanisms of seizure generation and spread because of the predictable seizure occurrence through an association with a particular trigger (Avanzini, 2003). Although the seizures of epilepsies without triggers may be recorded as spontaneous episodes with

video-EEG and with ictal SPECT scanning, predictable occurrence is needed to record a seizure with ictal fMRI, which has considerable advantages by providing high-resolution, tomographic localization of metabolic changes associated with the seizure. Reflex epilepsies also lend opportunities for insight into the integration of the epileptogenic zone into normal brain function by comparing patients’ cerebral responses to the trigger when a seizure occurs to when no seizure occurs, and by comparing the response to the trigger in patients to the response in healthy control individuals. Despite the opportunity and value of ictal fMRI in reflex epilepsies, recordings of either auras or behavioral seizures have not been widely obtained because of the difficulties in identifying the time of seizure onset and obtaining reliable images during seizure-related movement. Original reports used behavioral observation to determine the seizure onset time and identified regions of fMRI signal increase that were concordant with the behavioral indicators of the seizure focus (Jackson et al., 1994; Detre et al., 1996; Krings et al., 2000). These reports relied upon the seizures not producing sufficient movement to cause problematic imaging artifact. The issue of seizure-produced movement artifact was avoided in a more recent report of 3 patients who had seizures with significant movement during fMRI when the image analysis compared the 1-minute period prior to the seizure to a 1-minute period several minutes earlier (Federico et al., 2005). Significant fMRI signal increase

MUSICOGENIC EPILEPSY 475 was observed with localizations that were concordant the anterior frontal regions demonstrating the fMRI with the results of some or all of each patient’s standard findings. Overall, the fMRI localizations for the musicodiagnostic tests. With or without significant movement, genic seizures are concordant with the intracranial the ictal fMRI for all of these investigations depended EEG’s localizations and the fMRI provides supplemenon the seizure’s behavioral onset, which may follow tary information about a larger extent of involvement. the electrophysiologic onset by seconds to minutes. The fMRI results also provide better understanding Therefore, the results may not indicate the earliest epiof the phenomenon of musicogenic seizures. Morocz leptic changes, but they do support fMRI’s sensitivity and colleagues (2003) report the gyrus rectus as associfor early ictal changes. In contrast, reflex epilepsies have ated with the response to ictogenic music and both the an advantage over spontaneous seizures for investigatorbitofrontal and anterior temporal lobes as associated ing early seizure changes by limiting the earliest seizure with the occurrence of musicogenic auras.. This supports onset time to the time of the trigger, whereas an earliest the concept of musicogenic epilepsy as a limbic epilepsy possible seizure onset time cannot be defined for sponthat includes both temporal and frontal limbic regions. In taneous seizures. the illustrative case, fMRI signal change was present in EEG that is recorded during fMRI provides a marker the gyrus rectus and not the temporal lobe at the time just of seizure propagation after the trigger is delivered, but prior to the aura, which agrees with Morocz and colit does not provide the time of seizure onset. Comparileagues’ findings. However, the presented patient’s aura sons of scalp and intracranial EEG have shown that occurred after more than 2 minutes of epileptiform extensive propagation can be present before the first epiabnormality on the EEG, so the gyrus rectus finding leptiform abnormality develops on scalp EEG. Theremay be relevant to the epilepsy and not necessarily a fore, the occurrence of fMRI signal changes prior to component of music perception. the seizure’s EEG onset presents a question of whether Another sign of seizure propagation is evident in the the changes are due to normal function or the seizure. frontal-lobe signal changes that occur with the evolution This is due to fMRI’s lack of specificity for epilepsy, of the seizure into its behavioral manifestation. At the which contrasts with EEG’s high specificity for epilepsy. seizure’s onset, the frontal-lobe signal was limited and The earliest fMRI changes in the illustrative case right-sided. In the final 30 seconds of imaging, the fMRI included bilateral inferior parietal and perisylvian signal change expands frontally to become bilateral and regions, which are outside the identified epileptogenic more widespread. As expected, this is accompanied by zone, but these regions are adjacent to auditory cortex cerebellar signal change that also becomes bilateral that may be important in music perception, engaged in and more widespread. This greater and bilateral musicogenic epilepsy without being within the epileptofrontal-lobe involvement with behavioral onset agrees genic region, or both. If engaged in musicogenic epiwith the observation of widespread intracranial EEG lepsy, the regions may be part of an antiseizure ictal activity at the time of behavioral onset. It also demhomeostatic response to the seizure onset. Regardless onstrates fMRI’s superior sensitivity to scalp EEG of these considerations, the seizure control that has been because the simultaneous EEG demonstrated only minor achieved from resections sparing the parietal and perievolution. The EEG progressed during the seizure with sylvian regions indicates that these regions are not within an increase in the ictal rhythm’s amplitude and a the epileptogenic region. decrease in the amplitude of the background activity, The progression of ictal fMRI seizure localization but it did not indicate greater frontal-lobe involvement. through the seizure supports fMRI’s potential to moniAlthough this seizure had electrographic abnormality for tor a seizure’s evolution from preictal changes through a longer time than most temporal-lobe seizures before the EEG onset to the behavioral onset. This surpasses behavioral onset, the significant frontal-lobe changes the capacity of ictal SPECT, which provides one image occurred only at the end of the recorded period, so this of the ictus. Nevertheless, the illustrative case, 5 of the propagation pattern also may be observable for shorter reported cases with ictal SPECT, and the 3 reported cases temporal-lobe seizures. The progression to include bilatof ictal fMRI are concordant in indicating a temporaleral regions is the expected anatomic correlate to the loss lobe localization for musicogenic epilepsy. fMRI’s supeof awareness or responsiveness, which is conventionally rior sensitivity may explain its inclusion of the frontal understood to occur once the epileptic abnormality lobes, and the serial images from the presented case’s becomes bilateral on intracranial EEG. analyses may explain the frontal-lobe involvement as Mesial temporal-lobe epilepsy is the most common propagation from a temporal-lobe origin. Observation form of focal epilepsy. The epileptogenic zone typically of this propagation through intracranial EEG would includes the hippocampus, but the syndrome may be connot be possible for the 4 patients who had intracranial sidered more broadly as a limbic epilepsy. As such, olfacEEG because the electrode coverage did not include tory, emotional, and mnestic experiences are common.

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Auditory hallucinations, which arise from neocortical regions of the temporal lobes, are not as common (see Chapter 24), and this also supports the consideration of mesial temporal-lobe epilepsy as a limbic epilepsy. Nevertheless, seizures with neocortical onset may propagate into the limbic system and produce behavioral features of limbic seizures. Musicogenic seizures demonstrate this by most commonly manifesting as focal dyscognitive seizures with automatisms. However, musicogenic seizures also demonstrate the limbic system’s epileptic sensitivity to sensory input through neocortex. Apparently, the limbic system’s subsequent processing of the sound experience produces the seizure. Memory and emotion may both be involved, but the occurrence in an infant supports the possibility of an early-life brain’s intrinsic sensitivity to music even without the experiences and learning that music produces through development and over years of adulthood. Overall, the limbic system’s common involvement in musicogenic seizures and the successful treatment of musicogenic seizures with anteromesial temporal-lobe resections support the understanding that musicogenic epilepsy is a limbic epilepsy. As such, primary auditory cortex is not the typical generator of musicogenic seizures. With an anatomic basis in the limbic system, the affective experience of music is integral to the seizure development. This affective experience may be for a specific musical piece or musical theme, regardless of the instrument or voice performing it, or for a specific musical quality that an instrument or voice produces, regardless of the music piece (Brien and Murray, 1984). Cerebral processing of music includes both thematic and mechanic aspects, and clinical experience has shown that each may be integrated into epileptic dysfunction.

ACKNOWLEDGMENTS This study was supported by NINDS K23 grant NS044936 and the Leff Family Foundation.

REFERENCES Avanzini G (2003). Musicogenic seizures. Ann N Y Acad Sci 999: 95–102. Brien SE, Murray TJ (1984). Musicogenic epilepsy. Can Med Assoc J 131: 1255–1258. Brust J (2001). Music and the neurologist. Ann N Y Acad Sci 930: 143–152. Carlson C, St. Louis EK (2004). Vacuum cleaner epilepsy. Neurology 63: 190–191. Cho J-W, Seo DW, Joo EY et al. (2007). Neural correlates of musicogenic epilepsy: SISCOM and FDG-PET. Epilepsy Res 77: 169–173. Critchley M (1937). Musicogenic epilepsy. Brain 60: 13–27.

Critchley M (1977). Musicogenic epilepsy. In: M Critchley, RA Hensen (Eds.), Music and the Brain, Heinemann, London. Daly DD, Barry MJ (1957). Musicogenic epilepsy: report of three cases. Psychosom Med 19: 399–408. Detre JA, Alsop DC, Aguirre GK et al. (1996). Coupling of cortical and thalamic ictal activity in human partial epilepsy: demonstration by functional magnetic resonance imaging. Epilepsia 37: 657–661. Duanyu N, Yongjie L, Guojun Z et al. (2009). Surgical treatment for musicogenic epilepsy. J Clin Neurosci 17: 127–129. Engel Jr J (2001). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 42: 796–803. Engel Jr J (2006). ILAE classification of epilepsy syndromes. Epilepsy Res 70S: S5–S10. Federico P, Abbott DF, Briellmann RS et al. (2005). Functional MRI of the pre-ictal state. Brain 128: 1811–1817. Forman SD, Cohen JD, Fitzgerald M et al. (1995). Improved assessment of significant activiation in functional magnetic resonance imaging (fMRI): use of cluster-size threshold. Magn Reson Med 33: 636–647. Forster FM, Chun RWM, Forster MB (1963). Conditioned changes in focal epilepsy: I. In animals with intact central nervous system. Arch Neurol 9: 188–193. Gelisse P, Thomas P, Padovani R et al. (2003). Ictal SPECT in a case of pure musicogenic epilepsy. Epileptic Disord 5: 133–137. Genc BO, Genc E, Tastekin G et al. (2001). Musicogenic epilepsy with ictal single photon emission computed tomography (SPECT): could these cases contribute to our knowledge of music processing? Eur J Neurol 8: 191–194. Goldman RI, Stern JM, Engel Jr J et al. (2000). Acquiring simultaneous EEG and functional MRI. Clin Neurophysiol 111: 1974–1980. Illingworth JL, Ring H (2013). Conceptual distinctions between reflex and nonreflex precipitated seizures in the epilepsies: a systematic review of definitions employed in the research literature. Epilepsia 54: 2036–2047. Jackson GC, Connelly A, Cross JH et al. (1994). Functional magnetic resonance imaging of focal seizures. Neurology 44: 850–856. Kaplan PW (2003). Musicogenic epilepsy and epileptic music: a seizure’s song. Epilepsy Behav 4: 464–473. Kasteleijn-Nolst Trenite DGA (2012). Provoked and reflex seizures: Surprising or common? Epilepsia 53 (Suppl. 4): 105–113. Krings T, Topper R, Reinges MH et al. (2000). Hemodynamic changes in simple partial epilepsy: a functional MRI study. Neurology 54: 524–527. Lin K-L, Wang H-S, Kao P-F (2003). A young infant with musicogenic epilepsy. Pediatr Neurol 28: 379–381. Marrosu F, Barberini L, Puligheddu M et al. (2009). Combined EEG/fMRI recording in musicogenic epilepsy. Epilepsy Res 84: 77–81. Mehta AD, Ettinger AB, Perrine K et al. (2009). Seizure propagation in a patient with musicogenic epilepsy. Epilepsy Behav 14: 421–424.

MUSICOGENIC EPILEPSY Morocz IA, Karni A, Haut S et al. (2003). fMRI of triggerable aurae in musicogenic epilepsy. Neurology 60: 705–709. Nakano M, Takase Y, Tatsumi C (1998). A case of musicogenic epilepsy induced by listening to American pop music. Rinsho Shinkeigaku 31: 1067–1069. Pittau F, Tinuper P, Bisulli F et al. (2008). Videopolygraphic and functionalMRI study of musicogenic epilepsy. A case report and literature review. Epilepsy Behav 13: 685–692. Poskanzer DC, Brown AE, Miller H (1962). Musicogenic epilepsy caused only by a discrete frequency band of church bells. Brain 85: 77–92. Shaw D, Hill D (1947). A case of musicogenic epilepsy. J Neurol Neurosurg Psychiatry 10: 107–117. Shibata N, Kubota F, Kikuchi S (2006). The origin of the focal spike in musicogenic epilepsy. Epileptic Disord 8: 131–135. Stern JM, Tripathi M, Akhtari M et al. (2006). Musicogenic seizure localization with simultaneous EEG and functional MRI. Neurology 66 (Suppl. 2): 90.

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Sutherling WW, Hershman LM, Miller JQ et al. (1980). Seizures induced by playing music. Neurology 30: 1001–1004. Symonds C (1959). Excitation and inhibition in epilepsy. Proc R Soc Med 52: 305–402. Tayah TF, Abou-Khalil B, Gilliam FG et al. (2006). Musicogenic seizures can arise from multiple temporal lobe foci: intracranial EEG analyses of three patients. Epilepsia 47: 1402–1406. Wieser HG, Hungerbuhler H, Siegel AM et al. (1997). Musicogenic epilepsy: review of the literature and case report with ictal single photon emission computed tomography. Epilepsia 38: 200–207. Woolrich MW, Ripley BD, Brady M et al. (2001). Temporal autocorrelation in univariate linear modeling of FMRI data. Neuroimage 14: 1370–1386. Zifkin BG, Zatorre RJ (1998). Musicogenic epilepsy. In: BG Zifkin, F Andermann, A Beaumanoir et al. (Eds.), Reflex epilepsies and reflex seizures, Advances in Neurology, Vol. 75. Lippincott-Raven, Philadelphia.

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 27

Deafness in cochlear and auditory nerve disorders KATHRYN HOPKINS* School of Psychological Sciences, University of Manchester, Manchester, UK

INTRODUCTION Sensorineural hearing loss is the collective term for hearing damage to the cochlea and auditory nerve, and is by far the most common type of hearing loss in adults, accounting for over 90% of all cases (Davis, 1995; Cruickshanks et al., 1998; Wilson et al., 1998). Sensorineural hearing loss is a heterogeneous disorder, which can arise due to damage to several structures in the peripheral auditory system and has many causes. This chapter describes the pathologies that affect the cochlea and the auditory nerve and their perceptual consequences.

STRUCTURES AFFECTED BY SENSORINEURAL HEARING LOSS Sensorineural hearing loss can occur due to damage to one or several structures in the cochlea or auditory nerve. Here the role of each structure is briefly discussed, together with the results of animal studies investigating the effects of damage to each of these structures on auditory coding.

Outer hair cells Outer hair cells amplify basilar membrane motion (Ashmore, 1987). The amount of amplification is greatest at low input levels and at frequencies close to the characteristic frequency of the place on the basilar membrane where the hair cell is located (Rhode, 1971; Sellick et al., 1982). These properties mean that outer hair cells improve hearing sensitivity and lead to a compressive basilar membrane growth function, which is reflected in neural activity in the auditory nerve (Yates et al., 1990). If outer hair cells are damaged, this compression is lost and detection thresholds are elevated (Ryan and Dallos, 1975). The basilar membrane response becomes

more linear, and a reduced range of sound levels can be encoded (Patuzzi et al., 1989). Outer hair cells also substantially improve the frequency selectivity of the basilar membrane (the ability to separate complex sounds into their constituent frequencies). Outer hair cell dysfunction therefore also results in a reduction in the sharpness of basilar membrane tuning (Ruggero and Rich, 1991).

Inner hair cells Inner hair cells transduce basilar membrane vibration into electrical activity. Basilar membrane vibration causes stereocilia on the surface of inner hair cells to bend (see Fig. 1.1, Chapter 1). Tip links that connect adjacent stereocilia stretch, opening cation channels and allowing potassium ions to enter the cells, causing depolarization. Inner hair cells synapse with type I auditory nerve fibers, and depolarization of the inner hair cells increases the probability of action potential generation in these fibers. This provides the main route for transmission of information along the auditory nerve to the central auditory system. Several animal studies have investigated the effects of inner hair cell loss on auditory coding using carboplatin, which causes selective inner hair cell loss in some species. Takeno et al. (1994) found that thresholds for the compound action potential (which is a measure of neural activity in the auditory nerve) was reduced in proportion with the amount of inner hair cell loss caused by carboplatin administration. Wang et al. (1997) examined responses from individual auditory nerve fibers following selective inner hair cell loss as well as compound action potential thresholds. They found, like Takeno et al., that severe inner hair cell loss caused elevation of compound action potential thresholds, but that thresholds for many single auditory nerve fibers were normal, and had normal frequency tuning. Less

*Correspondence to: Kathryn Hopkins, University of Manchester, School of Psychological Sciences, Manchester, M13 9PL, UK. E-mail: [email protected]

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severe inner hair cell loss (15–28% along the length of the cochlea) did not result in significant elevation of compound action potential thresholds, although it did lead to reduced compound action potential amplitude at higher levels. These data are shown in Figure 27.1. The top panel shows compound action potential amplitudes for auditory nerve fibers at 8 kHz for control animals and animals subject to a single dose of carboplatin.

The bottom panel shows compound action potential thresholds as a function of frequency for the same groups. The effect of inner hair cell loss on auditory coding at higher levels of the auditory system is as yet unknown.

Stria vascularis The stria vascularis maintains the ionic composition of endolymph, which is found in the scala media and surrounds the inner and outer hair cells. Unlike most extracellular fluid, endolymph has a high concentration of potassium ions, and a low concentration of sodium ions, leading to a positive endocochlear potential. The correct ionic composition of endolymph is essential for normal cochlear function, because both the outer and inner hair cells rely on entry of potassium ions to cause depolarization; this leads to mechanic shortening in the case of outer hair cells, and auditory transduction in the case of inner hair cells if the stria vascularis is not functioning correctly, and the concentration of potassium ions in the scala media is insufficient. Sewell (1984) studied the effects of furosemide administration on auditory nerve responses. Furosemide blocks the Na+/K+ transporter in the stria vascularis that maintains the endocochlear potential, so this provides a way of examining the effects of stria vascularis dysfunction independently. Sewell found that furosemide administration led to elevated thresholds, both in single auditory nerve fibers and in the compound action potential. Tuning of individual auditory nerve fibers became broader, in a similar way as occurs in the case of outer hair cell loss. However, the tuning curves were qualitatively different to those reported following selective outer hair cell loss, in that the sensitivity to tones remote from the characteristic frequency of the nerve fiber was reduced (in the “tail” of the tuning curve), whereas this was not the case for tuning curves in the case of selective outer hair cell loss. A possible explanation for this observation is that dysfunction of the stria vascularis and endocochlear potential affects both outer and inner hair cells. Examples of tuning curves before and after furosemide treatment are shown in Figure 27.2.

Auditory nerve

Fig. 27.1. (A) Mean compound action potential (CAP) input/ output (I/O) functions at 8 kHz of the single-dose group (n ¼ 8 ears) and the normal control group (n ¼ 29; shaded area is 95% confidence interval). (B) Mean (n ¼ 8) CAP thresholds of single-dose carboplatin group and control group (n ¼ 29; shaded area is 95% confidence interval). SPL, sound pressure level. (Reproduced from Wang et al., 1997.)

Damage to the auditory nerve can take two forms: auditory nerve fibers can degenerate completely, or alternatively, demyelination can occur. Degeneration can occur secondary to inner hair cell loss – auditory nerve fibers degenerate if input from the cochlea is reduced or lost (Webster and Webster, 1981; Simpson, 2009). More recent evidence has shown that auditory nerve degeneration can also occur in the absence of cochlear damage (so-called primary auditory nerve degeneration). Kujawa and Liberman (2009) found that up to 50% of

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Fig. 27.2. Representative examples of the changes in single-fiber tuning curves following intravenous furosemide administration. In all cases, the preinjection (control) tuning curve is that with the lowest threshold. The lower panels contain plots of the difference between the preinjection tuning curve and those obtained following furosemide administration. SPL, sound pressure level; TM, tympanic membrane. (Reproduced from Sewell, 1984.)

auditory nerve fibers degenerated following a single period of noise exposure that did not cause permanent outer or inner hair cell damage in mice. The auditory brainstem response thresholds recovered to normal (following a period of temporary threshold shift) even though the loss of auditory nerve fibers was permanent, suggesting that sensitivity to weak sounds can be unaffected by substantial auditory nerve fiber loss. The amplitude of the auditory brainstem response to highlevel sounds was, however, reduced when compared with control animals; the authors hypothesized that coding of above-threshold sounds would be affected, even though detection thresholds appeared to be normal. Auditory nerve fibers are normally surrounded by a myelin sheath, which increases the speed of transmission of action potentials along the auditory nerve. El-Badry et al. (2007) examined the effects of myelin damage on the auditory nerve compound action potential and auditory brainstem response amplitudes. They found that both mild and severe myelin damage increased the transmission latency to the central auditory system, and that severe (but not mild) myelin damage causes a reduction in both the compound action potential and auditory brainstem response. The authors hypothesized that this reduction in amplitude occurred due to desynchronization of activity in different auditory nerve fibers, which might be expected if myelin damage is not uniform.

ETIOLOGY Many causes of sensorineural hearing loss have been documented; some of the most common are summarized in Table 27.1 and are discussed here.

Hereditary causes Mutations in many genes can cause sensorineural hearing loss (for a review, see Makary et al., 2011). Several genetic syndromes, such as Usher syndrome (Bentler, 2005), Jervell and Lange-Nielsen syndrome (Wilson et al., 1999), and Pendred syndrome (He et al., 2007), have sensorineural hearing loss as a symptom. Additionally hundreds of mutations have been identified that cause sensorineural hearing loss with no other associated symptoms (so-called non-syndromic hereditary hearing loss). The structures affected by hereditary hearing loss depend on the nature of the mutation; mutations have been identified that affect all of the structures described above. It should also be noted that there is emerging evidence for a genetic contribution to a susceptibility to many forms of acquired hearing loss. For example, susceptibility to noise-induced hearing loss (Herman et al., 1977), ototoxic drugs (Marmel et al., 2013), and agerelated hearing loss (Weiss and Rose, 1988) have all been shown to have a large genetic component.

Noise Exposure to high noise levels causes damage to the cochlear and auditory nerve, leading to sensorineural hearing loss. The degree of noise-induced hearing loss is related to both the level of the noise and the duration of exposure. Several mechanisms for noise-induced hearing damage have been identified. Outer hair cells can be damaged or lost as a result of mechanic damage, or due to the generation of reactive oxygen species, which can lead to cell death (Lebo and Reddell, 1972). Reactive oxygen species are produced as a normal product of

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Table 27.1 Common etiologies of sensorineural hearing loss Etiology

Examples

Structures affected

Mechanism

Hereditary

Usher syndrome, Lange-Nielsen syndrome, Pendred syndrome, others Aminoglycoside antibiotics, furosemide, salicylic acid, carboplatin, others Birth complications, cardiovascular problems, cigarette smoking

Heterogeneous

Heterogeneous

Hair cells, stria vascularis

See Table 27.2

Hair cells Stria vascularis

Reactive oxygen species lead to cell death Reduced endocochlear potential (reversible) Direct mechanic Reactive oxygen species lead to cell death Excitotoxicity Strial degeneration, accumulated insults (e.g., noise, hypoxia, otoxic drugs)

Ototoxic drugs Hypoxia

Noise

Occupational, recreational

Aging

–

Cochlear partition Hair cells Auditory nerve Hair cells, stria vascularis, auditory nerve

metabolism, but during noise exposure, reactive oxygen species production increases, and causes damage to several outer hair cell structures, including DNA. Likewise, reactive oxygen species can also damage inner hair cells, although inner hair cells appear less susceptible to damage. Glutamate excitoxicity is another mechanism of noise-induced hearing damage. Glutamate is an excitatory neurotransmitter, which is released at the synapse between inner hair cells and auditory nerve fibers. Excess glutamate is toxic and causes disruption of the synapse (Moore et al., 2012). This excitotoxicity was originally thought to cause only temporary damage, but more recent studies have found evidence of permanent degeneration of auditory nerve fibers following excessive noise exposure (Kujawa and Liberman, 2009; Lin et al., 2011b).

Ototoxic drugs Many drugs have been found to be associated with sensorineural hearing loss, and different substances are associated with damage to different structures. Table 27.2 lists some of the commonly used drugs that are known to be ototoxic, together with the hypothesized mechanisms of damage.

Hypoxia Hypoxia (either local or systemic) can occur for a variety of reasons, for example, due to birth complications, cardiovascular problems such as atherosclerosis, or cigarette smoking. Damage to the auditory system depends on hypoxia severity and duration, but has been reported to affect both the inner and outer hair cells of the cochlea (Mazurek et al., 2006).

Aging There is no doubt that the prevalence of sensorineural hearing loss increases dramatically with age (see Chapter 20). Figure 27.3 shows the prevalence of hearing loss estimated as a function of age for the British (Davis, 1989, 1995) and Australian (Wilson et al., 1998, 1999) populations. A similar increase in prevalence of hearing loss with age has been reported in the United States (Lin et al., 2011a). Both Davis (1995) and Wilson et al. (1999) reported that sensorineural hearing loss accounted for over 90% of all cases of hearing loss, and so most of the increase in prevalence with age can be attributed to sensorineural hearing loss. Age-related hearing loss is characterized by a progressive increase in thresholds at high frequencies. Schuknecht and Gacek (1993) described a series of histologic postmortem studies on human subjects with agerelated hearing loss. Schuknecht and Gacek reported that age-related hearing loss was associated with damage to the hair cells, stria vascularis, and auditory nerve, but that the relative damage to these structures varied among individuals. More recent work has found that primary auditory nerve degeneration occurs with age, even among individuals with no damage to the cochlea (Makary et al., 2011). The extent to which age-related hearing loss occurs due to purely age-related effects is, however, unclear. It is possible that hearing damage associated with aging may occur at least partly due to cumulative damage caused by exposure to environmental insults such as noise and ototoxic drugs. Animal studies can shed some light on this question by assessing the effects of aging on the auditory system while carefully controlling exposure

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Table 27.2 Hypothesized mechanisms of action for some of the most commonly used ototoxic drugs Otoxic drugs

Structures affected

Mechanism

Salicylic acid

Hair cells (in particular outer hair cells)

Cisplatin

Outer hair cells

Furosemide

Stria vascularis

Carboplatin

Selective inner hair cell damage in chinchillas, but affects both inner and outer hair cells in humans

Oxidative stress causing hair cell loss Reduced endocochlear potential Oxidative stress causing outer hair cell loss Reversible reduction in the endocochlear potential Inner hair cell loss in chinchillas Uncertain mechanism in humans

DIAGNOSIS

100 Davis et al. 1995

Prevalence (%)

80

The following section discusses the tests used to diagnose sensorineural hearing loss. No single test can definitively diagnose damage to a single structure, although by combining the results of several tests, the structures affected can be more accurately determined. Table 27.3 shows the most commonly used diagnostic tests, together with possible findings and interpretations.

Wilson et al. 1998

60

40

Threshold measurement 20

0

15 − 50

52 − 60

61 − 70

71 +

Age (years)

Fig. 27.3. Estimated hearing loss (HL) prevalence as a function of age for the Australian and British populations. HL was defined as mean audiometric thresholds at octave frequencies between 0.5 and 4 kHz greater than 25 dB HL. Sensorineural HL accounted for over 90% of cases across age groups. (Plotted from data reported by Davis, 1989, 1995, and Wilson et al., 1998, 1999.)

to noise and other insults. Mills et al. (1990) found that auditory evoked potential thresholds measured for quiet-reared gerbils (analogous to audiometric thresholds for human listeners) were elevated compared with young gerbils, providing evidence to support the idea that aging causes hearing loss independently of external otologic insults. Schulte and Schmiedt (1992) reported that the endocochlear potential and the activity of ion pumps in the stria vascularis were reduced in quiet-aged gerbils, providing a possible mechanism for age-related hearing loss.

Sensorineural hearing loss is usually diagnosed using pure-tone audiometry, for which the quietest detectible sounds are measured as a function of frequency (Hughson and Westlake, 1944). Patients are asked to indicate when they hear a sound, and the sound level is varied adaptively to determine a threshold value. Measured thresholds are compared with normative threshold values measured using young listeners with no known otologic abnormalities, to give a measure of threshold elevation in decibel hearing level (dB HL) (ANSI, 2004). Sensorineural hearing loss is differentiated from conductive hearing loss (where hearing loss occurs due to impaired transmission of mechanical vibration to the cochlea) by measuring audiometric thresholds via both air and bone conduction (Hood, 1957). Air conduction audiometry delivers sounds to the eardrum using either headphones or a loudspeaker; bone conduction audiometry uses a bone conductor on the skull (usually on the mastoid prominence or forehead) to stimulate the cochlea directly, bypassing the outer and middle ear. Sensorineural hearing loss is indicated if air and bone conduction thresholds are elevated by a similar amount; a conductive hearing loss is indicated if air conduction thresholds are elevated more than bone conduction thresholds.

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Table 27.3 Diagnostic tests commonly used to diagnose cochlear and auditory nerve disorders Test

Finding

Indication

Air conduction audiometry Bone conduction audiometry Otoacoustic emissions

Elevated thresholds

Conductive or sensorineural loss Sensorineural loss

Auditory brainstem response

Elevated thresholds Reduced or absent emissions Reduced or absent emissions with evidence of normal middle-ear function Elevated thresholds Absent or severely disordered response at all levels with evidence of normal outer hair cell function

Outer hair cell dysfunction or conductive loss Outer hair cell dysfunction Conductive or sensorineural hearing loss Inner hair cell or auditory nerve dysfunction

Analogous electrophysiologic techniques can also be used to estimate detection thresholds; the most commonly used procedures are measurement of the auditory brainstem response or the auditory steady-state response. Both of these techniques are used to determine the level at which a response that is synchronized with presentation of a sound stimulus can just be detected in electric activity recorded using electrodes placed on the scalp. The advantage of these procedures for estimating thresholds is that they do not require the cooperation of the patient, and so are often used when testing patients who are unable to cooperate with behavioral testing, such as young children.

non-linear distortion products generated in the cochlea and transmitted back through the middle ear to the outer ear, where they can be detected as sound using a sensitive microphone. Otoacoustic emissions are generated by outer hair cells, and so can be used to determine if outer hair cells are functioning normally. This allows hearing loss due to damage to the outer hair cells and other structures such as the inner hair cells and auditory nerve to be differentiated to some degree. However, the amplitude of otoacoustic emissions is only weakly correlated with degree of outer hair cell dysfunction (Bernstein et al., 2013), so they are only really useful in determining whether outer-cell damage is present or absent.

Differentiating damage to structures in the cochlear and auditory nerve

Diagnosing auditory nerve dysfunction

Measurement of detection thresholds using behavioral audiometry or analogous electrophysiologic techniques cannot alone be used to differentiate damage to different structures in the cochlear and auditory nerve. Further tests can give some information about the particular structures affected, although diagnostic techniques capable of definitively identifying damage to different structures in the human peripheral auditory system are not yet available. Furthermore, there is evidence that mild inner hair loss or even substantial auditory nerve fiber loss is not manifest by a change in detection threshold in animals (see above). Such damage is therefore not expected to be reflected in threshold measurements in humans, and so would go undetected with current diagnostic techniques.

Auditory nerve damage is suspected when there is evidence of normal cochlear function (for example, through the presence of otoacoustic emissions), but the auditory brainstem response is absent or highly disordered. Patients who meet these criteria are diagnosed with auditory neuropathy spectrum disorder (for a detailed review, see Chapter 28). However, this pattern of results could also occur due to selective inner hair cell loss (for example, due to an otoferlin mutation), or due to damage to the auditory brainstem. Likewise, these diagnostic criteria are unlikely to detect mild or moderate auditory nerve fiber loss, or auditory nerve damage that is coupled with cochlear dysfunction. Consequently, it is currently not possible to definitively diagnose auditory nerve damage in humans.

Otoacoustic emissions

THE EFFECTS OF SENSORINEURAL HEARING LOSS ON AUDITORY CODING

Otoacoustic emissions (Kemp, 2002) can be used to assess the integrity of outer hair cells. Otoacoustic emissions are

Sounds can be characterized by their changing frequency spectrum. Coding of this information in the peripheral

DEAFNESS IN COCHLEAR AND AUDITORY NERVE DISORDERS

The effects of cochlear damage on auditory coding RATE PLACE CODING Rate place coding in the auditory nerve relies on separation of a sound into its component frequencies. The ability of the auditory system to separate a complex sound into its constituent frequency components is known as frequency selectivity. Several studies have assessed the effects of sensorineural hearing loss on frequency selectivity, and all have shown a significant correlation between degree of hearing loss (as measured by the detection threshold) and the broadness of auditory filters, with more substantial hearing loss associated with broader auditory filters (Martin, 1974; Florentine et al., 1980; Peters and Moore, 1992; Hopkins and Moore, 2011). Figure 27.4 shows auditory filter bandwidths measured for 40 listeners with a range of audiometric thresholds at the center frequency of the

0.8

485

500 Hz 1000 Hz 2000 Hz

ERB / center frequency

auditory system can occur by two mechanisms: rate place coding and temporal coding. Rate place coding occurs when information is transmitted according to the profile of neural activity across an array of auditory neurons, where each neuron is “tuned” to a characteristic frequency. Temporal coding occurs when information is transmitted by the timing of neural spikes in relation to each other, either in a single neuron or a population of neurons. Auditory nerve fibers have a greater probability of firing at peaks in a sound waveform, a phenomenon that is known as “phase locking” (Rose et al., 1967). Phase locking occurs most robustly at low frequencies, and becomes less accurate as frequency increases. The exact frequency limit of phase locking varies among species (and is unknown in humans), but in most mammals this limit is thought to be around 4000–5000 Hz (Palmer and Russell, 1986). The relative usefulness of place and temporal information in normal auditory coding is still debated. For example, information about the frequency of a pure tone could be determined from auditory nerve firing patterns either by determining the characteristic frequency of the nerve fibers with the greatest firing rate, or by determining the reciprocal of the most common interspike interval of the neural responses (assuming the pure tone is below the limit of phase locking). Both types of information are available in auditory nerve-firing patterns and it is not yet clear how the information is used by the central auditory system. There is evidence that both rate place and temporal coding are affected by sensorineural hearing loss in humans; the effects of cochlear and auditory nerve damage on auditory coding (so far as they can be differentiated in human listeners) will be considered separately.

0.6

0.4

0.2

−10

0

10

20

30

40

50

60

70

Threshold (dB HL)

Fig. 27.4. Auditory filter bandwidths (plotted as equivalent rectangular bandwidths (ERB)/filter center frequency) as a function of audiometric threshold for 40 listeners with a range of audiometric thresholds at the filter center frequency. HL, hearing loss. (Adapted from Hopkins and Moore, 2011.)

filter. Filter bandwidths were estimated using a “notched noise” technique (Patterson, 1976). Thresholds were measured for a tone in the presence of a noise with a spectral notch centered on the tone frequency. Thresholds for several notch widths were measured, and these data used to derive an estimate for the auditory filter bandwidth at the tone frequency. Note that, although there is a strong correlation between audiometric threshold and filter bandwidth, there is considerable variability between participants with similar audiometric thresholds, and the amount of variability increases with increasing audiometric threshold. Rate place coding would also be expected to be affected by substantial inner hair cell loss. If all inner hair cells at a particular place in the cochlea are absent, the pattern of firing across the array of auditory nerve fibers will no longer provide an accurate representation of the frequency spectrum.

TEMPORAL CODING It has also been suggested that temporal coding may be impaired in listeners with sensorineural hearing loss. Listeners with cochlear hearing loss are poorer than normal-hearing listeners at tasks that are thought to rely on temporal coding, such as interaural phase discrimination (Lacher-Fouge`re and Demany, 2005; Strelcyk and Dau, 2009), low-frequency modulation detection (Lacher-Fouge`re and Demany, 1998; Buss et al., 2004), and the discrimination of harmonic and frequencyshifted tones (Hopkins and Moore, 2007, 2011).

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The mechanism of the deficit is uncertain. There are several possibilities: ●

●

●

Cochlear hearing loss may be associated with a phase-locking deficit. Woolf et al. (1981) found that phase locking to pure-tone stimuli was impaired in guinea pigs with cochlear hearing loss, although this effect has not been replicated in other mammalian species (Harrison and Evans, 1979; Kale and Heinz, 2010). The temporal processing difficulties may arise because of the poorer frequency selectivity associated with cochlear hearing loss (see above). The pattern of temporal information at the output of broadened filters is more complex, and may be uninterpretable by the central auditory system. In a situation where a narrowband signal is to be detected or discriminated in the presence of background noise, broadened auditory filters would pass more noise than narrower filters, so reducing the signal-to-noise ratio at the output of the filter, and reducing the fidelity of the temporal representation of the signal (Henry and Heinz, 2012). Some temporal models suggest that temporal information is extracted by comparing the phase at different points along the basilar membrane (Shamma, 1985; de Cheveigne and Pressnitzer, 2006). The phase response is altered in cochlear hearing loss (Ruggero et al., 1996) and so this could explain why listeners with sensorineural hearing loss are poor at tasks thought to rely on temporal coding.

The effects of auditory nerve damage on auditory coding Due to the problems identifying auditory nerve function in human listeners described in the diagnosis section, above, few studies have assessed the effect of auditory nerve damage on auditory coding directly. However, from a theoretic perspective, auditory nerve damage is likely to cause deficits in auditory coding. Similarly to inner hair cell loss, if auditory nerve fibers innervating a particular place on the basilar membrane are absent, the pattern of neural activity across the array of auditory nerve fibers will not accurately represent the frequency spectrum, so presumably affecting rate place coding. Temporal coding is also likely to be affected, even by less widespread auditory nerve fiber loss. Auditory neurons do not fire on every cycle of a stimulus; instead an accurate representation of a waveform is coded by a combination of neural activity across many nerve fibers. Hence, loss of nerve fibers is expected to reduce the fidelity of temporal coding. Demyelination of auditory nerve fibers is also expected to have an adverse effect on temporal coding; demyelination is unlikely to be

uniform across fibers, so differing degrees of myelin damage would be expected to have a desynchronizing effect on auditory nerve responses.

PERCEPTUAL CONSEQUENCES OF SENSORINEURAL HEARING LOSS As discussed in the sections on structures affected by sensorineural hearing loss and etiology, above, sensorineural hearing loss is a heterogeneous condition, which can occur due to damage to several structures in the peripheral auditory system. As discussed in the diagnosis section, above, it is currently not possible to conclusively diagnose damage to specific structures in the peripheral auditory in humans, and peripheral hearing damage is tentatively classified as of cochlear or neural origin based on the pattern of diagnostic tests and suspected etiology. Here, the perceptual consequences of hearing loss of suspected cochlear origin are discussed. However, the limitations of diagnostic tests in categorizing damage to different structures should be remembered. The perceptual consequences of auditory neuropathy spectrum disorder, which is often thought to be caused by damage to the auditory nerve, are discussed in Chapter 28. The perceptual consequences of cortical and brainstem lesions are discussed in Chapters 6, 9, and 29–33.

Perceptual consequences of cochlear damage LOUDNESS PERCEPTION Loudness is the perceptual attribute of sound related to intensity. Cochlear hearing loss is associated with abnormal loudness perception; detection thresholds are elevated, but the level of sound that is found uncomfortably loud is elevated by a smaller amount (Kamm et al., 1978). This means that the dynamic range of hearing is reduced, an effect known as loudness recruitment. Figure 27.5 shows mean loudness ratings for pure tones as a function of intensity for a group of normal-hearing listeners and three groups of listeners with cochlear hearing loss of 50, 55, and 60 dB HL at the tone frequency. The slope of the loudness function is steeper for the hearing-impaired listeners, and the size of the slope increases with increasing hearing loss. Loudness recruitment is likely to arise directly as a result of outer hair cell damage. As discussed in the section on structures affected by sensorineural hearing loss, above, outer hair cells apply gain at low levels and result in a shallow, non-linear basilar membrane response. The slopes of the loudness functions plotted in Figure 27.5 correspond well with basilar membrane growth functions for animals with normal hearing and various degrees of outer hair cell loss.

SLOPE OF LOUDNESS FUNCTION

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Fig. 27.5. Relation between the slope of the loudness function and the degree of hearing loss for 78 listeners with noiseinduced losses. The linear function was obtained by the least-squares method. (Reproduced from Hellman and Meiselman, 1990.)

FREQUENCY AND PITCH PERCEPTION Pitch is the attribute of auditory sensation that allows sounds to be ordered on a music scale. It is important for the perception of speech and music. For example, pitch is used to convey non-semantic information, such as distinguishing a question from a statement, and to provide emphasis. In tonal languages, pitch conveys semantic information, with different word meaning being signified by different pitch contours. Pitch-evoking stimuli usually consist of a series of harmonics that are integer multiples of a fundamental frequency (F0). A pitch is heard that corresponds to F0. The mechanisms underlying the perception of pitch are still debated, but fall into two categories: pattern recognition and temporal models. Pattern recognition models are based on the idea that the auditory system extracts information about the frequencies of individual harmonics, and derives a pitch based on the best-fitting harmonic series. Temporal models are based on the idea that information about pitch is extracted from the interspike intervals in the auditory nerve. The perception of pitch has usually been assessed by either assessing the ability to recognize musical melodies, or by measuring the discrimination thresholds for pitch-evoking stimuli, such as pure or complex tones. Most studies investigating pitch perception among listeners with cochlear hearing loss have found that, on average, pitch perception is poorer among those with a hearing loss. Frequency discrimination thresholds for pure tones (Turner et al., 1983; Nelson and Freyman, 1986; Simon and Yund, 1993) and complex tones (Moore and Peters, 1992; Arehart, 1994; Moore et al., 2006) are elevated and melody recognition is poorer for listeners with cochlear hearing loss. However,

Fig. 27.6. The relation between frequency discrimination and the absolute hearing threshold level (HTL) in right (A) and left (B) ears. Frequency discrimination threshold (DLF/F) is plotted versus HTL for each subject at each frequency where frequency discrimination was measurable in both ears. A regression line was fitted to the data. (Reproduced from Simon and Yund, 1993.)

considerable individual differences have been reported, with performance as good as normal-hearing listeners in some cases. For example, Figure 27.6 shows frequency discrimination thresholds plotted as a function of audiometric threshold for 34 listeners. There was a significant correlation between audiometric thresholds and frequency discrimination, but the correlation was only

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moderate, and some listeners with a substantial hearing loss performed as well as those with audiometric thresholds within the normal range. The mechanisms that underlie the poor pitch perception of listeners with cochlear hearing loss are uncertain. Two main ideas have been proposed: poor frequency selectivity and poor temporal coding. Poor frequency selectivity Frequency selectivity is associated with audiometric thresholds, as described in the section on the effects of cochlear damage on auditory coding, above. Most models of pitch perception predict that pitch perception will be adversely affected by reduced frequency selectivity. “Pattern recognition” models of pitch perception rely on the identification of resolved harmonics, which are fed into a central pattern recognizer that identifies the fundamental frequency that best fits the harmonic series. Reduced frequency selectivity is expected to reduce the number of resolved harmonics present in a complex tone, and so would be expected to impair pitch perception. Some temporal models of pitch perception also predict that reduced frequency selectivity would impair the perception of pitch. For example, Moore (1982) suggested that pitch is extracted by combining information from resolved and unresolved harmonics and determining the most common periodicity in the pattern of firing. Resolved harmonics are argued to convey more precise temporal information than unresolved harmonics, and so if frequency selectivity is reduced (so reducing the number of resolved harmonics), this is expected to impair perception of pitch. If the poor pitch perception of hearing-impaired listeners arises due to poor frequency selectivity, a strong correlation between tasks measuring pitch perception and frequency selectivity would be expected. Tyler et al. (1983) measured psychophysical tuning curves and frequency discrimination limens for normal-hearing subjects and listeners with a sensorineural hearing loss ranging from mild to moderate. Frequency selectivity (as measured by the high-frequency slope of psychophysical tuning curves) and frequency discrimination limens were poorer for the hearing-impaired than the normal-hearing subjects and there were moderate correlations between frequency selectivity and frequency discrimination limens for pure tones. However, these correlations became small and non-significant when audiometric threshold was partialed out, suggesting that impaired frequency selectivity could not entirely explain the poor frequency discrimination of the hearingimpaired listeners. Moore and Peters (1992) conducted a similar experiment investigating the relation between frequency

selectivity and frequency discrimination for pure and complex tones. Similarly to Tyler et al. (1983), they found that correlations between frequency selectivity and frequency discrimination thresholds for pure tones were very small and non-significant after audiometric thresholds were partialed out. However, correlations between frequency selectivity and fundamental frequency difference limens for complex tones were stronger, at least at some frequencies, and in some cases remained significant when audiometric thresholds were partialed out. Bernstein and Oxenham (2006) measured fundamental frequency difference limens for complex tones for normal-hearing listeners and listeners with sensorineural hearing loss. The lowest harmonic present in the complexes was varied. Fundamental frequency difference limens increased as the lowest harmonic number increased (consistent with previous studies), and they found that frequency selectivity, measured in the same listeners, was significantly correlated with the harmonic number at which F0 discrimination transitioned from good to poor. Together, these results suggest that poor frequency selectivity may at least partly explain why listeners with cochlear hearing loss have poorer pitch perception than normal-hearing listeners. Poor temporal coding A temporal coding deficit provides another possible explanation for the poor pitch perception experienced by hearing-impaired listeners. Again, poor temporal coding might be predicted to lead to poor pitch perception based on either pattern recognition or temporal models. Pattern recognition models rely on the coding of information about the frequencies of individual resolved harmonics, but do not make any assumption about whether the individual frequencies are coded using a rate place or temporal mechanism. If the latter of these two mechanisms is used, then pitch perception would be expected to be worse if temporal coding is impaired. Similarly, temporal models would predict impaired pitch perception if temporal coding was impaired. However, as noted in the section on the effects of cochlear damage on auditory coding, above, the apparent temporal coding deficit experienced by listeners with cochlear hearing loss may arise as a result of poor frequency selectivity, and so the effects are difficult to disentangle.

SPATIAL HEARING Spatial hearing refers to the ability to perceive and exploit information about the spatial position of a sound or sounds. Localization is the ability to determine the position of a sound – an essential skill for successful negotiation of our auditory environment. Localization in the horizontal plane relies mainly on binaural cues.

DEAFNESS IN COCHLEAR AND AUDITORY NERVE DISORDERS Interaural level differences (ILDs) arise because of the attenuation of sound with distance, and the “shadowing” effect of the head, which is particularly prominent at high frequencies. Interaural time differences (ITDs) arise because sounds outside the median plane arrive at one ear before the other. Localization in the vertical plane relies on detection of peaks and dips in the frequency spectrum of broadband sounds imposed by the external and torso, mainly at high frequencies, that vary according to elevation. Listeners with cochlear hearing loss report localization difficulties in everyday life (Noble et al., 1995), and listeners with an asymmetric hearing loss report more problems than those with a symmetric loss (Noble and Gatehouse, 2004). Consistent with this, Noble et al. (1994) found that localization of noise bursts in both the vertical and horizontal planes was moderately correlated with degree of hearing loss in a group of 66 listeners with varying degrees of cochlear hearing loss. The effect of sensorineural hearing loss on localization is greater when more than one sound source is present simultaneously. Figure 27.7 shows localization errors made by normal-hearing listeners and hearing-impaired listeners for two conditions: one in which a single target word was presented and the second in which five target words were presented simultaneously and listeners were required to localize a single target word. The difference between normal-hearing and hearing-impaired groups was significantly larger when many sounds were presented simultaneously. In order to understand the localization deficits experienced by hearing-impaired listeners it is helpful to

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consider the effect of cochlear hearing loss on discrimination of ITD and ILD cues. Hawkins and Wightman (1980) found that listeners with sensorineural hearing loss were poorer at ITD discrimination for narrow-band sounds at both low and high frequencies, and at low and high levels. Several more recent studies have found that interaural phase discrimination (closely related to ITD discrimination) is poorer for listeners with a cochlear hearing loss than listeners with normal hearing (Lacher-Fouge`re and Demany, 2005; Strelcyk and Dau, 2009; Hopkins and Moore, 2011), an effect that has been interpreted as evidence for a temporal processing deficit among these listeners. Few studies have examined the effect of hearing loss on interaural level discrimination, although there is some evidence that interaural level discrimination is also affected by cochlear hearing loss (Koehnke et al., 1995). However, the extent to which these elevations in interaural discrimination thresholds might explain the effect of hearing loss on localization is unknown.

BINAURAL UNMASKING Binaural unmasking refers to the increase in detectability or discriminability of a signal in noise that occurs due to differences in ITD or ILDs between the signal and masker. For normal-hearing listeners, this effect can be substantial. For example, Jeffress et al. (1952) reported that thresholds for detecting a tone in background noise were up to 14 dB better when the ITDs for the tone and noise were different compared with when they were the same (a phenomenon known as the binaural masking level difference). A similar effect has been reported for speech understanding in a spatially separated background; speech reception thresholds in noise are substantially better when the speech and noise are spatially separated (giving rise to differences in binaural cues) than when they are co-located (Hawley et al., 1999; Freyman et al., 2001). Many studies have found that the binaural masking level difference for pure tones is reduced among listeners with a cochlear hearing loss (Hall et al., 1984; Jerger et al., 1984; Strelcyk and Dau, 2009). Similarly, the amount of speech intelligibility benefit derived from spatial separation of speech and masking noise has been reported to be smaller for listeners with a cochlear hearing loss than listeners with normal hearing (Arbogast et al., 2005; Marrone et al., 2008).

SPEECH PERCEPTION Fig. 27.7. Mean root mean squared (RMS) errors in the control and mixture conditions for the two listener groups (normal hearing (NH) and sensorineural hearing loss (HI)). Error bars show standard errors of the mean. (Reproduced from Best et al., 2011.)

The perception of speech demands special attention because of its importance for communication, and the amount of research devoted to its perception. Speech perception with and without the presence of background noise is poorer for listeners with cochlear hearing loss

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30 40 50 60 −10 0 10 20 30 Pure tone average, 250 − 8000 Hz (dB HL)

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Fig. 27.8. Speech reception thresholds for speech in steady (left panel) and modulated (right panel) background noise for 40 listeners with a range of audiometric thresholds. Speech reception thresholds are plotted as a function of mean audiometric threshold at octave frequencies between 0.25 and 8 kHz. HL, hearing loss.

than listeners with normal hearing (Carhart and Tillman, 1970; Bonding, 1979; Bronkhorst and Plomp, 1989; Barrena¨s and Wikstr€ om, 2000). This can partly be explained by the reduced audibility caused by elevated audiometric thresholds; the greatest difference between normal-hearing and hearing-impaired listeners is observed when speech is presented at a low level (Humes and Roberts, 1990; Ching et al., 1998), and using masking noise to match audibility between normalhearing and hearing-impaired listeners reduces the difference in performance between the two groups (Humes and Roberts, 1990). However, audibility cannot entirely explain the differences in speech intelligibility between normal-hearing and hearing-impaired listeners. Hearing-impaired listeners perform more poorly that would be predicted from the speech intelligibility index, which predicts intelligibility based on the audibility of the signal, and is very accurate for normal-hearing listeners (Festen and Plomp, 1990; Smoorenburg, 1992; Ching et al., 1998). Speech perception deficits persist even when speech is fully audible (Turner and Cummings, 1999; Summers and Molis, 2004), and the magnitude of the remaining deficit is related to the degree of audiometric threshold elevation (Turner and Cummings, 1999; Hopkins and Moore, 2011). Speech perception in quiet appears to be less adversely affected than speech perception in background noise, especially for people with a mild hearing loss, although it is not clear to what extent this relates to ceiling effects for task performance when speech intelligibility is measured in quiet. The effects of hearing loss on speech perception in noise appear to be greater for noise that has temporal modulations than noise that is steady (Festen and

Plomp, 1990; Lorenzi et al., 2006; Hopkins and Moore, 2011). Figure 27.8 shows speech reception thresholds for 50% correct word identification in background noise for listeners with a range of audiometric thresholds. The correlation between audiometric thresholds and speech reception thresholds for modulated noise were similar, but the effect of hearing loss (in dB signal-to-noise ratio) was greater for the modulated noise than the steady noise. Normal-hearing listeners benefited from dips in the modulated masker, but the amount of benefit reduced as hearing loss increased. Many studies have investigated possible reasons for the speech perception deficits experienced by listeners with a cochlear hearing loss. Deficits in both rate place (Patterson et al., 1982; Glasberg and Moore, 1989; Dubno and Schaefer, 1995) and temporal (Lorenzi et al., 2006; Hopkins et al., 2008; Hopkins and Moore, 2011) coding have been proposed as possible explanations.

TREATMENT OF SENSORINEURAL HEARING LOSS In most cases, sensorineural hearing loss is irreversible, given the limits of current knowledge. Consequently, treatment focuses on management of the hearing loss rather than cure.

Hearing aids Hearing aids are the most common treatment for hearing impairment. They consist of a microphone, amplifier, and speaker, and the goal is to amplify sounds made inaudible by the hearing loss and deliver these to

DEAFNESS IN COCHLEAR AND AUDITORY NERVE DISORDERS the patient. Hearing aids are relatively successful in restoring audibility for most types of hearing loss. However, hearing aids do not restore auditory perception to normal in cases of sensorineural hearing loss, because of the suprathreshold perceptual deficits described in this chapter. Some attempts have been made to compensate for the perceptual problems encountered by hearing-impaired listeners with hearing aids. The most successful and widely implemented of these is the use of amplitude compression to compensate for the effects of loudness recruitment (Gatehouse et al., 2006). As described in the section on perceptual consequences of cochlear damage, above, listeners with cochlear hearing loss usually experience loudness recruitment, whereby weak sounds are inaudible, but intense sounds are just as loud as for people with normal hearing, meaning that the dynamic range of hearing is reduced. Amplitude compression attempts to compensate for this problem by amplifying low-level sounds more than high-level sounds. Another strategy for improving the perception of speech for hearing-aid users with sensorineural hearing loss is to attempt to improve the speech-to-noise ratio. As mentioned above, listeners with sensorineural hearing loss encounter particular problems when listening to speech in background noise, and these problems persist even if sound is amplified to a level that is audible. Speech intelligibility is strongly related to signal-to-noise ratio for both normal-hearing and hearing-impaired listeners, and so if the signal-to-noise ratio can be increased, an increase in speech intelligibility is expected. Several strategies have been proposed. The most successful so far is to combine the outputs of two microphones with differing directionality (the most typical configuration is a directional microphone oriented directly ahead, and an omnidirectional microphone). Assuming that the speech and background are spatially separated, this can result in an improvement in signal-to-noise ratio, and a corresponding improvement in speech intelligibility (Bentler, 2005).

Cochlear implants Cochlear implants are used to treat severe to profound cochlear hearing loss. Cochlear implants consist of a microphone and processor (usually located behind the ear), a transmitter (located on the skull behind the ear, usually held in place with a magnet), a receiver (implanted under the skin), and an array of electrodes in the cochlea. Each electrode stimulates a different place in the cochlea, which corresponds to a different characteristic frequency. Sounds are processed by filtering into frequency channels; signals from each channel are used to stimulate different electrodes along the

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length of the electrode array. Similar noise reduction techniques can be employed as for hearing aids; the noise reduction occurs before the main cochlear implant processing.

SUMMARY ●

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Sensorineural hearing loss arises because of damage to the inner ear. Often several structures are affected, including the inner and outer hair cells of the cochlea, the stria vascularis, and the auditory nerve. Sensorineural hearing loss has many causes, including genetic mutations affecting the structures of the inner ear and environmental insults such as noise, ototoxic substances, and hypoxia. The prevalence of sensorineural hearing loss increases dramatically with age. Clinical diagnosis is most commonly accomplished by measuring detection thresholds (audiometric thresholds), and comparing these to normative values to determine the degree of hearing loss. Often it is not clinically possible to distinguish between hearing loss caused by damage to the cochlear and auditory nerve. The most obvious perceptual consequence of sensorineural hearing loss is insensitivity to weak sounds. Other adverse perceptual consequences include loudness recruitment, poor perception of pitch and auditory space, and difficulty understanding speech, particularly in the presence of background noise. Sensorineural hearing loss is usually incurable. Treatment focuses on restoring the audibility of sounds made inaudible by hearing loss using either hearing aids or cochlear implants.

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Schulte BA, Schmiedt RA (1992). Lateral wall Na, K-ATPase and endocochlear potentials decline with age in quietreared gerbils. Hear Res 61: 35–46. Sellick PM, Patuzzi R, Johnstone BM (1982). Measurement of basilar membrane motion in the guinea pig using the M€ossbauer technique. J Acoust Soc Am 72: 131–141. Sewell WF (1984). The effects of furosemide on the endocochlear potential and auditory-nerve fiber tuning curves in cats. Hear Res 14: 305–314. Shamma SA (1985). Speech processing in the auditory system II: Lateral inhibition and the central processing of speech evoked activity in the auditory nerve. J Acoust Soc Am 78: 1622–1632. Simon HJ, Yund EW (1993). Frequency discrimination in listeners with sensorineural hearing loss. Ear Hear 14: 190–199. Simpson A (2009). Frequency-lowering devices for managing high-frequency hearing loss: a review. Trends Amplif 13: 87–106. Smoorenburg GF (1992). Speech reception in quiet and in noisy conditions by individuals with noise-induced hearing loss in relation to their tone audiogram. J Acoust Soc Am 91: 421–437. Strelcyk O, Dau T (2009). Relations between frequency selectivity, temporal fine-structure processing, and speech reception in impaired hearing. J Acoust Soc Am 125: 3328–3345. Summers V, Molis MR (2004). Speech recognition in fluctuating and continuous maskers: effects of hearing loss and presentation level. J Speech Lang Hear Res 47: 245–256. Takeno S, Harrison R, Ibrahim W et al. (1994). Cochlear function after selective inner hair cell degeneration by carboplatin. Hear Res 75: 93–102.

Turner CW, Cummings KJ (1999). Speech audibility for listeners with high-frequency hearing loss. Am J Audiol 8: 47–56. Turner CW, Burns EM, Nelson DA (1983). Pure tone pitch perception and low-frequency hearing loss. J Acoust Soc Am 73: 966–975. Tyler RS, Wood EJ, Fernandes MA (1983). Frequency resolution and discrimination of constant and dynamic tones in normal and hearing-impaired listeners. J Acoust Soc Am 74: 1190–1199. Wang J, Powers NL, Hofstetter P et al. (1997). Effects of selective inner hair cell loss on auditory nerve fiber threshold, tuning and spontaneous and driven discharge rate. Hear Res 107: 67–82. Webster M, Webster DB (1981). Spiral ganglion neuron loss following organ of Corti loss: a quantitative study. Brain Res 212: 17–30. Weiss TF, Rose C (1988). A comparison of synchronization filters in different auditory receptor organs. Hear Res 33: 175–179. Wilson D, Walsh PG, Sanchez L et al. (1998). Hearing impairment in an Australian population, Centre for Population Studies in Epidemiology, Department of Human Services, Adelaide. Wilson DH, Walsh PG, Sanchez L et al. (1999). The epidemiology of hearing impairment in an Australian adult population. Int J Epidemiol 28: 247–252. Woolf NK, Ryan AF, Bone RC (1981). Neural phase-locking properties in the absence of outer hair cells. Hear Res 4: 335–346. Yates GK, Winter IM, Robertson D (1990). Basilar membrane nonlinearity determines auditory nerve rate-intensity functions and cochlear dynamic range. Hear Res 45: 203–219.

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 28

Auditory neuropathy 1

ARNOLD STARR1* AND GARY RANCE2 Departments of Neurology and Neurobiology, University of California, Irvine, CA, USA 2

School of Audiology, University of Melbourne, Melbourne, Australia

INTRODUCTION Objective measures of hearing thresholds using auditory brainstem responses (ABRs) were championed by Galambos and his associates four decades ago (Hecox and Galambos, 1974; Galambos and Despland, 1980) and are now used routinely to provide objective measures of auditory nerve and brainstem responses in neonates and adults (Norton et al., 2000). While the tests were of great benefit for objectively defining “deafness,” there were exceptions that tested this assumption. Some subjects with “hearing problems” had relatively normal audiometric thresholds but absent or severely abnormal ABRs (Kaga and Tanaka, 1980; Worthington and Peters, 1980; Hildesheimer et al., 1985; Satya-Murti et al., 1983; Kraus et al., 1984). We identified that their deafness was due to abnormal auditory nerve function in the presence of normalfunctioning cochlear sensory hair cells. Figure 28.1 displays measures (audiogram, distortion product otoacoustic emissions (OAEs), ABRs to clicks and to tones, and auditory cortical potentials) from an individual with auditory neuropathy (AN) and a normal-hearing control (normal). The AN subject in Figure 28.1 had a mild loss of audibility, impaired speech perception out of proportion to the audibility changes, ABRs with absent waves I–III, and barely detectable wave V that was delayed in latency. In contrast, the cochlear hair cell measures (DPOAEs) and cochlear microphonics (CMs) were normal. Cortical N100 potentials were present and delayed in latency (Starr et al, 1991, 1996). The pattern of these results was consistent with a hearing disorder (Starr et al., 1991) due to abnormal auditory nerve functions. Some of the subjects were found to also have cranial nerve (vestibular, optic nerve) and/or peripheral neuropathies,

supporting the idea that the auditory nerve was also affected by neuropathic disorders. The term “auditory neuropathy” was used to describe the group of patients we studied (Starr et al., 1996). We also recognized that inner hair cell disorders affecting ribbon synapse function would display similar clinical features. The hearing disorder of AN affected processing of acoustic temporal cues that are essential for: (1) speech comprehension; (2) localization of sounds; and (3) separating signals from background noise (Starr et al., 1991; Zeng et al., 2005). Examination of temporal bones from subjects dying with AN showed inner and outer hair cells to be normal in number and appearance, whereas auditory ganglion cells and nerve fibers were both reduced in number and demyelinated (Starr et al., 2003). Loss of auditory nerve fibers would attenuate neural input while demyelination would affect the synchrony of neural conduction. We consider that both the loss of auditory nerve fibers and altered neural transmission contribute to the abnormalities of both ABRs and hearing. Abnorml ABRs and normal hair cell measures were identified in neonates with otoferlin (OTOF) mutations that affected glutamate neurotransmitter release from inner hair cell ribbon synapses. The locus of the auditory nerve disorder in this mutation was presynaptic and has been shown to affect ribbon synaptic function (Varga et al., 2006; Rodrı´guez-Ballesteros et al., 2008). We anticipate that patients with abnormal ABRs and normal cochlear hair measures will also be identified in disorders of neurotransmitter reuptake and auditory dendritic receptor. We have been asked to comment on other terminologies used for individuals with abnormal ABRs and preserved cochlear hair cell activities. The most common ones are “auditory neuropathy spectrum disorder” and

*Correspondence to: Arnold Starr, Department of Neurology, University of California, 154 Med Surge I, Mail Code: 4290, Irvine, CA 92697, USA. Tel: +1-949-230-7269, E-mail: [email protected]

496

A. STARR AND G. RANCE do use objective measures (e.g., ABRs) that can localize the sites of auditory nerve dysfunction as affecting auditory nerve and inner hair cell ribbon synapses (Moser et al., 2013). Most importantly, there are many specific etiologies that have been identified as causing AN (Starr et al., 2001; Santarelli, 2010). We suggest that the term postsynaptic AN be used when there is loss and/or demyelination of auditory nerves. When inner hair cells are affected the term presynaptic AN is appropriate. The term “auditory neuropathy/auditory dyssynchrony” is used to indicate that there is reduction of neural synchrony of auditory nerve fibers in patients with AN. The concept is attractive but as yet there is no quantitative measure of the degrees of dyssynchrony. We suggest that ABRs may be able to provide such measures of changes of neural synchrony. For instance, in patients with postsynaptic AN the ABR to the initial click could be normal but was then delayed and lost to subsequent clicks in the train (e.g., conduction slowing: Wynne et al., 2013). Dyssynchrony in this instance had a time course of expression. Moreover, both a reduction in signal intensity and a decrease in signal-to-noise ratio in normal-hearing subjects can result in both ABR and psychoacoustic measures that are similar to AN. We now depend on psychoacoustic methods in trained observers to quantify the effects of dyssynchrony of auditory perceptions. Objective measures of both brainstem and cortical potentials may prove a way of quantifying the magnitude change in central auditory processing in normal hearing and in auditory neuropathies (Kraus et al., 2000; Michalewski et al., 2005). We will review below diagnostic features of AN, including audiologic and psychoacoustics, etiologies (e.g., developmental, genetic, metabolic, degenerative, iatrogenic), their associated pathologies, and the effects of specific therapies.

DIAGNOSIS The diagnosis of AN relies on electrophysiologic tests with ancillary support from neuroimaging and audiologic assessment.

Electrophysiologic procedures Fig. 28.1. Measures of auditory function in a normal control and a subject with auditory neuropathy. DPOAEs, cochlear hair cell measures; ABRs, auditory brainstem responses; AEPs, auditory evoked potentials; CM, cochlear microphonics.

“auditory neuropathy/auditory dyssynchrony.” The term “spectrum disorder” is used when there is both a paucity of objective measures and knowledge of their etiology. Spectrum disorder is inappropriate for AN since we

ABRs in AN are absent or attenuated in amplitude as well as delayed in latency (Table 28.1) (Starr et al., 1996). The conduction velocity of the auditory nerve can be measured only when both waves I and II are present (Butinar et al., 2008). Some of the details of performing these measures are detailed below. Cochlear hair cell microphonics are typically preserved and can be defined by separately averaging ABRs to condensation and to rarefaction stimuli. Subtracting

AUDITORY NEUROPATHY Table 28.1

ABRs Acoustic evoked middle-ear muscle reflexes Cochlear microphonics Otoacoustic emissions Electrocochleography

Absent or abnormal Typically absent Normal Normal CAP broad and low amplitude Absent

ABRs, auditory brainstem responses; CAP, compound action potential.

the ABR condensation from rarefaction clicks attenuates the neural components, revealing CM that are of opposite polarity to condensation and rarefaction stimuli. Addition of the ABRs to condensation and rarefaction stimuli will cancel CMs and enhance neural components (Starr et al., 1991; Berlin et al., 1998). Both inner hair cell summating potentials and the compound action potential (CAP) of auditory nerve (wave I of the ABR) can be most clearly identified using electrocochleography (Santarelli and Arslan, 2002). The method helps to localize the sites of auditory nerve dysfunction as involving inner hair cells and/or auditory nerve (Santarelli, 2010). This information can assist the clinician in assessing the likely benefits of cochlear implants. Typically, if the dysfunction is limited to the inner hair cells, cochlear implants will be very beneficial. The technique requires general anesthesia for infants and children but can be done under local anesthesia in adults.

AUDITORY CORTICAL POTENTIALS A cortical potential can be recorded to the onset of acoustic signals at a peak latency of approximately 100 ms. The potential is of positive polarity in children and changes to a negative polarity by around 8 years of age. The N100/P100 is present in AN even when ABRs are absent. Rance and colleagues (2002) showed that 50% of school-aged children with AN were without an N100 or P100 and its absence was highly correlated with impaired speech perceptual abilities. The presence of a preserved N100 of normal latency provided an objective measure of neural synchrony at the cortical level (Fig. 28.2). In adults, the latency of N100 to brief tones is also sensitive to the onset of temporal features of the stimulus. N100 latency is prolonged as stimulus onset is

SN

AN

0

Normal

Amplitude (1 µV/div)

Results

Amplitude (1 µV/div)

Test

/daed/

Normal

Objective electrophysiologic findings in auditory neuropathy

Neurophonics

497

440 Hz

100 200 300 400 500 Latency (ms)

SN

AN

0

100 200 300 400 500 Latency (ms)

Fig. 28.2. Grand mean cortical event-related potential waveforms in response to tones (left panel) and to speech (right panel) for children with normal hearing (top traces), sensorineural (SN) hearing loss (440 Hz: n ¼ 17; /dæd/: n ¼ 15, middle traces), and auditory neuropathy (AN) (n ¼ 11, bottom traces). Daed is the phonetic representation of the word “dad.” (Reproduced from Rance, 2005, with permission.)

slowed (Onishi and Davis, 1968) but is relatively independent of stimulus intensity. In AN subjects, N100 latencies to brief tone bursts, while present, are abnormally delayed in latency (approximately 40 ms) and the magnitude of the delay is independent of audibility changes (Michalewski et al., 2009). Cortical measures can be used to quantify temporal processing deficits of auditory nerve and/or inner hair cell ribbon synapses (Wynne et al., 2013). Currently it is difficult to distinguish between disorders of auditory dendrites (noise trauma), auditory axons accompanying neurologic disorders (both a form of deafferentation), altered neural conduction, and ribbon synaptic abnormalities. All these conditions affect auditory nerve and brainstem activity, reflected by ABR. We anticipate that further studies of changes of ABR latency and amplitude of ABR components will help to distinguish among etiologies. For instance, AN accompanying degenerative etiology such as Charcot– Marie–Tooth (CMT) will show progressive latency delays and reduction in amplitudes of ABR components (Starr et al., 2003). These measures also may be used to quantify the course of the disorder and provide objective measures of therapies in clinical trials (Rance et al., 2010). ABR abnormalities (Fig. 28.3) can be helpful in localizing the site of auditory nerve abnormality. Wave I, generated by distal portions of auditory nerve, is typically preserved in proximal disorders of the auditory nerve (e.g., acoustic neuromas) but absent in both presynaptic (OTOF-related ribbon synaptic disorders) and

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neuropathic disorders of auditory nerve. Conduction times between waves I and II (the latter generated by proximal auditory nerve; Martin et al., 1995) can reveal abnormal slowing of auditory nerve conduction (Butinar et al., 2008). Prolongation of latency difference between waves I and V (>4.5 ms) reflects slowed conduction between auditory nerve and lateral lemnisci.

Fig. 28.3. Auditory brainstem response waveforms obtained for children with Charcot–Marie–Tooth (CMT) disease. The top tracing shows the combined waveform for a normal control group. The second is the averaged waveform for children showing slow conduction between waves I (auditory nerve) and III (cochlear nucleus) consistent with demyelination of auditory nerve (CMT1). The third is the averaged waveform for children with CMT2, showing axonal loss and reflected by normal conduction times between waves I and III and V, but reduced amplitude of wave V. The bottom tracing is for a single child who showed no repeatable components I, II, and V to stimuli at maximum presentation levels (90 dB nHL) but whose audibility was impaired. The asterisks in this case are cochlear microphonics. (Reproduced from Rance et al., 2012a.)

The relative amplitude of wave V to wave I is normally >1. When this ratio is less than 0.5, the site of auditory nerve disorder is proximal rather than distal (Starr and Achor, 1975; Rance et al., 2010). Cochlear hair cell activities are normal. These include microphonics (CMs), reflecting outer and inner hair cell intracellular potential changes; OAEs, reflecting contractions of outer hair cells, are present in newborns with AN (Table 28.1). They become absent in approximately 30% of these infants by 2 years of age (Rance et al., 1999). CMs are preserved in those subjects that have lost OAEs (Starr et al., 1998). Thus, for diagnosing AN, the CMs are a reliable measure of preserved hair cell activities (Starr et al., 1991). Neurophonics or frequency-following responses are field potentials of auditory brainstem structures to low-frequency tones ( Ser). Brain 126 (Pt 7): 1604–1619, Erratum in: Brain 2003; 126(Pt 7):1718. Teagle H, Roush P, Woodward JS et al. (2010). Cochlear implantation in children with auditory neuropathy spectrum disorder. Am J Audiol 20: 159–170. Trautwein P, Shallop J, Fabry L et al. (2001). Cochlear implantation of patients with auditory neuropathy. In: YS Sininger, A Starr (Eds.), Auditory Neuropathy, Singular Publishing, San Diego, CA, pp. 203–232. Ueda N, Kuroiwa Y (2008). Sensorineural deafness in Guillain-Barre´ syndrome. Brain Nerve 60 (10): 1181–1186. Varga R, Avenarius MR, Kelley PM et al. (2006). OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele. J Med Genet 43 (7): 576–581. Vinay, Moore BCJ (2007). Ten(HL)-test results and psychophysical tuning curves for subjects with auditory neuropathy. Int J Audiol 46 (1): 39–46. Worthington DW, Peters JF (1980). Quantifiable hearing and no ABR: paradox or error? Ear Hear 1 (5): 281–285.

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Wynne DP, Zeng FG, Bhatt S et al. (2013). Loudness adaptation accompanying ribbon synapse and auditory nerve disorders. Brain 136 (Pt 5): 1626–1638. Yellin MW, Jerger J, Fifer RC (1989). Norms for disproportionate loss in speech intelligibility. Ear Hear 10 (4): 231–234. Zeng F-G, Liu S (2006). Speech perception in individuals with auditory neuropathy. J Speech Lang Hear Res 49: 36.

Zeng F-G, Oba S, Starr A (2001). Supra threshold processing deficits due to desynchronous neural activities in auditory neuropathy. In: DJ Breebaart, AJM Houstma, A Kohlrausch et al. (Eds.), Physiological and Psychophysical bases of Auditory Function, Shaker Publishing, Maastricht, Netherlands, pp. 365–372. Zeng FG, Kong YY, Michalewski HJ et al. (2005). Perceptual consequences of disrupted auditory nerve activity. J Neurophysiol 93 (6): 3050–3063.

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 29

Hearing disorders in brainstem lesions GASTONE G. CELESIA* Department of Neurology, Loyola University of Chicago; Chicago Council for Science and Technology, Chicago, IL, USA

INTRODUCTION Brainstem lesions involving auditory pathways and/or nuclei should result in hearing abnormalities, yet often the involvement of the auditory system is either overlooked or the lesions are silent (Lide´n, 1969; KorsenBengtsen, 1970; Levine et al., 1994). Hausler and Levine (2000) noted that, in strokes involving the brainstem “vestibular signs and symptoms are common” while “hearing disturbances are much less frequent”; a similar observation has been reported in multiple sclerosis (MS). The purpose of this chapter is to provide a review of the brainstem auditory system and the effects of brainstem lesions on auditory processing. We will address the issue of whether brainstem lesions are truly silent and whether in these instances classic audiometry is adequate in assessing hearing.

BRAINSTEM AUDITORY SYSTEM The details of the anatomy and physiology of the auditory pathways are described in Chapter 1. Here we briefly summarize the points pertinent to the development of clinical symptomatology. The acoustic fibers of the VIIIth nerve enter the brainstem at the pontomedullary junction and terminate in the cochlear nuclei. Their outputs (Fig. 1.10, Chapter 1) project to the ipsilateral and contralateral superior olivary complexes, trapezoid nuclei, lateral lemniscus nuclei, inferior colliculi (IC), and middle geniculate bodies (Moore, 2000; Brugge, 2013). Tonotopic representation from the cochlea is preserved in the cochlear nuclei (Fig. 29.1) and at each successive auditory relay station, including the auditory cortex (Moore and Osen, 1979; Lauter et al., 1985; Brugge, 1994; Talavage et al., 2004). The cochlear nuclei are the first station of arrival of information transmitted by primary cochlear

afferents via the auditory nerve. In a postmortem examination of an infant who died from erythroblastosis due to an Rh-immune disorder, Dublin (1974) reported a tonotopic representation in the cochlear nucleus. In this case the organ of Corti and spiral ganglion were within normal limits. The dorsal cochlear nucleus was essentially unaltered. The ventral nucleus, especially the superior division, showed degeneration of spheroid cells in particular. The cell degeneration was seen in the dorsal portion of the ventral nucleus and corresponded with the audiographic dip encountered characteristically in posterythroblastotic hearing. The tonotopic representation of the human cochlear nucleus has since been confirmed by studies to develop auditory prostheses for the profoundly deaf (McCreery et al., 1998; McCreery, 2008). The cochlear nuclei output is transmitted over parallel pathways both ipsilateral and contralateral to a wide number of nuclear groups of the pons, midbrain, and thalamus (Møller, 2003; Brugge, 2013); consequently neurons in the brainstem auditory pathways receive input from both ears, with the contralateral input being greater than the ipsilateral one (Puletti and Celesia, 1970; Møller, 2003). Binaural interaction occurs at three levels of the brain: the superior olivary complex, the nuclei of the lateral meniscus, and the IC (Moore, 1991, 2000). Interaural time and interaural level differences have a critical role in the ability to localize the source of sound in space (Moore, 2000; Brugge, 2013). Among the various auditory brainstem nuclei there are extensive anatomic connections via the commissure of Probst and the IC commissure. Two important features of the auditory pathways are as follows: 1.

Structures rostral to the cochlear nuclei process binaural information; the superior olivary complex is the first station in the central auditory pathways

*Correspondence to: Gastone G. Celesia, MD, FAAN, 3016 Heritage Oak Lane, Oakbrook, IL 60523, USA. E-mail: g.celesia@ comcast.net

510

G.G. CELESIA cerebellar artery (SCA) and the lateral pontile arteries, all branches of the basilar artery. The medial geniculate body is vascularized by the laterosuperior midbrain arteries branches of the posterior cerebral artery (Haymaker, 1969).

PREVALENCE OF HEARING DISORDERS IN BRAINSTEM DISEASES

Fig. 29.1. Structure of the human cochlear nuclei showing the orderly cochlear base-to-apex bifurcation of incoming auditory nerve axons. The cochleotopic projection to the ventral cochlear nucleus (VCN) and dorsal cochlear nucleus (DCN) imposes a high-to-low frequency tonotopic organization to both nuclei. CPA represents small cap cells and OCA region of octopus cells. (From Brugge 2013 as adapted from Moore and Osen, 1979 with permission.)

2.

where the information from the two cochlear nuclei converges. Dysfunction below or within the cochlear nuclei will produce ipsilateral abnormalities, while disorders rostral to the cochlear nuclei may result in bilateral abnormalities. The multiplicity of parallel and overlapping auditory pathways and the extensive connections of the auditory brainstem nuclei not only are responsible for binaural interaction but also assure redundancy in the system. This redundancy may explain why small brainstem lesions are often clinically silent.

The brainstem receives its blood supply via two vertebral arteries, the basilar artery and the two posterior cerebral arteries. The medulla, pons, and midbrain (Fig. 29.2) have multiple blood supply (Haymaker, 1969; Duvernoy, 1999; Takahashi, 2010) with anastomoses among the various arteries that assure a redundancy of vascularization for the brainstem. The cochlear and vestibular nuclei in the upper medulla and lower pons are vascularized by the anterior inferior cerebellar artery (AICA), a branch of the vertebral or basilar artery. The cochlea receives its blood supply from the internal auditory artery (Fig. 29.3) (also called the labyrinthine artery) that most often arises from the AICA (Kim et al., 1999), although in some individuals is a branch of the basilar artery (Mazzoni, 1972; Adams and Liberman, 2010). The auditory nuclei and pathways of the upper pons and lower midbrain are vascularized by the superior

Any disorder of the brainstem (neoplasms, vascular disorders, infections, trauma, demyelinating disorders, neurodegenerative diseases, malformations) that involves the auditory pathways and/or centers may result in hearing abnormalities. It is not known how often a brainstem lesion causes hearing dysfunction; we are not aware of any prospective studies on the prevalence of such abnormalities. The only report on the prevalence of hearing loss in brainstem disorders corrected for age and sex is a retrospective study by Luxon (1980) from the National Hospital Queen Square, London. Luxon studied 309 patients with brainstem disorders examined from 1941 to 1976, and noted that 181 or 58.6% had objective evidence of hearing loss shown by pure-tone audiograms (Table 29.1), while 128 or 41.4% of patients had no hearing loss. To exclude aging related hearing disorders, the authors removed age-corrected audiograms with hearing levels under 10 dB at all frequencies. The hearing deficit was unilateral in 49 (15.9%) and bilateral in 132 (42.7%) patients. Only 26 subjects (8.4%) complained of hearing difficulties. The etiology varied, including brainstem malignant tumors (84), vertebrobasilar insufficiency (57), MS (52), and other disorders (116), such as syringobulbia, angiomas, abscesses, collagen diseases, encephalomyelitis, degenerative disorders, tuberculosis, and benign cysts. Smaller studies limited to specific disorders of the brainstem have been reported in the literature and are summarized in Table 29.1. Retrospective studies (Luxon, 1980; Nakashima et al., 1999) yielded fewer hearing abnormalities than prospective ones (Jerger and Jerger, 1974; Musiek and Pinheiro, 1987; van der Poel et al., 1988; Levine et al., 1994; Aharonson et al., 1998; Lee et al., 2002; Rance et al., 2010), an occurrence of 52.8% versus 65.8% respectively. However, these prospective studies were small and contained a selection bias, being limited to some diseases seen in specific referral centers. The occurrence of auditory abnormalities in the studies of Luxon (1980) and Nakashima et al. (1999) may have been underestimated because psychoacoustic methods to evaluate central auditory function were not used. The studies of Musiek and Pinheiro (1987), Levine et al. (1994), and Aharonson et al. (1998) employed only one specific auditory test, therefore not evaluating the full spectrum of hearing. The importance of the type of test used is noted

HEARING DISORDERS IN BRAINSTEM LESIONS

511

Fig. 29.2. Arterial supply of the brainstem. (A) Upper medulla; (B) lower pons; (C) middle pons at the level of the fifth nerve; and (D) the upper pons at the level of the decussation of the fourth nerve. (E) Midbrain at the level of the inferior colliculus; (F) midbrain at the level of superior colliculus. The anterior inferior cerebellar artery is a branch of the vertebral or basilar artery; the superior cerebellar artery, the paramedian and the lateral pontile arteries are branches of the basilar artery. The laterosuperior midbrain arteries and the lateral basis peduncular arteries are branches of the posterior cerebral artery. The paramedian midbrain arteries are branches of the posterior cerebral and basilar arteries. The areas supplied by various arteries are drawn with different colors (purple for the anterior inferior cerebellar artery, blue for the superior cerebellar artery, light blue for the lateral basis peduncular arteries, yellow for the paramedian pontile arteries, light green for the lateral pontile arteries, and dark green for the anterior choroidal artery). The auditory nuclei and pathways are drawn in red, while hatched regions represent areas of overlapping vascularization. (Modified from Haymaker, 1969.)

53.5% of MS and 25% of isolated brainstem demyelination patients; however, when IATD discrimination test was employed, the deficits increased to 82% and 33% respectively. It is clear that the assessment of central auditory processing cannot be limited to classic audiograms but requires the use of a battery of behavioral and physiologic tests (Bellis, 2003; Musiek and Chermak, 2006; Schow and Seikel, 2006).

EVALUATION OF BRAINSTEM-RELATED HEARING DISORDERS

Fig. 29.3. Arterial circulation to the inner ear. (Modified from Kim et al., 1999.)

in the study of van der Poel et al. (1988); these authors evaluated two tests of binaural hearing: (1) intensity discrimination of alternating monaural clicks and (2) interaural time difference discrimination (IATD) of binaural clicks in 28 patients with definite MS and 12 patients with an isolated brainstem lesion compatible with demyelination. Intensity discrimination defects were found in

Deficits of auditory function from disorders affecting the auditory pathways past the cochlear nuclei may not be detected by classic audiometry but require a battery of behavioral tests that assess specific central auditory processes (Jerger and Hayes, 1976; Musiek and Pinheiro, 1987; Levine et al., 1994; Griffiths, 2002; Bellis, 2003; Musiek and Chermak, 2006; Schow and Seikel, 2006; Shemesh, 2008; Musiek et al., 2011). The American Academy of Audiology (2010) suggests test batteries that include: “sound localization and lateralization, auditory discrimination, auditory temporal processing, auditory pattern processing, dichotic listening, auditory performance in competing acoustic signals,

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Table 29.1 Prevalence of hearing disorders in brainstem diseases Hearing loss Author(s), year

Disorder

Total number

Number

Percent

Jerger and Jerger, 1974 Luxon, 1980 Musiek and Pinheiro, 1987 Levine et al., 1994 van der Poel et al., 1988 Aharonson et al., 1998 Nakashima et al., 1999 Lee et al., 2002 Rance et al., 2002 Total

Intra-axial brainstem Mix (MS, stroke, tumors, etc.) Mix (MS, stroke, tumors, etc.)* MS MS MS and pontine strokes† MS Unilateral AICA strokes{ Friedreich’s ataxia

16 309 22 38 40 22 43 12 14 516

10 181 10 27 27 16 5 11 9 296

62.5 58.6 45 71 67.5 72.7 11.5 92 64.3 57.4

*

Test limited to performance on frequency patterns. Test limited to lateralizing abnormalities. { The deficit was cochlear in 6 and mixed cochlear and retrocochlear in 4. MS, multiple sclerosis; AICA, anterior inferior cerebellar artery. †

Table 29.2 Testing battery for brainstem disorders Audiometry Pure-tone audiogram Psychoacoustic tests Tests of monaural low-redundancy speech perception Filtering selected frequencies (e.g., high- or low-pass filtering) Time compression of the speech signals Embedding speech in background noise or verbal competition Tests of temporal processes The Gaps-in-Noise (GIN) Frequency (or Pitch) Pattern Sequence Test Duration Patterns Test Dichotic listening (speech) tests Tests of localization/lateralization and other binaural interactions Masking level difference (MLD) Listening in Spatialized Noise-Sentences Test Electrophysiologic tests Otoacoustic emission Auditory brainstem evoked responses

and auditory performance with degraded acoustic signals.” A comprehensive battery of tests is proposed in Table 29.2. Pure-tone audiogram is “essential” (Griffiths, 2002) to exclude an inner-ear hearing disorder. The American Academy of Audiology (2010) suggests the additional utilization of distortion product otoacoustic emissions to similarly exclude cochlear (outer hair cell) dysfunction.

The presence of an inner-ear deficit does not exclude involvement of the brainstem; Griffiths (2002) pointed out that it is also “possible for a degree of cochlear” deafness to “co-exist with other disorders.” Furthermore, ipsilateral hearing loss is common with lesions of the auditory nerve and/or cochlear nuclei. Brainstem auditory evoked potentials (BAEPs), although quite sensitive in detecting brainstem lesions and pinpointing their locations, correlate poorly with auditory function, as abnormal BAEPs have been reported in subjects with normal hearing (Legatt et al., 1988; Hu et al., 1997; Vitte et al., 2002; Celesia, 2011).

Psychoacoustic testing As binaural interaction and sound localization are first processed in the medulla and pons, psychophysical testing emphasizing these properties should be employed (Table 29.2) in suspected brainstem disorders. Psychoacoustic tests allow “the demonstration of deficits that may be related to the symptoms from which the patients suffer” (Griffiths, 2002). Because these tests rely on a subjective response, they require repeated responses to achieve reliable parameters. To improve the diagnostic yield, a test battery approach has been advocated (Jerger and Hayes, 1976; Chermak and Musiek, 1997; Musiek and Chermak, 2006; American Academy of Audiology, 2010). This approach is very time consuming and further raises concern about cost-effectiveness. Can we reduce the number of tests without reducing their sensitivity and specificity? Bellis (2003) advocates the use of masking level difference (MLD) as the: “most

HEARING DISORDERS IN BRAINSTEM LESIONS sensitive behavior technique for assessing brainstem integrity.” Abnormalities of MLD have been reported in lesions of the pontomedullary junction by several authors (Olsen et al., 1976; Lynn et al., 1981; Musiek et al., 1989; Pillion et al., 2008). Others have claimed that dichotic listening testing is an effective alternative to analyze brainstem auditory function (Hariri et al., 1994; Fischer et al., 1995; Cho et al., 2005). Musiek et al. (2011) studied the sensitivity, specificity, and efficiency of commonly used behavioral central auditory processing test batteries in 20 individuals with known lesions of the central auditory nervous system and related auditory symptoms. The four tests used were dichotic digits (DD), competing sentences, frequency patterns (FP), and low-pass filtered speech. They found that the test battery providing the best balance between sensitivity and specificity was a two-test battery comprising dichotic digits and frequency patterns. They estimated the cost of DD-FP testing to be less than $20. These results need independent confirmation; nevertheless they suggest that a slimmed-down battery of tests may be satisfactory for the diagnosis of central auditory processing disorders and specifically brainstem auditory disorders. Clinically we are faced with two possible scenarios: patients with brainstem disorders without auditory complaints and patients with brainstem disorders and hearing loss.

PATIENTS WITH BRAINSTEM DISORDERS WITHOUT AUDITORY COMPLAINTS

This group consists of patients with a diagnosis of diseases affecting the brainstem, such as brainstem infarcts, hemorrhages, neoplasms, infections, and demyelinating disorders. The issue in these cases is whether there is an additional auditory disorder increasing the burden of known neurologic deficits. Classic examples are MS patients with signs of ataxia and/or other brainstem deficits (internuclear ophthalmoplegia, dysarthria, cranial nerve deficits) but without auditory complaints, that when tested showed disorders of sound localization and of IATD (Levine et al., 1993, 1994; Furst et al., 1995, 2000).

513

As shown in Table 29.3, abnormal lateralization of sound was also present in patients with stroke. Of 29 patients studied (16 with MS and 13 with strokes), Aharonson et al. (1998) found that 72.4% had abnormalities of sound lateralization. When the lesion is in the superior olivary complex, the trapezoid body, and/or the lateral lemniscus the hearing deficit is often bilateral, whereas in lesions of the VIIIth nerve and cochlear nuclei the deficit is ipsilateral. Sometimes these patients may complain of difficulties listening in background noise, or “understanding rapid or degraded speech” (Bamiou et al., 2001), although they have normal peripheral hearing; in short, they show evidence of central auditory processing disorders.

PATIENTS WITH BRAINSTEM DISORDERS AND HEARING LOSS

This group of patients developed either gradual hearing loss or sudden hearing loss. In either case they show a sensorineural deficit on pure-tone audiometry (Fig. 29.4). The deficit is usually unilateral and can occur from either extra- or intra-axial lesion of the brainstem. Jerger and Jerger (1975) studied 45 patients with expanding lesions of the brainstem, including 28 extra-axial and 17 intra-axial lesions. Each patient was tested with puretone sensitivity, Be´ke´sy audiometry, acoustic reflex, rollover of the performance-intensity function for phonemically balanced words and synthetic sentence identification test. Although there was considerable overlap between the two groups, patients with intra-axial brainstem disorders usually had normal acoustic reflex, puretone, and Be´ke´sy audiograms and the deficits were either bilateral or to the contralateral ear only (Fig. 29.5). Patients with extra-axial lesions had abnormal acoustic reflex, pure-tone, and Be´ke´sy audiograms and the deficit was to the ipsilateral ear only (Jerger and Jerger, 1975). While auditory tests are indispensable in determining the nature of the hearing deficits they are unsatisfactory in establishing the location and nature of the disorders. Neuroimaging techniques are necessary to establish the etiologic diagnosis in most cases.

Table 29.3 Sound lateralization in multiple sclerosis and strokes

Multiple sclerosis Stroke Total

Total

Normal

Abnormal

Center oriented

Side-oriented

16 13 29

5 3 8

11 10 21

7 7 14

4 3 7

Data from Aharonson et al. (1998).

514

G.G. CELESIA Percent Abnormalities 100 90 80 70 60 50 40 30 20 10 0 Pure Tone A.

Bekesy A.

Acoustic R.

Intra-axial

PB max

PB rollover

Extra-axial

Fig. 29.5. Summary of auditory test results for the intra-axial and extra-axial brainstem groups. The percentage of patients with abnormal results on the involved ear is presented for each test. (Modified from Jerger and Jerger, 1975.)

Fig. 29.4. Pure-tone audiograms and brainstem auditory evoked potentials in 2 patients with unilateral sudden hearing loss as the first monosymptomatic manifestation of multiple sclerosis. R, right; L, left. The horizontal scale represents 1 ms, while the vertical scale represents 0.3 mV. (Reproduced from Drulovic et al., 1993, with permission.)

Fig. 29.6. Axial magnetic resonance imaging, T1 W image revealing a hyperintense lesion within the right intra-auricular meatus (IAM), consistent with an IAM lipoma. This signal was suppressed on fat-saturated sequences and was static at 5-year follow-up. (Reproduced from Sriskandan and Connor, 2011, with permission.)

Neuroimaging Magnetic resonance imaging (MRI) of the brain, with special emphasis on the brainstem, is the preferred method to diagnose brainstem disorders. Bognar et al. (1994) compared computed tomography (CT) and MRI scans in 12 patients with histologically proved tectal plate gliomas. MRI showed the lesion in all cases, while CT scans failed to show the tumor in 4 patients. Cueva (2004) studied 312 patients (between the ages of 18 and 87) with asymmetric sensorineural hearing loss (SNHL) and prospectively compared MRI and BAEP results. Thirty-one (9.94%) patients of the study population of 312 were found on MRI to have lesions causing their SNHL. Twenty-two of the 31 patients had abnormal BAEPs while 9 patients (7 with small vestibular

schwannomas) had normal BAEPs. The author concluded that MRI is “the screening test of choice” for the evaluation of asymmetric SNHL (Cueva, 2004). MRI is now a recognized “gold standard” test for symptoms pertaining to the inner ear and for the detection of retrocochlear pathology in both adults (Fig. 29.6) and children (Schick et al., 2001; Powell and Choa, 2010; Pennings et al., 2011; Poussaint et al., 2011). MRI can visualize a small acoustic neuroma within the inner auditory canal and is now the standard to screen for small tumors (Newton et al., 2010; Yoshida et al., 2011). Vascular lesions of the brainstem are also detected by MRI (Kim et al., 2006; Hendrikse et al., 2009; Lee et al., 2009; Ga´llego Cullere´ and Erro Aguirre, 2011). Similarly,

HEARING DISORDERS IN BRAINSTEM LESIONS Conductive hearing loss Unilateral hearing loss Pure tone audiogram

Sensorineural deafness

II

I

515 III

CD-ST

A Audiometric IAD ≥ 15 dB 0.5 to 3 kHz

V

MRI

Normal

ABNORMAL

BAEPs, Otoacoustic emission, Psychoacoustics

II

I

III

B

V

CD-ST

CD-ST

Fig. 29.7. Algorithm for the diagnosis of unilateral sensorineural hearing loss. IAD, interaural difference; CD-ST, clinical diagnosis-start therapy; MRI, magnetic resonance imaging; BAEPs, brainstem auditory evoked potentials.

MRI is the preferred diagnostic test to confirm the diagnosis of MS (McDonald et al., 2001; Polman et al., 2005). Although MRI has a clear role in the diagnosis of retrocochlear hearing disorders, its high cost precludes its use as a screening test. Cheng and Wareing (2012) reported the MRI findings in 7494 cases of sensorineural hearing disorders “across ENT clinics” and noted that MRIs were abnormal in 2088 (27.8%) patients, including 284 (3.8%) vestibular schwannomas and 209 (2.8%) ischemic infarcts. Similarly, in sudden cases of hearing loss the diagnostic yield of MRI is low, varying from 4% to 34.5%. with vestibular schwannomas representing only 2.5–3.8% of all cases (Fitzgerald and Mark, 1998; Stokroos et al., 1998; Schick et al., 2001; Cadoni et al., 2006; Chau et al., 2010). Because of this low diagnostic yield and high cost, the need has arisen to formulate guidelines as part of “decision making for MRI screening of acoustic tumors” (Cheng and Wareing, 2012) and other unilateral SNHL. In Figure 29.7 we propose an algorithm for patients presenting with unilateral hearing loss based on an audiometric protocol. In cases of sensorineural deafness with interaural difference greater than 15 dB at 0.5–3 kHz, the subjects should undergo an MRI. If the MRI is negative, additional audiologic tests are warranted, including otacoustic emission (abnormal in cochlear disorders affecting the cochlear outer hair cell), BAEPs (sensitive to auditory nerve and brainstem disorders), and other psychoacoustic tests. The latter may better assess the central nature of the hearing disorders and suggest remedial interventions.

Brainstem auditory evoked potentials BAEPs are a tool to study the function of the brainstem auditory nuclei and tracts and they provide “a look at

I

V

III

C

0

5

10

msec

Fig. 29.8. Brainstem auditory evoked potentials (BAEPs) in brainstem disorders. (A) Normal BAEP. (B) BAEP of a 31-year-old male with a pontine glioma. Wave III and V are delayed and interval I–V is prolonged at 5.4 ms. Wave V is also small in amplitude. (C) BAEP in a 24-year-old male with a left acoustic neuroma. Wave I was within the upper limits of normal (latency of 1.88 ms); wave V was delayed (6.88 ms) and the interval I–V prolonged at 5 ms. The vertical calibration bar represents 0.25 mV.

physiological anatomy” (Chiappa, 1997). However, abnormalities of BAEPs do not imply the presence of a hearing deficit (Hu et al., 1997; Vitte et al., 2002; Celesia, 2011) and are etiologically non-specific (Chiappa, 1997). In view of these limitations, what is the role of BAEPs in brainstem disorders? As is made clear in the paragraphs to follow, opinions vary and there is currently no consensus regarding when to use BAEPs. Hendrix et al. (1990) studied 225 consecutive cases of asymmetric SNHL with a variety of diagnostic tests. Eighty-six percent of these patients had a cochlear dysfunction, while the remaining 14% had a retrocochlear lesion. All 31 patients with retrocochlear abnormalities had an “abnormal auditory brainstem response.” These authors suggested that MRI should be performed in patients with BAEP abnormalities indicating a retrocochlear lesion, rather than in all patients with asymmetric SNHL. BAEPs are very sensitive to brainstem abnormalities (Fig. 29.8), thus they are useful in evaluating subclinical or yet undetected damage to the auditory system (Hosford-Dunn, 1985; Lisowska et al., 2001; Church et al., 2007; Pessin et al., 2008; Pillion et al., 2008;

516

G.G. CELESIA

Jiang et al., 2010). Martinez-Arizala et al. (1983) suggest that BAEPs could be used as “a screening tool for patients whose clinical picture is suggestive of structural abnormalities of the posterior fossa.” Hosford-Dunn (1985) suggests that BAEPs are a screening test for the detection of brainstem disorders. BAEPs are useful in assessing the auditory system in young children because they do not require their cooperation. Church et al. (2007) reported that, in cases of craniostenosis, BAEPs showed prolongation of I–III interpeak interval in 65% of children with normal hearing. They recommend that “auditory brainstem response diagnostics become standard clinical care for this patient group as the best way to detect auditory nerve compression.” Wellman et al. (2003) tested 68 children survivors of bacterial meningitis and reported that 22 cases (32.3%) had abnormal BAEPs; 11 of these patients had a verified SNHL. Because early identification and remedial amplification lead to better academic and language outcomes, these authors advocate routine inpatient audiologic screening of postmeningitic children.

HEARING ABNORMALITIES IN ISOLATED LESIONS OFAUDITORY BRAINSTEM CENTERS Diseases of the brainstem usually involve many structures, producing a plethora of neurologic deficits (Haymaker, 1969; Voordecker et al., 1988; Urban and Caplan, 2011), often relegating “auditory symptoms in the background” (Cho et al., 2005). Rarely, a small lesion is limited to the auditory system. Voordecker et al. (1988) observed that: “intrinsic brain-stem lesions that affect only unilaterally a portion of the auditory pathways without distortion or pressure on adjacent structures are exceptional.” Tracts and nuclei in the medulla-pons are in close proximity to each other, thus rarely a disease state affects only one structure. These limiting factors must be considered in our understanding of the published reports of isolated lesions of the brainstem.

Table 29.4) ipsilateral to the lesion (Johnson, 1977; Starr et al., 1996; Ottaviani et al., 2002; Berlin et al., 2003; Rance, 2005; Pennings et al., 2011). In auditory neuropathy BAEPs are absent but the middle- and long-latency auditory evoked responses have been reported to be within the normal limit (Kraus et al., 2000; Rance et al., 2002).

Unilateral lesions of the cochlear nuclei Unilateral lesions of the cochlear nuclei are reported in occlusion of the AICA and in cerebellopontine angle tumors compressing the upper medulla. In both cases the vestibular nuclei and other structures are also implicated. The auditory-processing abnormalities are ipsilateral to the lesion (Table 29.4) with abnormal pure-tone audiogram, speech detection threshold, tone decay test, dichotic listening, and BAEPs (Hausler and Levine, 2000; Lee et al., 2002). The deficit profile of lesions of the cochlear nuclei is similar to the VIIIth-nerve involvement.

Unilateral lesions of the superior olivary complex The superior olivary complex is the initial station of the binaural signal integration (Illing et al., 2000; Moore, 2000; Yin, 2002), thus a unilateral lesion may result in impairment of interaural time and level differences and sound localization (Table 29.4). Levine et al. (1993) reported isolated demyelinating lesions of the superior olivary complex in MS. The acoustic abnormalities (hearing loss, elevated threshold on audiograms, impaired speech discrimination) were predominantly ipsilateral to the lesion, whereas the otoacoustic emission tests were abnormal contralaterally, and the acoustic reflexes were either normal or abnormal contralateral to the lesion. Ipsilateral sound localization deficit and impaired binaural fusion were also noted (Levine et al., 1993; Levine and Hausler, 2001). BAEPs showed delayed waves III and V with prolonged I–V interval ipsilateral to the lesion (Levine et al., 1993).

Disorders limited to the auditory nerve Disorders limited to the auditory nerve include neuropathies and intracanalicular vestibular schwannoma (also called acoustic neuroma). When the disease is limited to the auditory nerve without involvement of the cochlea, the cochlear microphonic, the summating potentials of the electrocochleogram and the otoacoustic emission are normal (Starr et al., 1996; Santarelli and Arslan, 2002; Berlin et al., 2003; Rance, 2005). However, acoustic reflexes, pure-tone audiogram, speech discrimination, speech detection threshold, tone decay test, dichotic listening, and BAEPs are abnormal (Fig. 29.6 and

Unilateral lesions of the lateral lemniscus Unilateral lesions of the lateral lemniscus have been reported to be clinically silent on standard testing, but their effects can be revealed using careful psychoacoustic testing (Table 29.4), which shows abnormal sound localization and interaural time perception (Levine et al., 1994; Hausler and Levine, 2000; Cho et al., 2005). Lee et al. (2008) described normal speech and pure-tone audiometry, normal tympanometry, and acoustic reflexes but hyperacusis in a case of right pontine hemorrhage involving the lateral lemniscus;

HEARING DISORDERS IN BRAINSTEM LESIONS

517

Table 29.4 Auditory-processing abnormalities in unilateral brainstem lesions Auditory process

Eighth nerve

Medulla

Pons

Superior olivary Cochlear nuclei complex

Pons

Pons

Midbrain

Trapezoid body

Lateral lemniscus

Inferior colliculus

Clinical findings Reported Loss of hearing Loss of hearing Loss of hearing ipsilateral ipsilateral symptoms ipsilateral Ipsilateral tinnitus, vertigo No tinnitus/ vertigo in auditory neuropathy Neuro-otologic Ipsilateral findings deafness Electrophysiologic testing Audiogram Elevated threshold (ipsilateral) Retrocochlear hearing loss (ipsilateral) Acoustic Absent reflexes ipsilateral Normal contralateral Cochlear Normal microphonic Otoacoustic Normal emissions

BAEPs

Middle-latency ERP

Sometimes tinnitus ipsilateral

Sometimes None, sometimes None or tinnitus contralateral auditory (contralateral) tinnitus hallucinations and/or “Not hearing as Sometimes auditory hyperacusis well” hallucinations Sometimes hyperacusis

Ipsilateral deafness

Ipsilateral deafness Normal

Normal

Normal

Elevated threshold (ipsilateral)

Normal or elevated Normal threshold (ipsilateral)

Normal

Normal

Normal Absent contralaterally Normal ipsilateral Normal Normal

Normal

Normal

Normal

Normal

Normal or mildly Absent impaired ipsilateral (contralateral) Normal contralateral Normal Normal

Abnormal contralateral Normal ipsilateral Delayed wave III Ipsilateral Ipsilateral Wave wave and V (ipsilateral) wave I and V bilaterally Prolonged I–V I normal, V prolonged Delayed II and or wave interval V prolonged I normal (ipsilateral) I–V intervals wave V and prolonged I–V interval prolonged Absent in auditory neuropathy

Normal

Normal

Abnormal contralateral

Delayed and Delayed wave attenuated V (contralateral wave V; or bilateral) prolonged I–V and III–V I–V interval intervals bilateral prolonged worse (contralateral contralateral or bilateral); sometimes wave V depressed or absent (contralateral) Normal Abnormal contralateral Continued

518

G.G. CELESIA

Table 29.4—Continued Auditory process

Eighth nerve

Medulla

Pons

Superior olivary Cochlear nuclei complex Psychoacoustic testing Speech detection Impaired threshold ipsilateral Speech Impaired discrimination ipsilateral

Dichotic listening Binaural fusion Binaural interaction (masking level difference: MLD) Frequency pattern recognition Frequency pattern sequence Duration pattern sequence test

Sound-source localization in space

Impaired ipsilateral Impaired ipsilateral Impaired ipsilateral

Pons

Pons

Midbrain

Trapezoid body

Lateral lemniscus

Inferior colliculus

Normal

Normal

Impaired ipsilateral Impaired ipsilateral

Normal or impaired ipsilateral Normal Sometimes impaired (ipsilateral)

Impaired ipsilateral Impaired ipsilateral Impaired ipsilateral

Impaired

Impaired contralateral Impaired contralateral

Impaired Impaired

Impaired

Normal

Impaired with competing ipsilateral signals Impaired Abnormal contralateral contralateral Impaired Impaired contralateral contralateral Impaired Normal

Normal

Normal

Abnormal to stimulation contralateral ear Impaired (center- Impaired Impaired for biased) contralateral source localized in contralateral hemifield

Impaired

BAEPs, brainstem auditory evoked potentials; ERP, event-related potential.

however they did not test for sound localization. The patient also had uncomfortable paresthesia in her left body. Cho et al. (2005) in a pontine hemorrhage noted normal speech and pure-tone audiometry while dichotic listening testing revealed an extinction of contralateral ear input. Levine et al. (1993) noted that a unilateral lesion in the region of the lateral lemniscus affected IATD for low-frequency stimuli. However the deficit was less severe than bilateral lesions of the lateral lemniscus.

Unilateral lesions of the trapezoid body Furst et al. (1995, 2000) demonstrated in patients with MS that lesions of the trapezoid body affect sound localization: patients tended to hear all the sounds toward the

middle of the head (center-oriented or biased). Cambier et al. (1987) reported that one patient with a lesion of the trapezoid body had “central type hypoacusis and a severe disorder of localization of sounds.” Levine et al. (1993) noted that a unilateral lesion of the trapezoid body produced an interaural level discrimination abnormality.

Unilateral lesions to the inferior colliculus Unilateral lesions to the IC are rare (Durrant et al., 1994; Litovsky et al., 2002; Champoux et al., 2007a, b; Stimmer et al., 2009). Litovsky et al. (2002) studied a 48-year-old man with a small traumatic hemorrhage of the right dorsal midbrain, including the IC. They reported normal audiograms bilaterally, abnormal BAEPs with a decrease

HEARING DISORDERS IN BRAINSTEM LESIONS

519

Fig. 29.9. Single-source localization results. Data for one normal control subject and for patient RJC are shown in the left and middle columns, respectively, for three stimulus configurations depicted in the right column. RJC is a 36-year-old right-handed man, who suffered a small traumatic hemorrhage of the right brainstem involving the inferior colliculus. From top to bottom, these are the frontal, right, and left conditions. The numbers in each configuration represent the angles of the speakers in the room relative to the center of the subject’s head. Gray areas denote the hemifield contralateral to the lesion site. Each plot shows the proportion of trials on which responses occurred at each position, as a function of the true (target) source positions, demarcated by dot size. (Reproduced from Litovsky et al., 2002, with permission.)

in wave V amplitude following left (contralateral)-ear stimulation. The patient had a deficit in sound localization contralateral to his IC lesion (Fig. 29.9). Echo suppression was abnormally weak compared with that seen in control subjects, but only for sources contralateral to the lesion. Although speech discrimination and detection threshold tests were normal, the patient complained of having trouble understanding speech in noisy environments. Stimmer et al. (2009) reported on a 48-year-old man with an acute circumscribed hemorrhagic lesion of the left IC. The patient complained of right-ear tinnitus but no other otoneurologic signs or symptoms. Auditory brainstem response revealed prolonged III–V interpeak latencies from stimulating either ear. Champoux et al. (2007a, b) reported on a 12-year-old boy with a “circumscribed lesion of the right IC without additional neurological damage”; the subject suffered a traumatic hemorrhagic lesion at age 9 years. An extensive battery of psychophysical hearing tests revealed normal peripheral auditory functioning bilaterally (Table 29.4); dichotic listening, duration pattern sequence test, and sound source localization were abnormal contralaterally (Fig. 29.10); speech recognition was impaired in the presence of a competing ipsilateral signal

(Champoux et al., 2007a, b). The authors concluded that “recognition of low-redundancy speech presented monaurally, recognition of tone duration patterns, binaural separation and integration, as well as sound-source localization in space depend on the integrity of the bilateral auditory pathways at the IC level” (Champoux et al., 2006, 2007b; Paiement et al., 2009). A follow-up in the same patient showed that cortical activation in response to binaural stimulus presentations as monitored by functional MRI (fMRI) produced a stronger activation in the contralateral hemisphere rather than the well-balanced bilateral activation patterns seen in normal subjects. Auditory pathways failed to re-establish normal cortical activation patterns in response to binaural stimulation following the unilateral lesion of the IC. The authors concluded that the IC is an essential auditory relay and that its loss cannot be significantly compensated (Paiement et al., 2009). Durrant et al. (1994) limited their study to threechannel Lissajous trajectories of the auditory brainstem responses in a human with a focal lesion of the right IC. They found an intact wave IV but a negligible, if not totally absent, wave V with stimulation of the left (contralateral) ear.

520

G.G. CELESIA

R Left

Center

Right

Visual fields

A B C A⬘ B⬘ C⬘

A

Percentage of /ba/ response (%)

L

B

100 Normal (n = 7) FX

50

0 Left

Center

Right

Fig. 29.10. Illustration of subject FX. The upper illustration shows the coronal, sagittal and axial magnetic resonance imaging scans showing a small lesion in the right inferior colliculus (arrow). R, right; L, left. The lower illustration part (A) is the schematic representation of the experimental setup. In all trials the auditory stimuli were presented in the free field via loudspeakers positioned on each side of the participant. The visual stimuli were presented at various locations: directly in front of the subject (B-B’), five degrees to the left (A-A’) or to the right (CC’) of the point of fixation. The area in black drawn on the participant’s stylized head represents the site of FX’s lesion at the level of the right inferior colliculus. Part (B) shows the performance for the incongruent stimuli. Data are shown for three experimental conditions in which the visual stimuli were presented either in the center of the monitor or in the participant’s left or right hemifield. The percentage of /ba/ responses given are plotted for FX (triangle) and for the group of matched controls (square). Dashed lines represent values 2 SD above the mean for the control group, indicating abnormal audiovisual speech integration. (Modified from Champoux et al., 2006.)

Isolated bilateral lesion of the inferior colliculi Isolated bilateral lesion of the IC have also been described (Johkura et al., 1988; Jani et al., 1991; Hu et al., 1997; Vitte et al., 2002; Hoistad and Hain, 2003; Kimiskidis et al., 2004; Musiek et al., 2004), with some inconsistent results. Johkura et al. (1988) reported a case of traumatic small hemorrhage involving the IC bilaterally and without evidence of a temporal-lobe lesion. The patient was unable to comprehend spoken words, although he had intact speech production, reading and writing abilities. Comprehension of environmental sounds was also affected. Among the receptive musical abilities, discrimination of intensity, tone, and rhythm was preserved, while recognition of melody was impaired. Pure-tone audiometry was normal. BAEP waves I–IV were normal, but wave V had reduced amplitude and prolonged latency bilaterally. Musiek et al. (2004) reported on a 21-year-old male with a subarachnoid bleed affecting both ICs who experienced central

deafness. Dichotic listening was abnormal bilaterally, BAEPs were normal, whereas middle and late auditory evoked potentials were significantly abnormal. Hu et al. (1997) described a 48-year-old woman with bilateral contusions of the IC (Fig. 29.11). The patient was able to speak, read, and write; her cognitive functions were normal, but she was unable to hear. She did not respond to either pure-tone or speech stimuli. Impedance audiometry revealed normal middle-ear pressure and mobility bilaterally. The crossed and uncrossed stapedial reflexes and the BAEPs were normal bilaterally. Hoistad and Hain (2003) presented a 43-year-old man with bilateral lesions of the IC due to central nervous system lymphoma. He had normal pure-tone audiogram but severely reduced bilateral word recognition scores. Kimiskidis et al. (2004) studied a 48-year-old woman who suffered a hemorrhage localized at the quadrigeminal plate (including the IC). Her pure-tone audiogram revealed bilateral mild SNHL and speech audiometry showed persistent word deafness. Acoustic reflexes

HEARING DISORDERS IN BRAINSTEM LESIONS

521

Fig. 29.11. Magnetic resonance imaging (MRI) of a 48-year-old woman who became totally deaf after a head injury that caused contusions of both inferior colliculi. (A) Axial T1-weighted MRI with Gd-DTPA enhancement (slice thickness ¼ 7 mm; interval ¼ 8 mm) showed enhanced lesions in both inferior colliculi, consistent with subacute contusional hemorrhage (arrows). (B) Axial T2-weighted MRI revealed abnormal signals in the inferior colliculi (arrows). (C) Enlarged view of midbrain from (A). (Modified from Hu et al., 1997.)

were normal bilaterally. Transient evoked otoacoustic emissions were normal from both ears, with however a failure for their amplitude to be suppressed with contralateral sound stimulation. BAEPs were of normal amplitude and latencies bilaterally. Vitte et al. (2002) described two cases with bilateral symmetric lesions of the IC. Both cases had MRI showing either an infarct or a hemorrhage. Both were able to speak, read, and write, but were unable to hear. They had a mild bilateral SNHL, normal impedance audiometry, stapedial reflexes, and BAEPs.

Isolated bilateral lesion of pontomedullary region There are very few reports of bilateral lesions of the pontomedullary region predominantly affecting the auditory system. Egan et al. (1996) described a 64-year-old woman with a midline pontine hematoma who had bilateral deafness, right abducens paresis, loss of proprioception in both arms and in both legs, with normal touch and pinprick sensation. She had limb ataxia and bilateral extensor plantar responses. Pure-tone audiometry showed bilateral moderately severe SNHL. Speech discrimination was absent bilaterally, ipsilateral acoustic reflexes were preserved, whereas contralateral reflexes were absent. BAEPs showed bilaterally preserved wave IV and V. The authors interpreted the findings as related to a lesion of the “ventral acoustic stria decussating in the trapezoid body.” Significant hearing loss was also noted by Cohen et al. (1996) in cases of central pontine hemorrhage.

AUDITORY HALLUCINATIONS IN BRAINSTEM DISORDERS Hallucinations caused by brainstem lesions were first noted by Lhermitte in 1922 as purely visual phenomena. Cascino and Adams (1986) were the first to report auditory hallucinations in 3 patients with brainstem disorders (Table 29.5). These authors described the phenomena varying from simple buzzing and “clanging like motors

of machines” or “like sheets of metal being banged together” to music like “bells chiming” or “organ notes.” Auditory hallucinations differ from tinnitus because they are more complex than a simple buzzing or ringing and often are perceived as real. However, the boundary between tinnitus and auditory hallucinations is blurred and often authors include cases of tinnitus among their cases of hallucinations. Additional reports have been published since, under variable terminology: peduncular hallucinations, brainstem hallucinosis, and auditory illusions (Table 29.5). Sometimes the hallucinations are musical, as in the case reported by Silva and Brucki (2010), consisting of a continuous repetition of a Carmen Habanera aria. In a few cases the patient experienced both auditory and visual hallucinations (Cambier et al., 1987; Taylor et al., 2005; Silva and Brucki, 2010), although the auditory component is the predominant one. Of the reported 20 cases, 14 lesions (70%) were localized in the pontine tegmentum (Fig. 29.12), four (20%) in the midbrain (IC), one in the middle geniculate body, and one in the thalamus, probably involving the middle geniculate body (Table 29.5). All these lesions involved auditory structures (cochlear nuclei, acoustic stria, superior olive, trapezoid body, lateral lemniscus, and middle geniculate body), in agreement with Shergill et al. (2001) that: “hallucinations in a given modality seem to involve areas that normally process sensory information in that modality.” The etiology varied from hemorrhage to trauma, infections, neoplasm, and demyelinating disorders. Hearing loss was frequent, but not necessary to the development of the hallucinations. The pathophysiology of these auditory hallucinations is uncertain. Cascino and Adams (1986) favored “a release mechanism” in their cases. Cambier et al. (1987) suggested that “Auditory deafferentiation could predispose to auditory hallucinosis”; in these cases presumably the structural lesion producing deafferentiation resulted in release of inhibition, leading to activation of the auditory cortical system. Cambier et al. (1987) suggested that auditory

Table 29.5 Brainstem auditory hallucinations

Authors

Type of Age Sex hallucinations

Side of Duration of hallucinations hallucinations

Hearing loss

Associated visual Other neurologic hallucinations phenomena

33

F

Sounds, musical Bilateral (piano playing)

>18 months

42

F

Sounds, musical (bells chiming)

>8 years but Unilateral right No intermittent

53

F

6 months, till death

Bilateral

No

Cambier 56 et al., 1987

F

Sounds Bilateral (humming, metal banging) Musical Bilateral (melodies, songs)

Few weeks

No

55

F

Sounds, musical (melodies, songs)

Bilateral

24 days

74

F

Musical, verbal, sounds

Bilateral

20 days

61

M

Musical (melodies) sounds

Bilateral, worse on the left

15–20 days

Bilateral and loss of sound localization Bilateral and loss of sound localization Bilateral and loss of sound localization Bilateral and loss of sound localization

54

M

Musical (bells) sounds

Bilateral

31 days

Cascino and Adams, 1986

Right

Unilateral right No

none

Site of lesion

Etiology

AVM, subarachnoid Left wall fourth hemorrhage ventricle and pontine tegmentum

Left VI, left face hypoesthesia, right hemihypesthesia Right Horner, VI and VII, right ataxia, left hemihypoesthesia Confusion, bilateral ptosis, diplopia, left hemiparesis Left hemisensory loss, right VII

Right pontine tegmentum

Hemorrhage

Tectum of midbrain (inferior colliculi) right cerebellum Right pontine tegmentum

Metastatic tumor

No

Right VI, left hemianesthesia

Right paramedian pontine tegmentum

Infarct

No

Right VI,VII, left hemianesthesia, left-limb ataxia

Right paramedian pontine tegmentum

Infarct

Yes

Right hemisensory Left paramedian pontine tegmentum loss and right ataxia Internuclear ophthalmoplegia, left VII Inferior colliculi and Internuclear pontine tegmentum ophthalmoplegia, ataxia Left hemisensory loss

No

Infarct

Hemorrhage

Infarct

Lanska et al., 55 1987

M

Musical and verbal

Bilateral

Several months

Bilateral

No

Forcadas and 72 Zarranz, 1994

F

Musical (childhood songs)

Bilateral

Few months

hyperacusia

Yes

62

F

Not stated

Not stated

Few months

Not stated

Yes

Inzelberg 75 et al., 1993 Murata et al., 55 1994

F

Musical (melody) Bilateral

Few weeks

Bilateral

No

M

Musical (chirping Right of cicadas, songs)

18 days

Bilateral

No

Baurier and 47 Tuca, 1996

M

M

Bilateral, 5 days more to the right Left 1 month

Bilateral more No to the right

43

Left

No

49 Fukutake and Hattori, 1998 Schielke 57 et al., 2000

M

Sound (child crying, water falling) Musical (orchestral melodies, and songs) Sounds (roaring waves and bells)

Right

10 minutes

Bilateral hyperacusis

No

Transient dysarthria Right middle geniculate body and hypoesthesia left thigh

Hemorrhagic infart

Musical (boy singing songs)

Right

5 weeks

Bilateral hyperacusis

No

Left pontine Right hemiparesis tegmentum and hemihypoesthesia Left 1 and 1/2 syndrome, left VII

Brainstem abscess

Douen and Bourque, 1997

M

left internal opthalmoplegia, left VI, left Horner impaired sound localization Right VI, VII, ataxia Left hemisensory loss, left hemiparesis Left hemisensory loss, left hemiparesis Internuclear ophthalmoplegia, ataxia Right hemiparesis, dysphasia Left hemiparesis and hemisensory loss, right VII

Left dorsal pons

Hemorrhage

Right paramedian pontomedulla

Infarction

Right paramedian pontine tegmentum

Hemorrhage

Left thalamus

Ischemic infarct

Right dorsal pontine Hemorrhage tegmentum extended to left pontine tegmentum Right paramedian pons Hemorrhage

Left upperextremity weakness Left V, VII, VIII, IX, Left middle cerebellar peduncule X and left-limb ataxia

Listeria rhombencephalitis

Continued

Table 29.5—Continued

Authors

Type of Age Sex hallucinations

Side of Duration of hallucinations hallucinations

Hearing loss

Associated visual Other neurologic hallucinations phenomena

Taylor et al., 24 2005

F

Verbal

Bilateral

2 weeks

None

Yes

Silva and Brucki, 2010

F

Musical (aria of Carmen Habanera)

Bilateral

10 days

None

Yes

M

Verbal

Not stated

Transient during migraine aura

None

No

43

Lo et al., 2011 22

Site of lesion

Periacqueductal lower Internuclear midbrain ophthalmoplegia, ataxia Diplopia, right Right cerebellar dysmetria, left peduncle and VII, right V gait pontine tegmentum ataxia Right frontal Left posterolateral headaches mesencephalic peduncle

Etiology Multiple sclerosis

Brainstem encephalitis

Migraine

HEARING DISORDERS IN BRAINSTEM LESIONS

Fig. 29.12. Sagittal (left) and transverse (right) magnetic resonance imaging on hospital day 17 (during the time the patient experienced musical hallucinosis) shows an abscess in the left paramedian pontine tegmentum. (Modified from: Schielke et al., 2000.)

hallucinations are related to hypnagogic hallucinations as the dream mechanisms are released by the normal inhibitory control. The alternative hypothesis is that these phenomena are due to excitation of neurologic structures as caused by seizure discharges; however, there has been no example of proven brainstem paroxysmal excitation.

BRAINSTEM CLINICAL DISORDERS Many diseases can involve the brainstem, as shown in Table 29.6, and whenever they include the auditory pathways and/or centers they will produce hearing deficits. Clinically the hearing loss is sensorineural and, as we discussed previously, if the lesion is extra-axial the deafness is ipsilateral to the lesion, whereas intra-axial lesions result most often in bilateral or contralateral hearing loss (Jerger and Jerger, 1975; Egan et al., 1996). In the section on hearing abnormalities in isolated lesions of auditory brainstem centers, above, we presented the auditory deficits induced by the rare occurrence of small lesions of the brainstem; however, most frequently brainstem disorders involve large areas and result in more severe auditory deficits as well as deficits in other modalities (Fig. 29.13). Because therapy is related to the etiology of the disorders a correct diagnosis is mandatory. A careful clinical history and a full neuro-otologic examination are prerequisites of any diagnostic consideration. Among the many disorders that may involve the brainstem, the most frequent pathologies are cerebellopontine angle tumors, brainstem strokes, and MS. We will briefly discuss their clinical features.

Vestibular schwannomas and cerebellopontine angle tumors The most frequent extra-axial brainstem neoplasms are localized in the cerebellopontine angle. In all, 96–98% of these cerebellopontine angle tumors are benign (Valvassori, 1988; Nadol and Martuza, 2005; Re´gis

525

and Roche, 2008), and 75–90% of these benign tumors are represented by vestibular schwannomas (these tumors are also called acoustic neuromas or neurinomas). Brackmann and Bartels (1980) reported that in a series of 1354 cerebellopontine angle tumors 90% were vestibular schwannomas. Similarly, Moffat etal. (1993) found that, out of 305 cerebellopontine angle tumors, 246 (80.7%) were vestibular schwannomas. Stangerup et al. (2010a) evaluated the incidence of sporadic unilateral vestibular schwannomas in Denmark from 1976 to 2008. A total of 2283 new cases of vestibular schwannomas were diagnosed and registered in a national database covering 5.0–5.5 million inhabitants. The incidence of vestibular schwannomas appears to be about 19 tumors per million per year. Of the other benign cerebellopontine angle tumors, 5–13% are meningiomas, 3–6% cholesteatomas, the reminder representing schwannomas of the VIIth and other cranial nerves, arachnoid cyst, lipomas (Fig. 29.6), and granulomas (Lalwani, 1992; Long, 1992; Tekkok et al., 1992; Nadol and Martuza, 2005; Springborg et al., 2008). Only approximately 2% of cerebellopontine angle tumors are malignant, either primary or metastatic (Brackmann and Bartels, 1980; Nakada et al., 1983; Link et al., 2002; Nadol and Martuza, 2005; Akamatsu et al., 2012), and they are characterized by rapid development of symptoms and by invasion of other structures in the area (Brackmann and Bartels, 1980; Hanabusa et al., 2001; Nadol and Martuza, 2005).

SYMPTOMATOLOGY The most frequent presenting symptoms of vestibular schwannomas (and, by extrapolation, of other cerebellopontine tumors) are unilateral hearing loss and tinnitus. As shown in Table 29.7 there is considerable variation in the reported symptoms of vestibular schwannomas. Johnson (1977) stated that 95% of the 500 patients with surgical verified vestibular schwannomas had “initial symptoms of varying degrees of hearing loss.” More recent studies show a lower percentage of hearing impairment. Caye-Thomasen et al. (2007) studied 156 patients with purely intracanalicular vestibular schwannoma and found that the mean pure-tone average (PTA) was 51 dB hearing level (HL) and the mean speech discrimination score was 60% at diagnosis. Similarly, Stangerup et al. (2010b) reported that, of 1144 patients with vestibular schwannoma, 491 patients (53%) presented with good hearing. In their patients, speech discrimination was better than 70%. Pennings et al. (2011) noted unilateral hearing loss in 87% of 47 patients with intracanalicular vestibular schwannomas; their mean pure-tone audiogram was 37.5 dB HL and the mean word recognition score was 66.2%. Surprisingly, there was no reliable correlation between tumor size or location and hearing loss (Nadol et al., 1996;

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G.G. CELESIA

Table 29.6 Brainstem disorders Disorder

Syndrome

Eighth-nerve disorders Acoustic/vestibular schwannoma (neuroma)

Auditory neuropathy Diabetic neuropathy Cochlear nerve aplasia Arachnoid cyst of the internal auditory canal Meningeal carcinomatosis Brainstem strokes Occlusion internal auditory artery (also called labyrinthine artery) (branch of AICA) Lateral inferior pontine syndrome (occlusion of AICA) Lateral superior pontine syndrome (occlusion of superior cerebellar artery) Intralabyrinthine haemorrhage Brainstem haemorrhage Midbrain haemorrhage Brainstem neoplasms Cerebellopontine angle tumors Brainstem gliomas (diffuse pontine glioma, focal brainstem glioma) Metastatic neoplasms Cavernous angioma of brainstem Brainstem demyelinating disorders Multiple sclerosis affecting the pons or mesencephalon Brainstem infections Brainstem abscess Brainstem encephalitis Brainstem trauma Quadrigeminal plate trauma (contusion) Other brainstem disorders Cholesterol cyst of petrous apex

Capillary telangiectasia of the pons Pontocerebellar hypoplasia type III (CLAM) Mucopolysaccharidosis VI Mitochondrial encephalomyopathies

Clinical symptoms

Unilateral ipsilateral hearing loss and tinnitus, vertigo; if compression of brainstem ataxia and other cranial nerve (VII, V) symptoms and signs Bilateral hearing loss Bilateral hearing abnormalities Unilateral ipsilateral sensorineural hearing loss Unilateral ipsilateral hearing loss Unilateral or bilateral hearing loss, vertigo, and imbalance Sudden ipsilateral deafness; tinnitus and vertigo

Ipsilateral ataxia, nystagmus, vertigo, tinnitus ipsilateral deafness, ipsilateral seventh-nerve palsy, ipsilateral hypoesthesia of face Severe ipsilateral ataxia, Horner’s syndrome, contralateral impairment, pain temperature of face and body, impairment of dichotic listening and sound localization Sudden ipsilateral deafness and intense vertigo Sudden deafness and vertigo, other symptoms related to affected areas Bilateral tinnitus, hyperacusis and abnormal dichotic listening and neuro-ophthalmologic signs if superior colliculi involved Unilateral ipsilateral deafness, ipsilateral ataxia, tinnitus Other symptoms related to extent of brain compression Partial deafness, impaired sound localization, limb ataxia, other symptoms may be present depending on extent of the tumor Ipsilateral, contralateral, or bilateral deafness; other symptoms depend on extent of tumor Sudden deafness, fluctuating hearing loss, Me´nie`re-like vertigo Partial ipsilateral deafness, impaired sound localization, other symptoms related to extent of the lesion or lesions Frequent sixth- and seventh-nerve involvement, partial hearing loss, symptoms vary depending on location of lesions Brainstem and cerebellar signs, mild hearing involvement Impaired sensorium Bilateral deafness Ipsilateral deafness, ipsilateral ataxia, tinnitus, other symptoms related to extent of brain compression and other nerve involvement Sudden-onset tinnitus and sensorineural hearing loss Developmental delay, short stature, microcephaly, hearing impairment, optic atrophy Progressive bilateral hearing impairment Progressive bilateral hearing impairment

AICA, anterior inferior cerebellar artery; CLAM, cerebellar atrophy with progressive microcephaly.

HEARING DISORDERS IN BRAINSTEM LESIONS

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Fig. 29.13. Case HE is a 41 year-old female who presented with sudden onset of deafness in the left ear. On examination she also had a mild ataxia with tandem gait. The upper part of the figure shows the pure-tone audiogram indicating a mild sensorineural hearing loss in the left ear with impaired speech audiometry in the same side. Brainstem auditory evoked potentials showed a normal wave I, a wave II of low amplitude but normal latency, and a very prolonged I–V interval, suggesting impaired auditory processing past the cochlear nuclei in the left brainstem. Magnetic resonance imagingI showed a large demyelinating lesion in the pons. She also had two smaller demyelinating lesions in the white matter of the left hemisphere. She was diagnosed with multiple sclerosis. AD, right ear; AS, left ear. Table 29.7 Symptoms of vestibular schwannomas Symptoms at diagnosis

Percent

Hearing loss Sudden hearing loss Tinnitus Disturbance of balance (vertigo, dizziness, ataxia) Headaches Facial numbness Facial weakness Lower cranial nerve involvement Hydrocephalus

50–95 5–22 15–80 15–75 25–33 35–50 16–50 2 10

Caye-Thomasen et al., 2007). The hearing loss is usually gradual, with occasionally the patient being unaware of it. Johnson (1977) noted that only 68% of 425 patients with surgically verified vestibular schwannoma were aware of their hearing impairment. Sudden unilateral hearing loss has also being described in 5–22% of cases (Chow and Garcia, 1985; Berg et al., 1986; Ogawa et al., 1991; Yanagihara and Asai, 1993; Saunders et al., 1995; Nadol and Martuza, 2005). Vertigo or some other form of unsteadiness has been reported in about 50% of cases.

Caloric testing showed a higher occurrence of vestibular hypofunction (96% of 46 cases) (Ojemann et al., 1972). Other symptoms are related to the size of the tumor and the extent of involvement of other structures. Involvement of the VIIth nerve is particularly frequent, with various degree of facial weakness (Table 29.7).

AUDIOMETRY AND OTHER DIAGNOSTIC TESTING While the hearing deficit in vestibular schwannoma is sensorineural, pure-tone audiograms show a great variety of abnormalities (Johnson and House, 1964; Ottaviani et al., 1999). Some authors (Eggston and Wolff, 1947; Cambon and Guilford, 1958) have suggested that audiograms showing low-frequency loss and near normal high-frequency hearing may indicate the possibility of vestibular schwannomas. Ottaviani et al. (1999) reported U-shaped SNHL on pure-tone audiometry and mildly impaired speech discrimination with small tumors and severe low- and middle-frequency hearing loss with impaired speech discrimination with larger tumors. Several authors have pointed out that, when the hearing threshold level for pure tones is minimally affected, while speech discrimination is disproportionately reduced, a retrocochlear pathology should be suspected, and acoustic neurinoma would be the most likely etiology (Canty, 1978; Van Dijk et al., 2000).

528

G.G. CELESIA

Increased detection-threshold or no detectable acoustic emission was noted in VIIIth-nerve tumors by Bonfils and Uziel (1988), while Lide´n and Korsan-Bengtsen (1973) stated that an elevated stapedius reflex threshold was a “consistent finding in acoustic neuromas.” Prior to the routine availability of MRI, brainstem auditory testing was used to screen for suspicion of cerebellopontine tumors. As we described in the section on brainstem auditory evoked potentials, above, BAEPs can only indicate the presence of a sensorineural deficit and additionally suggest involvement of intramedullary structures (Legatt et al., 1988; Chiappa, 1997; Montaguti et al., 2007; Celesia, 2011).

(e)

hair cell degeneration secondary to neuronal loss in the VIIIth nerve. 2. neurotoxicity: (a) toxic tumor metabolites (proteinaceous deposit in inner-ear fluid caused by tumor metabolites) (b) alterations of biochemic properties of innerear fluids. If the tumor expands into the cerebellopontine angle, compression of the brainstem may occur, resulting in additional involvement of nervous structures and if there is interference with cerebrospinal fluid flow, development of hydrocephalus may occur.

PHYSIOPATHOLOGY

NEUROIMAGING

The sudden onset of hearing loss, the cochlear involvement, and the lack of correlation between tumor size and hearing loss in some vestibular schwannomas cast doubts that the only cause of symptoms is by compression of the VIIIth nerve. Cochlear involvement has been demonstrated in approximately 50% of vestibular schwannomas (Igarashi et al., 1974; Bonfils and Uziel, 1988; Prasher et al., 1995; Norman et al., 1996; Telischi, 2000). It is now acknowledged that the symptoms of intracanalicular vestibular schwannomas are related to two possible mechanisms (Igarashi et al., 1974; Prasher et al., 1995; Takhur et al., 2012): mechanical compression and/or infiltration of: (a) the cochlea (Fig. 29.14) (b) the auditory (and vestibular) nerve (c) the internal auditory artery (d) the efferent olivocochlear bundle

The role of neuroimaging in the diagnosis of brainstem disorders and cerebellopontine angle tumors has been discussed already in the section on neuroimaging, above. Here we briefly summarize the importance of neuroimaging in the diagnosis of vestibular schwannomas (Fig. 29.15). Two neuroimaging modalities have been used: high-resolution CT and MRI. A consensus is emerging that, for most of the cases, magnetic resonance is the imaging modality of choice for lesions of the cerebellopontine angle and internal auditory canal (Zamani, 2000; Adunka et al., 2007; Saliba et al., 2010; Sriskandan and Connor, 2011; Yoshida et al., 2011). However, when visualization of the internal auditory canal and/or of the bony cochlear nerve canal is needed, then high-resolution CT is best as it allows better evaluation of bony structures (Adunka et al., 2007).

Fig. 29.14. Transmission electron micrograph of intracochlear schwannoma cells demonstrating the presence of bundles of extracellular fibrous longspacing collagen (“Luse bodies,” arrows). (Reprinted from Yoshida et al., 2011, with permission.)

Fig. 29.15. Coronal magnetic resonance imaging, T1 W, postcontrast image of the right intra-auricular meatus (IAM), which contains an enhancing schwannoma with further abnormal enhancement of the cochlea and vestibule, consistent with transmodiolar (small arrow) and transmacular (large arrow) extension, respectively. (Reproduced from Sriskandan and Connor, 2011, with permission.)

1.

HEARING DISORDERS IN BRAINSTEM LESIONS

NEUROFIBROMATOSIS TYPE 2 (NF2) Approximately 7% of patients with vestibular schwannomas have NF2 (Evans et al., 2005). NF2 is a genetic disorder due to a defective tumor suppressor gene located on chromosome 22q12.2. The defective protein produced by the gene is “called merlin or schwannomin” (Asthagiri et al., 2009; Houshmandi et al., 2009; Schulz et al., 2013). NF2 is rare, with a prevalence of about 1 in 60 000 (Gareth and Evans, 2009). Although NF2 is a genetic disorder, approximately 40% of the identified cases are sporadic, related to new mutations (Evans et al., 2005; Gareth and Evans, 2009). Some of the milder cases and up to 20% of cases without a family history of the disease are mosaic (Ruttledge et al., 1966; Gareth and Evans, 2009). Approximately 25% of all constitutional mutations in the NF2 tumor suppressor gene are splicing mutations (Ellis et al., 2011). The clinical presentation may be variable, but the presence of bilateral vestibular schwannoma is always indicative of NF2. In 1988 the National Institutes of Health gathered a conference to establish the criteria for the diagnosis of neurofibromatosis. Additional criteria have been added since then and are described in Table 29.8 (National Institutes of Health Consensus Development Conference, 1988, Gutmann et al., 1997; Gareth and Evans, 2009). Clearly the presence of more than one central nervous system tumor should raise the diagnosis of NF2.

529

2010; Stangerup et al., 2010b; Arthurs et al., 2011; Pennings et al., 2011). Surgical intervention is recommended in tumors showing rapid growth and in tumors growing outside the internal auditory canal impinging in the surrounding neurologic structures (Nadol and Martuza, 2005; Re´gis and Roche, 2008; Noudel et al., 2009; Whitmore et al., 2010). The treatment for NF2 is more complex, related to the multiplicity of tumors and/or lesions (Asthagiri et al., 2009; Odat et al., 2011). Asthagiri et al. (2009) suggest that the optimum treatment should be multidisciplinary. Recently novel therapies have been proposed aimed at inducing inhibition of angiogenesis and regulation of the epidermal growth factor receptor family of receptors (Fong et al., 2011; Blakeley, 2012; Plotkin et al., 2012; Yener et al., 2012). The effectiveness of this chemotherapy is still under evaluation.

Brainstem strokes affecting the auditory system Strokes affecting the brainstem auditory system are represented predominantly by the following syndromes: occlusion of the internal auditory artery syndrome, lateral inferior pontine syndrome, and lateral superior pontine syndrome.

OCCLUSION OF THE INTERNAL AUDITORY ARTERY

TREATMENT MODALITIES The aim of the treatment is to remove the tumor while preserving hearing and other neurologic functions. In any therapeutic consideration the cost/benefit ratio requires careful consideration. The size of the tumor and its growth rate are important variables in the management of vestibular schwannoma (Agrawal et al.,

Occlusion of the internal auditory artery is very rare and it occurs secondary to arteriosclerosis in the vertebrobasilar system or embolism. The artery supplies both the cochlea and the labyrinth (Fig. 29.3) and the occlusion is characterized by sudden unilateral deafness, tinnitus, and vertigo (Millikan et al., 1959; Kim et al., 1999; Levine and Hausler, 2001) (Table 29.9).

Table 29.8 Diagnostic criteria for neurofibromatosis type 2 (NF2) Definite NF2

Probable NF2

Bilateral vestibular schwannoma (VS) or

Unilateral VS plus any two of: meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities

Family history of NF2 or Unilateral VS diagnosed before age 30 or Any two of the following: Meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities

Multiple meningiomas (two or more) plus any two of: meningioma, glioma, neurofibroma, schwannoma, and cataract

Modified from National Institutes of Health Consensus Development Conference (1988), Gutmann et al. (1997), and Garreth and Evans (2009).

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G.G. CELESIA

Table 29.9 Classic stroke syndromes affecting the brainstem auditory system Ipsilateral/ contralateral

Syndrome

Artery

Clinical signs

Infarction of internal auditory artery Lateral inferior pontine syndrome

Internal auditory artery

Sudden profound sensorineural deafness Vertigo and tinnitus Hearing impairment Horner’s Facial weakness Ataxia of limbs Impaired pain and temperature of face Impaired pain and temperature of body Horner’s Ataxia of limbs Impaired gait (falling to side of lesion) Impaired pain and temperature of face and body Sometimes central facial weakness Impaired dichotic listening Impaired sound localization Vertigo and tinnitus

Lateral superior pontine syndrome

Anterior inferior cerebellar artery (AICA)

Superior cerebellar artery

Ipsilateral Ipsilateral Ipsilateral Ipsilateral Ipsilateral Ipsilateral Contralateral Ipsilateral Ipsilateral Contralateral Contralateral Contralateral Contralateral

Table 29.10 Neuro-otologic findings in 82 patients with infarction of anterior inferior cerebellar artery Symptoms

Number abnormal

Percent abnormal

Presented with vertigo Associated with other neurologic symptoms or signs Associated with ocular motor dysfunction Combined audiovestibular loss Normal audiovestibular function Isolated auditory loss Isolated vestibular loss Prodromal audiovestibular disturbance

80 81 79 49 24 3 4 13

97.6 98.8 96.3 59.8 29.3 3.7 4.9 15.9

Data from Lee et al. (2009).

THE LATERAL INFERIOR PONTINE SYNDROME The lateral inferior pontine syndrome is caused by occlusion of the AICA and related ischemic infarct of the lateral inferior pons (Fig. 29.2). Occlusion of AICA is the most frequent of the brainstem strokes involving the auditory system. The syndrome is characterized by sudden onset of vertigo, nystagmus, ipsilateral facial weakness, deafness, and tinnitus, ipsilateral ataxia and hypoesthesia of the face (Adams, 1943; Amarenco et al., 1993; Lee et al., 2002; Choi et al., 2006) (Table 29.10). Lee et al.

(2009) prospectively identified 82 consecutive patients with AICA-territory infarction diagnosed by MRI. Each patient underwent a neuro-otologic evaluation, including bithermal caloric tests, pure-tone audiogram, stapedial reflex threshold evaluation, speech discrimination, and BAEPs. The most common “pattern of audiovestibular dysfunction was the combined loss of auditory and vestibular function (n ¼ 49 [60%]). A selective loss of vestibular (n ¼ 4 or 5%) or cochlear (n ¼ 3 or 4%) function (Table 29.10) was rarely observed” (Lee et al., 2009). In 6 patients the site of the auditory deficit was localized in the cochlea, in 1 patient in the retrocochlear region

HEARING DISORDERS IN BRAINSTEM LESIONS (presumably the cochlear nuclei), while in 4 patients the severity of the hearing loss precluded any localization. One patient had no hearing deficit.

THE LATERAL SUPERIOR PONTINE SYNDROME The lateral superior pontine syndrome is caused by occlusion of the SCA and is characterized by sudden onset of ataxia of limbs and gait with falling to the side of the lesion, ipsilateral Horner’s syndrome, horizontal nystagmus, contralateral face and body impairment of pain and temperature, and vertigo (Davison et al., 1935; Luhan and Pollack, 1953) (Table 29.9). Luhan and Pollack (1953) reported on 6 cases of occlusion of the SCA, 3 with postmortem verification. Hearing impairment was noted in 3 cases, was not reported in 2, and was “grossly normal” in 1. The hearing abnormalities were ipsilateral in 2 patients and contralateral in 1. In none of the cases was detailed audiologic testing performed. They commented: The lateral lemniscus lies in close proximity to the pain pathways in the rostral pons and may be damaged. The lateral lemniscus is mainly a crossed tract but many of its fibers arise from the cochlear nuclei of the same side. Individual variations undoubtedly exist. This bilateral projection from the cochlear nuclei would tend to mask any hearing impairment resulting from slight damage to the lateral lemniscus (Luhan and Pollack, 1953). Amarenco and Hauw (1990) commented that, in spite of infarction of the lateral lemniscus and the IC in more than half of the reported cases, hearing complaints were not described. In a study of 23 patients with infarcts of the SCA without involvement of the territory of other cerebellar arteries from the Raymond Escourolle Laboratory of Neuropathology at the Hoˆpital de la Salpetrie`re, Amarenco and Hauw (1990) found that the “classic” syndrome of occlusion of SCA is “very rare.” Their autoptic findings showed considerable variability in brainstem tissue involvement: for instance, the lateral lemniscus was infarcted in only 12 cases (52%) and the IC in 3 (13%), while cerebellar involvement occurred in all cases. These authors further commented that occlusion of the SCA was often associated with occlusion of the distal basal or vertebral artery. They stated: “This pathologic involvement resulted in either a clinical ‘rostra1 basilar artery syndrome,’ close to the ‘top of the basilar syndrome’ or a deep coma often associated with tetraplegia; these syndromes overshadowed signs of cerebellar involvement” and we add, overshadowed signs of acoustic deficits. More recent studies of the effect of unilateral lesions of the lateral lemniscus indicate that, while pure-tone

531

and speech audiometry may be normal, there is contralateral impaired dichotic listening (Cho et al., 2005).

Multiple sclerosis hearing abnormalities In MS hearing abnormalities are often overlooked because they can only be detected by psychoacoustic hearing tests dependent upon brainstem processing (Levine et al., 1993, 1994; Furst et al., 1995). As we described in the section on prevalence of hearing disorders in brainstem diseases, hearing abnormalities in MS may be as frequent as 70%. Levine et al. (1994), in their studies of MS, concluded that “multiple sclerosis lesions of the auditory pons are not silent.” The reader is referred to Chapter 36 of this volume for more details.

MANAGEMENT OF BRAINSTEM HEARING DISORDERS The neurologic deficits in brainstem lesions are often overwhelming, pushing the hearing deficits “in the background” (Cho et al., 2005). The clinician needs to address both the therapy of the disease causing the lesion and the rehabilitation of all neurologic deficits, including the auditory problems. Once the acute intervention has improved and/or stabilized the etiologic disorders (e.g., infarct, infection, neoplasm, demyelinating disorder), we need to address the auditory concerns. As we discussed in the section on evaluation of brainstem-related hearing disorders, above, a detailed evaluation is essential to determine the nature and extent of the auditory deficit. A multidisciplinary team, including audiologists, speech pathologists, and neuropsychologists, may be the best approach to assure a comprehensive management (American Academy of Audiology, 2010). The team will determine whether hearing aids are necessary and/or sufficient and/or whether additional intervention is indicated. Environmental modifications (such as improved room acoustics, assistive listening systems), auditory training (such as dichotic listening training, clear speech), and language strategies may be recommended. The aim of the intervention is to improve auditory processing and related cognitive and behavioral changes.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 30

Central auditory processing disorders in children and adults TERI JAMES BELLIS1* AND JENNIFER D. BELLIS2 Department of Communication Sciences and Disorders, USD Speech-Language-Hearing Clinics and Division of Basic Biomedical Sciences, University of South Dakota, Vermillion, SD, USA

1

2

Auditory Neuroscience Laboratory, Department of Communication Sciences and Disorders, University of South Dakota, Vermillion, SD, USA

INTRODUCTION Central auditory processing disorders (CAPD) can affect children and adults of all ages. Etiologies ranging from trauma to neurotoxic substances and neurologic disease or insult may cause dysfunction in the central auditory nervous system (CANS), resulting in a CAPD (American Academy of Audiology, 2010). In addition, CAPD may coexist with and/or mimic other disorders that affect listening, learning, and communication, particularly in children. Musiek et al. (1985; Musiek and Gollegly, 1988) postulated three primary underlying etiologies of CAPD in children: (1) neuromorphologic disorders, including atypical left/right anatomic asymmetries in planum temporale, ectopic areas, and polymicrogyri (65–70%); (2) neuromaturational delay (25–30%); and (3) neurologic disorder, disease, or insult (2 SD below the mean on each test) was used. While this may provide clinicians with a minimum test battery to diagnose the presence of CAPD in the least amount of time, thus resulting in the most beneficial cost/benefit ratio, it should be noted that this approach may not be sufficient for intervention-planning purposes. Similarly, in a series of studies examining performance on central auditory tests and corresponding visual analogs in normally hearing adults (n ¼ 10), normally hearing children (n ¼ 10), children with ADHD (n ¼ 10), and children who meet current consensus definitions for diagnosis of CAPD (American Speech-LanguageHearing Association, 2005a; American Academy of Audiology, 2010; n ¼ 7), Bellis and colleagues

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Table 30.2 Categories of behavioral central auditory tests, processes assessed, and selected examples of each Test category

Processes assessed

Selected examples

Dichotic speech tests

Binaural separation Binaural integration Binaural fusion

Dichotic Digits Dichotic Consonant-Vowels Staggered Spondaic Word test (SSW) Competing Sentences Dichotic Rhyme

Temporal patterning/processing tests

Temporal ordering/sequencing Frequency discrimination Duration discrimination Temporal resolution

Frequency Patterns Duration Patterns Gaps-In-Noise (GIN)

Monaural low-redundancy speech tests

Auditory closure

Low-Pass Filtered Speech Time Compressed Speech with and without Reverberation

Binaural interaction tests

Binaural interaction Localization/lateralization (informally)

Binaural Fusion tests Masking Level Difference (MLD) Listening in Spatialized Noise Sentence Test (LISN-S)

Auditory discrimination tests

Auditory discrimination

Frequency and Duration justnoticeable differences (JNDs) Speech-language measures of speech-sound discrimination

demonstrated that each of the central auditory tests alone was sufficient to differentiate among groups when intratest comparison measures were employed (Bellis et al., 2008, 2011; Bellis and Ross, 2011). Specifically, when overall test performance was considered, children in the CAPD and ADHD groups performed similarly, exhibiting poorer performance than normal controls. However, when intratest ear comparisons of ear advantage (dichotic sentences and digits) and response condition (temporal patterning) were considered, performance for each individual central auditory test differentiated the CAPD group from the nonCAPD groups, with the CAPD group demonstrating a significantly larger right-ear advantage on the dichotic speech tests and a significantly larger humming– labeling difference on the temporal patterning tests (Fig. 30.4). The addition of visual analogs added no diagnostic advantage, despite previous suggestions that the inclusion of such analogs is critical for the differential diagnosis of CAPD from higher-order, supramodal disorders such as ADHD (Cacace and McFarland, 2005). Although a single test – when interpreted appropriately – may be sufficient to differentiate children with CAPD from those with attention-related deficits or from typically developing children, it is unlikely that one test

would provide sufficient process-based information to inform intervention efforts. It is for this reason that the American Academy of Audiology (2010) guidelines suggest a test battery approach consisting of measures that assess a variety of processes. Our clinical experience demonstrates that, even when five or six tests are included in the battery, behavioral central auditory testing rarely takes longer than 45 minutes to 1 hour to complete. These observations are confirmed by Musiek (personal communication). The American Speech-Language-Hearing Association (2005a) and American Academy of Audiology (2010) stress that diagnostic tests of central auditory function should be demonstrated to be both sensitive and specific for the identification of CANS lesions. Although few would argue that such a lesion-based approach would be appropriate for the testing of adults (and children) with known or suspected neurologic disease or disorder, some have questioned the utility of using confirmed lesions of the CANS as the “gold standard” for diagnostic tests of central auditory processing in children with “developmental CAPD.” It may be that future research using electrophysiologic and/or imaging techniques may provide a more appropriate gold standard against which to compare this population. However, it should also be emphasized that, at the

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Right Left

85 80 75 70 65

Percent Correct

Percent Correct

Group 1 (Normal) 105 100 95 90

Auditory

105 100 95 90 85 80 75 70 65

Right Left

Auditory

Visual Modality

Visual Modality

Percent Correct

Group 3 [(C)APD] 105 100 95 90 85 80 75 70 65

Right Left

Auditory

Visual Modality

Fig. 30.4. Responses from three groups of children: normal (n ¼ 10), attention-deficit hyperactivity disorder (ADHD) (n ¼ 10), and central auditory processing disorders (CAPD) (n ¼ 7) on three tests of central auditory function and their corresponding visual analogs. Children with ADHD and CAPD performed more poorly overall than typically developing children on all tasks when overall performance is considered. However, when intratest analyses (i.e., ear/visual-field differences, humming–labeling response differences) are considered, children with CAPD can be differentiated from those with ADHD and from normal controls. (Reproduced from Bellis et al., 2011.)

present time, the evaluation of central auditory function using tests shown to be valid for the identification of documented CANS dysfunction provides the best guide for test selection. Children with “developmental CAPD” demonstrate patterns of performance across these tests that are identical to those of children and adults with known CANS lesions (Bellis and Ferre, 1999; Bellis, 2002, 2003). Similarly, Boscariol et al. (2009, 2010, 2011) demonstrated that children with previously undetected neuromorphologic abnormalities also present with these same patterns. A final point to be considered is that, due to the variability in neuromaturation (particularly of the corpus callosum) in younger children, most behavioral central auditory diagnostic tests cannot be reliably administered and interpreted until the age of approximately 7 or 8 years. After this age, age-specific normative values are available and must be used for interpretation purposes. In younger children, the American Academy of Audiology (2010) guidelines suggest that the presenting complaints, perhaps combined with electrophysiologic measures and/or screening tests, may provide a guide for the identification of functional auditory strengths and weaknesses. This guide may help to determine the need for auditory-based intervention, but should not be taken as evidence of a diagnosis of CAPD until a valid diagnostic test battery can be administered.

Interpretation of behavioral central auditory tests Interpretation of the behavioral central auditory test battery initially involves comparing the individual’s performance against age-matched normative values. However, because higher-order, pansensory or global disorders, or motivational factors may affect overall performance, inter- and intratest pattern analysis is critical for the accurate diagnosis of CAPD (American SpeechLanguage-Hearing Association, 2005a; American Academy of Audiology, 2010; Bellis and Ross, 2011; Bellis et al., 2011). The American Speech-LanguageHearing Association (2005a) and American Academy of Audiology (2010) suggest that a CAPD be diagnosed only when performance is abnormal relative to agespecific normative values on at least two tests of central auditory function and a consistent inter- and/or intratest pattern of performance indicative of CANS dysfunction can be demonstrated. Poor performance across all test measures, or an inconsistent pattern of performance (e.g., left-ear deficit on one test combined with a rightear deficit on another test, improvement of performance with reinforcement or reinstruction, significantly poorer performance near the end of a test as compared to the beginning) should be taken as evidence of a higher-order cognitive, attention, motivation, or related confound rather than a CAPD.

CENTRAL AUDITORY PROCESSING DISORDERS IN CHILDREN AND ADULTS A multidisciplinary approach to assessment is critical for both differential diagnosis and intervention purposes, because of possible comorbidity of CAPD with other disorders involving attention, learning, language, and communication. Only when the behavioral central auditory test results of a given individual are placed within the context of his or her functioning across other domains can the relative contribution of a CAPD to real-world complaints be estimated and a comprehensive, ecologically valid, individualized intervention program be developed (Bellis, 2002, 2003; American Speech-LanguageHearing Association, 2005a; Chermak and Musiek, 2007, in press; American Academy of Audiology, 2010).

Electrophysiologic tests for CAPD diagnosis Although the standard, click-evoked ABR has not been shown to be particularly sensitive to the identification of CAPD in most instances, it is very useful in cases of trauma, pathology, or other dysfunction of the brainstem auditory pathways. In contrast, recent research has demonstrated that the measurement of ABR in response to complex signals, such as speech, instead of to simple click or tone-burst stimuli may have immense utility in illuminating central auditory pathway abnormalities in children and adults with auditory-based learning concerns, including CAPD, and determining the need for auditory intervention (e.g., Kraus et al., 1996; Banai et al., 2005, 2007). Billiet and Bellis (2011) studied 10 children diagnosed with dyslexia who exhibited normal speech-evoked ABRs, 10 children diagnosed with dyslexia who exhibited abnormal speech-evoked ABRs, and 10 age-matched controls. Their results indicated that, of the children diagnosed with dyslexia who exhibited Dichotic Digits Test- REA

Frequency Pattems Test-HLD 40

30

30

20 REA

HLD

REA

547

normal speech-evoked ABRs, 100% exhibited behavioral central auditory test findings indicative of CAPD. In contrast, the majority of children who exhibited abnormal speech-evoked ABR performed within the normal range on the behavioral CAPD test battery. These findings suggest that the speech-evoked ABR may identify CANS dysfunction and drive intervention for some children who may be missed by the standard behavioral central auditory test battery (Billiet and Bellis, 2011; Fig. 30.5). In recent years, the middle-latency response (MLR) has been shown to be of substantial utility in the identification of involvement of the thalamocortical central auditory pathways. However, due to substantial intersubject variability in amplitude and latency of MLR response components, the most useful indices for abnormalities appear to be intrasubject comparisons of response amplitude across multiple electrode sites (e.g., left hemisphere, right hemisphere, midline) and between stimulus ears (Musiek et al., 1989; Schochat et al., 2010; Weihing et al., 2012a). Cortical event-related auditory potentials, including the obligatory cortical potentials and the P300, also have been shown to be useful in the identification of dysfunction in auditory regions of the brain, including temporal lobe (Chermak and Musiek, 2011). There is little general agreement regarding when auditory electrophysiologic measures should be included in a central auditory test battery. Some have suggested that they always be included (e.g., Jerger and Musiek, 2000); however, this approach is likely not feasible in most clinical settings. The American Academy of Audiology (2010) suggests that electrophysiologic evaluation be conducted when traditional behavioral testing cannot be completed (e.g., due to age or native language)

10

20

HLD

10

0

0 Group 1

Group 2

Group 3

Group 1

Group 2

Group 3

Competing Sentences Test- REA 50

REA

40 30 REA 20 10 0 Group 1

Group 2

Group 3

Fig. 30.5. Intratest analysis measures on three central auditory tests from three groups of children: those with dyslexia and abnormal brainstem timing as measured by speech-evoked auditory brainstem responses (group 1, n ¼ 12), those with dyslexia and normal brainstem timing (group 2, n ¼ 20), and normal controls (group 3, n ¼ 10). Results indicate that children with dyslexia exhibited significantly larger right-ear advantages (REA) on dichotic speech tasks and significantly larger humming-labeling differentials (HLD) on frequency patterns testing when compared to normal controls. (Modified from Billiet and Bellis, 2011.)

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or results of such testing are inconclusive, when a neurologic disorder or disease requiring medical follow-up is suspected, or when objective documentation of central auditory involvement is needed. In addition, these measures may provide data suggestive of treatment prognosis as well as documenting treatment efficacy in some individuals (Tremblay et al., 2001; Tremblay and Kraus, 2002; Tremblay, 2007; Sharma et al., 2009; Schochat et al., 2010; Kraus, 2012).

INTERVENTION FOR CAPD Intervention recommendations for CAPD are based on the demonstrated auditory processing deficits and related listening and related complaints (Bellis, 2003; American Academy of Audiology, 2010). Further, just as auditory processing involves both bottom-up and top-down factors, intervention for CAPD should include both bottom-up and top-down activities. The individual’s diagnostic test findings, case history, and information from other multidisciplinary professionals such as speech-language and psychoeducational specialists should be taken into consideration when developing a comprehensive, ecologically valid intervention plan for CAPD. Most importantly, the intervention plan should be deficit-specific and individualized to the child or adult in question. The ultimate goals of intervention for CAPD should be the remediation of the demonstrated auditory deficits and the minimization of the impact of the disorder on the individual’s daily life functions. This is typically done through focusing on three areas: environmental modifications, compensatory strategies/ central resources training, and direct skills remediation (Bellis, 2002, 2003; American Speech-LanguageHearing Association, 2005a, b; Chermak and Musiek, 2007, in press; American Academy of Audiology, 2010). Although intervention recommendations should be individualized and deficit-specific, some common interventions that may be useful for different profiles of CAPD are enumerated in Table 30.3.

Environmental modifications Environmental modifications include both bottom-up and top-down approaches in that they address methods of enhancing access to the auditory signal as well as strategies for imparting information in order to render the signal more easily comprehensible. For example, bottom-up (i.e., signal-driven) environmental accommodations may include, but are not limited to, preferential seating, clear speech, and use of hearing-assistive technology. Top-down (i.e., strategy-driven) modifications may include activities such as pre-teaching new information/vocabulary to assist auditory closure, repetition or

rephrasing of information, and use of visual aids (American Speech-Language-Hearing Association, 2005a; American Academy of Audiology, 2010). It is interesting to note that, although environmental modifications are generally designed to improve access to information rather than to treat the disorder per se, recent research has suggested that the use of hearingassistive technology may, in fact, lead to improvements in listening and related (e.g., reading, spelling) skills (Hornickel et al., 2012). In this study, the authors examined reading performance in 38 normally hearing children diagnosed with dyslexia, half of whom had been fitted with an assistive listening device in the classroom for a period of 1 year. Results indicated that those children who had utilized hearing-assistive technology improved on measures of phonologic awareness and reading whereas those who were not fitted with such technology did not demonstrate these improvements. These results indicate that the use of hearing-assistive technology may drive auditory neuroplasticity in children (Fig. 30.6). Most importantly, as with all aspects of intervention, decisions regarding which environmental modifications to implement in a given situation should be individualized and specific to the child’s or adult’s presenting difficulties and diagnostic findings. There is no “onesize-fits-all” list of environmental accommodations appropriate for all individuals with CAPD, although the basic principles of improving the signal-to-noise ratio and using clear speech benefit all listeners, particularly those with disorders such as CAPD.

Central resources training Compensatory strategies/central resources training utilize a top-down treatment approach. The goals of central resources training are to minimize the impact of the CAPD through recruiting and strengthening higherorder, top-down cognitive, attention, language, and related processes and to address possible secondary motivational and related deficit areas. These strategies may include metalinguistic and metacognitive techniques such as self-instruction, cognitive problem solving, assertiveness/attribution training, auditory memory enhancement, and other activities. Strategies such as these provide benefits allowing for enhanced listening, communication, social, and learning outcomes not directly addressed through auditory training (Katz, 1983; Musiek and Chermak, 1995; Sloan, 1995; Chermak and Musiek, 1997, in press; Chermak, 1998; Musiek, 1999; Bellis, 2002, 2003; American SpeechLanguage-Hearing Association, 2005a). It is important to note that, although specific studies regarding efficacy of central resources training in cases of CAPD per se are

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Table 30.3 Common intervention techniques for different subtypes of CAPD

Environmental modifications

Compensatory strategies/ central resource training activities

Right hemisphere (non-languagedominant cortex)

Placement with “animated” teacher; avoid hints/subtleties in conversation; avoid abstract language

Metamemory and metalinguistic techniques; schema induction using social scripts; key word extraction

Left hemisphere (primary auditory cortex)

Preferential seating with visual access to teacher; classroom acoustic modifications; hearingassistive technology; repetition rather than rephrasing of key information; pre-teaching of new vocabulary

Auditory closure; vocabulary building; problem solving; attribution training; active listening techniques

Corpus callosum/ interhemispheric

Avoid use of multimodal cues; classroom acoustic modifications; hearing-assistive technology

Attribution training; active listening techniques; problem solving

CAPD deficit profile

Direct remediation activities Non-speech (e.g., frequency, duration) discrimination training Temporal patterning training Prosody training Temporal resolution training Speech-sound discrimination Phonologic awareness activities Speech-to-print skills Dichotic listening training (to address speech-innoise skills) Dichotic listening training Interhemispheric activities Localization training

Fig. 30.6. Frequency-modulated (FM) system use increases the consistency of auditory brainstem representation of speech. (A) Responses from dyslexic children before FM system use with the formant transition (7–60 ms) and vowel (60–180 ms) portions of the speech syllables marked. (B) Response consistency, quantified as the correlation between responses collected during the first half of the recording session (light gray) and those collected in the second half of the recording session (dark gray), improved with FM system use during the formant transition for this representative individual. The more consistent response at posttest is reflected by a higher r-value. (C) After FM system use for one school year, children with dyslexia had more consistent speech-evoked brainstem responses, particularly for the response to the formant transition (red triangles; trending at P ¼ 0.036). Significant changes were not seen in response to the vowel portion (black circles). (D) Control children with dyslexia who did not use the FM systems show no change in response consistency in either the formant transition (red triangles) or the vowel (black circles) portions of the response. (E) Response consistency also does not change for typically developing controls in either the formant transition (red triangles) or the vowel (black circles) portions. (Reprinted from Hornickel et al., 2012, with permission.)

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lacking, research into resource allocation, discussed previously, clearly indicates that top-down processes provide important scaffolding for bottom-up auditory skills. Thus, improving “upstream” cognitive and related skills and abilities allows for greater resources to be available “downstream” for acoustic signal processing (Pichora-Fuller et al., 1995).

Direct remediation The goal of direct skills remediation is to improve the specific auditory deficits that have been identified by a battery of validated tests of central auditory function (American Speech-Language-Hearing Association, 2005a, b; Chermak and Musiek, 2007, in press; American Academy of Audiology, 2010; Bellis et al., 2012). This is done through targeted, behavioral auditory training activities focused on the identified areas of deficit. Auditory training may be either formal or informal. Formal auditory training activities typically take place within a clinical setting and include well-controlled acoustic stimuli presented through audiologic equipment. Informal auditory training may be done outside the clinic, including at school and in the patient’s home. Because of the need for frequent treatment sessions, informal auditory training is particularly important in rural areas where patients may live some distance from the nearest CAPD clinic. In addition, there are several computer software programs currently available that address various aspects of auditory training. Auditory training activities may include. but are not limited to, procedures targeting speech- and non-speechsound discrimination; temporal resolution; auditory pattern recognition; localization/lateralization of sound; and speech-in-competition (e.g., speech-in-noise and/or dichotic listening training). Additionally, exercises that address multimodal interhemispheric transfer may be indicated in some cases. Auditory discrimination and sequencing, which are essential components of language and reading, are often areas of difficulty for a child diagnosed with CAPD and thus should be considered during a course of auditory training (Wright et al., 2000; Foxton et al., 2004). Auditory training has been shown to result in both functional and structural improvements in the CANS in both animals and humans (Galbraith et al., 1995; Jancke et al., 2001; Tremblay and Kraus, 2002; Hayes et al., 2003; Bao et al., 2004; Foxton et al., 2004; Johnson et al., 2005, 2008; Russo et al., 2005; Chermak and Musiek, 2007; Chermak et al., 2013 in press; Alonso and Schochat, 2009; de Villers-Sidani et al., 2010; Schochat et al., 2010; Strait and Kraus, 2011; Bellis et al., 2012; Kraus, 2012). After just a week of direct auditory training, some studies have shown

behavioral and electrophysiologic benefits in normal subjects (Kraus et al., 1996; Tremblay et al., 2001). Tremblay and colleagues (2001) investigated the ability of 10 normally hearing young adults to learn to discriminate variants of the consonant-vowel syllable /ba/ that differed in voice-onset time (10 ms versus 20 ms). Initially, the participants could not discriminate between the two signals; however, using an adaptive training paradigm, they were able to learn to differentiate the signals. Concurrently, the N1-P1 complex of the cortical event-related potential, evoked by the same stimuli, demonstrated training-induced increases in amplitude that corresponded to the participants’ performance improvements. Alonso and Schochat (2009) also documented changes in auditory event-related potentials (P300) and central auditory performance following formal, clinic-based auditory training in a group of 29 children diagnosed with CAPD (Fig. 30.7). Studies demonstrating the efficacy of other forms of auditory training also have been emerging in the literature. For example, Moncrieff and Wertz (2008) administered a quasi-dichotic listening therapy to 8 (experiment 1) and 13 (experiment 2) children with diagnosed CAPD. Different stimuli were routed through each of two speakers in the sound field and interspeaker intensity was gradually adjusted over time. Treatment sessions occurred several times per week for a total of 12–24 sessions, depending on the participant. Posttreatment results demonstrated significant improvements in dichotic listening abilities and concomitant listening comprehension measures. Fast Rate

Slow Rate P2

P1

P2

P1

N1

–20 msec

N1 P2 P1 P1

P2 –10 msec

N1 n=10

n=7 0.5 µv

–100 0 100 200 300 400 500 msec

N1

–100 0 100 200 300 400 500 msec

Fig. 30.7. Pre- and posttraining grand averaged waveforms measured from electrode Cz. Pretraining waveforms are thin. Posttraining waveforms are thick. As subjects learned to identify the difference between the 220 and 210 ms voice-onset time (VOT) stimuli, N1-P2 peak-to-peak amplitude increased. (Reprinted from Tremblay et al., 2001, with permission.)

CENTRAL AUDITORY PROCESSING DISORDERS IN CHILDREN AND ADULTS 551 Musiek et al. (2008) also demonstrated the effectiveaffected by the surgical removal of the lesion. Instead, ness of a dichotic listening therapy in a group of 14 chilher reading and spelling skills (which had been intact dren diagnosed with CAPD. In their study, the dichotic and progressing at an age-appropriate rate preoperastimuli were varied in interaural temporal lag time, with tively) had “stalled” at the fifth-grade level, showing shorter temporal lags being more challenging than lonlittle improvement thereafter. These findings were ger lags. After 10 weeks of training, a significant accompanied by complaints of significant difficulties improvement in dichotic listening abilities was noted hearing in noise and substituting similar-sounding and was accompanied by parent and teacher reports of phonemes in perception of verbal input, all of which hearing-in-noise improvements. started following the surgery at age 10 and had Similar posttreatment improvements have been noted become progressively more noticeable. Receptive and following frequency and duration discrimination trainexpressive language abilities, as well as cognitive abiliing (McArthur et al., 2008), computer-based auditory ties, were demonstrated to be age-appropriate through skills training (Sharma et al., 2012), and acoustic contour standardized tests. (pitch and duration patterns) training (Foxton et al., A comprehensive central auditory test battery was 2004). In addition, recent research has begun to demonadministered, consisting of both psychophysical and strate the impact of music training on auditory and learnelectrophysiologic measures. KA was cooperative ing abilities (Schon et al., 2004; Marques et al., 2007; throughout testing and no indicators of attention, cogniMoreno et al., 2009; Parbery-Clark et al., 2009; Pantev tive, or linguistic confounds were apparent. Five behavand Herholz, 2011; Kraus, 2012). Chapter 12 of this volioral central auditory tests were administered: (1) ume provides additional information on the effect of Dichotic Rhyme (Musiek et al., 1989); (2) Dichotic Digits musical experience and training on auditory and related (Musiek, 1983); (3) Competing Sentences (Auditec processing. version); (4) Time-Compressed Speech with and without Notwithstanding these and similar studies indicating Reverberation (Tonal and Speech Materials for Audieffectiveness of auditory training in addressing auditory tory Perceptual Assessment, v. 2.0); and (5) Frequency complaints of those with CAPD, there is a clear need for Patterns (Pinheiro and Ptacek, 1971; Ptacek and additional, well-controlled treatment efficacy research Pinheiro, 1971). using both children and adults with precise, consensusResults indicated that KA exhibited abnormal perforbased CAPD diagnoses. Following is a case study mance on four of the five tests administered, including a illustrating the diagnostic and intervention concepts left-ear deficit on Dichotic Rhyme, a bilateral deficit on introduced in this chapter. Dichotic Digits and Competing Sentences, and a bilateral deficit on Time-Compressed Speech, which demonstrated significant worsening with the addition of reverCASE STUDY beration. Conversely, her performance in non-sensitized The patient, KA, was a 17-year-old healthy female who conditions (i.e., repetition of number sequences and senpresented at our clinic with primary complaints of signiftences in non-competing conditions, repetition of monoicant difficulty hearing in noise, “mishearing” auditory syllabic words in non-degraded conditions) was well input leading to misunderstanding of auditory-verbal within normal limits, indicating that the abnormalities communications, and reading and spelling difficulties. observed could be attributed to the acoustic modificaShe had been an accomplished musician (piano, violin) tions rather than to generalized language, memory, or from a very early age. related confounds. At the age of 10, KA underwent a stereotactic volWhen taken together, results of behavioral testing umetric resection of a right posterior temporal-lobe met American Speech-Language-Hearing Association glioma. Prior to the surgery, KA complained of (2005a) and American Academy of Audiology (2010) headaches and visual disturbances; however, she diagnostic criteria for CAPD, including performance did not endorse any auditory, learning, or related outside of the normal range for age on at least two tests complaints and was performing at age level in all of central auditory function and an inter- and intratest benchmarks. Postoperatively, KA complained of pattern of performance consistent with CANS dysfunchyperacusis (particularly in the right ear), headaches tion. The observed central auditory deficits appeared to in the right side of the head, and episodes of synbe affecting the processes of binaural separation, binaucope. No postsurgical visual concerns were reported. ral integration, and auditory closure, all of which are critA postoperative magnetic resonance imaging scan ical for successful auditory perception in competition was unremarkable. and with degraded auditory stimuli. When she arrived for CAPD evaluation, KA and her Following the behavioral central auditory evaluation, parents reported that her musical abilities had not been a comprehensive auditory electrophysiologic evaluation

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was also completed. Click-evoked ABR testing revealed essentially normal neural transmission of auditory stimuli through brainstem auditory pathways. In contrast, MLR recordings were normal with right-ear stimulation, but were significantly reduced in amplitude or absent over left- and right-hemisphere electrode sites with left-ear stimulation. This finding indicated abnormal transmission of auditory signals through the thalamocortical auditory pathways with left-ear stimulation, resulting in an “ear effect” for the ear contralateral to the site of dysfunction (Musiek et al., 1989; Weihing et al., 2012a). Cortical auditory event-related potentials, including P300, also were obtained and were within normal limits across all electrode sites with both left- and right-ear stimulation. Recommendations for intervention were made, including environmental modifications, central resources training, and direct auditory remediation. To target the deficient processes of binaural separation/ integration, direct remediation in the form of dichotic listening training was recommended (Bellis, 2002, 2003). Twelve weeks following the initial evaluation, KA returned for a central auditory re-evaluation. She had undergone the intensive dichotic listening training for the recommended 6 weeks. At this time, both KA and her mother reported a marked improvement in hearing-in-noise and other listening skills. School records supplied by her mother confirmed a significant improvement in KA’s reading and spelling skills, and she was currently achieving grades of A and B in her courses. Posttreatment behavioral central auditory test results revealed performance within the normal range for age for all measures (Fig. 30.8). These results indicated significant improvement in binaural separation and integration abilities. Interestingly, KA’s auditory closure skills, as measured by her performance on time-compressed speech testing with and without reverberation, also demonstrated significant improvement, despite not having been explicitly trained. Posttreatment MLR testing mirrored the behavioral results, indicating normal thalamocortical transmission of auditory signals with both right-ear and left-ear stimulation (Fig. 30.9). These findings provided objective evidence of improved neural integrity underlying central auditory function. Given the short training period (6–12 weeks), the age of the patient (17 years), and the absence of other intervention activities during the time since initial evaluation, these improvements could not be attributed to maturation, environmental factors, or other contributors. Instead, when taken together, the results of both behavioral and electrophysiologic testing suggested significant improvement in both auditory behaviors and underlying neural substrates resulting from targeted, intensive auditory training.

CENTRAL TEST DATA % 100

Dichotic Rhyme

Competing Dichotic Time-Comp Time-Comp Frequency Sentences Digits Speech Sp w/ Reverb Patterns

X

O

X

O

X

O

L

90 80

X

X O

O

70 60 50 40

O X

30 20

O

X O

X

O

O X

X

10 0 Normal Range-12-adult X = Left Ear O = Right Ear

Fig. 30.8. Pretherapy (gray) and posttherapy (black) behavioral central auditory test results from right ear (O) and left ear (X). Shaded areas represent normative ranges for age. Note the improved performance after therapy.

This case study illustrates the use of diagnostic central auditory measures to guide deficit-specific intervention and demonstrates both behavioral and neurophysiologic improvements following targeted, intensive auditory training. In our clinic, KA is not an atypical case. We have seen nearly identical results with a host of other children and adults both with and without frank neuropathology but with diagnosed CAPD. Further, in those cases in which reading, spelling, and other learning difficulties coexisted with the CAPD, improvements in those skills also were apparent, despite not having been explicitly addressed. We hope that future research can assist in illuminating the underlying neural mechanisms responsible for these improvements, particularly in non-auditory, learning-related abilities.

CONCLUSIONS In conclusion, CAPD can affect anyone of any age. Various etiologies for CAPD may include neurologic disorders, genetic diseases, neurotoxins, and trauma; however, in many cases, no identifiable neuropathology may be evident, particularly in children. Nonetheless, the most widely accepted definitions of CAPD emphasize that the disorder is neurobiologic in origin and affects perceptual processing (and neural transmission) of auditory information in the CANS. Diagnosis of CAPD requires the administration of behavioral and electrophysiologic central auditory tests that have been shown to be sensitive, specific, and efficient for the identification of dysfunction in various

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Fig. 30.9. Middle-latency auditory evoked responses pre- and posttherapy. Note the improved responses following therapy. In each set of responses, the top tracing indicates responses obtained at C3, the middle tracing indicates responses obtained at C4, and the bottom tracing indicates responses at Cz.

regions of the CANS. Intervention for CAPD should be individualized, deficit-specific, and multidisciplinary in nature, and should include bottom-up and top-down approaches to improve access to information in the listening/learning environment; recruit and strengthen higher-order cognitive, language, and related skills through central resources training; and directly remediate the auditory deficits identified through diagnostic testing.

REFERENCES Alonso R, Schochat E (2009). The efficacy of formal auditory training in children with (central) auditory processing disorder: behavioral and electrophysiological evaluation. Braz J Otorhinolaryngol 75 (5): 726–732. American Academy of Audiology (2010). Guidelines for the diagnosis, treatment, and management of children and adults with central auditory processing disorder. Available online at, http://www.audiology.org/resources/documentlibrary/ Documents/ait.pdf, Retrieved: May 15, 2013. American Speech-Language-Hearing Association (2005a). (Central) auditory processing disorders [technical report]. Available online at, http://www.asha.org/docs/html/ TR2005-00043.html, Retrieved: May 15, 2013.

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CENTRAL AUDITORY PROCESSING DISORDERS IN CHILDREN AND ADULTS Jerger J, Musiek F (2000). Report of the consensus conference on the diagnosis of auditory processing disorders in schoolaged children. J Am Acad Audiol 11: 467–474. Johnson K, Nicol T, Kraus N (2005). Brainstem response to speech: a biological marker of auditory processing. Ear Hear 26 (5): 424–434. Johnson KL, Nicol T, Zecker SG et al. (2008). Developmental plasticity in the human auditory brainstem. J Neurosci 28: 4000–4007. Katz J (1983). Phonemic synthesis. In: E Lasky, J Katz (Eds.), Central auditory processing disorders: Problems of speech, language, and learning, University Park Press, Baltimore, pp. 269–272. Katz J, Stecker N, Henderson D (1992). Central auditory processing: A transdisciplinary view, Mosby Year Book, St. Louis. Kompus K, Specht K, Ersland L et al. (2012). A forcedattention dichotic listening fMRI study on 113 subjects. Brain Lang 121 (3): 240–247. Kraus N (2012). Biological impact of music and softwarebased auditory training. J Comm Disord 45: 403–410. Kraus N, McGee T, Carrell T et al. (1996). Auditory neurophysiologic responses and discrimination deficits in children with learning problems. Science 273 (5277): 971–973. Malloy L, Bellis T (2013) The effect of recurrent impacts and impulses on electrophysiologic measures in collegiate football players. Poster presented at the American Academy of Audiology annual conference, Anaheim, CA. Marques C, Moreno S, Castro S et al. (2007). Musicians detect pitch violation in a foreign language better than nonmusicians: Behavioral and electrophysiological evidence. J Cogn Neurosci 19: 1453–1463. Martin E, Lu W, Helmick K et al. (2008). Traumatic brain injuries sustained in the Afghanistan and Iraq wars. J Trauma Nurs 15 (3): 94–99. McArthur G, Ellis D, Atkinson C et al. (2008). Auditory processing deficits in children with reading and language impairments: can they (and should they) be treated? Cognition 107 (3): 946–977. Moncrieff D, Wertz D (2008). Auditory rehabilitation for interaural asymmetry: preliminary evidence of improved dichotic listening performance following intensive training. Int J Audiol 47 (2): 84–97. Moore D, Rosen S, Bamiou D et al. (2013). Evolving concepts of developmental auditory processing disorder (APD): a British society of audiology APD special interest group ‘white paper.’ Int J Audiol 52: 3–13. Moreno S, Marques C, Santos A et al. (2009). Musical training influences linguistic abilities in 8-year old children: more evidence for brain plasticity. Cereb Cortex 19: 712–723. Musacchia G, Sams M, Nicol T et al. (2006). Seeing speech affects acoustic information processing in the human brainstem. Exp Brain Res 168: 1–10. Musiek FE (1983). Assessment of central auditory dysfunction: The Dichotic Digits Test revisited. Ear Hear 4: 79–83. Musiek FE (1999). Habilitation and management of auditory processing disorders: overview of selected procedures. J Am Acad Audiol 10: 329–342.

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Schochat E, Musiek F, Alonso R et al. (2010). Effect of auditory training on the middle latency response in children with (central) auditory processing disorder. Braz J Med Biol Res 43 (8): 777–785. Schon D, Magne C, Besson M (2004). The music of speech: music training facilitates pitch processing in both music and language. Psychophysiology 41: 341–349. Sharma M, Purdy SD, Newall P et al. (2006). Electrophysiological and behavioral evidence of auditory processing deficits in children with reading disorder. Clin Neurophysiol 117: 1130–1144. Sharma M, Purdy S, Kelly A (2009). Comorbidity of auditory processing, language, and reading disorders. J Speech Lang Hear Res 52: 706–722. Sharma M, Purdy S, Kelly A (2012). A randomized control trial of interventions in school-aged children with auditory processing disorders. Int J Audiol 51: 506–518. Shinn J, Baran J, Moncrieff D et al. (2005). Differential attention effects on dichotic listening. J Am Acad Audiol 16 (4): 205–218. Sloan C (1995). Treating auditory processing difficulties in children, Singular, San Diego. Strait D, Kraus N (2011). Can you hear me now? Musical training shapes functional brain networks for selective auditory attention and hearing speech in noise. Front Psychol 2: 113. Tremblay K (2007). Training-related changes in the brain: evidence from human auditory evoked potentials. Semin Hear 28: 120–132.

Tremblay K, Kraus N (2002). Beyond the ear: central auditory plasticity. Otorinolaringologia 52: 93–100. Tremblay K, Kraus N, McGee T et al. (2001). Central auditory plasticity: changes in the N1-P2 complex after speechsound training. Ear Hear 22 (2): 79–90. Watson C, Kidd G (2002). On the lack of association between basic auditory abilities, speech processing, and other cognitive skills. Semin Hear 23: 83–93. Watson C, Kidd G (2009). Associations between auditory abilities, reading, and other language skills in children and adults. In: T Cacace, D McFarland (Eds.), Current controversies in central auditory processing disorder (CAPD), Plural Publishing, San Diego, CA, pp. 217–242. Weihing J, Schochat E, Musiek F (2012a). Ear and electrode effects reduce within-group variability in middle latency response amplitude measures. Int J Audiol 51 (5): 405–412. Weihing J, Bellis T, Chermak G et al. (2012b). Current issues in the diagnosis and treatment of CAPD in children. In: D Geffner, D Swain (Eds.), Auditory processing disorders: Assessment, management, and treatment, Plural Publishing, San Diego, CA, pp. 3–32. World Health Organization (2002). Towards a common language for functioning, disability, and health: ICF. World Health Organization, Geneva. Wright B, Bowen R, Zecker S (2000). Nonlinguistic deficits associated with reading and language disorders. Curr Opin Neurobiol 10 (4): 482–486.

Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 31

Auditory neglect and related disorders ALEXANDER GUTSCHALK* AND ANDREW R. DYKSTRA Department of Neurology, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany

INTRODUCTION Clinical presentation of neglect Neglect is a neurologic syndrome that is frequently observed after right medial cerebral artery (MCA) stroke and other right-hemisphere lesions. Patients with acute, full-blown neglect are easily recognized by their gaze deviation towards the ipsilesional – typically right – side (Becker and Karnath, 2010), and their lack of awareness of contralesional – typically left-sided – events in their environment. When addressed from the left, patients with neglect often orient wrongly towards their right side. Lack of contralesional awareness may also include the patient’s own body such that, even in the absence of hemiplegia, they may cease to move their left arm and leg. Finally, patients are often unaware of their condition and its severity, a symptom that is known as anosognosia. A comprehensive review of the general clinical aspects of neglect is outside the scope of the current chapter, and we refer the reader to one of the many review papers and textbook chapters on the topic (Heilman et al., 2003; Husain, 2008; Corbetta and Shulman, 2011). While early reports of neglect symptoms date back to the 19th century (Oppenheim, 1885), the righthemisphere dominance of the syndrome was not generally acknowledged until later (Brain, 1941). Since then, many studies have evaluated the perceptual manifestations of neglect, especially in vision. In bedside tests, the most severely affected patients may be completely unaware of stimuli presented to the neglected visual hemifield, making it difficult to decide whether hemianopia is present in addition to hemispatial neglect (Husain, 2008). Detecting subtler cases of visual neglect may require more formal examination. So-called cancellation tests, in which patients are required to denote certain targets (e.g., the letter “A” (Weintraub and

Mesulam, 1985) or a schematic bell (Gauthier et al., 1989)) amongst a cluttered array, have proven particularly useful: the more severe the neglect, the more target items on the left, contralesional side will be missed (Rorden and Karnath, 2010). Another option to detect less severe deficits is the test introduced by Posner: here, patients are cued to the left or right before the presentation of a visual target, and patients suffering from mild neglect typically show prolonged reaction time for targets presented on the left, most prominently when invalidly cued to the right side (Posner et al., 1984). The Posner task is more time consuming, but also more sensitive than cancelation tasks in chronic and less severely affected patients (Rengachary et al., 2009). While visual deficits have clearly been the focus of neglect research to date, neglect is a multimodal disorder and similarly involves the auditory and somatosensory domains. We use the term “auditory neglect” in this chapter to refer to the auditory manifestations of a supramodal neurologic disorder (i.e., neglect), and do not mean to imply the existence of a unique disorder that manifests itself only in the auditory domain. Most auditory signs that are observed in neglect are lateralized to the left hemifield. The first of these signs is auditory extinction (Heilman and Valenstein, 1972), though it should be noted that unimodal auditory extinction (Fig. 31.1) can also be caused by lesions to auditory cortex. The second classic sign of auditory neglect is disruption of spatial perception with reduced accuracy of spatial perception on the left and a bias of sound lateralization towards the right. In our view, however, the most distinctive sign of auditory neglect is alloacusis (Brain, 1941), where patients attribute the source of all sounds to their right. More recently, it has been shown that neglect is also associated with non-spatial auditory deficits, in particular in tasks that require sustained auditory attention (Robertson et al., 1997), or the comparison

*Correspondence to: Alexander Gutschalk, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Tel: +49-6221-56 36811, Fax: +49-6221-56 5258, E-mail: [email protected]

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Fig. 31.1. Schematic of auditory extinction. Patients with leftsided auditory extinction can generally report single words presented to the right (A) or left (B), but report only the right-ear word with dichotic stimulation (C). Similarly, patients are able to locate single sounds to the left or right ear, but locate synchronous left- and right-ear stimuli to the right.

of subsequently presented sounds (Cusack et al., 2000). Maybe with the exception of alloacusis, none of these auditory deficits is sufficiently specific for neglect, but alloacusis is more typical in severely affected, acute cases and subsides in most patients after a while. As we suggest below, the combination of auditory extinction or auditory spatial bias and impaired sustained auditory attention might provide a more specific clinical definition of neglect in the auditory domain, which can also be applied to patients with chronic or less severe forms of neglect where alloacusis has subsided or is not present.

Extinction Extinction is a potential clinical indication of neglect, although the exact relationship between the two is disputed: patients who show sensory extinction are still able to detect and identify single stimuli presented either to the left or right side, but often fail to detect a left-sided (i.e., contralesional) stimulus when it is presented simultaneously with a right-sided, ipsilesional stimulus. Two different sets of procedures and instructions are typically used to test extinction: one is to use similar stimuli on both sides and ask the patient from which direction the stimulus was perceived. Alternatively, two different stimuli may be presented and the patient is then asked to identify the perceived stimuli (Fig. 31.1).

Extinction can be observed with visual, auditory, and somatosensory stimulation (Oppenheim, 1885), and can also be observed between modalities, such that a rightsided visual stimulus may extinguish a left-sided auditory stimulus (Diamond and Bender, 1965). Some authors consider extinction a milder clinical presentation of neglect that occurs in patients with smaller lesions or where other symptoms of neglect may have subsided over time (Hier et al., 1983; Posner et al., 1984; Rengachary et al., 2011). Others have suggested that extinction is a distinct syndrome that may often co-occur with neglect, but that visual neglect and extinction can be doubly dissociated (Vallar et al., 1994; Vossel et al., 2011). A study that investigated the incidence of visual neglect and extinction in patients with acute MCA stroke found that both are clearly righthemisphere syndromes and that visual extinction is not observed more frequently with left-sided lesions than neglect (Becker and Karnath, 2007). In their study, 26% of acute right-hemisphere stroke patients (n ¼ 42) showed signs of visual neglect and 24% showed visual extinction; in left-hemisphere patients (n ¼ 51) the percentage was 2.4% and 4.9%, respectively. As we will see in the next section, the situation is somewhat more obscure in the auditory domain, where extinction can also be observed after lesions of auditory cortex in the absence of accompanying clinical signs of neglect (Gutschalk et al., 2012).

AUDITORY BEHAVIORAL DEFICITS IN NEGLECT AND SIMILAR DISORDERS Auditory extinction An early report of auditory extinction by Oppenheim described a patient with left MCA stroke and good hearing in both ears who did not detect the ticking of a watch held next to her right ear when another watch was simultaneously held next to her left ear (Oppenheim, 1885). Auditory extinction was also observed in a series of patients in which small bells, whistles, jangling keys, finger snapping, and other small objects were used to create different sounds at the left and right ears while listeners were asked to identify the sounds (Diamond and Bender, 1965). The authors also reported that extinction of leftsided sound by right-sided visual or somatosensory stimulation was especially prevalent in patients with neglect, which they termed “left hemispatial disorientation syndrome.” The first study to provide detailed localization information regarding the lesion sites typically associated with neglect used technetium-99 scans in 17 patients with auditory extinction and other signs of clinical neglect; 9 patients had lesions in the right inferior parietal lobe, one in the left frontal lobe, and 7 had lesion sites that could not be determined (Heilman and

AUDITORY NEGLECT AND RELATED DISORDERS Valenstein, 1972). The potential involvement of damage to the inferior parietal lobe in neglect was indirectly confirmed in four rhesus monkeys showing auditory extinction after removal of the lower parietal lobe and posterior superior temporal gyrus (STG) (Heilman et al., 1971). Note, however, that the possible impact of the STG lesion on auditory cortex was not discussed by the authors. A later study reported that the frequency of auditory extinction was not significantly different between acute left- and right-hemisphere lesions, but persisted more frequently in right-hemisphere lesions when the same patients were evaluated again after 30 days or more (De Renzi et al., 1984). The authors studied 144 patients (69 right- and 75 left-hemisphere strokes) and found contralateral extinction in 45% of right- and 36% of left-hemisphere patients. A number of patients also showed ipsilesional extinction, the source of which is unclear at this point. Especially in left-hemisphere patients, but also in some right-hemisphere patients, auditory extinction was not generally coupled to neglect or visual extinction. CT scans showed that in most cases of auditory extinction associated with cortical lesions, auditory cortex and parietal cortex were involved (compare illustration in Fig. 31.2). Subcortical lesions associated with persistent auditory extinction consistently extended into the sublenticular portion of the internal capsule, likely destroying major parts of the auditory thalamocortical radiation. The authors therefore concluded that extinction is, at least in a subset of patients, caused by an imbalance within the afferent auditory pathway, and may therefore be a sensory phenomenon (De Renzi et al., 1984).

Auditory extinction in dichotic speech tests Dichotic speech tests (see Chapter 18), in which listeners are asked to identify different words, spoken digits, or phrases presented independently to the left and right ears via headphones, were introduced with the availability of sound recordings (Broadbent, 1952; Cherry, 1953). In the context of functional neuroanatomy, these tests were first applied in a population of patients with temporallobe lesions who showed contralesional extinction that was attributed to involvement of the auditory pathway (Kimura, 1961; Schulhoff and Goodglas, 1969). Dichotic speech tests have more recently been used as a diagnostic tool for auditory neglect (Hugdahl et al., 1991; JacquinCourtois et al., 2010), sparking a discussion as to whether auditory extinction in dichotic speech tests can be used to diagnose auditory neglect (Beaton and McCarthy, 1993; Hugdahl and Wester, 1994). In an attempt to make the dichotic speech test more specific for neglect, as opposed to auditory cortex lesions, it has been suggested

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Fig. 31.2. Magnetic resonance imaging of a patient with auditory neglect 1 year after a subtotal right medial cerebral artery (MCA) stroke (the patient had received hemicraniectomy for malignant MCA infarction). The lesion comprises substantial parts of the lower parietal lobe (A), parts of prefrontal cortex, and the superior temporal plane. As in many patients with neglect, the auditory cortex (B) is also affected, whereas the auditory cortex in the left hemisphere is still intact. Major parts of primary auditory cortex reside in Heschl’s gyrus (B, C), secondary areas are in planum temporale (PT) and the posterior end of the superior temporal gyrus (STG). Auditory test results of this patient have been previously reported (Gutschalk et al., 2012).

to lateralize the two speech elements by interaural time differences (ITD) instead of by ear (Bellmann et al., 2001; Spierer et al., 2007), based on the contralateral processing bias for monaural stimuli. These authors showed that extinction in ITD-lateralized tests was not observed in all patients who demonstrated extinction in classic dichotic tests, and suggested that extinction in the ITD-lateralized test indicated a deficit more specific to

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spatial representation, supposedly explained at a processing level beyond auditory cortex and more specifically related to neglect. This partial dissociation was first demonstrated in 4 patients (Bellmann et al., 2001) and then in a series of 15 more patients. However, when a similar ITD-based test was applied to a patient sample that included patients with auditory cortex lesions with and without neglect, dichotic and ITD-lateralized tests were found to be highly correlated (Gutschalk et al., 2012). The latter study demonstrated that auditory extinction can be observed in patients with auditory cortex lesions of either hemisphere (Fig. 31.3), both with and without neglect, as well as in patients with neglect in whom auditory cortex is intact. Thus, while the dissociation of monaural and ITD-lateralized dichotic tests remains of interest for further research (Fig. 31.4), its diagnostic value is currently unclear. A third group of patients who show extinction in dichotic speech tests have lesions affecting the transcallosal tract connecting the auditory cortices on the left and right. Patients with left-hemisphere speech dominance with such lesions show extinction of left-ear speech, as was first shown in a patient who had undergone callosotomy for epilepsy (Sparks and Geschwind, 1968). Note

Fig. 31.3. Auditory extinction in dichotic speech test. Listeners reported the words they heard in the left and right ear (mean  standard error). Control data (n ¼ 25) are plotted in gray; the patient data are plotted in black. Patients either had a lesion of the left or right auditory cortex (AC), or they were included because visual neglect was present. The neglect group was again separated into patients with and without a lesion of the right auditory cortex (n ¼ 7 in each of the four groups). Listeners generally extinguished more words contralateral to the lesion (difference error, left panel). However, 2 patients in the left AC group showed ipsilesional extinction (see Fig. 31.4), reducing the mean effect. The overall error rate (right panel) was higher in patients with left-sided lesions, probably because some aphasia was present. There was otherwise no statistical difference in the amount of extinction between patient groups. (Modified from Gutschalk et al., 2012.)

that lesions of the transcallosal pathway may occur in the left, right, or middle, and that the position of the lesion has no effect on the side of extinction in dichotic speech test. This is thought to be due to a stronger contralateral processing bias in the presence of competing dichotic stimuli such that information presented to the

Fig. 31.4. Patient with an infarction in the left medial cerebral artery territory that destroyed (A) part of medial Heschl’s gyrus (including the primary auditory cortex) and adjacent planum temporale (Gutschalk et al., 2012). The subcortical part of the lesion extends to the lateral ventricle and up to the parietal lobe, thereby dissecting the transcallosal auditory pathway. (B) Lateral parts of the left auditory cortex remain unaffected. (C) The patient missed many contralateral, right-ear targets in the psychoacoustic pattern discrimination test (PPDT) (see Fig. 31.5). (D) In contrast, extinction for words was ipsilateral to the lesion in a dichotic setup and only mildly affected in an interaural time difference-based setup. Thus, there is a double dissociation of a contralateral deficit in the PPDT, supposedly related to the auditory cortex lesion, and an ispilateral deficit in the dichotic word test, supposedly related to the lesion of the transcallosal auditory pathway.

AUDITORY NEGLECT AND RELATED DISORDERS 561 left ear is processed initially in the right hemisphere and, first. A different pattern was observed for leftdue to the lesion to the transcallosal tract, is not transhemisphere lesions (n ¼ 17), where extinction was more ferred to the left hemisphere’s speech regions. Ipsilefrequently observed for the trailing sounds, such that sional extinction, most frequently after left-sided ipsilesional extinction was observed more frequently in lesions of the transcallosal auditory pathway, has been this case. Since the patient selection did not control for termed “paradoxical extinction” (Sparks and lesions of the auditory cortex or underlying white matGeschwind, 1968; Damasio and Damasio, 1979). The latter, it is conceivable that the pattern for left-hemisphere ter authors studied 20 patients, of which 13 showed cases could primarily reflect lesions of auditory cortex, extinction. Four of 8 patients with lesions in the left whereas the pattern in right-hemisphere lesions could hemisphere, and 1 of 5 patients with right-hemisphere reflect auditory extinction in a predominantly multilesions showed ipsilesional extinction. Notably, the one modal context, although most patients did not show clinright-hemisphere patient with ipsilesional extinction ical signs of visual neglect at the time of the was shown to have right-hemisphere dominance for laninvestigation. guage in the Wada test. When there is an additional lesion of the auditory corTarget detection tasks tex, patients with lesions of the transcallosal pathway Dichotic auditory target detection tasks have been show left-ear extinction in speech and right-ear deficits in non-speech dichotic tests (Gutschalk et al., 2012), a applied in order to diagnose either auditory neglect pattern that was found in 2 of 7 patients with left (De Renzi et al., 1989) or lesions of the telencephalic auditory-cortex lesions (Fig. 31.4). This double dissociaauditory pathway (Blaettner et al., 1989): A target detection of speech and non-speech auditory extinction clearly tion task proposed to be specific for neglect is the detecdemonstrates that auditory extinction is a symptom that tion of 8–20-ms-long gaps in an ongoing, 4-minute-long can be caused by at least two independent underlying pure tone presented via headphones (De Renzi et al., 1989). The test was first presented in a monaural variant, pathologies and that auditory extinction is more heterowhere all gaps occurred in the same ear. Thereafter, geneous than visual extinction. In summary, dichotic speech tests are sensitive and the tone was presented in both ears, while the interrupeasy to apply, but they are usually not sufficient to diftion occurred randomly in either the left or right ear. ferentiate neglect from other conditions. In particular, Overall, 30 patients with right- and 15 patients with patients with right-hemisphere lesions may show conleft-hemisphere lesions of various etiologies were tested. tralesion extinction due to an auditory cortex lesion, Predominantly contralesional misses were observed for neglect, a transcallosal lesion, or any combination nine right-hemisphere lesions, particularly when the stimuli were dichotic, but also in some cases for monauthereof. In left-hemisphere lesions, the test may be limral stimuli. Most patients also showed auditory extincited by aphasia, and even patients with mild aphasia (as those shown in Fig. 31.3) have overall higher error rates tion, but 7 more patients with right-hemisphere lesions on both sides. showed auditory extinction and normal target detection. Moreover, 2 patients without auditory extinction who showed auditory neglect as defined by the gap detection Extinction and temporal order task showed no signs of visual neglect (although one In patients with auditory extinction, a perceived time showed visual and tactile extinction). An unpublished delay has been shown for contralesional stimuli: when replication of their test using 200-ms-long gaps in ongolisteners are required to adjust the time delay between ing noise confirmed a high rate of missed gaps in left and right ear tones such that they hear the two synpatients with neglect; however, this deficit was not chronously, they typically adjust the contralesional stimstrongly lateralized (Leifert-Fiebach, 2008). ulus to be presented earlier by 50–300 ms (Karnath et al., Another dichotic target detection task was conceived 2002; Sinnett et al., 2007; Barrett et al., 2010), as has to study auditory telencephalic hearing disorders. In this been demonstrated in overall 13 patients with rightpsychoacoustic pattern discrimination test (PPDT), parhemisphere lesions. ticipants must detect monaural, randomly presented This comparison requires that listeners actually perintensity (Fig. 31.5A) or duration deviants amongst a ceive both stimuli. The relationship between onset asynstream of uniform dichotic noise bursts or click trains chrony and extinction has been evaluated in more detail (Blaettner et al., 1989). The authors studied 62 patients in a study that showed that temporal asynchrony can mitwho had suffered a stroke at least 3 months ago igate extinction (Witte et al., 2012). For right-hemisphere (42 in the left and 15 in the right hemisphere) and lesions (n ¼ 17), contralesional stimuli were typically 48 controls. Contralesional misses in the PPDT were extinguished irrespective of which sound was presented associated with anatomic lesions of the auditory cortex

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A. GUTSCHALK AND A. DYKSTRA The association of lateralized deficits in the PPDT with auditory cortex lesions was recently confirmed in a study that also applied the test to a group of patients with clinical signs of neglect (Gutschalk et al., 2012). While 13 of 14 patients with neglect had basic difficulty performing the task and missed many targets on both sides, their deficit was consistently lateralized to the contralesional ear only when a lesion involving the auditory cortex was additionally present (Fig. 31.5B). Patients with auditory cortex lesions who did not show clinical signs of neglect only showed such general problems performing the task in 2 of 14 cases (one left- and one righthemisphere lesion).

Non-spatial auditory deficits in neglect

Fig. 31.5. (A) Schematic of the psychoacoustic pattern discrimination test (Blaettner et al., 1989). Every 600 ms, 200-ms noise bursts are presented to both ears. Targets, where the level is 10, 6, or 4 dB higher in one ear, occur randomly after 6–10 repetitions. Listeners are instructed to press a response button as soon as they detect a target among the stream of standards. (B) Data of the control group (n ¼ 26) are plotted in gray; patient data are plotted in black (mean standard error). The number of subjects is indicated separately for each level because the procedure adapts to patient performance. Patients with auditory cortex (AC) lesions show predominantly contralateral deficits (difference error, left column). Patients with neglect showed a higher error rate (missed targets, right column), but no significant lateralization when their AC was intact. (Modified from Gutschalk et al., 2012.)

and thalamocortical radiation in cranial computed tomography (CCT) and auditory evoked potentials. Of the 46 patients who had such a lesion in CCT, 74% were correctly classified based on the PPDT test score.

A general deficit of sustained auditory attention has also been found with a non-lateralized auditory target detection test (Robertson et al., 1997). In these so-called “elevator counting tests” (Wilkins et al., 1987), listeners are required to count the numbers of tones in subsequently presented sound sequences, a task that is very simple for normal listeners, but which produced considerable problems for the patients showing signs of visual neglect. A correlation between visual neglect tests and auditory target detection was evaluated in a group of 44 patients who had a right-hemisphere stroke the previous year. Taken together with the results discussed earlier, it seems likely that problems with auditory target detection constitute a non-spatial auditory deficit of neglect, whereas strongly lateralized deficits, at least in the PPDT (Blaettner et al., 1989; Gutschalk et al., 2012), could indicate additional lesions to auditory cortex. However, there is another auditory deficit that has been observed in patients with visual neglect that is not readily explained by the above observations (Cusack et al., 2000). This study showed that, while patients with signs of visual neglect (n ¼ 9) performed well for tasks in which a sound feature can be identified within a single interval, they are severely impaired for tasks that require the comparison of two or more sounds. The authors interpreted their result to indicate a deficit of allocating attention between auditory objects. By using different time intervals between sounds, they could show that this deficit is not explained by the prominently prolonged duration of the attentional blink observed for visual target detection in patients with neglect (Husain et al., 1997). In spite of the fact that these tests showed such large discriminability between patients and controls, these non-spatial auditory tests have, to the best of our knowledge, not yet been utilized in clinical settings.

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Alloacusis Alloacusis is a unique clinical sign of auditory neglect that can be easily assessed in bedside tests alongside auditory extinction: patients showing alloacusis attribute the source of all sounds to the ipsilesional hemifield. Thus, the detection of alloacusis requires asking the patient “where” a stimulus is perceived. The answer in patients with right-hemisphere lesions is uniformly “on the right,” irrespective of whether the sound is presented to the left ear, right ear, or both ears simultaneously. Alloacusis was first reported in the 1940s (Brain, 1941), and has since been replicated in more than 15 patients who also showed other signs of neglect (Denny-Brown et al., 1952; Diamond and Bender, 1965; Soroker et al., 1997; Clarke et al., 2000; Bellmann et al., 2001; Zimmer et al., 2003; Gutschalk et al., 2012). In our own experience, alloacusis is often observed in patients with acute, severe right-MCA stroke, who typically also show full-blown visual neglect. When these severely affected patients are addressed from the left, they often orient to the right in search of the speaker. This observation might be explained by the finding of alloacusis, i.e., the patients detect the sound but misattribute the sound source to the right. In our experience, severe alloacusis subsides within a few days in a majority of cases but can persist for months or years in some patients. It is currently unclear whether alloacusis can be dissociated from extinction or if auditory extinction is generally present in patients with alloacusis. Patients with alloacusis who were also tested with dichotic speech tests additionally showed extinction (Bellmann et al., 2001; Gutschalk et al., 2012), but it cannot be excluded that the latter could have been caused by auditory cortex or transcallosal lesions. It has been reported that occasional alloacusis in a free-field target identification task was associated with lower contralesional identification rates with single as well as with double stimulation (Soroker et al., 1997). This combination of symptoms was typically found in right-hemisphere patients only, but was not correlated with the presence of visual neglect.

Sound lateralization Disturbance of auditory spatial perception is not always as prominent as in alloacusis. A number of tests (Fig. 31.6) have been used to reveal more subtle deficits of auditory lateralization using free-field stimulation (Ruff et al., 1981; Vallar et al., 1995; Zatorre and Penhune, 2001) or headphones (Bisiach et al., 1984; Kerkhoff et al., 1999; Tanaka et al., 1999; Clarke et al., 2000; Pavani et al., 2001; Zimmer et al., 2003). In one

Fig. 31.6. Lateralization perception can be tested in the free field (A) with a set of loudspeakers arranged in a circle, usually made invisible to the listener. The sound is then played from one speaker and the listener is asked to indicate the position where he or she perceives the sound. In this setting, sounds are perceived outside the head. Simpler setups use headphones (B), and lateralize the sound for example with interaural time differences (ITD). Here, the sound is perceived inside the head, and the listener is typically asked to indicate the lateralization of the sound. (C) Data obtained with a setup similar to panel B for the same patients and controls shown in Figures 31.3 and 31.5 (Gutschalk et al., 2012). Perceived lateralization of the neglect patients was typically more to the right (black) compared to the rating of the control group (gray). Note that the variability in this test is quite high; for example, patients with alloacusis rate all sounds at the far right. AC, auditory cortex.

such study, listeners were required to indicate the position from where they perceived lateralized sounds (Ruff et al., 1981; Bisiach et al., 1984; Clarke et al., 2000; Bellmann et al., 2001; Zatorre and Penhune, 2001; Zimmer et al., 2003; Spierer et al., 2009;

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Gutschalk et al., 2012). Based on these studies, there is converging evidence that disturbance of auditory lateralization is more frequent and more severe after righthemisphere lesions. Across studies, the most consistent finding was that patients displaced lateralized sounds towards the side of the lesion, i.e., most frequently towards the right. These findings are based on a sample of 267 patients comprising 119 patients with left- (L) and 148 patients with right-hemisphere (R) lesions (Ruff et al., 1981: L ¼ 14, R ¼ 15; Bisiach et al., 1984: L ¼ 51, R ¼ 56; Tunaka et al., 1999: L ¼ 15, R ¼ 29; Zimmer et al., 2003: L ¼ 9, R ¼ 15; Zatorre and Penhune, 2001: L ¼ 5, R ¼ 8; Spierer et al., 2009: L ¼ 25, R ¼ 25). A number of authors have tried to derive the subjective straight ahead in these patients, i.e., the physical stimulus lateralization in binaural stimulation (free field or headphone) that patients perceive as arising from the midline. Based on the observation that sounds emanating from the left or midline are perceptually displaced towards the right, one may assume that auditory midline perception has been shifted towards the left (Tanaka et al., 1999; Zimmer et al., 2003), i.e., a physically leftlateralized sound is perceptually rated as midline. In contrast, two studies found the auditory midline shifted towards the right in neglect patients (Vallar et al., 1995; Kerkhoff et al., 1999). It has been suggested that the reason for this discrepancy might lie in the instruction, and that the displacement of sound to the left is only with reference to the more strongly right-lateralized visual midline perception (Zimmer et al., 2003). Another suggestion (Pavani et al., 2004) is that the difference depends on whether the lateralized percept is perceived within the head (as with simple interaural time or frequency differences) or outside the head (with free-field listening or head-related transfer functions). However, there is at least one study that used free-field listening and found ipsilesional lateralization bias in patients with right-hemisphere lesions and neglect (Pinek et al., 1989). Another type of test to reveal deficits in lateralization required listeners to decide whether two subsequent sounds emanated from the same or different sources in space (Pavani et al., 2001; Zatorre and Penhune, 2001). The results confirmed that deficits of lateralization perception are typically observed in patients with right-hemisphere lesions. (Note that performance in these two-interval tasks may be additionally reduced because of non-spatial deficits (Cusack et al., 2000). The lateralization of the behavioral deficit to contralesional space suggests, however, that there is also a specific spatial deficit.) The most frequently reported lesion site to produce the above-summarized deficits is in the right inferior parietal lobe and right temporoparietal junction (Ruff et al., 1981; Bisiach et al., 1984; Bellmann et al., 2001;

Pavani et al., 2001; Zimmer et al., 2003; Spierer et al., 2009). In many cases, there appears to be a close relationship between visual neglect and deficits in auditory lateralization (Zimmer et al., 2003; Pavani et al., 2004; Gutschalk et al., 2012). However, deficits in auditory lateralization have also been observed, albeit rarely, in patients with left-hemisphere lesions (Clarke et al., 2000; Zimmer et al., 2003) and lesions to the right anterior temporal lobe (Zatorre and Penhune, 2001). No signs of visual neglect were documented in these patients, such that a general equivalence between deficits in auditory lateralization and visual neglect cannot be derived from the available data. There is good evidence, however, that lesions of the primary auditory cortex on both sides do not cause the severe deficits that are observed with right parietal lesions (Zatorre and Penhune, 2001; Gutschalk et al., 2012). A general issue in comparing the incidence of behavioral deficits between right- and left-hemisphere lesions is aphasia, which may be so severe that informed consent cannot be obtained and task instruction is impossible. Since many of these patients may have large left-sided lesions, there could be a bias for larger lesions on the right or a lack of patients with lesions in the left temporoparietal junction. However, given the large number of patients studied with lateralization tests in the past, the finding of a right-hemisphere dominance for pathologic findings in these tests is now well established. One study additionally showed that the lesions in their left- and right-hemisphere patients were highly similar (Spierer et al., 2009). Finally, it has been demonstrated that other auditory tasks, discussed in previous sections, revealed similar deficits after lesions in either hemisphere (de Renzi et al., 1984; Blaettner et al., 1989; Clarke et al., 2000; Gutschalk et al., 2012), despite excluding some patients because of aphasia.

Other deficits of spatial hearing The acuity of auditory spatial perception in patients with visual neglect is reduced not only with respect to lateralization, but also to localization of sound elevation (Pavani et al., 2002), with the deficit being more prominent for sounds in the contralesional (left) hemifield (n ¼ 4). The performance in this task has been shown to depend on gaze direction, such that the contralesional deficit was reduced when the patients’ gaze was directed towards the left (Pavani et al., 2005). It is also the case that the perception of sound movement may be reduced after right parietal lesions (Griffiths et al., 1996); the patient in this case report could not detect sound movement, but was able to dissociate whether a tone was presented to the left or right ear. Nevertheless, it is noted that the patient also had biased

AUDITORY NEGLECT AND RELATED DISORDERS lateralization perception for static sound sources, and subsequent studies that used static as well as moving sounds to test for deficits of spatial hearing usually found deficits in both tests in patients with right parietal lesions (Bellmann et al., 2001; Spierer et al., 2009).

NEURAL BASIS OF NEGLECT Lesion sites Auditory neglect has been most typically reported with lesions of inferior right parietal cortex and the temporoparietal junction (Fig. 31.7) in studies focusing on auditory extinction (Heilman and Valenstein, 1972) as well as those that focused on disturbances to auditory spatial perception (Ruff et al., 1981; Spierer et al., 2007). Some authors have also stressed the importance of the right posterior STG (Zimmer et al., 2003), whereas disturbed auditory lateralization without other signs of neglect has also been observed with lesions of the anterior STG (Zatorre and Penhune, 2001). Lesions of the STG may frequently extend into the more medial auditory core and belt regions (see above), which can cause auditory extinction (Gutschalk et al., 2012) that is not necessarily associated with neglect. Among the reported cases with signs of auditory neglect, there are also patients with lesions in the frontal lobe (Hugdahl et al., 1991) or basal ganglia (Bellmann et al., 2001), highlighting the fact that the types of lesions that can cause auditory neglect are as diverse as those known to cause visual neglect (Damasio et al., 1980;

Fig. 31.7. Topography of perisylvian areas in the right hemisphere thought to cause neglect when destroyed. The inferior parietal lobe (IPL) is the area most traditionally associated with neglect. Its dorsal limitation is the intraparietal sulcus. The IPL comprises the supramarginal gyrus and the angular gyrus. Another area thought to be important in the context of neglect and auditory lateralization perception is the superior temporal gyrus (STG). The transition from STG to the supramarginal gyrus is the temporoparietal junction (TPJ), another lesion focus in neglect patients. Less frequently, neglect has been reported with isolated lesions of the lower frontal lobe (marked is the inferior temporal gyrus) or the anterior insula.

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Vallar and Perani, 1986; Karnath et al., 2001; Mort et al., 2003; Verdon et al., 2010).

Models of neglect Most models to explain neglect are based on results observed in vision and suggest that neglect is a disorder of spatial attention. An early model suggested a balance between attentional vectors in the left and right hemisphere, and that their imbalance is stronger after rightsided lesions (Kinsbourne, 1970). Others have suggested a general specialization of the right hemisphere for attention and arousal (Heilman et al., 1978; Mesulam, 1981); this type of model can also explain some of the non-spatial deficits observed with auditory neglect (Robertson et al., 1997). To explain core spatial deficits in neglect, it has been assumed that the right hemisphere could orient attention to both sides in space, whereas the left hemisphere would predominantly orient to contralateral space (Mesulam, 1981), but this assumption has been challenged more recently (Corbetta and Shulman, 2011). Finally, a problem of disengaging attention from the ipsilesional side towards the contralesional side has been suggested based on cuing tasks (Posner et al., 1984). In this model, attention cannot be directed towards the left hemifield because it cannot be disengaged from the right. Disengaging attention has been attributed to the right temporoparietal junction. Thus, directing attention is not the disturbed mechanism in this model. In the context of auditory neglect, attention-based models are particularly well suited to explain the extinction phenomena reviewed above. Another line of models has considered neglect a primary disorder of spatial representation (Bisiach et al., 1981) rather than attention in space. One suggestion is that mapping of spatial information between different coordinate systems – such as retinal, egocentric, and allocentric (Karnath, 1997) – is defective. As a result, the coordinate system would be rotated towards the right with shrinkage of the left hemifield, which causes the deficit of contralesional exploration typically observed in neglect.

Functional Imaging A recent model of neglect (Corbetta and Shulman, 2011) is based on functional imaging studies in healthy volunteers and patients with neglect: in this model a dorsal attention system, required to voluntarily direct attention in space, is dissociated from a ventral, stimulus-driven attention system. While the dorsal attention system is thought to possess a topographic representation of space, this representation appears to be mostly contralateral, i.e., each hemisphere predominantly associated with

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its respective contralateral side of space. In contrast, the ventral attention system is strongly right-lateralized and is comprised of the same brain areas often associated with neglect (the temporoparietal junction, ventrolateral prefrontal cortex, and the anterior insular) (Corbetta and Shulman, 2002). Moreover, functional imaging studies in patients with neglect show that patients with lesions to the structures associated with the ventral attention system show abnormally low task-evoked activation (Corbetta et al., 2005), as well as modulated functional connectivity (He et al., 2007), in the dorsal attention system, more prominently in the right hemisphere. Followup studies with the same patients demonstrated that when activity in the dorsal attention system had normalized, the spatial neglect symptoms subsided (Fig. 31.8). This suggests that the degraded spatial processing characteristic of neglect may reflect the ventral lesion’s functional impact on the dorsal attention system, rather than being a direct consequence of structural damage to the ventral system. This model (Corbetta and

Shulman, 2011) can elegantly explain the heterogeneity of lesion sites in patients with neglect as well as their tendency to recover behaviorally. In contrast, the nonspatial deficits often experienced by neglect patients (Robertson et al., 1997) might be a more direct result of damage to the ventral attention system. Only a handful of electroencephalograph (EEG) and magnetoencephalograph (MEG) studies have investigated patients with auditory neglect. One such EEG study used free-field stimulation and an oddball paradigm in which rare deviant stimuli are interspersed amongst more frequent standard stimuli. The additional activity evoked by the deviants compared to the standards in the auditory cortex is known classically as the mismatch negativity, or MMN (Na¨a¨ta¨nen et al., 2007). In patients with neglect, the MMN was observed to be smaller when the stimulus stream was presented to the left side compared to when it was presented to the right side, a result not observed in control participants (Deouell et al., 2000). In the same study, the N1 evoked

Fig. 31.8. Functional magnetic resonance imaging (fMRI) activation maps in a Posner task (visual stimulus presentation) from the study by Corbetta et al. (2005). (A) The task produces widespread activation in a normal control group. In patients with neglect, the activity is prominently reduced. (B) While the lesions in the patient group are mostly confined to more ventral areas, activity in more dorsal parietal and frontal areas is also reduced. (C) When the same patients were studied again after 39 weeks, their left-sided attention deficits were substantially improved. This goes along with recovered activation levels in fMRI in areas that are not part of the lesion in the right, but also in the left hemisphere. SMCX, somatosensory and motor cortex; IPS, intraparietal sulcus; STL, superior temporal lobe; FEF, frontal eye field; R TPJ, right temporoparietal junction; SMG, supramarginal gyrus; STG, superior temporal gyrus; DLPC, dorsolateral prefrontal cortex; IFG, inferior frontal gyrus. (Reproduced from Corbetta et al., 2005, with permission from Nature publishing group.)

AUDITORY NEGLECT AND RELATED DISORDERS by the standard stimuli was smaller over the right compared to the left hemisphere, but did not differ based on side of presentation. A subsequent evaluation of the auditory-evoked N1 in patients with neglect showed that stimuli presented to the left ear evoked a smaller N1 than the same stimuli presented to the right ear (Tarkka et al., 2011). Note, however, that neither of these studies controlled whether auditory cortex was intact in their patients, and part of their findings might therefore be related to auditory cortex lesions. Nevertheless, the typical rightwards lateralization of auditory cortex activity (Ross et al., 2005; Shaw et al., 2013) was found to be reduced in patients with neglect and structurally intact auditory cortex (Gutschalk et al., 2012), independently of stimulus lateralization. In summary, there is some evidence to suggest that auditory neglect might involve modulation of early processing at the level of the auditory cortex, a finding that finds a parallel in reduced activity in the right visual cortex in patients with visual neglect (Corbetta et al., 2005; Vuilleumier et al., 2008).

CONCLUSION What is auditory neglect? The heterogeneity of lesion sites and broad spectrum of behavioral deficits in patients with neglect have prompted some authors to suggest that neglect is a heterogeneous disorder, with individual behavioral profiles directly related to the anatomic loci of the lesion(s) found in each patient (Verdon et al., 2010). Others have emphasized a core of neglect symptoms (Corbetta and Shulman, 2011; Karnath and Rorden, 2012), including an attentional bias towards the egocentric ipsilesional (right) side. In vision, this deficit is reliably measured by the amount of contralesional (left) omissions in cancellation tasks (Karnath and Rorden, 2012). Little has been said about whether auditory manifestations of neglect should be considered core features of neglect. In our opinion, alloacusis is the most obvious auditory manifestation of clinical neglect. While alloacusis is not present in all neglect patients, to the best of our knowledge there is no report of a patient with severe alloacusis who did not also show other core symptoms of neglect. (Note, however, that occasional alloacusis has been observed in patients who did not show signs of visual neglect at the time of testing (Soroker et al., 1997)). This is informally confirmed by our own clinical experience. Disturbance of lateralization is probably a less severe variant of similar origin and is also strongly correlated with neglect. However, the diagnosis of biased lateralization requires standardized tests that are not readily available at the patient’s bedside. Moreover, such deficits have also been observed in the

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absence of core neglect symptoms, making them a less reliable sign of auditory neglect. Auditory extinction is present in many patients with core neglect in our experience, but suffers from a lack of specificity since there are other conditions, such as lesions of the auditory cortex or the auditory transcallosal pathway, which can also cause auditory extinction. It is therefore difficult based solely on behavioral testing to differentiate whether a patient with neglect additionally suffers from a lesion of the auditory cortex. This difficulty parallels the problem of testing for hemianopia in patients with full-blown visual neglect, because single contralesional stimuli can be missed due solely to neglect without the additional requirement of a lesion to visual cortex. In contrast, a lesion of the primary visual cortex can be easily excluded in patients exhibiting extinction instead of full-blown neglect. Because of this heterogeneity of auditory extinction, we would expect that, while auditory extinction should still be more frequently found with right- than left-hemisphere lesions, auditory extinction will be more frequently observed after left-sided lesions than visual extinction (Becker and Karnath, 2007). Thus, while auditory extinction and disturbed auditory localization are frequent clinical findings in patients with neglect, the diagnosis of neglect cannot be confirmed based on these symptoms alone: imagine a patient with a lesion of the right anterior STG extending more posteriorly on the superior temporal plane and including the primary auditory cortex. Such a lesion could cause both disturbed auditory lateralization and extinction without other signs of neglect, whereas a similar lesion in the left would only cause auditory extinction. We would not classify this patient as suffering from auditory neglect. One then wonders whether diagnosis of neglect can be made purely by examination conducted in the auditory modality, or whether neglect, as it is canonically known from the visual literature, could ever manifest itself exclusively in the auditory domain? One potential tool for differentially diagnosing neglect outside of vision could be the additional presence of a non-spatial deficit in auditory target detection (Robertson et al., 1997; Gutschalk et al., 2012). If diminished target detection is taken as a core feature of neglect, then this, in the presence of the two other auditory characteristics of neglect, could suffice, although this requires further evaluation.

Which workup should be used? Bedside testing for auditory neglect can be accomplished by simple finger snapping next to the patient’s ear and asking whether the snapping was heard at the left, right, or both ears. This test is most sensitive for alloacusis,

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where the patient will label all three stimuli as emanating from the right. If alloacusis is not present, this test can be used to test for auditory extinction, where snapping next to the left and right ear is correctly classified, but snapping synchronously next to both ears will typically be attributed to the ipsilesional ear. While this test is easy to apply, other more rigorous tasks might be more sensitive. Dichotic speech tests are not specific for auditory neglect, but they are quite sensitive in our experience and take comparatively little time. An additional test for spatial perception should be applied to pick up disturbance of spatial perception. We use a simple task in which noise bursts are presented randomly with five different ITDs, and listeners are required to indicate the perceived lateralization to the left or right on a sliding scale (Gutschalk et al., 2012). To test for extinction-like deficits that are unrelated to neglect, in particular after lesions to auditory cortex, the psychoacoustic pattern discrimination test introduced above can be used (Blaettner et al., 1989). It appears that neglect patients without auditory cortex lesions do not show lateralized deficits in this test, but a more general deficit in auditory target detection might be picked up instead (Robertson et al., 1997; Gutschalk et al., 2012). The deficit of sustained attention and target detection might alternatively be picked up more simply and specifically with the elevator counting test (Wilkins et al., 1987; Robertson et al., 1997).

Can auditory neglect be treated? A number of approaches have been explored for rehabilitation of neglect patients (Kerkhoff and Schenk, 2012), most commonly utilizing visual exploration with feedback. More recent techniques have sought to reorient patients towards their left side using optokinetic stimulation, neck muscle vibration, vestibular stimulation, or prism adaptation. Another line of recent experimental therapies applies non-invasive neurostimulation with repetitive transcranial magnetic stimulation and transcranial direct current stimulation (Hesse et al., 2011). Most of these approaches are under exploration and their effect has not yet been proven in larger controlled studies. While auditory neglect has not been tested in most therapy studies, it is often assumed that therapy effects transfer to other modalities because of the multimodal nature of the disorder, but this requires explicit confirmation in our opinion. Only a few studies have specifically reported rehabilitation effects on auditory aspects of neglect. Two studies investigated the effect of prism adaptation, in which prism glasses are used that displace the optic image by 10–15 to the right, on auditory neglect. Patients undergoing prism adaptation are trained to make reaching

movements until they are adapted to the prism displacement. When the glasses are subsequently removed, there is an after-effect towards the left, which has been shown to transiently improve performance in patients with neglect (Rossetti et al., 1998). One study found that prism adaptation significantly reduces auditory extinction as measured in a dichotic speech test (JacquinCourtois et al., 2010). The other study used a target detection task and found improvement in both visual and auditory target detection that was similar for ipsiand contralesional stimuli (Eramudugolla et al., 2010). The effect of prism adaptation on auditory extinction lasted for 2 hours (Jacquin-Courtois et al., 2010). Longer-lasting effects on visual measures have been reported for repetitive application of prism adaptation (Frassinetti et al., 2002). Another technique that produces an after-effect is optokinetic stimulation. This technique has been shown to normalize the auditory midline perception in patients with neglect for 30 minutes after a single application, and longer effects after repetitive application (Kerkhoff et al., 2012). Effects on sound lateralization in normal listeners have also been found for neck muscle vibration (Lewald et al., 1999), providing indirect evidence that this technique might also show an effect on auditory neglect. Finally, auditory phasic alerting has been used to ameliorate visual neglect on the left, irrespective of whether the auditory stimulus was applied to the left or right side (Robertson et al., 1998). Similar effects on visual neglect are achieved with auditory sustained attention training (Van Vleet and DeGutis, 2013), further stressing the multimodal nature of neglect. Studies with larger patient samples will be necessary to evaluate these techniques towards an evidence-based rehabilitation of neglect that includes the auditory modality.

Open questions While a profile of auditory neglect is emerging from the literature reviewed in this chapter, many questions must first be answered in order to gain a more complete understanding of auditory neglect. One is the nature of auditory extinction, which apparently is a more heterogeneous phenomenon than visual extinction. Further studies are required to dissociate the subtypes of auditory extinction and explore, for example, whether perceived temporal asynchrony (Karnath et al., 2002; Witte et al., 2012) or extinction across modalities (Diamond and Bender, 1965) can be used to define more exactly auditory extinction in the context of neglect (or, more generally, supramodal extinction), and dissociate it more clearly from other causes of auditory extinction. Moreover, it will be interesting to see if auditory

AUDITORY NEGLECT AND RELATED DISORDERS extinction requires a bilateral and synchronous stimulus presentation, or if other situations of perceptual competition, for example informational masking (Gutschalk et al., 2008; Kidd et al., 2008), may more strongly reduce auditory awareness in neglect. Finally, non-spatial deficits in auditory neglect (Robertson et al., 1997; Cusack et al., 2000) deserve more attention by future studies. Not only may these fundamental deficits be used to develop new tests for clinical evaluation of auditory neglect, it is also conceivable that these deficits are more important for the patients’ rehabilitation than are the spatial signs of auditory neglect, which are rarely a cause of severe disability in chronic neglect patients, first, because sustained auditory attention is clearly important in everyday life, and second, because non-spatial deficits may be more directly related to the primary lesion site and might therefore require more time to subside.

ACKNOWLEDGMENTS Supported by Bundesministerium f€ ur Bildung und Forschung (BMBF) program “junior research group bioimaging,” grant 01EV0712. We thank Dr. Maurizio Corbetta for granting permission to reproduce Figure 31.8.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 32

Auditory agnosia L. ROBERT SLEVC* AND ALISON R. SHELL Department of Psychology, University of Maryland, College Park, MD, USA

INTRODUCTION Imagine chatting with a friend at a crowded outdoor cafe´, background music playing, a couple arguing at the next table, and cars driving by. The auditory information reaching your ears in this situation is a mixture from all these sources (and more), yet ultimately yields a representation of the auditory scene in which you are able to successfully follow your conversation. Although the ability to identify and process these sounds may seem nearly effortless in normal circumstances, the complexity of our auditory world becomes clear in light of neurologic conditions that can lead to strikingly distinct deficits in auditory perception. These impairments of auditory perception and/or recognition that are not attributable to hearing or cognitive deficits are termed auditory agnosia. Auditory agnosia is distinct from peripheral hearing loss and also distinct from impaired hearing acuity as a result of bilateral damage to primary auditory cortex – a condition termed cortical deafness (although perhaps more appropriately called central deafness or cerebral deafness given that it may result from damage to the projections to auditory cortex rather than cortical damage per se; Tanaka et al., 1991; Griffiths, 2002). Whereas cortically deaf patients typically behave as if they were deaf (despite normal peripheral hearing and brainstem evoked potentials), patients with auditory agnosia are aware of sounds but have difficulty with sound identification. Auditory agnosia is also distinct from language perception deficits associated with the posterior (sensory) aphasias, although both cortical deafness and sensory aphasia can evolve into auditory agnosia (e.g., Mendez and Geehan, 1988; Slevc et al., 2011).

DEFINITIONS Auditory agnosia has not received as much attention as the visual agnosias; however it is similar in that it can be a

general deficit affecting all domains of auditory perception, or can be relatively specific, largely affecting only one type of sound perception/recognition. Patients can have agnosia specific to speech perception, called verbal auditory agnosia or pure word deafness; agnosia specific to music perception, called amusia; or agnosia specific to non-speech environmental sounds, called non-verbal auditory agnosia or environmental sound agnosia. There is, unfortunately, considerable terminological variability in the literature; here we use auditory agnosia to refer broadly to all subtypes of agnosia for auditory stimuli; however note that “auditory agnosia” is sometimes used more narrowly to refer specifically to environmental sound agnosia (i.e., agnosia for environmental sounds in the presence of preserved perception of speech and (sometimes) music; e.g., Vignolo, 1982, 2003). These specific deficits of auditory perception have garnered much interest despite their rarity because they may reveal the distinct cognitive and anatomic units of auditory perception and thus inform the extent to which auditory perception relies on a modular, and possibly domain-specific, architecture. However the extent to which auditory agnosia reflects separable domains of auditory perception is still debated: claims that the agnosias reflect damage to a modular system, where separate domains of auditory stimuli are processed independently (e.g., Peretz et al., 1994), contrast with claims that the agnosias result from deficits of varying severity to a domain of a general auditory processing system (e.g., Griffiths et al., 1999). The generalist approach gains some support from the fact that dissociations between auditory processing domains in these agnosia subtypes are rarely “pure”; instead most cases show at least some degree of overlapping deficits. Although this is widely acknowledged, the prevalence of overlapping (and non-overlapping)

*Correspondence to: L. Robert Slevc, Department of Psychology, University of Maryland, College Park, MD 20742, USA. E-mail: [email protected]

574 L.R. SLEVC AND A.R. SHELL deficits is not well documented, perhaps due simply to likely requires an ad hoc approach designed for a particthe practical constraints of carrying out extensive testing ular patient to determine which (if any) specific subtype across multiple types of stimuli. In addition, it is not yet of auditory agnosia (as detailed below) is the appropriate clear exactly what constitutes an affected domain in diagnosis. these subtypes. For example, is verbal auditory agnosia Although it is difficult to make a precise estimate, specific to speech sounds or does it instead reflect a defauditory agnosia appears to be quite rare and, accordicit in some more basic (non-speech) aspect of auditory ingly, the specific subtypes are even less common. analysis that is disproportionately involved in speech Polster and Rose (1998) point out several reasons why perception? Overlapping deficits are to be expected if agnosia might be less commonly observed in the auditory they reflect difficulty with particular aspects of auditory than in the visual domain. One such reason is that there is analysis that differentially, but not exclusively, affect greater neuroanatomic redundancy in the auditory than particular domains of sound processing (Griffiths in the visual system; in contrast to vision, where each et al., 1999). As detailed below, work that has carefully hemisphere receives information from only half of the examined different aspects of auditory analysis suggests visual field, auditory information arrives to each hemithat cases of auditory agnosia do not tend to support sphere from the entire auditory scene. Because of this, domain specificity at the level of language, music, or unilateral lesions to auditory areas often leave sound environmental sounds (although there are cases with processing relatively functional overall and thus audiremarkable dissociations of these types, e.g., Metztory agnosia typically requires bilateral lesions to the latLutz and Dahl, 1984; Peretz et al., 1994). Instead, these eral temporal lobes (which usually only occurs with two cases can illuminate the types of distinct mechanisms separate cerebrovascular accidents). A second reason involved in sound processing, thereby informing our for the rarity of auditory agnosia diagnoses is that audiunderstanding about the basic cognitive and neural protory agnosia may often be obscured by other deficits; for cesses involved in auditory perception more generally example, verbal auditory agnosia may not be obviously (e.g., Zatorre et al., 2002; Scott and Wise, 2004; distinguishable from other forms of posterior aphasia Hickok and Poeppel, 2007; Giraud and Poeppel, 2012). (especially as auditory agnosia often evolves from initial Auditory agnosia typically results from cerebrovaspresentations of sensory aphasia). In any case, there is a cular accidents, although other causes are possible, relative scarcity of data on auditory agnosia. This, comincluding herpes simplex encephalitis (Buchman et al., bined with the considerable variability in clinical presen1986), Landau–Kleffner syndrome (Metz-Lutz, 2009; tation and in exactly what is tested across cases, means Stefanatos, 2011), and dementia (Otsuki et al., 1998; that there is not yet a consensus on the specific etioloGoll et al., 2010a; Gibbons et al., 2012). There are also gies, or even the specific symptoms, associated with congenital forms of agnosia, which have been documenthese subtypes of auditory agnosia. ted mostly for musical perception (congenital amusia; An influential distinction has been made between see Peretz and Hyde, 2003; Stewart, 2011; and apperceptive and associative forms of auditory agnosia Chapter 33, this volume). To arrive at a diagnosis of audi(e.g., Vignolo, 1982; Buchtel and Stewart, 1989). This tory agnosia, it is necessary to first establish that a apperceptive/associative distinction comes from work patient’s sound-processing deficit is not due to periphon visual agnosia, where Lissauer (1890; cited in Farah, eral hearing problems via audiometric testing (pure2004) suggested that object recognition could be tone, speech, or immittance audiometry), otoacoustic impaired via an apperceptive deficit, due to problems emission testing, brainstem auditory evoked potentials, with visual object processing, or via an associative defior other audiometric methods (Hall and Mueller, 1997; cit, due to problems associating intact perceptual inforsee Chapters 17 and 18 of this volume). Of course, as mation with object representations. The division of auditory agnosia typically occurs in older adults, some apperceptive and associative deficits is less straightfordegree of age-related hearing loss is to be expected ward in audition than in vision, as it is not entirely obvi(see Chapter 20, this volume); however a diagnosis of ous what constitutes an auditory object (Griffiths and auditory agnosia requires any hearing loss to be suffiWarren, 2004). Nevertheless, early conceptions of audiciently mild to not explain the patient’s deficit. tory agnosia were primarily associative (e.g., Lichtheim, It is also necessary to rule out possible “top-down” 1885; Bastian, 1897), assuming that basic perceptual prodeficits that could affect auditory perception, for examcessing (apperception) was intact and the deficit resulted ple, attentional, linguistic, or memory deficits, as from an inability to link a perceived pattern to an approassessed by standard neuropsychological tests. If both priate auditory object, or sound meaning. Other theories peripheral hearing and general cognitive and linguistic assume that auditory agnosia is best characterized as abilities are intact, then additional testing can be done an apperceptive disorder, pointing to the fact that to determine the extent and domain of agnosia. This agnosia subtypes typically overlap, which likely reflects

AUDITORY AGNOSIA underlying problems with sound analysis (Goldstein, 1974; Buchtel and Stewart, 1989; Griffiths et al., 1999; Griffiths, 2002). Still, while considerable work argues that auditory agnosia (and its subtypes) may indeed reflect relatively basic problems perceiving and/or analyzing sound patterns (e.g., Albert and Bear, 1974; Buchtel and Stewart, 1989; Phillips and Farmer, 1990; Poeppel, 2001; Vignolo, 2003; Stefanatos, 2008; Slevc et al., 2011), there are cases that seem better characterized as associative deficits (e.g., Franklin et al., 1996; Saygin et al., 2010). This apperceptive/associative distinction might thus be expected to link different forms of auditory agnosia to different anatomic etiologies (e.g., Buchtel and Stewart, 1989; Goll et al., 2010b). This chapter does not take apperceptive/associative as its primary organizational principle (but see Goll et al., 2010b, for such an approach). Instead, we divide auditory agnosia into four major categories – (1) general auditory agnosia; (2) agnosia for speech (verbal auditory agnosia or pure word deafness); (3) agnosia for environmental sounds; and (4) agnosia for music (amusia) – and discuss apperceptive and associative variants within each subtype (for other reviews, see Polster and Rose, 1998; Griffiths et al., 1999, 2012; Simons and Lambon Ralph, 1999; Griffiths, 2002; Bauer and McDonald, 2003; Lechevalier et al., 2003; Goll et al., 2010b; Stefanatos

575

and DeMarco, 2012). This taxonomy of auditory agnosia subtypes is, of course, somewhat problematic as even the rare cases of domain specificity do not typically show perfect dissociations (if multiple domains are even assessed). In addition, these categories do not make up an exhaustive set of auditory perceptual deficits; for example, one auditory perceptual deficit not addressed here is selective to sound localization rather than identification (e.g., Clarke et al., 2000, 2002; Adriani et al., 2003). Although this could be considered as a type of auditory agnosia, our focus is on deficits in sound identification and/or discrimination so we do not discuss deficits in auditory spatial perception here (instead, see Chapter 31, this volume). Finally, it is important to acknowledge that cases with similar types of impairment may or may not involve disruption of the same underlying process(es), thus cases should be evaluated individually instead of attempting to make conclusions from the average performance of a group from a particular clinical category (Caramazza, 1984). That said, a division into a tractable number of subtypes may be a necessary simplification in order to make any generalizations from the highly variable and unique series of individual case studies that make up our knowledge of auditory agnosia. Table 32.1 thus indicates the common pattern of spared

Table 32.1 Subtypes of auditory agnosia Verbal

Phonagnosia

Amusia

Typical clinical features

NonGeneral Apperceptive Associative Apperceptive Associative verbal

Apperceptive Associative

Hearing ability (audiometric sensitivity) Speech comprehension Speech repetition Non-speech sound recognition Non-speech sound discrimination Pitch perception Rhythm perception Timbre perception Recognition of familiar melodies Voice discrimination Recognition of familiar voices

+

+

+

+

+

+

+

+

–

–

–

+

+

+

+

+

– –

– +

+ +

+ +

+ +

+ –

+ +/–

+ +

–

+

+

+

+

+/–

+/–

+

– – – –

+/
+/
+/
* +/


+ + + +/–*

+/
+/– +/– +

+ + + +

+/– +/– +/– +/–

– – – –

+ + + –

– –

+/
+/


+ +

– –

+ –

+ +

+ +

+ +

Typical perceptual abilities in auditory agnosia subtypes. + intact abilities; – impaired abilities; +/– mixed findings; *likely patterns, but based on insufficient evidence.

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L.R. SLEVC AND A.R. SHELL temporal and spectral auditory analysis (Tanaka et al., 1987; Mendez and Geehan, 1988). General auditory agnosia is most often associated with bilateral temporal damage: of 27 cases cited here that report both a clear deficit in at least two domains of auditory perception and reasonably clear lesion localization, 17 involved bilateral temporal damage (including insular cortex) and 5 involved other types of bilateral damage (mostly subcortical). Although general auditory agnosia is likely the most common type of auditory agnosia, most investigations have focused on the specific subtypes (as will be evident below). In some cases, this truly reflects investigations of patients with relatively specific deficits, but in others it is rather a matter of terminology, where a patient who might be best diagnosed with general auditory agnosia is instead labeled as a case of some specific subtype due to insufficient testing to reveal the extent of cross-domain deficits. For example, in a careful analysis of a patient previously diagnosed with pure word deafness (verbal auditory agnosia), Pinard et al. (2002) found considerable deficits also in environmental sound and musical perception.

Fig. 32.1. Typical lesion laterality for auditory agnosia subtypes, divided into deficits of auditory analysis (apperceptive agnosias; bottom) and deficits of sound identification (associative agnosias; top) deficits. Most cases involve lesions to left, right, or both temporal cortices, although many cases involve subcortical and/or more extensive cortical lesions.

and impaired abilities associated with different subtypes of auditory agnosia, and Figure 32.1 indicates the typical laterality of lesions underlying different agnosia subtypes.

GENERAL AUDITORYAGNOSIA Although much of the interest in auditory agnosia comes from specific subtypes, the most common presentation is of general (or global) agnosia across all auditory domains (e.g., Oppenheimer and Newcombe, 1978; Miceli et al., 1980; Auerbach et al., 1982; Miceli, 1982; Kazui et al., 1990). General auditory agnosia can develop from what initially appears to be cortical deafness (Ziegler, 1952; Mendez and Geehan, 1988; Godefroy et al., 1995), and can sometimes resolve into more specific subtypes of auditory agnosia (e.g., Motomura et al., 1986; Engelien et al., 1995). General auditory agnosia is characterized by impaired recognition of all types of auditory stimuli, including speech, environmental sounds, and music. This broad deficit suggests an underlying problem with sound recognition that affects all domains of auditory perception, and indeed general auditory agnosia is associated with deficits in both

VERBAL AUDITORY AGNOSIA (WORD DEAFNESS) Agnosia specific to speech sounds is often called pure word deafness (and sometimes also called word sound deafness or just word deafness). This is, critically, distinct from posterior (sensory) aphasia in that other domains of linguistic processing, including reading, writing, and speaking, are relatively intact, although agnosia is often still accompanied by some degree of aphasic symptoms (for reviews, see Goldstein, 1974; Buchman et al., 1986; Poeppel, 2001; Badecker, 2005; Stefanatos et al., 2005b). Verbal auditory agnosia often evolves from Wernicke’s aphasia, in that paraphasias and reading and writing deficits resolve without corresponding improvement of speech perception and repetition (e.g., Albert and Bear, 1974; Slevc et al., 2011). The term pure word deafness is somewhat misleading as the syndrome does not typically seem to be an agnosia for words per se, but rather agnosia for speech sounds. That is, verbal auditory agnosia is most often apperceptive in nature. In addition, word deafness is rarely (if ever) pure; in a review of 37 reports of pure word deafness, Buchman et al. (1986) argued that word deafness never occurred without other auditory processing impairments (but see Coslett et al., 1984; Metz-Lutz and Dahl, 1984; Yaqub et al., 1988; Takahashi et al., 1992). We thus use the term verbal auditory agnosia here to emphasize its relationship to other auditory agnosias (Wang et al., 2000). Although there is still relatively little research given the rarity of this syndrome, verbal auditory

AUDITORY AGNOSIA agnosia is arguably the most well-studied subtype of auditory agnosia. This greater concentration of work on verbal auditory agnosia does not necessarily reflect a greater prevalence compared to other agnosia subtypes; rather, it likely reflects greater rates of diagnosis and referrals because speech perception deficits can be particularly detrimental to overall functioning. Verbal auditory agnosia is sometimes grouped with the aphasias as a language disorder, and taken as evidence for speech specificity at an early stage of auditory perception. This fits with claims that even the very early stages of speech sound perception occur in a languagespecific way (e.g., Liberman and Mattingly, 1989; Liberman and Whalen, 2000) and with evidence for very early left lateralization of speech perception (e.g., Na¨a¨ta¨nen et al., 1997; Hornickel et al., 2008). However there is also considerable evidence that the early stages of speech processing occur bilaterally (for discussion, see Hickok and Poeppel, 2004, 2007, and Chapter 9, this volume), and that lateralization differences may instead reflect hemispheric specializations for more basic auditory processes. Indeed, verbal auditory agnosia typically results from bilateral temporal lesions in the superior temporal cortex (or subcortically, affecting the relevant projecting auditory radiations; see Chapter 1, Fig. 1.9): of 63 reports with sufficiently detailed lesion data (Wang et al., 2000; J€ orgens et al., 2008; Slevc et al., 2011; and earlier cases reviewed by Poeppel, 2001), 43, or almost 70%, involve bilateral lesions. Patients with verbal auditory agnosia are aware of speech but describe it as sounding like a foreign language (Albert and Bear, 1974), as distorted and cartoonlike (Wee and Menard, 1999), as rapidly fading (Klein and Harper, 1956), or with descriptions like “voice comes but no words” (Hemphill and Stengel, 1940). Speech production in verbal auditory agnosia is relatively normal (Table 32.1), although in some cases production is overly loud and has abnormal prosody (e.g., Otsuki et al., 1998; J€ orgens et al., 2008). Speech perception is typically improved by relying on cross-modal information such as lip reading and from “top-down” contextual information (e.g., Saffran et al., 1976; Coslett et al., 1984; Buchtel and Stewart, 1989; Slevc et al., 2011; Robson et al., 2012). Perception is also sometimes improved by dramatically slowing the speech signal (Albert and Bear, 1974; Stefanatos et al., 2005a), perhaps by ameliorating some patients’ particular difficulty with rapid temporal aspects of the speech signal (see below). Although verbal auditory agnosia is often claimed to only rarely result from unilateral damage (e.g., Poeppel, 2001; Bauer and McDonald, 2003), unilateral cases are by no means vanishingly rare. In fact, the first described cases of verbal auditory agnosia were in patients with unilateral left temporal lesions (Kussmaul, 1877;

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Lichtheim, 1885) and, as mentioned above, approximately 30% of cases with clearly identifiable lesions have only unilateral damage. These unilateral lesions are overwhelmingly left-lateralized; there is only a single report of a right-hemisphere lesion associated with verbal auditory agnosia (Roberts et al., 1987). Interestingly, this was not obviously a case where language was rightlateralized: the patient showed a strong right-hand bias and had no family history of left-handedness. (Note also that this patient’s deficit was probably not specific to speech – he reported an acquired inability to appreciate music or recognize familiar melodies as well as some difficulty recognizing environmental sounds – although it is unclear how severe these other deficits were as nonspeech perception was not formally tested.) A common way to reconcile these two anatomic etiologies is to think of verbal auditory agnosia as a disconnection syndrome (Lichtheim, 1885; Geschwind, 1965; Gazzaniga et al., 1973; Takahashi et al., 1992), as illustrated in Figure 32.2. By this account, bilateral temporal damage prevents auditory input from either hemisphere from reaching speech-processing mechanisms (i.e., Wernicke’s area; for example, see Fig. 32.2A). Unilateral damage must not only interrupt ipsilateral transmission of left-hemisphere auditory input to speech-processing areas, but also destroy contralateral projections from right-hemisphere auditory analysis (Fig. 32.2B and C). In fact, this is essentially the early conception of verbal auditory agnosia as a primarily associative deficit (Lichtheim, 1885; Bastian, 1897; see Goldstein, 1974, for a review), in which the “left auditory word center” (i.e., Wernicke’s area) is dissociated from auditory input (by this account, the “word center” itself was assumed to be spared given preserved speech production). If verbal auditory agnosia is a disconnection syndrome, then unilateral cases of verbal auditory agnosia should be accompanied by damage to cross-hemispheric whitematter pathways from primary auditory cortex in the

Fig. 32.2. Three hypothesized lesion profiles that could result in verbal auditory agnosia / word deafness, according to a disconnection approach. A, auditory area; M, medial geniculate body; W, Wernicke’s area; X, lesion. (Adapted from Takahashi et al., 1992; brain outlines courtesy of Akira O’Connor.)

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Fig. 32.3. (A) Anatomic magnetic resonance imaging images from a patient with verbal auditory agnosia following a lefthemisphere lesion. (B) Region of interest (ROI) used to define Heschl’s convolutions in the right hemisphere, and (C) whitematter pathways passing through the ROI shown in (B) as assessed with diffusion tensor imaging (DTI). (Reproduced from Slevc et al., 2011.)

undamaged hemisphere. So far, however, the only study that has investigated white-matter connectivity patterns in a patient with unilateral verbal auditory agnosia (using diffusion tensor imaging; see Chapter 16, this volume) found preserved cross-hemispheric white-matter pathways (Slevc et al., 2011; Fig. 32.3). These preserved pathways suggest that such a disconnection is not the only cause of verbal auditory agnosia with unilateral damage (although note that the preserved existence of whitematter tracts does not necessarily imply their preserved functionality). Instead, it may be that verbal auditory agnosia (at least in cases with unilateral damage) is not an associative disorder, but rather an apperceptive deficit in some aspect of auditory processing that is both left-lateralized and disproportionately involved in speech perception.

Apperceptive verbal auditory agnosia As noted above, considerable work suggests that verbal auditory agnosia may be best characterized as an apperceptive disorder, reflecting an auditory processing deficit that disproportionately affects speech (Albert and Bear, 1974; Buchtel and Stewart, 1989; Phillips and Farmer, 1990; Griffiths et al., 1999; Poeppel, 2001; Griffiths, 2002). A particularly influential proposal is that verbal auditory agnosia might result from an underlying deficit in rapid temporal processing that is particularly important for the perception of some speech sounds, especially for some consonants that are

characterized by rapid temporal transitions on the order of tens of milliseconds (e.g., Shannon et al., 1995). A rapid temporal processing deficit could disproportionately affect speech perception as the processing of environmental sounds and of music likely relies more on pitch and spectral cues (de Cheveigne´, 2005) and on temporal cues occurring over relatively longer time periods. Evidence for a rapid temporal processing deficit in verbal auditory agnosia comes from the observation that individuals with verbal auditory agnosia often have particular difficulty with temporally dynamic aspects of speech stimuli, such as place of articulation and voicing contrasts in consonants, compared to temporally protracted aspects of speech such as vowels (Saffran et al., 1976; Auerbach et al., 1982; Miceli, 1982; Yaqub et al., 1988; Praamstra et al., 1991; Wang et al., 2000; Stefanatos et al., 2005a; Slevc et al., 2011). Verbal auditory agnosia also is associated with pronounced deficits in perception of rapid temporal changes in non-speech stimuli (Fig. 32.4), including most (5 out of 6) cases that have evaluated click fusion and gap detection thresholds (Fig. 32.4C; Albert and Bear, 1974; Tanaka et al., 1987; Otsuki et al., 1998; Yaqub et al., 1988; J€orgens et al., 2008; but see Stefanatos et al., 2005b) as well as 3 cases with impaired discrimination of non-speech sine-wave stimuli differing in rapid temporal transitions (Fig. 32.4B; Wang et al., 2000; Stefanatos et al., 2005b; Slevc et al., 2011). Temporal processing deficits are not, however, uniquely associated with verbal auditory agnosia; impairments on click fusion tasks have also been reported in other forms of auditory agnosia (in 9 of 10 tested cases: Albert et al., 1972; Auerbach et al., 1982; Motomura et al., 1986; Buchtel and Stewart, 1989; Kazui et al., 1990; Best and Howard, 1994; Godefroy et al., 1995; Mendez, 2001; Stefanatos, 2008; but see Lambert et al., 1989). In 3 of these cases, a gradual improvement in temporal processing (as assessed with click fusion thresholds) accompanied recovery from auditory agnosia (Motomura et al., 1986; Best and Howard, 1994; Godefroy et al., 1995), lending further (although correlational) support to this relationship. It is not yet clear how such an apperceptive deficit in rapid temporal processing relates to the different lesion profiles of verbal auditory agnosia. One proposal is that an apperceptive temporal processing deficit, or a prephonemic variant of verbal auditory agnosia, reflects an underlying deficit in temporal acuity due to bilateral lesions, whereas an associative, phonemic variant results from left-hemisphere damage (Auerbach et al., 1982; Poeppel, 2001). However, other theories point to a lefthemisphere specialization for rapid temporal analysis, fitting with general theories of auditory processing that propose language lateralization reflects an underlying left-hemispheric specialization for rapid temporal

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other cases), raising the possibility that unilateral cases of verbal auditory agnosia might reflect a somewhat “higher-level” deficit of temporal processing despite preserved “lower-level” temporal perception. While these findings have been taken as evidence that speech perception deficits in verbal auditory agnosia often do result from an underlying deficit in rapid temporal processing (e.g., Phillips and Farmer, 1990; cf. work on developmental language deficits, e.g., Merzenich et al., 1993; Tallal, 2004), it is important to note that not all cases of verbal auditory agnosia are associated with impairments in basic temporal acuity (e.g., Stefanatos et al., 2005b), and some show deficits even with relatively slow temporal changes on the order of hundreds of milliseconds (e.g., Wang et al., 2000; J€orgens et al., 2008). Furthermore, an attempt to improve rapid temporal processing via a training paradigm in one verbal auditory agnosia patient led to improvements only on discrimination of non-speech stimuli (Slevc et al., 2011), supporting claims that the demands speech perception places on rapid temporal processing are somewhat overstated (McGettigan and Scott, 2012). Nevertheless, the bulk of evidence suggests that rapid temporal processing deficits may underlie at least some cases of auditory agnosia. A better understanding of the precise role of temporal processing deficits in auditory agnosia will depend on more consistent testing of complex sound perception in agnosia patients using wellvalidated psychoacoustic techniques (e.g., Griffiths et al., 1999). Fig. 32.4. Example stimuli for tests used to assess rapid temporal processing in (verbal) auditory agnosia. (A) Synthesized speech stimuli from a /ba/-/da/ continuum, differing in the rapid (40 ms) onset transition in the second formant (F2) and (B) non-speech analogs of F2 in (A). (Adapted from Slevc et al., 2011). (C) Schematic of gap detection and click fusion tasks.

analysis and a right-hemispheric specialization for either spectral analysis or for temporal analysis over a longer time window (e.g., Poeppel, 2001; Zatorre and Belin, 2001; Boemio et al., 2005; Hickok and Poeppel, 2007; Poeppel and Monahan, 2008; but see McGettigan and Scott, 2012). This distinction implies that cases of verbal auditory agnosia due to unilateral (left-hemisphere) damage might reflect an underlying deficit in rapid temporal processing, and, indeed, at least three case reports of unilateral verbal auditory agnosia have found particular difficulties with rapidly changing stimuli (Wang et al., 2000; Stefanatos et al., 2005b; Slevc et al., 2011). Stefanatos et al.’s (2005b) patient NH showed impaired perception of rapid temporal transitions but did not show a complementary deficit in basic click fusion threshold (click fusion data were not available in these

Associative verbal auditory agnosia Although early conceptions of verbal auditory agnosia were associative in nature (see above discussion on the disconnection approach), there are very few reports of clearly associative forms of verbal auditory agnosia. The cases that do exist are often termed word-meaning deafness, first reported by Bramwell (1897; reprinted in Ellis, 1984), or occasionally described as a variant of transcortical sensory aphasia (e.g., Heilman et al., 1981). Word-meaning deafness is characterized by intact ability to repeat speech, discriminate phonemes, and perform auditory lexical decisions, but impaired ability to comprehend spoken words (Kohn and Friedman, 1986; Franklin et al., 1994, 1996; Hall and Riddoch, 1997; Plasencia et al., 2006; Wirkowski et al., 2006). These patients thus may have the somewhat surprising ability to write down a word or phrase that they do not understand and then successfully understand what they have written (Hall and Riddoch, 1997; Francis et al., 2001). Auditory comprehension of abstract words may be worse than of concrete words (Franklin et al., 1994, 1996), although this seemingly conceptually based

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dissociation has also been explained in terms of an apperceptive deficit that essentially causes “noisy” input to the semantic system (Tyler and Moss, 1997). “Pure” cases of word-meaning deafness are very rare, with only two prototypical patients in the literature – KW (Hall and Riddoch, 1997; Francis et al., 2001) and DrO (Franklin et al., 1996; Tyler and Moss, 1997) – and only a handful more when including less clear-cut cases (Heilman et al., 1981; Ellis, 1984; Kohn and Friedman, 1986; Franklin et al., 1994; Plasencia et al., 2006; Wirkowski et al., 2006). KW, DrO, and 5 of the 7 other cases appear to have suffered unilateral left cortical lesions, although note that similar lesions can also result in an apperceptive form of verbal auditory agnosia (e.g., Wang et al., 2000; Slevc et al., 2011). Unfortunately, word-meaning deafness is not yet well understood even by the standards of auditory agnosia, and the few reports available suggest substantial heterogeneity in the associated perceptual/cognitive deficits.

PHONAGNOSIA Agnosias for speech are not always lexical in nature; phonagnosia is an apparent auditory parallel to prosopagnosia (impaired visual recognition of faces; e.g., Gainotti and Marra, 2011), characterized by difficulty recognizing familiar voices (Van Lancker and Kreiman, 1987; Van Lancker et al., 1989; Hailstone et al., 2010). Phonagnosia can occur in an apperceptive form, characterized by difficulty discriminating between voices after either left or right temporal damage, and an associative form, characterized by an inability to recognize voices after right parietal damage (Van Lancker et al., 1989; Lang et al., 2009). Phonagnosia can also accompany frontotemporal lobar degeneration (Hailstone et al., 2010) or can arise as a developmental deficit (Garrido et al., 2009). The extent to which phonagnosia can occur in the absence of other auditory perceptual or person identification deficits remains unclear; some patients with phonagnosia do appear to be able to successfully recognize speech and environmental sounds; however the deficit is more often associated with other forms of auditory agnosia and/or with other types of person recognition deficits such as prosopagnosia (see, e.g., Table 32.2; Neuner and Schweinberger, 2000).

AGNOSIA FOR ENVIRONMENTAL SOUNDS Auditory agnosia can also occur with (relatively) intact speech perception, but impairment in perceiving and/or comprehending non-speech environmental sounds (Spreen et al., 1965; Albert et al., 1972; Motomura et al., 1986; Fujii et al., 1990; Taniwaki et al., 2000). For example, Spreen et al.’s (1965) patient identified

Table 32.2 Summary of experimental neuropsychological profiles in phonagnosia patients QR and KL

Voices

Other sounds

Faces

Domain

Case QR

Case KL

Identification Familiarity Emotion recognition Perception Musical instrument matching Environmental sound recognition Recognition Perception

# # N N #

# # N N N

N

N

N* N

## N

#

impaired performance relative to controls. impaired performance relative to both controls and other case. * When matched to voices for difficulty. N, normal performance. Reproduced from Hailstone et al. (2010). ##

the sound of scissors as “a clock ticking” and rattled keys as “a chain jingling or a bell ringing.” This selective nonspeech perceptual deficit is sometimes called auditory agnosia or non-verbal auditory agnosia (e.g., Vignolo, 1982, 2003; Saygin et al., 2010); however, here we use the more specific term environmental sound agnosia, referring specifically to difficulty in identifying familiar non-speech sounds. Many cases of environmental sound agnosia also involve deficits of musical perception (e.g., Spreen et al., 1965; Lambert et al., 1989; Eustache et al., 1990; Vignolo, 2003), although this is difficult to evaluate precisely as musical perception is often not tested at all (e.g., Clarke et al., 2000) or only tested in a very general way (e.g., successful recognition of familiar songs (Eustache et al., 1990; Saygin et al., 2010) may be possible even in the presence of abnormal musical processing). Nevertheless, at least two reports suggest that environmental sound agnosia can exist independently of both musical and speech perception deficits (Motomura et al., 1986; Saygin et al., 2010). There are relatively few investigations of environmental sound agnosia in the absence of verbal auditory agnosia, perhaps because such deficits are less detrimental to everyday functioning than verbal auditory agnosia, and so tend to go unreported. Vignolo (1982) points out the additional reason why careful tests of environmental sound perception have rarely been conducted: only recently have batteries of recorded environmental sounds been easily available for testing (e.g., Saygin et al., 2003), and many cases simply involve the observation that a patient identifies or even just reacts appropriately to some small set of easily produced sounds.

AUDITORY AGNOSIA Environmental sound agnosia has been associated with a variety of lesion locations. Typically, it occurs as a result of cortical damage, which can be unilateral (to the left or right hemisphere) or bilateral (Schnider et al., 1994). However there are also cases arising from subcortical lesions to the auditory radiations bilaterally (Godefroy et al., 1995; Taniwaki et al., 2000). These different lesion etiologies may be linked to different forms of environmental sound agnosia: an apperceptive form, where identification errors are acoustically similar to the target (e.g., mistaking cat meows for someone singing), has been associated with right-hemisphere lesions (Fujii et al., 1990), and an associative form, where targets are additionally confused with semantically related sources (e.g., choosing a dog as the source of a cat meow), has been associated with left-hemisphere lesions (Vignolo, 1982; Schnider et al., 1994; but see Clarke et al., 1996). Other work suggests more complicated dissociations in associative environmental sound processing. For example, Trumpp et al. (2013) report a patient with damage to left posterior superior and middle temporal gyrus who showed difficulty identifying everyday object sounds with high acoustic relevance (e.g., telephone), but normal identification of sounds from animals and musical instruments. This patient showed a similar dissociation in lexical decision and in verbal fluency (abnormally slow lexical decisions and generating abnormally few exemplars only for sound-related objects), suggesting that an associative environmental sound deficit may also impair aspects of conceptual representations, and fitting with the idea that modality-specific perceptual information is an important aspect of conceptual knowledge (e.g., Barsalou, 2008).

AMUSIA The testing of musical sound analysis after cerebrovascular accident (or after any other cause of acquired auditory agnosia) is more challenging than testing speech or environmental sound perception because, unlike in these other domains, experience and training with music vary widely across the population and so it is not possible to assume a common baseline level of musical ability. A majority of work that has attempted to directly test for amusia has relied on a standardized diagnostic battery: the Montreal Battery for Evaluation of Amusia (Peretz et al., 2003). Here, we only briefly discuss acquired agnosia for musical perception; for more detailed treatment of acquired amusia, see Chapter 34 and for discussion of congenital amusia, see Chapter 33. In brief, amusia can also occur in apperceptive and associative forms. Apperceptive cases of acquired amusia are characterized by perceptual deficits in musical

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perception in the face of preserved musical production (Griffiths et al., 1997; Ayotte et al., 2000). Such sensory amusia generally results from right-hemisphere lesions (Stewart et al., 2006), although cases have also been reported with bilateral damage (e.g., Peretz et al., 1994). Music is a complex auditory stimulus, and while relatively little work has contrasted different aspects of musical perception, it does appear that agnosia can be relatively specific to different musical features. For example, there are reports of amusia confined to perception of pitch (Peretz et al., 1994), timbre (Kohlmetz et al., 2003), or rhythm (Mavlov, 1980). In addition, some aspects of musical perception can be selectively spared: Mendez (2001) reports a patient with global agnosia who developed an increased appreciation for music, perhaps relying on spared rhythm perception. An associative form of amusia was reported by Peretz (1996), whose patient CN showed preserved processing of pitch, timbre, and rhythm, but an impaired ability to recognize melodies and sing from memory (despite preserved ability to recognize familiar song lyrics) following bilateral temporal lesions. Such associative cases appear to be rare; however, it is difficult to assess the prevalence of musical agnosia (of any type) as such deficits do not often greatly disrupt everyday life, and so are likely to go unreported.

AUDITORYAFFECTIVE AGNOSIA Auditory affective agnosia or sensory aprosodia refers to selective impairments in recognizing affective information in speech despite relatively normal production of emotional prosody (Heilman et al., 1975; Darby, 1993). This is sometimes classified as a paralinguistic variant of verbal auditory agnosia (e.g., Bauer and McDonald, 2003). However the deficit seems likely to reflect problems understanding how variations in pitch, timbre, and volume reflect aspects of emotional communication and/or the speaker’s emotional state, and so may be better thought of as a form of associative amusia. Auditory affective agnosia is often associated with right posterior damage, especially in the right temporal operculum (Gorelick and Ross, 1987; Ross and Monnot, 2008), and is likely associated with other kinds of pragmatic impairments associated with right-hemisphere damage (e.g., Brownell et al., 1983). Alternatively, auditory affective agnosia might reflect an apperceptive deficit in perceiving the musical aspects of speech, which would then be closely related to apperceptive amusia (Patel, 2008). These possibilities have not yet been directly contrasted, as patients with impairments in auditory affective perception have not been carefully tested on other domains of affective perception or on perception of the musical features corresponding to affective speech.

582 L.R. SLEVC AND A.R. SHELL Thus it remains unclear whether auditory affective agnoThis met with some success, although improvements sia is a separate form of associative auditory agnosia, a may have partially reflected an adopted strategy of more general consequence of affective deficits, or a subcovertly spelling and visualizing the target words. type of apperceptive amusia. Another treatment approach, based on theories of a rapid temporal processing deficit underlying verbal auditory agnosia, is to employ treatment specifically TREATMENT FOR AUDITORYAGNOSIA designed to improve temporal processing. Stefanatos There have been few attempts to treat the perceptual defet al. (2005b) found that extended formant transitions icits associated with auditory agnosia; those that exist in digitally synthesized speech stimuli did not lead to have investigated a diverse set of patients and have notable improvements in phonemic discrimination in met with only mixed success. Essentially all treatment their verbal auditory agnosia patient, but did show that studies so far focus on the remediation of speech perceptemporally extending the duration of naturally produced tion deficits, either in patients with verbal auditory agnowords and sentences led to some improvement in comsia specifically or, more commonly, in patients with a prehension (Albert and Bear, 1974). Slevc et al. (2011) variety of perceptual and/or aphasic symptoms. The employed a similar sound manipulation strategy in a most common approach along these lines has simply training task, using a treatment designed to improve been to provide training on minimal-pair discrimination rapid temporal processing in developmental language or phoneme identification tasks, sometimes supported deficits (Merzenich et al., 1993; see Tallal, 2004, for a by visual cues (Morris et al., 1996; Wee and Menard, review) over a relatively long treatment period (43 ses1999; Maneta et al., 2001; Tessier et al., 2007). Morris sions over 2.5 months). Although their verbal auditory et al.’s (1996) patient had severe difficulties with speech agnosia patient improved in the ability to discriminate perception (but intact environmental sound perception) rapid temporal transitions in non-speech stimuli (sinein the context of broader aphasic symptoms. They wave sweeps; Fig. 32.4B), this was not accompanied by administered an adaptive syllable discrimination trainany improvements in discrimination of synthesized ing, where the patient first practiced discriminating speech stimuli or in speech perception more generally. between syllables differing in three distinctive features Thus there is little evidence overall for successful treat(voice, place, and manner of articulation) then, as perment programs for speech perception in auditory agnoformance improved, syllables differing on two of these sia, although this may simply reflect the limited number features, then syllables differing in only one distinctive of treatment studies to date. feature. Although their patient did improve on minimalEven less work has investigated treatment of other pair discrimination and repetition following 6 weeks (12 types of sound processing in auditory agnosia; in fact, sessions) of this training, he did not show commensurate there do not appear to be any documented treatment improvements in comprehension. studies targeting deficits in environmental sound or Maneta et al. (2001) reported a treatment study for music perception. In terms of spontaneous recovery, another aphasic patient with a particularly severe speech some patients recover from auditory agnosia altogether perception deficit (perception of non-speech sounds was (e.g., Fujii et al. 1990), while other cases show either no not tested). This treatment program used a similar prorecovery or persistence of specific perceptual deficits gram of minimal-pair discrimination training, plus addidespite recovery of other forms of sound identification. tional training on lip reading (via diagrams of lip shapes Saygin et al. (2010) present an interesting case of a plus exaggerated lip movements during the discriminapatient with a unilateral left-hemisphere lesion to tion tasks) and on cued speech (hand signals correspondWernicke’s area (Fig. 32.5) who recovered his speech ing to voicing, manner, and place of articulation); perception abilities but was left with severe environhowever they found no improvements in speech sound mental sound agnosia. They suggest that speech percepdiscrimination after 12 sessions. Tessier et al. (2007) tion may have recruited intact auditory processing areas found more encouraging results for a patient with gentypically associated with non-verbal processing (i.e., eral auditory agnosia: phoneme recognition, discriminaspeech perception may have “taken over” environmental tion, and speech comprehension were improved after a sound perception) – a hypothesis supported by functreatment program that involved intensive phoneme distional magnetic resonance imaging evidence showing crimination and phoneme recognition tasks accompahis selective responses to speech in areas associated with nied by visual cues (written representations of the general (non-speech-specific) auditory processing in phonemes) that were gradually delayed and removed. controls (specifically, right anterior temporal cortex Francis et al. (2001) report a treatment program for a and left perilesional temporal cortex; see also Engelien patient with word-meaning deafness that involved a et al., 1995). While speculative, this suggests the possibilseries of reading and auditory comprehension exercises. ity of functional reorganization of the auditory system

AUDITORY AGNOSIA

Fig. 32.5. Magnetic resonance imaging of patient M’s lesion. Five selected axial images are shown to depict the extent of lesion. Neurologic convention. (Reproduced from Saygin et al., 2010.)

and highlights the need to consider how functional reorganization after brain damage may alter correlations between brain and behavior (Musso, 1999; Leff et al., 2002).

CONCLUSION Much of the interest in auditory agnosia comes from the apparent specificity of the agnosia subtypes, including verbal auditory agnosia (or word deafness), environmental sound agnosia, and amusia. Auditory agnosia thus plays an important role in a larger debate about the underlying nature of auditory perception. It is certainly the case, however, that clear dissociations between disordered perception of speech, of environmental sounds, and of music are quite rare. This may indicate that the auditory agnosias are not, in fact, distinct deficits at the level of language, music, and environmental sounds, but instead reflect relative degrees of impairment of underlying aspects of auditory analysis that disproportionately affect different domains of processing (e.g., Griffiths et al., 1999; Poeppel, 2001). However, it is also possible that this taxonomy does reflect distinct deficits that are simply difficult to observe in the “natural experiments” that the neuropsychologic literature provides. That is, patients rarely, if ever, have circumscribed lesions in specific regions of interest; instead, lesions often affect large areas of neural tissue, and lesion locations are a function of vascular anatomy and other physiologic constraints. In addition, lesions do not simply disrupt the lesioned region, but also affect a much broader set of functional neural networks. Thus, while lesion evidence can demonstrate that a brain region is necessary for some function, it cannot show that the region is sufficient, as that function may depend as much or more on other aspects of a larger network. These limitations are not specific to the study of auditory agnosia, but are part of a general set of caveats common to most neuropsychologic studies. A few other such

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caveats deserve mention. For one, behavioral deficits also change over time, both as a function of physiologic recovery and as patients develop compensatory cognitive processes. Because of this, it is not always trivial to separate normal functioning from abnormal (but perhaps effective) processing based on alternative adopted strategies (Francis et al., 2001; Saygin et al., 2010). A second caveat is that the interpretation of any particular pattern of performance may also be confounded due to comorbidity with other deficits. Auditory agnosia refers to a deficit in auditory perception in the face of relatively preserved hearing and cognitive/linguistic functioning; however most cases show at least some degree of impairment in other areas. In addition, most studies lack premorbid measures of the relevant abilities, making it difficult to objectively evaluate the extent of impairment. Finally, few studies comprehensively evaluate different aspects of auditory processing, resulting in cases of apparent domain specificity without appropriate evidence (for example, a doctor’s jangling of keys is not a comprehensive test of environmental sound perception; cf. Pinard et al., 2002). Fortunately, progress is being made on many of these fronts. Significant advances in the understanding of auditory agnosia are likely to accompany the use of more sophisticated behavioral assessments; for example, the use of careful psychoacoustic methods to investigate complex sound perception at levels intermediate between pure-tone audiometry and complex speech sounds (Griffiths et al., 1999). Advances will also likely accompany more sophisticated methods for brain imaging; for example, measures of white-matter tractography (see Chapter 16, this volume) provide a straightforward way to investigate disconnection accounts (Slevc et al., 2011). Additional advances will likely come with more comprehensive theories of auditory perception and cognition, informed both by the auditory agnosias and by neuroimaging work on non-disordered populations. The different types of auditory perceptual deficits grouped under the term auditory agnosia provide an important window into our understanding of auditory perception and cognition. While there may yet be more questions than answers, a growing body of work investigating auditory agnosia is increasing our understanding of our remarkable ability to process complex sounds.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 33

Congenital amusias 1

B. TILLMANN1,3*, P. ALBOUY1,2,3, AND A. CACLIN2,3 Auditory Cognition and Psychoacoustics Team, Lyon Neuroscience Research Center, Lyon, France 2

Brain Dynamics and Cognition Team, Lyon Neuroscience Research Center, Lyon, France 3

University Lyon 1, Lyon, France

INTRODUCTION Numerous research studies in music cognition have provided evidence for sophisticated music processing in the general population, even without any explicit musical training. Via mere exposure to music in everyday life, non-musicians acquire knowledge about the musical system of their culture, which then shapes music perception and memory (e.g., France`s, 1958; Tillmann et al., 2000; Bigand and Poulin-Charronnat, 2006). Recent research has also shown this musical capacity for production, notably for non-musicians’ singing, which is considerably more precise than generally assumed (Dalla Bella et al., 2007). Together with research on music perception capacities in infants (e.g., Hannon and Trehub, 2005), these findings have also been discussed in terms of humans’ innate predisposition for music. However, for some individuals, a deficit of music processing has been reported and suggested as a lifelong deficit. The affected individuals have difficulty detecting when someone sings out of tune (including themselves), recognizing familiar tunes without lyrics, detecting a wrong or out-of-tune note, and memorizing even short melodies. This deficit has been referred to as tone deafness, dysmusia, dysmelodia, and more recently, as congenital amusia, thus reflecting the hypothesis that individuals may be born with this music-processing deficit (e.g., Kalmus and Fry, 1980; Peretz and Hyde, 2003). Note that currently, most research refers to congenital amusia, while some to tone deafness. In the present chapter, we will cover research using both labels, but refer more generally to congenital amusia.

In contrast to cases of acquired amusia following brain damage (see Chapter 34; Peretz et al., 1997; Tillmann et al., 2007), congenital amusia occurs without brain damage or sensory deficits. This musical disorder occurs despite normal performance on tests of intelligence, auditory processing, cognitive functioning, and language processing, and it is not due to a lack of environmental stimulation to music (see Ayotte et al., 2002; Peretz et al., 2002; Foxton et al., 2004, for extensive testing). Congenital amusia has been described as a deficit in music production and perception. It thus needs to be distinguished from the phenomenon that has been termed “poor singing” (e.g., Dalla Bella et al., 2007; Pfordresher and Brown, 2007), referring to individuals who only have production deficits, but who do not have perceptual difficulties. It needs also to be distinguished from the general non-musician population who might be lacking confidence in their musical capacities and refer to themselves as tone-deaf, but who are actually not (Cuddy et al., 2005; Sloboda et al., 2005). Even though the disorder has been recognized for a long time (Allen, 1878), it has been systematically studied only relatively recently (Ayotte et al., 2002), mainly thanks to the development of the Montreal Battery for the Evaluation of Amusia (MBEA) (Peretz et al., 2003; available at http://www.brams.umontreal.ca/plab/ publications/article/57). In the MBEA, six subtests address various components of music perception and memory, notably the pitch dimension (detection of an out-of-key note, a contour violation, or interval changes), the time dimension (rhythm and meter perception), and incidental memory (i.e., melodies used in

*Correspondence to: Barbara Tillmann, CNRS UMR5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon, Equipe Cognition Auditive et Psychoacoustique, 50 Avenue Tony Garnier, F-69366 Lyon cedex 01, France. E-mail: [email protected]

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Fig. 33.1. Group data for amusic and control participants together with individual data points (13 amusic participants and 14 control participants) for three tasks requiring the processing of the pitch dimension. (A) Performance (percentage of correct responses) for the scale subtest of the Montreal Battery for the Evaluation of Amusia (MBEA) (Peretz et al., 2003). (B) Pitch detection threshold (task measuring the smallest pitch difference, in semitones, that participants can detect; see procedure in Tillmann et al., 2009). (C) Performance (hits minus false alarms (FAs)) in a short-term memory task, indicating whether two six-tone melodies (S1, S2) were the same or different, with different trials being changed on the melodic contour (Albouy et al., 2013a). Note that results of the amusic group (average performance) are significantly worse than the results of the control group for all three tasks, while individual data show considerable overlap between the two groups in the pitch threshold task, but not in the MBEA and the short-term memory task. Note that the same participants from our pool in Lyon have performed the three tasks (A, B, C).

preceding subtests) (see Fig. 33.1A for example performances on the MBEA). An adaptation of this battery has been proposed recently for the testing of children (Peretz et al., 2013). Another test used to define a population with a musical deficit is the Distorted Tune Test. This test investigates participants’ capacity to discriminate intervals between tones in a melody (Kalmus and Fry, 1980; Drayna et al., 2001; Jones et al., 2009a). However, it uses well-known tunes (in North America) and is thus dependent on participants’ long-term memory knowledge of a cultural musical repertoire. The MBEA is based on newly composed melodies, and it has been used successfully across various countries and cultures (North America, Europe (e.g., France, United Kingdom, Greece), China, and New Zealand). As the MBEA is time consuming (taking approximately 1 hour 30 to 2 hours), a shorter online test has been proposed more recently (Peretz et al., 2007). Similarly, the test battery for children (the MBEMA) is proposed in a long and a short version (Peretz et al., 2013). The musical deficit has been estimated to affect about 4% of the general population (Kalmus and Fry, 1980). This estimate has been criticized as it depends on the test used, how the cut-off scores are defined, and the skew in distributions (Henry and McAuley, 2010). This criticism is not specific to congenital amusia, but it also affects prevalence reports for other disorders, such as dyslexia, dyscalculia, or developmental prosopagnosia (Henry and McAuley, 2010). Furthermore, there exists considerable uncertainty when assessments are only based on verbal reports without direct testing, notably because of individuals’ underestimation of their capacities as well as response bias due to difficulty in admitting that they do not like or understand music.

The hypothesis of a genetic origin of this disorder has received support from a family aggregation study (Peretz et al., 2007) and a twin study (Drayna et al., 2001). Peretz et al. (2007) tested nine amusic families and 10 control families: 39% of first-degree relatives in the amusic families showed the same disorder (in contrast to only 3% in the control families). The incidence of amusia as a heritable disorder is of similar magnitude compared to that reported for other cognitive functions (e.g., specific language impairment, absolute pitch). Note that the calculation of the risk factor is based on the information from the siblings and the hypothesis of a population prevalence of 4% (thus also subjected to the criticism of Henry and McAuley, 2010). Nevertheless, these findings provide the basis for future research aiming to map the genetic loci for hereditary amusia. Recently, congenital amusia has been also reported in childhood, thus providing some further evidence for the definition as a lifelong disorder (Lebrun et al., 2012). The research domain interested in congenital amusia is currently expanding. In addition to behavioral methods, neurophysiologic methods are now increasingly used (voxel-based morphometry (VBM), diffusion tensor imaging, electro- or magnetoencephalography (EEG/MEG), and functional magnetic resonance imaging (fMRI)), aiming to define anatomic and functional brain anomalies of this deficit, thus going beyond a phenomenologic description of the deficit and contributing also to our understanding of unimpaired neural circuitry underlying music processing (perception, memory, production). Furthermore, investigating congenital amusia has been promoted as a possibility to study the interaction between influences due to genes, environment, and behavior, in particular for music cognition and its relation to other cognitive capacities (Peretz, 2008).

CONGENITAL AMUSIAS

Currently, the most extensively investigated hypothesis about the main deficit in congenital amusia concerns the pitch dimension, notably as pitch is a major component of music structures. As we shall see below, this predominance of pitch-processing studies in the congenital amusia literature also originates from seminal studies showing that pitch was more affected than rhythm (e.g., Allen, 1878; Peretz et al., 2003). While the first studies have focused on pitch perception deficits (i.e., pitch discrimination), more recent studies have pointed to deficits regarding pitch memory – even in cases with unimpaired pitch discrimination capacities.

300 (1244Hz) Pitch in cents (Hz)

A DEFICIT ON THE PITCH DIMENSION: PERCEPTION AND MEMORY

Time (ms)

1046Hz 350 ms

300 A (848Hz) xx

x

x

100

Pitch perception

80 60 Pxx65 years from Adelaide metropolitan area of South Australia From Blue Mountains Hearing Study: Adults > 49 years from two postcodes in Blue Mountains, Australia 1394 participants with complete data at baseline From Blue Mountains Hearing Study: Adults > 49 years from two postcodes in Blue Mountains, Australia

Audiometry Medical conditions Past noise exposure

Hearing tested on average two (maximum four) occasions, at 3.1–6.8 years’ time interval

History of stroke independently associated with baseline levels of hearing: correlation coefficient b ¼ 2.52, P ¼ 0.02 history of stroke not predictive of change in hearing thresholds over 11 years

Audiometry Subjects asked whether their hearing loss had a gradual or sudden onset Stroke diagnoses (MONICA criteria)

Hearing tested on three occasions at 5-year time intervals

OR of reporting stroke 1.55 (95% CI, 1.01–2.38) higher in subjects with vs without hearing loss marginally non-significant OR 2.04 (95% CI, 1.20–3.49) of reporting stroke with increasing hearing loss severity

Gopinath et al., 2009

OR, odds risk; CI, confidence interval; MONICA, MONItoring of trends and determinants in CArdiovascular disease.

HEARING DISORDERS IN STROKE 635 broadly in keeping with results from a study partially Lee et al. (2002) reviewed the clinical findings in overlapping the previous study Australian population 12 cases with AICA infarction who were identified over of 1394 older adults (Gopinath et al., 2009), that found a 2-year period. Hearing loss together with tinnitus was that, while the odds risk for reporting a previous history present in 11 cases (i.e., in 91%, consistent with the 87.7% of stroke in those with vs those without hearing loss was prevalence reported by Lee’s later study: Lee, 2008). Six raised but marginally non-significant, the odds risk of cases were thought to be cochlear, 1 retrocochlear, while reporting stroke was significantly higher for those with in 4 it was not possible to establish the site of the lesion moderate to severe hearing loss (Table 35.1). due to the presence of severe to profound hearing loss Within the stroke population, hearing loss is present confounding interpretation of the absent auditory brainin the majority of stroke sufferers. Formby et al. stem responses (ABR) and acoustic reflexes. In 7 cases (1987) investigated hearing impairment directly associthere was some recovery of hearing over weeks to ated with stroke after excluding patients who had a premonths. Gait and limb ataxia, thought to be of cerebellar vious otologic history or occupational noise exposure. origin, as well as vertigo and nystagmus (with absent or They reported that 61.7% of 243 stroke patients had a reduced caloric test response), attributed to involvement pure-tone average of >25 dB at 500, 1000, and of the vestibular end-organ, and/or vestibular nerve, 2000 Hz for the better ear. O’Halloran et al. (2009) brainstem nuclei or flocculus, were present in all 12 cases. tested stroke patients in a stroke ward and found that Additional clinical features included facial palsy (in 3), 41 out of 52 patients (79%, confidence interval (CI) trigeminal sensory loss (in 6), and Horner’s syndrome 67–90%) had at least mild or greater hearing impair(in 2). The mechanism for the AICA stroke was stenosis ment. A smaller study on 60 patients with past history of the lower and/or mid basilar artery in 5 patients (which of stroke suggested that age, the presence of lacunar could be due to atheroma or thrombus), while 2 patients stroke, multiple, bilateral ischemic focuses, and arterial had a dolichoectatic basilar artery, and 2 out of the hypertension increased the risk of hearing loss remaining 5 patients who had normal magnetic reso(Przewoz´ny et al., 2008). nance angiography (MRA) had cardiac disease. In a subsequent study, Lee (2009) reviewed 82 AICA territory cases and reported cochlear infarction in 52 (63%) with Sudden-onset hearing loss due to ischemic ipsilateral cochlear infarction without vestibular involvestroke of the vertebrobasilar territory ment in 3 (3%). Most of these cases (49: 60%) had a comSudden hearing loss after stroke is less common than bined audiovestibular dysfunction. other neurologic impairments. A large prospective study Hearing loss and tinnitus may also be prodrome of 685 consecutive cases with vertebrobasilar ischemic symptoms of AICA stroke, attributed to isolated labyrinstroke identified sudden hearing loss in 42 and reported thine infarction that may precede the AICA territory an overall prevalence of sudden hearing loss of 6% (Lee, infarction by a few days (Lee et al., 2001, 2003; Kim 2008). Sudden hearing loss was defined as deterioration et al., 2009), most commonly in patients who have vasof hearing thresholds by 30 dB in at least three frequencular risk factors. Occasionally the hearing loss can be cies noted over 72 hours. AICA stroke was more likely to transient and recurrent (Park et al., 2008), possibly due lead to hearing deficits than PICA stroke, with 35 AICA to initial hypoperfusion of the IAA. cases (83%) vs 5 PICA cases (12%) vs 2 isolated brainPICA stroke is less common than AICA. The clinical stem infarct cases (5%). Within the different infarct terpresentation in 5 cases with PICA infarcts (Lee, 2008) ritory subtypes, sudden hearing loss occurred in 87.5% included hearing loss on the side of the stroke, with of cases with isolated AICA infarct, in only 3.4% of cochlear features in 3 cases and possibly combined cases with isolated PICA infarct, and in 0.63% of cases cochlear/retrocochlear features in 2. All 5 cases had verwith isolated brainstem infarct. tigo (and ipsilateral to the stroke, canal paresis on caloric The type of hearing loss in both AICA and PICA is testing), gait ataxia, bidirectional gaze evoked nystagreported to be predominantly cochlear (Lee et al., mus, and severe unsteadiness on the lesion side. 2002; Lee, 2008) but can also be mixed cochlear/retrocoHearing loss for both AICA and PICA infarcts is chlear, and, less frequently, retrocochlear only (Lee mostly unilateral. However, this will depend on the et al., 2002). However, it should be noted that, with affected territory, and there are case reports with bilatthe exception of tests such as auditory brainstem evoked eral hearing loss, when there is more extensive damage. responses and acoustic reflexes, very few studies have Chian et al. (2013) reported the case of a patient with conducted any psychoacoustic tests, for example of bilateral progressive hearing loss and mild cerebellar localization and of temporal resolution, that may help symptoms. Brain magnetic resonance imaging (MRI) decide if the hearing loss is peripheral or central showed infarction of the PICA territory bilaterally with (Ulbricht, 2003). inferior cerebellar involvement while MRA identified a

636 D.E. BAMIOU critical basilar artery stenosis, although the right AICA and did not report any other symptoms, such as tinnitus could not be visualized. Local intra-arterial thrombolysis or palinacusis. One of these two cases had a cochlearinitiated 6 hours after onset of symptoms led to subsetype hearing loss, the other probably combined. quent visualization of the right AICA and to recovery of hearing with only a mild residual hearing loss in the Sudden hearing loss after hemorrhagic left ear at 6-month follow-up. On the basis of these findlesions affecting the vertebrobasilar territory ings, the authors suggested that a hypoperfusion injury Hemorrhage within the brainstem territory may also preof the cochlear nuclei in the pons (that derive their blood sent with hearing loss due to involvement (by means of supply from the AICA) in addition to bilateral PICA infarction was responsible for this presentation (Chian several different mechanisms) of cochlear nuclei, oliet al., 2013). Lee et al. (2001) reported a case with bilateral vary complex, and/or trapezoid body. In addition to hearing loss (thought to be cochlear), more prominent on the hearing loss, such cases will have abnormalities in the right than on the left, with additional right-sided signs brainstem tests that will be consistent with the localizaof AICA infarction (left beating vestibular nystagmus tion of the lesion. Cohen et al. (1996) reported on 4 cases and absent caloric response on the right, right facial of central pontine hemorrhage with documented auditory dysfunction. All cases had abnormalities of the palsy, right reduced facial sensation, right-limb ataxia). ABR and/or acoustic reflexes and masking-level differThe brain MRI showed hyperintense foci in the right dorsolateral pons and cerebellar peduncle and possibly on ence. Nakane et al. (2006) report a case with quadriplegia the left cerebellar peduncle, while MRA showed stenosis and bilateral hearing loss who had only wave I present on of the distal vertebral artery and the middle third of the both sides in the auditory brainstem response test. This basilar artery. After anticoagulation treatment all was due to a hematoma that extended from the lower patient symptoms improved, except the hearing loss in to the upper part of dorsal pons, that appeared to damthe right ear, which remained profound. There are also age the cochlear nuclei and trapezoid body. Goyal et al. (2010) however reported a case with central pontine hemsome case studies with low brainstem infarction associorrhage due to capillary telangiectasia that was associated with bilateral hearing loss (e.g., Shimomura et al., 1990; Yaguchi et al., 2000), in which the hearing loss is ated with bilateral hearing loss but normal ABR. a combination of ischemia of the end hearing organ as Hearing loss had resolved 6 months later. The authors well as of the lower pons, i.e., both peripheral and proposed that the hearing deficit was due to disruption central-type hearing deficits. of the ventral acoustic striae that decussates in the trapezoid body. Hemorrhage affecting the vertebrobasilar territory Sudden hearing loss after ischemic stroke of may be due to rupture of vascular malformations. Cavthe upper brainstem and midbrain ernous hemangiomas are rare, but are frequently situBecause of the multiple decussations of the auditory ated within the low brainstem, and may present with pathway and its characteristic increasing redundancy brainstem-type audiovestibular symptoms, including from the periphery to the cortex, ischemic stroke above hearing loss (e.g., Dumas and Schmerber, 2004). the level of the low brainstem is more likely to result in Figure 35.1 presents imaging and audiologic investigaauditory-processing deficits rather than in peripheraltions in a case with a spontaneously ruptured pontine type hearing loss (for a review of hearing disorders in cavernoma in a 37-year-old female patient who was brainstem lesions, see Chapter 29), but there are excepadmitted with a 3-day history of left-sided paresthesia, tions. Cerrato et al. (2005) report a case with lacunar progressive weakness, and left-sided clumsiness, diploinfarction of the superior cerebellar artery territory that pia, frontal headaches, as well as right-ear hearing loss, involved the right lateral lemniscus and the inferior coltinnitus and hyperacusis, right facial palsy, and gradual liculus, with bilateral hearing loss (a sensation of bilatdrowsiness. Audiometry initially showed normal pureeral “ear wadding” and hypoacusia) as one of the tone thresholds on the left with profound hearing loss dominant symptoms at presentation. Hearing loss was in the right ear while tympanic reflexes were only present more pronounced on the left than on the right side on from the left ipsilateral recording (Fig. 35.1A). Auditory audiometry, while the ABR interwave III–V interval brainstem evoked responses (not shown) showed absent on the left was prolonged. The authors explained the waves on the right and normal waves on the left. There hearing deficits on the side contralateral to the stroke was subsequent full recovery of audiometric thresholds by the fact that acoustic fibers are mostly crossed at after resolution of the edema and the hearing loss on the the level of the inferior colliculus. Lee (2008) also right was thought to be retrocochlear. An MRI scan with reported on 2 patients with upper brainstem infarction MRA demonstrated a brainstem cavernoma with signal on MR, both of whom had an ipsilateral hearing loss change extending medially from the posterior part of the

HEARING DISORDERS IN STROKE

637

Fig. 35.1. Patient with spontaneous ruptured brainstem cavernoma. (A) Audiometry showing normal pure-tone thresholds on the left with profound hearing loss in the right ear and tympanic reflexes that are only present from the left ipsilateral recording. (B) A magnetic resonance imaging scan with magnetic resonance angiography demonstrates a brainstem cavernoma.

internal capsule into the low part of the medial geniculate body and the lateral part of each inferior brachium (Fig. 35.1B). Aneurysms of the distal AICA are rare. Hearing loss and/or tinnitus can be presenting features, usually due to mass-type effects on the cerebellopontine angle rather than the hemorrhage (Zager et al., 2002). Hearing loss can also be a residual neurologic deficit after aneurysm surgery. Yamakawa et al. (2004) identified 56 reported cases of AICA aneurysms associated with subarachnoid hemorrhage between 1948 and 2002, including their own, who had an aneurysm within the internal auditory meatus. Following surgery of the aneurysm, hearing loss was reported in 29 (including Yamakawa’s case) out of 55 cases who survived. The authors reported that, from the reviewed cases, a deeper location of the aneurysm within the meatus increases the risk for persistence of the hearing disturbance more postoperatively, regardless of the preoperative degree of hearing loss. Less common mechanisms by which hemorrhage in this territory can cause hearing loss include extension of the hemorrhage

to the eighth nerve through the subpial space, as in a case of right cerebellar peduncle hemorrhage presenting with hearing loss and tinnitus (Matsuda et al., 1993).

“Central” or “cortical” deafness Central or cortical deafness is a rare and dramatic clinical presentation. The first description of this rare disorder is attributed to Wernicke and Friedlander (1883). They reported a patient with bilateral temporal-lobe lesions but with no apparent damage to the hearing organ, who showed no awareness of sounds. Wernicke and Friedlander coined the term “cortical deafness,” which has been used since as well as the term “central deafness.” The term “deaf-hearing” has also been used for cases who show some response to sound, postulated to be reflexive, but with no sound awareness (Garde and Cowey, 2000). The clinical presentation is similar to cochlear-type profound deafness, in that these patients do not show consistent response to sounds and give raised thresholds

638

D.E. BAMIOU

on audiometry. However, peripheral detection of sounds is either intact or partially impaired. This is indicated by present responses in lower-level tests of the sensory endorgan such as transient evoked otoacoustic emissions (e.g., Musiek et al., 2007). Auditory nerve and low brainstem tests, including acoustic reflexes and auditory brainstem evoked responses, are similarly elicited by normal or lower sensation levels than expected in view of the audiometric results (e.g., Tanaka et al., 1991; Musiek et al., 2007). These findings contrast with abnormal results in evoked potentials that arise from the thalamocortical pathway and beyond, such as middlelatency and late auditory evoked potentials, indicating that the behavioral lack of response to sounds is due to impaired perceptual awareness of the sound.

Figures 35.2 and 35.3 present imaging and audiologic test results of a case with central deafness due to stroke of bilateral auditory cortices. The patient suffered a right temporoparietal infarct in 1997 and a subsequent left posterior cerebral artery infarct in 2006, following which she presented with no response to sound and severe expressive dysphasia. On hearing tests conducted 2 years after the second stroke there was no response to sound on audiometry; however otoacoustic emissions (Fig. 35.2A), auditory brainstem evoked responses (Fig. 35.2B) and acoustic reflexes were present, indicating central deafness. The patient’s axial computed tomography scan that had been conducted 3 days after the second stroke in 2006 (Fig. 35.3B) showed a cerebrospinal fluid attenuation area in the right hemisphere

Fig. 35.2. Case of central deafness due to stroke of bilateral auditory cortices. (A) Normal otoacoustic emissions in right and left ear. (B) Normal auditory brainstem evoked responses in right and left ear.

HEARING DISORDERS IN STROKE

639

Fig. 35.3. Case of central deafness due to stroke of bilateral auditory cortices. (A) Normal acoustic reflexes in right and left ear. (B) Axial computed tomography scan after the second episode of stroke showing an old infarct on the right and a more recent infarct in the left temporoparietal region.

measuring 3.3  2.9 cm, consistent with an old infarct, and a slightly larger area of intermediate attenuation in the left hemisphere with mild mass effect. In these cases, behavioral responses to sounds can be absent or inconsistent, while the audiometric responses when tested tend to be variable (Musiek et al., 2007). Patients may occasionally show a reaction to a sound for which they report no awareness to family members (Tanaka et al., 1991; Cavinato et al., 2012). Patients may grow tired even after short hearing test sessions (Garde and Cowey, 2000). Several cases will show no improvement (e.g., Bahls et al., 1988; Semenza et al., 2012), although both response variability (Tanaka et al., 1991) and audiometric thresholds may in some cases improve over the first few weeks to months after the stroke (Griffiths et al., 2010). There are occasional reports of patients with sudden cortical deafness who initially do not realize they are deaf, as in the case of a patient with consecutive infarcts of the right and left middle cerebral artery territory, with (premorbid) low intelligence, reported by Leussink et al. (2005), and consistent with Anton’s eponymous syndrome for both blindness and deafness resulting from focal brain lesions (Anton, 1899). Finally, the clinical presentation will evolve from cortical deafness to other auditory syndromes that include agnosia (for environmental sounds,

music, and/or words) and other more basic sound dimension-processing deficits (Mendez and Geehan, 1988), and it has been proposed that all these presentations might form a continuum of the auditory processing spectrum (Polster and Rose, 1998). Anatomically, the most frequent cause for this presentation is the presence of bilateral vascular lesions that may occur simultaneously or sequentially (Musiek and Lee, 1998), that involve primary, secondary, and association auditory cortices in Heschl’s gyrus and in the planum temporale (Griffiths et al., 2010). The disorder may also occur with subcortical primary lesions that do not involve the Heschl’s gyri or cortical areas but result in an effective disconnection between sensory and perceptual processing (Polster and Rose, 1998). For example, Nishioka et al. (1993) reported the case of a patient with bilateral putamen hemorrhage, with resolution of hearing over 2 months. Other subcortical areas reported to be affected in similar cases include the inferior colliculus, the cerebellum, the internal capsule, the thalamic regions, and the medial geniculate body (Musiek and Lee, 1998). There are also case reports of subarachnoid hemorrhage leading to vasospasm of the middle cerebral artery with cortical deafness that resolves. For example, Tabuchi et al. (2007) reported a case of reversible cortical auditory dysfunction caused by aneurysmal

640

D.E. BAMIOU

Fig. 35.4. Structural magnetic resonance imaging (MRI) and positron emission tomography (PET) activation study results in the patient reported by Engelien et al. (2000). First row: structural MRI scan. Second row: PET activation study results superimposed on to the patient’s individual T1-weighted MRI for categoric comparisons of unattended stimulation versus no stimulation (rest). Third row: PET activation study results superimposed on to the patient’s individual T1-weighted MRI for categoric comparisons of selectively attended versus unattended auditory stimulation. (Reproduced from Engelien et al., 2000, with permission.)

subarachnoid hemorrhage in both middle cerebral artery territories without pre-existing lesions. There are counterarguments about the extent of neuroanatomic damage that is necessary to produce this presentation, and one must bear in mind that the central auditory nervous system is highly redundant, with several relay stations from periphery to cortex, multiple interconnections between right and left at different levels, and parallel afferent pathways to the secondary auditory cortices. The presence of extensive bilateral damage of Heschl’s gyri may thus not be sufficient for cortical “deafness,” and the contribution of attention-related neural substrates, that have been spared or affected by the stroke, in the clinical presentation, has been discussed by several authors. Studies of primates indicate that bilateral auditory cortex destruction will raise sound thresholds but will not completely abolish sound responsiveness (Heffner and Heffner, 1986). Engelien et al. (2000) reported a patient with extensive bilateral damage of primary auditory cortices who showed no awareness of sound; however, when selectively attending to the auditory modality he achieved conscious perception of sound. His pure-tone audiogram tested with the standard procedure showed profound hearing loss but thresholds improved to “nearly” normal when attention-primed. Positron emission tomography conducted with the patient attending to sound demonstrated increases in cerebral blood flow

in the lateral prefrontal and medial temporal cortex as well as in caudate nuclei bilaterally (Fig. 35.4). The authors proposed that the neural substrate for selective attention in the prefrontal cortex may modulate the mediation of conscious sound awareness within the remaining auditory system, with contribution by the basal ganglia. Semenza et al. (2012) reported a case with persistent cortical deafness, on whom attentional priming had no effect. The patient had extensive cortical bilateral damage, including left and right Heschl gyri and the right frontal cortex as well as in subcortical structures. A tractography study showed extensive impairment in fractional anisotropy and diffusivity of the anterior portion of the right superior longitudinal fasciculus and the right uncinate fasciculus which connect frontal and temporal brain structures, and the authors proposed that this disconnection might have been to some extent responsible for the symptom persistence. Information on intervention for these cases is even more limited, and it is unclear whether improvements when noted are a result of the intervention or of spontaneous resolution or a result of the natural progress of the disease. Musiek et al. (2007) implemented a speech and language rehabilitation program targeting the patient’s language deficits together with use of augmentative and alternative communication devices that included a pocket talker, an FM trainer, and a word prediction program, but benefits of these communication devices were

HEARING DISORDERS IN STROKE limited. Garde and Cowey (2000) attempted to teach their patient to become aware of her reflexive response to sounds; however this knowledge was not well retained between four such teaching sessions (conducted for the purposes of testing rather than rehabilitation). They also suggested that lip reading may be used as a strategy to support communication with these patients.

AUDITORY-PROCESSING DEFICITS AFTER STROKE It is beyond the scope of this chapter to discuss severe – in terms of clinical presentation – auditory cognition disorders that may present after stroke, such as auditory neglect (see Chapter 31), auditory agnosia (see Chapter 32), or amusia (see Chapter 34). These are thought to be uncommon, but alternatively these may remain undiagnosed in the patient who does not have a language impairment, or may be thought to be unimportant in the presence of aphasia (Polster and Rose, 1998). It should be noted that such deficits, in their less severe forms, will not necessarily be reported by patients unless they are explicitly questioned. A hearing questionnaire study of patients with unilateral cerebrovascular auditory cortex lesions found that 49% of these patients reported auditory perceptual problems on the questionnaire, most commonly affecting sound localization or understanding speech in situations with simultaneous speakers (Blaettner et al., 1989), but the majority of these patients had reported intact hearing prior to the

641

administration of the questionnaire. Our previous study of 9 patients with stroke lesions of the insula and adjacent cortex found temporal resolution and sequencing deficits (Bamiou et al., 2006). None of these patients had been referred for audiologic assessment; however, when specifically questioned, 6 out of 9 reported auditory difficulties in various domains since the stroke. We subsequently assessed 21 patients with stroke of the auditory brain documented on brain MRI in the chronic phase of stroke, excluding patients with aphasia, versus 23 age- and hearing-matched controls by means of a hearing questionnaire and auditory-processing tests (Bamiou et al., 2012). Severe and significant functional limitation (z score >3) with recognition and/or with localization of sounds was reported by 9 (43%) and with speech-in-noise recognition by 6 (28%) of the stroke patients in a range of everyday communication situations (Table 35.2). None of these patients had a previous diagnosis of auditory agnosia or neglect. These reported deficits did not correlate with hearing thresholds, but correlated strongly with some of the clinical auditoryprocessing tests, and with damage to the corresponding brain networks specialized for this function, as reported by others (Rey et al., 2007). There is evidence to suggest that these deficits will persist long-term in these patients. Figure 35.5 presents auditory-processing and audiometry results in a patient tested 2 years after a left temporoparietal stroke. Rey et al. (2007) assessed sound recognition, localization, and sound movement perception in 24 patients with

Table 35.2 Patient-reported sound recognition, sound localization, and speech in noise deficits expressed as z scores (compared to normative data) in stroke subjects. Significant deficits (z > 3) were identified in 9/20 subjects assessed in the chronic stage of stroke

Case

Lesion

1 3 5 7 8

Infarct, large right parietal AVM Infarct, right short gyri and long gyri of the insula Infarct, right putamen + insula limen Infarct, left insula, striatum, frontal and temporal gyri Hematoma, left posterior part striatum, posterior limb of internal capsule, lacunar infarcts in basal ganglia 2.8-cm diameter cavernoma hemorrhage/right brainstem and cerebellum Infarct, right striatum, thalamus, posterior corona radiata, posterior limb internal capsule Infarct, right insula, inferior frontal gyrus Infarct, right medial frontal gyrus

10 14 16 20

AVM, arteriovenous malformation.

Sound recognition z score

Sound localization z score

Speechin-noise z score

5.13 3.25 2.63 9.50 8.25

10.50 6.50 6.50 10.50 5.50

2.8 1.2 3.2 4.4 2.2

1.64

5.75

3.2

5.75

5.50

3.2

3.67 5.00

Not computable 9.50

4 3.6

642

D.E. BAMIOU

Fig. 35.5. Case study of a 58-year-old patient who suffered a left temporoparietal stroke. He had been a hearing-aid user for 3 years before the stroke and, while his hearing thresholds did not change after the stroke, he became aware of increased difficulties with listening to speech in noise. Auditory-processing test assessment 2 years after the stroke showed auditory-processing deficits consistent with the site of lesion, with a right-ear deficit on Dichotic Digits Test (DDT), which was the better-hearing ear in terms of audiometric thresholds, and abnormal Gaps-in-Noise (GiN) tests in both ears. Frequency pattern tests (FPT) were normal. Red circle, right ear, blue  left-ear test results.

focal hemispheric lesions in acute/subacute poststroke and reassessed them in the chronic stage. The authors reported an absence of a simple relation between extent of lesion, severity of behavioral test deficits, and test deficit recovery. However, patients who had deficits in both sound recognition and localization in the subacute or chronic poststroke stage tended to have lasting deficits. The UK Royal College of Physicians (2012) makes a broad recommendation for systematic assessment for such sensory-processing deficits, that may well be justified in view of the studies discussed in the previous paragraph. At present identification of cases who require assessment relies on high clinical acumen. Everyday life communication is highly demanding and complex, and the patient reporting auditory difficulties in the chronic stage after stroke may benefit from a more detailed assessment of auditory and related functions to inform the rehabilitation plan. Language-based interventions may promote language recovery after stroke (Cicerone et al., 2011), while the role of non-linguistic-based auditory training after stroke is at present less clear. There are however reports that simply listening to music or audiotapes (Sa¨rka¨m€ o et al., 2010) poststroke may lead to broad functional improvements in communication, although auditory-training improvements may not always generalize (e.g., Slevc et al., 2011), but this is still an unexplored area of research.

OTHER AUDITORY PHENOMENA: TINNITUS, AUDITORY HALLUCINATIONS, HYPERACUSIS, AND PALINACOUSIS Tinnitus (see Chapter 23) and music hallucinations (see Chapter 24) are “false” auditory percepts, in the sense that they are elicited without any external auditory stimuli, that are associated with abnormal “amplified” activity in brain networks that underpin sound and music perception respectively (Griffiths et al., 2010). Both these phenomena have been reported after stroke, and may present together with hyperacusis (i.e., the experience of comfortable-level sounds as being intolerably loud) and palinacousis (i.e., the experience of perseveration of the hearing sensation after the external auditory stimulus has stopped: see Chapter 25). Tinnitus may well be the most frequent auditory symptom that is spontaneously reported by stroke patients (Ha¨usler and Levine, 2000) that seems to be reported in association with subcortical lesions. Tinnitus with or without hearing loss is more prevalent after AICA than PICA infarction (Lee et al., 2003; Lee, 2008). There is a single case study reporting that gabapentin ameliorated poststroke bilateral tinnitus presenting a few days after a right basal ganglion hemorrhagic stroke (in the presence of an old right temporal infarct) (Chen and Yin, 2012). There are also occasional case reports of stroke in the basal

HEARING DISORDERS IN STROKE

643

Schematic representation of auditory assessment protocol post stroke At stroke ward prior to discharge

Sudden onset hearing loss or reported auditory related deficit/symptom post stroke? Yes

No

Conduct hearing screening test at ward e.g. hand-held audiometer, live voice speech test.

Obtain full audiological assessment prior to discharge. Inform discharge Summary with recommendations.

Fail

Review at follow up

Pass

Was Hearing Loss known and assessed prior to the Stroke? Suggest Audiology follow up at local services 3-6 months after discharge

No Yes

Obtain full audiological assessment prior to discharge. Inform discharge summary with recommendations.

A

Schematic representation of auditory assessment protocol post stroke At 3 month follow up clinic post stroke

Does the patient have a Hearing Aid? Yes

Does the patient report greater difficulties With hearing than before stroke?

Refer for full audiological assessment

Normal score

Refer for full audiological assessment

Administer a self-report hearing questionnaire Abnormal score

Yes

No

No action

B Fig. 35.6. Schematic representation of auditory assessment protocol poststroke.

ganglia territory leading to improvement of the perception of tinnitus that pre-existed the stroke. Lowry et al. (2004) reported a case of lifelong tinnitus that resolved completely following a left corona radiata vascular event, with no change in hearing thresholds. Larson and Cheung (2013) similarly reported a case with bilateral tinnitus who sustained a perioperative focal vascular injury following deep-brain stimulation for Parkinson disease. The patient reported bilateral tinnitus suppression, with complete abolition of the left-ear tinnitus and substantial reduction of the right-ear tinnitus 18 months later. Hyperacusis (with or without tinnitus) has also been linked with stroke of subcortical brainstem and midbrain

structures. Sudden-onset hyperacusis with tinnitus in the ear contralateral to the stroke were the presenting symptoms in a patient with a right dorsal pons hemorrhage, who had entirely normal hearing tests, including audiogram, acoustic reflexes, and auditory brainstem evoked responses. Tactile stimulation of the auricle exacerbated both the tinnitus and the hyperacusis, and the authors postulated that the lesion may have affected the pathway between the superior olivary nuclei and lateral lemniscus (Lee et al., 2008). Fukutake and Hattori (1998) reported a patient with a hemorrhagic infarct of the right posterior inferior thalamus, including the medial geniculate body. The

644 D.E. BAMIOU presenting feature was hyperacusis, with the sound of CONCLUSIONS the television being perceived as unpleasantly loud and Auditory symptoms and deficits after stroke: to some extent distorted predominantly in the right comments on current practice ear, while this percept sustained for another 10 minutes after the sound source had been turned off (palinacouAuditory deficits after stroke have not been as extensis). Severe hyperacusis with tinnitus has also been sively investigated as visual deficits, and unsurprisingly, reported as an early symptom of migrainous infarction recommendations for auditory function assessments in of cerebellum and the upper pons on both sides in a current clinical guidelines for stroke tend to be rudimen25-year-old patient with no risk factors for stroke (Lee tary. For example, the UK Royal College of Physicians et al., 2003). Of interest, Jankelowitz and Colebatch (2012) national clinical guidelines for stroke recommend (2004) recorded the acoustic startle response in that stroke patients should be assessed shortly after 32 patients with stroke (of the pons, internal capsule, admission for their “ability to hear and need of hearing and middle cerebral artery) and found an increased staraids,” while a broad recommendation is made that “any tle response in 8 cases in total across the three subgroups. person who appears to have perceptual difficulties Sound-induced flexion in a paralyzed limb was noticeshould have a formal perceptual assessment . . . followed able in 3 cases; however only some of the pontine lesion by intervention.” cases were symptomatic for the increased startle. It is not known to what extent recommendations for Auditory hallucinations may be simple (i.e., differhearing assessment are adhered to for every patient in ent types of noise or environmental sounds) or complex everyday clinical practice. Anecdotal experience indi(i.e., involving music, voice, or spoken words). Both cates that this does not happen routinely in a systematic types of auditory hallucination have been described in manner. Edwards et al. (2006) screened hearing in single case studies or in case series of patients with 53 patients with acute stroke who were admitted to hemorrhagic or ischemic infarction of the brainstem an academic stroke service, and compared the screening (Cascino and Adams, 1986; Cambier et al., 1987; test findings with the charted impairments. Twenty-two Galtrey et al., 2012). These are usually bilateral, associpatients (41%) failed the bedside sound repetition hearated in the majority of cases with hearing loss with ing screening test:hearing impairment had only been central-type features while they may coexist with other charted for 3 (6%) patients before the screening, inditypes of auditory deficit, such as localization of sound cating that 81% of those who failed the hearing test deficits. However, in a big prospective study of 521 would have remained unidentified without screening. stroke patients with no psychiatric disorders, only 4 There are also some indications that hearing impairpatients reported auditory hallucinations and all 4 had ment may well affect patient outcome. Landi et al. an ischemic lesion of the right temporal lobe (Lampl (2006) assessed physical functioning in 355 subjects et al., 2005). Their hallucinations consisted of hearing with stroke (mean age of 77.4 years) approximately themselves speaking in their own voice or hearing 10 months after their discharge to the community. familiar persons speaking to the patients in a wellThe presence of hearing impairment, as rated by the constructed manner, and some of these events were patient and with the benefit of the patient’s hearing perceived as having an unpleasant, bizarre, or even appliance if used on the Minimum Data Set for Home threatening content by the patients. This percept was Care instrument, was one out of four independent negbilateral in 3 and unilateral in 1 case only. All 4 cases ative predictors for physical decline, with an odds risk had a stroke of the right hemisphere and the areas of 1.83 (1.02–3.83). Landi et al. speculated that hearing affected by the stroke included Brodmann area 41, loss may restrict the patient’s participation in rehabilita42, the postauditory area Brodmann 22, the middle tion programs, and may thus lead to a lower level of upper region of the right temporal lobe, the right insula, physical performance. and right superior temporal gyrus. All these patients The previous studies provide some empiric evidence had normal hearing, while 1 case had a subsequent to indicate that stroke patients should be systematically stroke of the left temporal lobe a year later and develassessed for hearing loss that may otherwise be missed, oped central deafness. Proposed mechanisms for these as the presence of hearing loss may affect the patient’s illusory auditory percepts may be a disruption of the poststroke physical outcome. At present, there is little, if descending olivocochlear or corticofugal auditory pathany, such information on the impact of other types of ways (Galtrey et al., 2012) or corticocortical connections sound perception deficits poststroke on patient func(Lampl et al., 2005) by the stroke, leading to deafferentioning and quality of life, while the prevalence of such tation, or the presence of lesion within the network for deficits remains unknown, since there are even fewer the perception/imagery of sound may lower the threshstudies that systematically assess such deficits in stroke old for spontaneous activity (Calabro` et al., 2012). sufferers than studies of hearing loss. However, when

HEARING DISORDERS IN STROKE such deficits are present, they can be diverse (Polster and Rose, 1998), may go undetected unless specifically sought for (Blaettner et al., 1989), and may impact on patient communication in everyday life in the chronic stage of stroke, as reported by patients (Bamiou et al., 2012).

Assessment of auditory function after stroke: what should we do and why? Detailed testing of every single patient may not be practical in a busy clinical setting; however screening the patient’s hearing before the patient leaves the stroke ward with a short test and minimum set of questions and subsequently screening the patient’s hearing needs by means of a questionnaire given at the early chronic stage poststroke, when deficits are likely to be permanent, may be a cost-effective bare-minimum assessment approach. This assessment may gather useful information for the rehabilitation team and the patient’s environment for all patients and may help identify those patients who have high levels of deficits and disability in order to decide the need for additional investigation and input on a case-by-case basis (Fig. 35.6). Subsequent detailed assessment of selected cases may include a detailed diagnostic interview and individually tailored testing of affected modules (Griffiths et al., 2010) within the audiology unit. The patient with significant auditory deficits and functional limitations may require a range of rehabilitation and remediation approaches. For example, hearing-aid amplification in a case of a patient who has both hearing loss and auditory neglect will not alleviate the neglect, since manipulation of the sound volume has no influence on the neglect (Williams and Coleman, 2008), but it may help optimize hearing on the unaffected side. In a patient with hearing loss and a language disorder, hearing aids will provide better access to the sound stimuli used for languagebased interventions, which may promote language recovery after stroke (Cicerone et al., 2011), particularly when the language-related training activities have a high cognitive and linguistic load assist (Hatfield et al., 2005). The role of non-linguistic-based auditory training after stroke is less clear. There are reports that simply listening to music or audiotapes (Sa¨rka¨m€ o et al., 2010) poststroke may lead to broad functional improvements in communication, but improvements may not generalize to untrained auditory stimuli, while temporal processing training may improve the temporal deficits, but not word deafness (Slevc et al., 2011). Other remedial strategies, such as the application of personal frequency modulation systems in stroke sufferers who report significant speech-in-noise difficulties after stroke despite

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the presence of reasonably preserved hearing thresholds, are unexplored, but our own pilot data indicate that such interventions may hold promise.

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stimulation electrode with infarction in area LC. J Neurosurg 118: 192–194. Lee H (2008). Sudden deafness related to posterior circulation infarction in the territory of the non-anterior inferior cerebellar artery: frequency, origin and vascular topographical pattern. Eur Neurol 59: 302–306. Lee H (2009). Neuro-otological aspects of cerebellar stroke syndrome. J Clin Neurol 5: 65–73. Lee H, Whitman GT, Lim JG et al. (2001). Bilateral sudden deafness as a prodrome of anterior inferior cerebellar artery infarction. Arch Neurol 58: 1287–1289. Lee H, Sohn SI, Jung DK et al. (2002). Sudden deafness and anterior inferior cerebellar artery infarction. Stroke 33 (12): 2807–2812. Lee H, Whitman GT, Lim JG et al. (2003). Hearing symptoms in migrainous infarction. Arch Neurol 60: 113–116. Lee E, Sohn HY, Kwon M et al. (2008). Contralateral hyperacusis in unilateral pontine hemorrhage. Neurology 70: 2413–2415. Leussink V, Andermann P, Reiners K et al. (2005). Sudden deafness from stroke. Neurology 64: 1817–1818. Lowry LD, Eisenman LM, Saunders JC (2004). An absence of tinnitus. Otol Neurotol 25: 474–478. MacDonald BK, Cockerell OC, Sander JW et al. (2000). The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 123: 665–676. Matsuda Y, Inagawa T, Amano T (1993). A case of tinnitus and hearing loss after cerebellar hemorrhage. Stroke 24 (6): 906–908. Mazzoni A (1972). Internal auditory artery supply to the petrous bone. Ann Otol Rhinol Laryngol 81: 13–21. Mendez MF, Geehan Jr GR (1988). Cortical auditory disorders: clinical and psychoacoustic features. J Neurol Neurosurg Psychiatry 51: 1–9. Murray CJ, Lopez AD (1996). Evidence-based health policy – lessons from the Global Burden of Disease Study. Science 274: 740–743. Musiek FE, Lee WW (1998). Neuroanatomical correlates to central deafness. Scand Audiol Suppl 49: 18–25. Musiek FE, Baran JA, Shinn JB et al. (2007). Central deafness: an audiological case study. Int J Audiol 46: 433–441. Nakane H, Sugimori H, Wakugawa Y et al. (2006). A case of hearing loss and quadriplegia after a pontine hemorrhage. J Neurol Sci 241 (1–2): 91–94. Nishioka H, Takeda Y, Koba T et al. (1993). A case of cortical deafness with bilateral putaminal hemorrhage. Neurolog Surg (Japan) 21: 269–272. O’Halloran R, Worrall LE, Hickson L (2009). The number of patients with communication related impairments in acute hospital stroke units. Int J Speech Langu Pathol 11: 438–449. Park JH, Kim H, Han HJ (2008). Recurrent audiovestibular disturbance initially mimicking Me´nie`re’s disease in a patient with anterior inferior cerebellar infarction. Neurol Sci 29: 359–362. Polster MR, Rose SB (1998). Disorders of auditory processing: evidence for modularity in audition. Cortex 34: 47–65.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 36

Hearing disorders in multiple sclerosis 1

MIRIAM FURST1* AND ROBERT A. LEVINE2 School of Electrical Engineering, Tel Aviv University, Tel Aviv, Israel

2

Department of Ear, Nose and Throat and Head and Neck Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

INTRODUCTION Multiple sclerosis (MS) is a chronic inflammatory disease characterized by inflammation and focal destruction of myelin in the central nervous system (CNS) and spinal cord. As an exacerbating and remitting immunemediated disorder of interfascicular oligodendrocyteproduced myelin, MS can impair acutely and transiently any CNS neural system, including the auditory system. However, when MS patients are not in the midst of an acute exacerbation, difficulty with hearing is a rare complaint. Yet, there are several auditory tasks that MS patients often failed to perform normally. There are two main objective measures for detecting the involvement of MS in the auditory pathway: (1) evoked potentials (EP) and (2) magnetic resonance imaging (MRI). Auditory evoked potentials (AEP) reflect the neuroelectric activity within the auditory pathway, from the auditory nerve to the cerebral cortex, in response to an acoustic stimulus or event. The most studied AEP are the brainstem auditory evoked potential (BAEP), the auditory middle-latency response (AMLR) and the cognitive potential (P300). BAEP, which consists of seven waves generated by one or more structures along the auditory pathway, assesses the integrity of the auditory pathway from the auditory nerve to the brainstem (see Chapter 17). AMLR, consisting of a series of waves that appear after the BAEP, reflects the activation of several subcortical structures. P300 is an endogenous, event-related potential (ERP) and its generation involves skills such as attention, auditory discrimination, memory, and semantic perspective. In recent years, MRI has become the most reliable test for diagnosing MS (Polman et al., 2005). MS lesions that overlap the brainstem auditory pathway are rarely detected. Only when an MRI protocol is optimized for

detecting and localizing MS brainstem lesions in the auditory pathway is it possible to find correlations between hearing dysfunction and MS. In this chapter, we will first describe the MRI protocol that was specifically developed for detecting and localizing brainstem lesions, followed by a review of the auditory tasks that MS patients performed abnormally and for which correlations were found between the site of lesion and auditory performance.

PROTOCOL FOR DETECTING LESIONS IN THE BRAINSTEM AUDITORY PATHWAY A special protocol was developed in order to detect lesions in the brainstem auditory pathway (Levine et al., 1993b; Tadmor et al., 1994; Tenny, 1994). MRI scans are obtained with T2-weighted, spin-echo pulse sequences. The data were then collected from three orthogonal planes of the brainstem: axial (perpendicular to the long axis of the brainstem), coronal (parallel to the plane of the floor of the fourth ventricle), and sagittal (perpendicular to the plane of the floor of the fourth ventricle and in the plane of the long axis of the brainstem). Contiguous 5-mm sections are obtained using T2 spin-echo sequences. A region of abnormally high signal is considered a lesion if it is found in at least two of the three orthogonal planes. A digitized anatomic model of the human brainstem was constructed from a serially sectioned adult human brain (Levine et al., 1993b). It included edges of the brainstem, auditory nuclei, and auditory fiber tracts. A special semiautomated non-linear matching algorithm was developed in order to estimate the location of the auditory pathway on each MRI section (Tadmor et al., 1994; Tenny, 1994). Figure 36.1 is an example from a representative subject. It is a set of nine scans upon

*Correspondence to: Miriam Furst, School of Electrical Engineering, Tel Aviv University, Tel Aviv 69978, Israel. Tel: 972-36408050, E-mail: [email protected]

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Fig. 36.1. Location of auditory pathway (white outlines) in nine sections of a typical subject magnetic resonance imaging (MRI) scan, as estimated by a semiautomated algorithm that relates the MRI scan to a computerized human brainstem anatomic atlas. First column: axial sections ordered from caudal to rostral. Middle column: coronal sections ordered from ventral to dorsal. Last column: sagittal sections ordered from left to right. CN, cochlear nucleus; TB, trapezoid body; LL, lateral lemniscus; IC, inferior colliculus. (Reproduced from Furst et al., 2000.)

which the estimate of the brainstem auditory pathway is superimposed (white outlines). In the left column, three axial planes are shown; panels A1 and A2 represent caudal planes that include part of the trapezoid body (TB), while panel A3 represents a more rostral plane that includes part of the lateral lemnisci (LL). In the second column, coronal planes are shown from ventral (C1), where only part of the TB is included, to dorsal, where only small parts of the LL and TB are included (C3). The middle panel (C2), which is 5 mm apart from either of the other panels, includes most parts of the auditory pathway, the cochlear nucleus (CN), the TB, LL, and inferior colliculus (IC). The right column presents sagittal planes from right (S1) to left (S3) through the midline (S2). Since the entire brainstem auditory pathway can be contained in one or two coronal planes, a schematic coronal representation of the auditory pathway (Richter et al., 1983) is used to plot the location of detected lesions, as can be seen in Figure 36.2. The detected

lesions were superimposed on the schematic diagram of the brainstem auditory pathway. The schematic diagram in Figure 36.2 includes detected lesions that were found in different planes and are indicated by different patterns: vertical lines for sagittal planes, horizontal lines for axial planes, and polka dots for coronal planes.

PSYCHOPHYSICAL HEARING ASSESSMENT In the following section we review hearing tests that are relevant to MS. It includes standard audiologic tests such as pure-tone threshold and speech intelligibility, and more specialized tests. The additional tests are binaural, since MS is a CNS disorder and the binaural tests must involve CNS processing of the outputs from each ear.

Pure-tone threshold Pure-tone threshold are usually measured at the frequencies 0.25, 0.5 1.0, 2.0, 4.0, and 8.0 kHz at each ear. The

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Correlation between pure-tone threshold and BAEP in MS patients was widely studied (see review by Chiappa, 1980). The most common deficits that were observed in BAEP of MS patients are: (1) a prolonged interpeak interval between waves I and V; and (2) a reduced amplitude or absence of wave V. However, abnormality in BAEP does not necessarily indicate abnormal pure-tone threshold. There are many patients whose BAEP was abnormal, but their monaural puretone thresholds were all in the normal range (Jewett and Williston, 1971; Chiappa, 1980; Mustillo, 1984; Levine et al., 1993a).

Speech intelligibility

Fig. 36.2. Lesion of a patient with multiple sclerosis plotted on a coronal schematic of the brainstem auditory pathway. Regions of high signal are coded by different patterns corresponding to the magnetic resonance imaging plane on which it was detected: sagittal plane, vertical lines; axial plane, horizontal lines; coronal plane, polka dots. 8th N, auditory nerve; VCN, ventral cochlear nucleus; DCN, dorsal cochlear nucleus; VAS, ventral acoustic stria; SOC, superior olivary complex; CNIC, central nucleus of inferior colliculus; CIC, commissure of inferior colliculus; LL, lateral lemniscus; TB, trapezoid body. (Reproduced from Levine at al., 1993b.)

hearing level is determined according to the American National Standard Institute ANSI S3.6 (American National Standard Institute, 1996). In the literature there are several reports of MS-related hearing threshold deficits. These MS-related hearing losses occur when the MS involves the peripheral and brainstem auditory pathway (Jabbari et al., 1982; Daugherty et al., 1983; Shea and Brackmann, 1987; Franklin et al., 1989; Drulovic´ et al., 1993; Bergamaschi et al., 1997; Oh et al., 2008). However, a well-controlled study of pure-tone thresholds concluded that they were not elevated in chronic MS. Moreover, even in MS patients, whose lesion overlapped the auditory pathway, the pure-tone thresholds were not significantly different from the thresholds of MS patients whose lesion did not overlap the auditory pathway (Doty et al., 2012). Yet, there are cases where pure-tone threshold deficit is the only presenting symptom of MS, as in sudden hearing loss. Sudden unilateral hearing loss may result from etiologies affecting cochlea, eighth nerve, or more central auditory tracts. It usually appears early in the course of the disease but in most reported cases the prognosis was good, with ultimately little or no residual hearing deficit (e.g., Ozunlu et al., 1998; Oh et al., 2008; Hellmann et al., 2011).

A common audiologic test is a speech reception threshold (SRT). The SRT is defined as the minimum level at which a subject can correctly identify 50% of twosyllable words. A similar test can be done at higher levels with monosyllabic, phonetically balanced words. It is referred to as a speech discrimination test and is scored by the percentage of words identified correctly. In general MS subjects perform normally in this task when the standard clinical level (70 dB above the SRT) is used. When the task is made more difficult, for example by using lower levels, then the performance of chronic MS subjects is significantly poorer than age-matched controls (Mustillo, 1984; Jerger et al., 1986; Levine et al., 1994). Those difficulties indicate deficits in cognitive processing such as attention and auditory discrimination. They are closely related to abnormalities found in late AEP, especially latency delay of the P300 wave (Matas et al., 2010). It occurs at about 300 ms latency from the stimulus onset in young adults, with larger amplitude over the central-parietal scalp regions. The P300 is elicited by discrimination task, the oddball paradigm, which consists of a series of frequent and target stimuli, randomly administered in the proportion of 4:1 respectively. The subject’s task is to evaluate the occurrence of the significant stimulus, the target one, engaging expectancy, attention, and memory during the performance. Studies that compared MS patients with controls in such tests yielded a significant increase in P300 latencies. An example of such a difference was demonstrated by Magnano et al. (2006) and is shown in Figure 36.3. Average ERPs of two groups of subjects are shown – a group of normal subjects and a group of MS patients. The black arrow in Figure 36.3 indicates the latency of P300 in both normal subjects and MS patients. The prolonged latency of P300 in the MS patients is clearly demonstrated. Moreover, many studies indicate a significant correlation between auditory P300 latency and crucial demyelinating

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M. FURST AND R.A. LEVINE ability to judge ITDs and ILDs. We will discuss in detail some of the most relevant tests.

Auditory ERPs

20.0 Normal Controls Voltage (mV)

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P300

Interaural discrimination tests

0.0

−10.0 −20.0 −200.0

−100.0

100.0

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500.0

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Fig. 36.3. Comparison of grand average event-related potential (ERP) responses in target detection from controls (top) and patients with multiple sclerosis (MS: bottom). The black arrow indicates the latency of P300. (Reproduced from Magnano et al., 2006.)

plaques seen in MRI on frontal horn and brainstem (Honig et al., 1992; Sailer et al., 2001; Magnano et al., 2006; Matas et al., 2010).

Binaural hearing MS patients’ abilities in binaural hearing are more vulnerable than can be detected in standard audiologic tests (pure-tone threshold and speech intelligibility), probably because MS is a CNS disorder and binaural hearing is by definition primarily a CNS function, since it integrates the sounds from both ears to make a judgment about the sound, such as where the sound is located. The auditory dysfunction in MS is probably caused by disruption of temporal processing, which is especially required when binaural integration is performed (Mustillo, 1984). In binaural perception, both ears receive auditory stimuli and the brainstem nuclei compare the sound coming from each ear to make judgments, such as where the sound is coming from, i.e., right–left localization. For such judgments, decisions are made based upon either the differences in time parameters of the sound from the two ears (interaural time differences (ITD)) or the differences in loudness of the sound coming from the two ears (interaural level differences (ILD)). Another binaural process is involved in improving a subject’s ability to detect sounds in a noisy background. Using earphones it is possible to assess separately a subject’s

One way to assess binaural functioning is to determine the “just noticeable difference” (JND), which is the smallest ITD or ILD that a subject can detect reliably. Usually the JND is estimated by using a two (or three)interval, two-alternative, forced-choice paradigm. An example is as follows. Two successive presentations are made: (1) a reference stimulus which is diotic (both ears receive identical sounds), which is normally perceived in the midline; and (2) a test stimulus that is dichotic (the two ears receive different sounds), with either ITD or ILD, which is normally perceived to the side. In each trial, the order of the two intervals is randomly switched. The subject’s task is to indicate in which direction (to the right or to the left) the two successive stimuli move relative to each other. The test interval is updated after every trial according to the subject’s response. The task becomes easier when the subject’s answer is wrong and more difficult if correct. The experimental session is terminated after usually six to eight “turnarounds,” i.e., when the test stimulus has been changed from easy (increase ITD or ILD) to difficult (decrease ITD or ILD), or vice versa. Averaging the six to eight “turnarounds” is then defined as the JND of the parameter being tested. Investigators have been using different types of stimulus in order to determine the time JND and level JND in MS patients. The most common stimuli are trains of clicks, noise bursts with different frequency content, or tones. The normal JND values were obtained from control normal-hearing subjects, where normal range is usually defined as the mean 3 S.D. In Figure 36.4, four examples are shown in order to demonstrate the relationship between MS patients’ performance in the time and level JND tests, their BAEPs to monaural stimulation, and the location of their lesion along the auditory pathway. In all the examples, the MS patients had lesions that involved the brainstem auditory pathway. Figure 36.4A represent subject 572, who had a lesion in the right middle cerebellar peduncle which appeared lateral to the right LL. This patient had normal BAEPs when either ear was stimulated. The high- and low-pass level JNDs were both normal. The time JND for highpass noise was clearly elevated, while the time JND for low-pass noise was just above the normal range. Figure 36.4B shows subject 576, who had a pontine lesion that overlapped the left auditory pathway in the region of the rostra1 superior olivary complex (SOC) and TB and the caudal LL. BAEPs from right- and left-ear stimulation were similar with normal waves

Fig. 36.4. See figure caption on next page.

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I through IV, but wave V was clearly abnormal. Time JNDs were both clearly abnormal, with level JNDs both normal. The third example (Fig. 36.4C) is from subject 577, who had a large lesion on the left involving the base of the pons. This lesion extended dorsally to involve the ventrocaudal parts of the left SOC and TB from nearly the level of the left pontomedullary junction where the ventral acoustic stria enters the TB, to just over the midline. The lesion did not extend throughout the entire region where the ventral acoustic stria meets the TB, but principally involved the ventromedial portion. A second left-sided lesion, detected in all three planes, was in the tegmentum. The BAEP of this subject were clearly abnormal. Waves I and II were normal on stimulation of the left ear, but waves III and V were absent. For right-ear stimulation only wave V was abnormal. The high- and low-pass time JNDs were highly abnormal for this subject. Both highand low-pass level JNDs were within normal limits. The last example (Fig. 36.4D) represents subject 583, who had a major lesion involving most of the left auditory pathway from the SOC to the rostra1 LL, apparently continuous in the rostral–caudal direction on both sagittal and axial scans. Two of these lesions encroached on the auditory pathway – one located in the SOC, the other in the caudal LL. Two other lesions were detected on the

right: one overlapped the TB, and the other was detected lateral and dorsal to the right LL. The subject’s BAEPs were abnormal. Waves I through III were normal when either ear was stimulated, but waves IV and V were absent when the right ear was stimulated. On the other hand, when the left ear was stimulated, wave V was abnormally low in amplitude. The I–V interpeak time was prolonged. The time JNDs for this subject were highly abnormal for both high- and low-pass noise bursts, while the level JNDs were both normal. It is clear from those examples that the relationship between BAEPs, discrimination tests, and lesion location along the auditory pathway is not simple. Table 36.1 summarizes the performance of 38 MS subjects in several binaural tests and the relationship to their BAEP (Levine et al., 1994). In studies that tested MS patients a huge variability in performance was obtained. There were subjects with performance in the normal range, others obtained significantly higher JND values, and there were those who could not perform the task at all. Among the different discrimination tests, time JND for noise bursts containing only frequencies above 4 kHz are the most commonly abnormal in MS patients (Table 36.1). Moreover, all subjects with abnormal time JND for low-pass noise bursts also had abnormal time JND for

Table 36.1 Behavioral and electrophysiologic interrelationship: percentage of abnormal performances Psychophysics

Evoked potentials Interaural discrimination Level difference

Time difference

Masking-level difference

Low frequency

High frequency

Low frequency

High frequency

10.5%

10.5%

7.9%

39.5%

76.3%

41.6%

Fig. 36.4—Cont’d. (A) Pathoanatomy, (B) electrophysiology, and (C) and psychophysics for subjects 572 (Fig. 36.4A), 576 (Fig. 36.4B), 577 (Fig. 36.4C), and 583 (Fig. 36.4D). The locations of the portions of regions of high signal (RHS) that involve the auditory pathway as determined by magnetic resonance scanning are shown at the top on a coronal projection drawing of a human brainstem. Brainstem auditory evoked potentials (BAEPs) obtained by right and left stimulations are shown with indication of waves I–V revealed by high-pass (HP) filtering of the BAEP and indication of wave L revealed from the low pass of the BAEP (LP). The subject’s JNDs are shown on four horizontal scales, which are linear for the level JNDs and logarithmic for the time JNDs. The left bracket indicates the lowest possible JND score (0.25 dB for level JNDs, 10
LS for time JNDs), the filled circle indicates the mean score for normal controls, and the right bracket indicates 3 SD above the mean for normal controls. The subject’s JND for each test is indicated by an X. If the subject’s JND is within the two brackets it is considered normal. CIC, commissure of inferior colliculus; CNIC, central nucleus of inferior colliculus; LL, lateral lemniscus; TB, trapezoid body; VAS, ventral acoustic stria; SOC, superior olivary complex; AN, auditory nerve; DCN, dorsal cochlear nucleus; VCN, ventral cochlear nucleus. (Reproduced from Levine et al., 1993b.)

HEARING DISORDERS IN MULTIPLE SCLEROSIS 655 clicks and high-pass noise bursts (Hausler and Levine, threshold is referred to as the BMLD. A typical normal 1980; Hausler et al., 1983; Levine et al., 1993a; Furst BMLD is about 15 dB. et al., 1995; Aharonson et al., 1998). Studies that tested MS patients found variable numMost patients who performed poorly in the ITD disbers of patients who performed abnormally in the crimination test had abnormal BAEP in response to monBMLD test. Usually in less than 40% of the patients aural clicks. In some cases there were no peaks after the BMLD was smaller than in the control group wave I. In other cases wave III was absent or its latency (Noffsinger et al., 1972; Hannley et al., 1983; was prolonged (Hausler and Levine, 1980; van der Poel Matathias et al., 1985; Hendler et al., 1990; Levine et al., 1988; Levine et al., 1993a). In particular, all MS subet al., 1994). Moreover, Levine et al. (1994) found that, jects with abnormal evoked responses had abnormal time in MS patients, BMLD performance is highly correlated JND for high-pass signals, but not vice versa. On the with discrimination of ITDs at high frequencies. other hand, as can be seen in Table 36.1, the time JNDs The correlation between BAEP and BMLD in MS for low-pass signals and BAEPs were closely related. patients is not very clear (Table 36.1), since there were However, there were subjects that failed in the discrimpatients whose BAEP was abnormal, with either a ination tests but whose BAEPs were in the normal range decrease in peak amplitude or latency increase, but and vice versa. who performed normally in the BMLD test. On the other Abnormal level JND is less frequent in MS patients; hand, some MS patients who performed abnormally in however, in studies that identified subjects with abnorthe BMLD task had normal BAEP. mal level JND, in almost all cases those subjects also had abnormal BAEPs (Furst et al., 1990; Picton et al., Lateralization experiments 1991; Levine et al., 1993a; Aharonson et al., 1998). For all other types of stimulus and for both time and level Another type of experiment that tests the ability of binJNDs, there were MS subjects who performed abnoraural hearing is the lateralization experiment. In this experiment, subjects are asked to indicate where in their mally, but no clear correlation was found between the head they perceive the location of a binaural stimulus. In psychoacoustic test and the BAEP. Time JNDs were clearly affected by pontine lesions a matching experiment, subjects are presented with a that involved the auditory system. Abnormal low-pass pair of successive stimuli. The first stimulus serves as time JND was obtained by patients whose lesions were a reference, and it contains a dichotic stimulus with either unilateral and caudal to the TB, or bilateral and ITD, and the second interval includes a similar dichotic rostra1 to the TB (Levine et al., 1993b). stimulus, but with ILD. The subject’s task is to match the perceived position of the second stimulus to the reference by changing ILD. Among the MS patients that were tested in this experiment, some could not perform the Binaural masking-level difference experiment (Furst et al., 1990; Furst and Algom, 1995). Another typical binaural discrimination test is the comTheir responses were inconsistent, since they appeared parison of the ability to detect signal in noise when listento perceive the same binaural clicks in different positions ing with two ears rather than one. The detection of a on repeated trials. signal in noise is improved when either the phase or level A more direct procedure that tests the lateralization differences of the signal at the two ears are not the same ability is to ask subjects to indicate where they perceive as the masker. This phenomenon is called binaural the dichotic stimulus in their head while listening to the masking-level difference (BMLD). Because the signal sounds through earphones. Subjects can use a keyboard and masker do not have the same time or level relationor a touch screen with equally spaced buttons, where the ships at the two ears, the signal and masker appear to center button corresponds to the middle of the head. For originate from different locations in space; hence, the example, in a keyboard of nine numbers, number 5 corBMLD appears to be related to the well-known responds to the center of the head, numbers 1–4 corre“cocktail party effect.” spond to the positions from the left ear toward the BMLD is typically measured with tones at low frecenter, and numbers 6–9 correspond to the positions quencies (250 or 500 Hz) and masking with gaussian from the center toward the right ear. During the experwhite noise. The threshold for the binaural tone in the imental session subjects are presented with dichotic stimpresence of continuous diotic (identical at the two earuli with a variety of ITDs and ILDs. phones) noise is measured under two conditions: with A typical normal performance obtained by a normalthe tone in phase at the two earphones or 180 out of hearing subject while using click stimuli is presented in phase at the two earphones. The degree to which the Figure 36.5 (Furst et al., 1995; Aharonson et al., 1998). out-of-phase threshold is superior to the in-phase The left panel represents the subject’s performance

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for click stimuli with ITDs and the right panel shows the response to click stimuli with ILDs. In both panels, the y-axis represents the nine positions defined by the test procedure, and the x-axis the interaural difference. When the stimulus to the right ear was earlier than to the left ear, ITD is indicated as a positive number ranged from 0 to 1 ms. On the other hand, when the stimulus to the left ear was earlier, ITD is indicated as a negative number, ranged from 1 to 0 ms. Similarly, when the stimulus to the right ear was louder than to the left

Fig. 36.5. Performance of a normal subject in the lateralization experiment for click stimuli. The histograms were obtained by counting the number of times the subject reported perceiving a certain position in response to dichotic stimuli with different interaural time differences (ITDs) and interaural level differences (ILDs). ITDs ranged from 0 to 1 ms and ILDs from 0 to 10 dB. Negative times refer to the left ear earlier. Negative levels refer to the left ear louder. (Reproduced from Aharonson et al., 1998.)

ear, ILD is indicated by a positive number ranged from 0 to 10 dB. A negative ILD is indicated when the stimulus to the left ear was louder than to the right ear. Each bin in the histograms in Figure 36.5 is equal to the relative number of times the subject indicated a certain position for a given interaural difference ITD or ILD. All the different positions were perceived as a function of ITD and ILD in about equal probability. Such a lateralization experiment can be obtained with different types of stimulus, such as click, tone bursts, and narrowband noise bursts. Two types of abnormal performance in the lateralization test were found among MS patients: a centeroriented and a side-oriented abnormaly, as can be seen in Figure 36.6 (Furst and Algom, 1995; Furst et al., 1995, 2000; Aharonson et al., 1998). A center-oriented abnormal lateralization was obtained by those subjects who were biased toward the center positions and tended to ignore the side positions. They perceived all the dichotic stimuli in the center of their head. A side-oriented abnormal lateralization was obtained by those subjects who were biased toward the side positions and tend to ignore the center positions. They perceived all the dichotic stimuli in the sides of their head and never at the center. They generally did not confuse between right and left, but appeared to arbitrarily choose right or left when a diotic stimulus was presented. Typical performances of a center- and a side-oriented performance are depicted in Figure 36.6. A very clear correlation was found between the lateralization test and the site of the MS lesion (Furst et al., 1995, 2000). All subjects with lesions involving the brainstem auditory pathway were found to have abnormal

Fig. 36.6. Performances of two subjects with multiple sclerosis in the lateralization experiment. (A) Center-oriented abnormal performance and (B) side-oriented abnormal performance. The histograms were obtained by counting the number of times the subject reported perceiving a certain position in response to dichotic stimuli with different interaural time differences (ITDs) and interaural level differences (ILDs). (Reproduced from Aharonson et al., 1998.)

HEARING DISORDERS IN MULTIPLE SCLEROSIS

657

Table 36.2 Correlation between binaural performances and multiple sclerosis lesion site Brainstem auditory pathway Binaural psychoacoustic experiments Lateralization

JND

Lesion site

ITD

ILD

None

Normal

Normal

Caudal to TB Rostral to TB Caudal + rostral of TB

ITD

LP: Normal HP: Normal/abnormal Center-oriented Normal LP: Normal HP: Abnormal Side-oriented Side-oriented LP: Normal HP: Abnormal Center-oriented Center-oriented LP: Abnormal HP: Abnormal

ILD

BMLD

Normal

Normal

Normal

Normal

Normal Normal/abnormal Normal/abnormal

JND, just noticeable difference; BMLD, binaural masking-level difference; ITD, interaural time difference; ILD, interaural level difference; TB, trapezoid body; HP, high-pass (containing only frequencies above 4 kHz); LP, low-pass (containing only frequencies below 1 kHz).

lateralization with at least one stimulus (clicks or highpass noise bursts), and all subjects with no detectable auditory pathway lesions had normal lateralization. Whenever a lesion was detected overlapping the auditory pathway, abnormal performance occurred. Centeroriented performance was principally associated with caudal pontine lesions and side-oriented performance with lesions rostral to the TB. In particular, when MS lesions were restricted to the caudal pons, only the time lateralization experiment was center-oriented; level was normal. When the MS lesion was rostral to the TB then lateralization was sideoriented for both ITD and ILD. For lesions involving both the caudal pons and more rostral auditory structures, lateralization testing was a center orientation for both time and level. Table 36.2 summarizes the correlation between MS patients’ performances in the binaural psychoacoustic experiments and the site of their lesion along the brainstem auditory pathway. The MS lesions were divided into four categories: (1) no lesions overlapping the brainstem auditory pathway; (2) lesions were detected caudal to the TB; (3) lesions were detected rostral to the TB; and (4) lesions were detected both caudal and rostral to the TB. The psychoacoustic binaural experiments were divided into three categories: (1) lateralization experiments; (2) JND of interaural differences (time and level); and (3) BMLD. It is clear from Table 36.2 that high-pass time JND was abnormal in many of the MS patients; however, it was not restricted to a specific lesion along the auditory pathway. In fact many times it was abnormal despite no detectable brainstem lesion and no other psychophysical

or electrophysiologic abnormality (Table 36.1). Furthermore, whenever any other psychophysical or electrophysiologic test was abnormal, the high-pass time JND was always abnormal. There were subjects with no pontine lesions who performed abnormally in this task. On the other hand, level JND is almost always normal in MS patients; it was abnormal only when MS plaques involved large parts of the brainstem auditory pathway. The most specific binaural test is the lateralization test. Abnormal performance is obtained only when MS lesions overlap the auditory pathway. Moreover the type of abnormality indicates the site of the MS lesions.

Correlation between BAEP and binaural performances A more direct correlation between BAEP and binaural performance was found for the binaural difference (BD) potential. BD waveform is obtained by adding the two monaural BAEPs and subtracting the corresponding binaural BAEP (Dobie and Norton, 1980; Levine, 1981; Wrege and Starr, 1981). The first positive peak (b) of the BD waveform, which occurs just after wave V peak of the monaural BAEPs, was found to be the most significant parameter for the correlation between BAEP and psychoacoustic properties. Whenever the amplitude of b was well above the noise floor, the dichotic click was perceived as a laterally fused image, namely dichotic clicks with any value of ILD (25 dB) or dichotic clicks with ITD smaller than 1 ms. Moreover, when ITD and ILD were such that the binaural click was perceived in the same position, the latencies of b obtained by both ITD and ILD were similar, and

658

M. FURST AND R.A. LEVINE 25 20

P5

P7

P9

P10

P20

15 15

10 Based on Same β Latency

Based on Same Sound Location

10

5

5 0

A

P3

20

ILD (dB)

Interaural Level Difference (dB)

25

0 25 20

0.

0.4

0.8

1.2

1.6

B

0.

0.4

0.8

1.2

1.6

15

Interaural Time Difference (msec)

10

Interaural Level Difference (dB)

25

5 20

0

15 10 Plots A and B Superimposed

5 0

C

0.

0.4

0.8

1.2

1.6

Interaural Time Difference (msec)

Fig. 36.7. Mean interaural time differences and interaural level differences matching curves (A) for psychophysical data based on sound lateralization and (B) for physiologic data based on latency. The error bars denote 1 SEM. The solid lines are the exponential matching curves. (C) The psychophysical and physiologic data are superimposed. (Reproduced from Furst et al., 1985.)

as a result the psychoacoustic matching curve for lateralization was predicted by the latency of b (Furst et al., 1985; Jones and Van der Poel, 1990). A demonstration of this phenomenon is presented in Figure 36.7. In Figure 36.7A, the mean performance of 7 normal subjects in the psychoacoustic data is shown. Each data point means that the perceived location of the sound was the same for the ITD and ILD corresponding to that point. For instance, the subjects’ perceived sound location for an ITD of 0.4 ms was the same as their perceived sound location for an ILD of 15 dB. Figure 36.7B represents the physiologic matching curve that was derived from the latency of b. Each data point means that the b latency was the same for the corresponding ITD and ILD. The solid lines in both figures (Fig. 36.7A and B) represent exponential curves that were best matched to the data points by means of minimum squared error, and expressed by the form ILD ¼ B(1  ekITD). In Figure 36.7C the two plots (Fig. 36.7A and B) are replotted together to demonstrate their similarity and to emphasize the conclusion that b latency is an adequate code for sound location. BD waveforms were successfully obtained from many MS subjects whose monaural BAEPs were detectable (Furst et al., 1990; Furst and Algom, 1995; Pratt et al., 1998). In particular, those subjects who either performed

0

0.5

1

1.5

0

0.5 1 1.5 ITD (msec)

0

0.5

1

1.5

Fig. 36.8. Interaural time difference (ITD) and interaural level difference (ILD) exponential matching curves for psychophysical data based on sound lateralization (broken lines) and for physiologic data based on latency (solid lines) for 6 different patients with multiple sclerosis indicated by P3, P5, P7, P9, P10, and P20. (Reproduced from Furst et al., 1990.)

normally in the lateralization experiment or were centeroriented in the time lateralization test had detectable BD waveforms. Subjects with center-oriented lateralization for ITD had abnormal matching curves; they reached a maximum ILD around 5 dB to match the different stimuli with ITD, whereas the average normal value of ILD that matches ITD stimuli is around 18 dB. Both normal and abnormal performances were predicted by the latency of b of the corresponding BD waveforms (Furst et al., 1990). Examples of such predictions are presented in Figure 36.8 for 6 different subjects. Each panel in Figure 36.8 represents a different MS subject, as indicated in the upper left of each panel. The solid lines were obtained by matching the b latency data of each subject to the exponential curve ILD ¼B (1  ekITD). Similarly, the broken lines were obtained from each subject’s psychologic data.

THEORETIC EXPLANATIONS Correlation between MS and audiologic tests Classically MS has been considered to have its principal effect upon neural function by slowing conduction velocities across a focal lesion – the aftermath of acute inflammation. Of late, more and more evidence is emerging consistent with other ways that MS can chronically disrupt neural function; it has been referred to as a “neurodegenerative process.” Currently, a widely accepted concept of MS is that it begins as an inflammatory process and then evolves into a neurodegenerative condition (McFarland, 2009, 2010). With the exception of high-pass time JND, most abnormal performances

HEARING DISORDERS IN MULTIPLE SCLEROSIS of MS patients can be understood by considering MS as a focal demyelinating disease. The high-pass time JND results cannot be accounted for by focal demyelinating lesions only. Therefore it appears that high-pass time JND may be important as a marker for MS as a neurodegenerative process. Further study may prove that high-pass time JND is a valuable tool for monitoring the neurodegenerative aspect of MS. Serial MRI scans have revealed that brains of MS patients lose volume at about 10 times the rate of healthy controls (Miller et al., 2002). Atrophy involves both cortical and deep gray matter and is more marked in cortex than white matter. Because the acute inflammation appears to be directed toward myelin, acute MS is thought to slow neural conduction through the lesion. When more severe, the process can block neural conduction altogether. Since slowing of conduction may not be uniform across the focal lesion, slowing of conduction will lead to dyssynchrony of the neural population. Hence neural processes strongly dependent upon synchrony will be more affected by an MS lesion than others. Dyssynchrony is one theory for the difference in findings for pure-tone audiometry and speech intelligibility. Pure-tone audiometry is not dependent upon speed of neural conduction or complex neural interactions, but understanding speech, especially under adverse conditions, is dependent upon complex neural interactions. Slowing of conduction, particularly non-uniformly across a family of neurons, can be expected to disrupt such complex neural interactions.

TWO-LEVEL DECISION-MAKING MODEL for CLICK LATERALIZATION MODEL

STIMULUS Little or No Interaural Differences

Left Cochlear Nucleus

Right Cochlear Nucleus

Left SOC

Right SOC

Level Time

Level Time

HIGHER CENTER(S)

A

“CENTER” TWO-LEVEL DECISION-MAKING MODEL for CLICK LATERALIZATION MODEL

STIMULUS Large Interaural Time Difference No Interaural Level Difference

Left Cochlear Nucleus

Right Cochlear Nucleus

Left SOC

Right SOC

Level Time

Level Time

HIGHER CENTER(S)

B

“RIGHT” TWO-LEVEL DECISION-MAKING MODEL for CLICK LATERALIZATION MODEL

STIMULUS No Interaural Time Difference Large Interaural Level Difference

Model for lateralization tasks The binaural dysfunction in MS is probably caused by disruption of temporal processing. A multilevel decision-making model (Aharonson and Furst, 2001) of sound lateralization is presented in order to explain the frequent abnormal performance of MS patients whose lesions overlap the brainstem auditory pathway. The model is presented schematically in Figure 36.9. The model assumes that each SOC receives inputs from both cochlear nuclei. In each SOC there are independent time and level comparators whose outputs then independently project to the higher center(s). The higher center(s) then uses the four possible inputs coming from the two SOCs to make a decision about the stimulus location in auditory space. In the normal auditory system receiving sounds with little or no interaural differences (Fig. 36.9A), the outputs of the two SOCs for both time and level channels project to the higher center(s). In contrast, for dichotic stimuli with larger ITDs (1) only one time comparator (from the SOC contralateral to the leading ear) actively projects to the higher center(s) (Yin and Chan, 1990); but

659

Left Cochlear Nucleus

Right Cochlear Nucleus

Left SOC

Right SOC

Level Time

Level Time

HIGHER CENTER(S)

C

“RIGHT”

Fig. 36.9. Two-level decision-making model for sound lateralization in normal subjects. The first level is the right and left superior olivary complexes (SOC). The second level is the higher auditory center(s) rostral to the pons (inferior and superior colliculi, medial geniculate bodies, and the auditory cortex). The trapezoid body is represented by the crossing arrows connecting the cochlear nuclei to the opposite SOCs. Each lateral lemniscus connects the output of the SOC to the higher center(s) and is represented by two vertical arrows: one for time (open arrowhead) and one for level (solid arrowhead). (A–C) The model’s active channels for three extremes of binaural stimulation. In quotation marks below the large open arrow is the correct response; it is “Right” for (B) and (C) because the right ear is receiving the earlier (B) or higher-level (C) stimulus. (Reproduced from Furst et al., 1995.)

660 M. FURST AND R.A. LEVINE (2) both level comparators actively project to the higher side will be desynchronized but the higher center(s) will center(s), since there are no ILDs for these stimuli decide correctly which part of auditory space the sound (Fig. 36.9B). Since latencies shorten as stimulus levels is coming from, since its decision will be based upon the increase, for larger ILDs, only one time comparator normal time and level channels coming up the (from the SOC contralateral to the ear receiving the more unaffected LL. intense sound) actively projects to the higher When the LL lesion is on the side with actively projectcenter(s) (Fig. 36.9C). There is no level output from ing time channel, the side of the higher center(s) with the the level comparator of the SOC ipsilateral to the ear normal LL receives a normal active level channel, but no receiving the less intense sound. time channel. On the side with the LL lesion, the higher In the case of an MS lesion involving the TB, the center(s) receives both desynchronized time and level demyelination of fibers in the TB will critically disrupt channels. This conflicting information is resolved by the temporal relationships between the right and left adding an additional decision process. This level acts inputs to both SOC time comparators. For any type of as follows: if the higher center(s) receives any time chandichotic stimuli, time channel outputs will not project signel input (even if desynchronized) from either side, then nificant activity to higher center(s); however, the level it ignores the inputs from both level channels and decides comparators will function normally, since they are unafon the image’s location only on the basis of the time fected by slight changes in timing of neuronal discharges. channel. Therefore lateralization for ILDs will be normal, while for dichotic stimuli with only ITDs, the higher Correlation between BAEP and binaural center(s) will make a decision based upon the inputs from discrimination tasks the SOC-level channels only. Since the level channels always indicate no interaural difference (i.e., center) The correlation between monaural BAEP of MS subjects for stimuli with only ITDs, this model then predicts that and their performance in the binaural discrimination tests is complex, as can be seen in Figure 36.4 and MS subjects with TB lesions will perceive stimuli with Table 36.1. From a detailed analysis, interrelationships only ITDs as coming from the center of auditory space. This model also accounts for the fact that MS subjects can be found between psychophysical performance with unilateral lesions overlapping the LL perceive dichand the BAEP, which can be summarized by the followotic stimuli with little or no interaural differences as coming simplified model (Fig. 36.10), as was suggested by ing from the side rather than the center of auditory space. Levine et al. (1993a) based upon Jeffress’ coincidence According to this model, when dichotic sounds have little network (Jeffress, 1948). or no interaural differences, the time and level channels of A group of brainstem neurons (open circles, Fig. 36.10A) is innervated symmetrically by inputs from both SOCs actively project to the higher center(s) almost both ears through axons with cell bodies in the cochlear synchronously. If the inputs from the two SOCs to the higher center(s) are received nearly synchronously, this nuclei. Each brainstem neuron behaves as a probabilistic model assumes that the higher center(s) decides that the coincidence detector such that, when action potentials stimulus is coming from the center of auditory space (otharrive nearly simultaneously from the two sides, their erwise, from one side of auditory space). With a unilateral effects sum and greatly increase the probability of an LL demyelinating lesion, the inputs of the two sides to the output spike. These brainstem neurons are frequencyhigher center(s) will be desynchronized; consequently, this selective, each receiving inputs representing local regions in the two cochleas that have the same charactermodel predicts that these stimuli will be perceived as comistic frequency (CF). High-CF neurons receive inputs ing from the side and not the center of auditory space. Dichotic stimuli with large ILDs are normally projectfrom the base of the cochlea, whereas low-CF neurons ing to the higher center(s) through only one LL for both receive them from the apex of the cochlea. the time and level channels. A desynchronizing lesion of To a wideband transient sound, high-CF auditory one of the LLs will not affect the decision of the higher nerve fibers tend to respond at the same time (group syncenter(s), since it has no choice but to choose the one side chrony), but low-CF units tend to respond at different with any kind of input from the SOC. Thus this model times depending upon their CFs (Kiang et al., 1965). This type of group synchrony from the high-CF neurons is also accounts for correct lateralization in the case of presumably also responsible for the distinct waves in dichotic stimuli with large ILDs. When dichotic stimuli with large ITDs are introduced, the BAEPs (Don and Eggermont, 1978) and we assume both SOCs actively project synchronously through both that it will be carried through to the brainstem auditory level channels, while projecting through only one time nucleus represented in Figure 36.10. channel. When the LL lesion is on the side with no For a normal subject, the same sound delivered to actively projecting time channel, the level channel on that both ears creates the perception of a midline-oriented

HEARING DISORDERS IN MULTIPLE SCLEROSIS Higher-Level Proccessor spike

Brainstern Processor

High CF

High CF

Low CF

Low CF

I

BAEPs (right) V III II IV

LpL HpL LpT HpT

A

JNDs

Higher-Level Proccessor

Brainstern Processor High CF

High CF

Low CF

Low CF

I II

LpL HpL LpT HpT

B

JNDs

Higher-Level Proccessor

Brainstern Processor High CF

High CF

Low CF

Low CF

I

II III V

LpL HpL LpT HpT

C

JNDs

Brainstern Processor High CF

I

High CF

V

III II

IV

LpL HpL LpT HpT

JNDs

D

Low CF

Low CF

Fig. 36.10. Schematic depiction of a theoretic model to account for the brainstem auditory evoked potential (BAEP)and psychophysical results. (A–D) the brainstem processor (vertical rectangle) is seen as a collection of neurons (open circles) that receive symmetric inputs from corresponding regions of the cochlea through the cochlear nuclei. To the right of each model is a depiction of how the BAEPs (to clicks to the right ear) and the just noticeable differences (JNDs) (open circles, normal; filled circles, abnormal) might appear in each case. (A) Case of a normal subject. (B) Multiple sclerosis (MS) lesion, affecting the fibers from the right side. (C) MS lesion also alters some fiber conduction times, but uniformly, so that group synchrony of the high characteristic frequency (CF) fibers remains. (D) The brainstem auditory apparatus is intact, but MS lesions involve the higher-level processor (stippled area). Four types of JND values are indicated: interaural level difference of low-pass signal (LpL); interaural level difference of high-pass signal (HpL); interaural time difference of low-pass signal (LpT); interaural time difference of high-pass signal (HpT). (Reproduced from Levine et al., 1993a.)

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sound source. Either amplitude or time differences in the same sound delivered to the two ears can produce the perception of a sound source off to the side of the midline and, thus, can be distinguishable from the symmetrically presented sound stimuli. In Figure 36.10, the brainstem processor (vertical rectangle) is seen as a collection of neurons (open circles) that receive symmetric inputs from corresponding regions of the cochlea through the cochlear nuclei. The stimulus is a wideband acoustic transient presented identically at the two ears. For simplicity, only one spike per fiber is represented. The position of the spikes indicates relative times of arrival of single-unit discharges at the brainstem processor, with time of arrival increasing for spikes from nerve fibers with lower CF. Dashed vertical lines are symmetrically placed on either side of the brainstem processor to serve as reference. Each brainstem neuron is a binaural spike pattern comparator that sends its output to a higher-level processor (horizontal rectangle). To the right of each model is a depiction of how the BAEPs (to clicks to the left ear) and the JNDs (open circles, normal; filled circles, abnormal) might appear in each case. Figure 36.10A is the case of a normal subject. In Figure 36.10B, an MS lesion, affecting the fibers from the left side (stippled oval), is seen as altering the conduction times of input neurons by varying amounts in different fibers; in one there is no spike due to conduction block. In this case many of the brainstem neurons would have a very different output than they do in Figure 36.10A. The functions of the higher-level processor that depend upon comparing the exact time of arrival of spikes to each brainstem neuron and integrating over the entire array of brainstem outputs would be disrupted, as reflected by the abnormal high- and low-pass time JNDs and center-oriented lateralization. The loss of group synchrony of the input fibers would also be reflected in the absence of recognizable waves following wave II of the BAEPs. This loss of group synchrony would also remove the type of synchrony that is essential for coherent waves in the BAEPs. Functions that require only comparing the spike counts coming from both sides within some time period might still be normal, as reflected in the normallevel JNDs and level lateralization. In Figure 36.10C, an MS lesion also alters some fiber conduction times, but uniformly, so that group synchrony of the high-CF fibers remains. Thereby, the later BAEPs are recognizable but delayed. Only the high-pass time JND is abnormal. In Figure 36.10D, the brainstem auditory apparatus is intact, but MS lesions involve the higher-level processor (stippled area). This situation could occur in MS subjects who performed abnormally on the high-pass time JNDs and had normal BAEPs.

662 M. FURST AND R.A. LEVINE If, as shown in Figure 36.10C, the MS lesion causes Figure 36.10B or C, due to MS-induced disruption of timmany fibers to have equivalent slowing of conduction, ing. When these delays are small (30 dB loss in at least one ear), and approximately 2013; Respondek et al., 2013). Huntington’s disease is 50% of adults over age 85 have hearing loss (Gates and another rare neurodegenerative disease that causes involuntary motor symptoms (i.e., chorea), dementia, Mills, 2005). Age-related hearing loss (presbycusis) first and psychiatric symptoms (Biglan et al., 2013). affects the high-frequency range, is progressive, and can FTD is a common cause of early age-of-onset demenbe caused by damage to either the peripheral or central tia (and is caused by significant atrophy in the frontal and auditory system (or both). Gates and Mills (2005) note temporal lobes of the brain. FTD can be subdivided into that persons with hearing loss often have difficulty two language-variant syndromes (progressive non-fluent understanding conversations and misperceive phonetically similar words, such as “map” and “mat.” Family aphasia and semantic dementia) and one behavior members or friends are often more aware of the change variant, called behavioral-variant FTD (bvFTD) (GornoTempini et al., 2011; Rascovsky et al., 2011). The in hearing function than the older person with hearing behavioral variant of FTD is characterized by changes loss. Hearing loss in older adults can also affect the abilin personality and social behavior (e.g., impulsivity, apaity to perceive and comprehend music, but few studies thy, decreased empathy, and diminished insight). Persons have explored this topic. with semantic dementia develop a progressive loss of the A number of studies have examined the relationship meaning (semantics) for both verbal and non-verbal conbetween hearing loss and cognitive decline in older adults. Gennis and colleagues (1991) reviewed 15 studies cepts, which is due primarily to atrophy of the temporal and concluded that hearing loss was more common in lobes of the brain. Persons who have progressive nonfluent aphasia develop progressive difficulty producing persons with dementia, but there was considerable hetlanguage (e.g., hesitant and effortful speech). Logopenic erogeneity in the study designs, and the underlying aphasia is another variant of primary progressive aphasia causes of the dementia were not always clear. Other characterized by slow speech and naming deficits and is studies suggest that the hearing loss in persons with thought to be caused by AD (Gorno-Tempini et al., 2008). dementia is more severe than older adults without cogMild cognitive impairment (MCI) is a term used for nitive decline (Uhlmann et al., 1989; Lin et al., 2011). Recent studies also suggest that adults with hearing loss the preclinical stage of dementia. MCI is associated with are more likely to develop AD or other dementias over mild declines in cognitive function, but the ability to perform daily living skills is still relatively preserved. There time. For example, Lin and colleagues (2013) found that is a high rate of progression from MCI to dementia hearing loss (pure-tone average >25 dB) was indepen(Petersen, 2011). dently associated with both increased rate of cognitive The majority of research about hearing and music in decline and incident cognitive impairment in a large samdementia has been done with persons who have AD. For ple of community-dwelling older adults.

HEARING AND MUSIC IN DEMENTIA Several recent studies suggest that adults with Parkinson’s disease may have a higher prevalence of age-related, high-frequency sensorineural hearing loss relative to healthy adults. One recent study involving 118 patients with Parkinson’s disease found a higher prevalence of age-dependent high-frequency hearing loss than age- and sex-matched controls (Vitale et al., 2012). Within this cohort, 26% had mild, 63% had moderate, and 11% had severe hearing loss. The Parkinson’s disease patients with hearing impairment were older, more likely to be male, and had a later age at onset than the Parkinson’s disease patients with normal hearing. The authors also noted that the Parkinson’s disease patients were generally unaware of their hearing loss. It is also important to remember that the patient with dementia may not complain of hearing loss symptoms. Gates and Mills (2005) recommended an examination of hearing function in any person with cognitive decline. They also note that tinnitus is a common comorbid condition with hearing loss and should be queried in persons with cognitive decline. It is possible that hearing loss symptoms are underreported in persons with neurodegenerative diseases, as they may be regarded as secondary to concerns about memory or are confused as memory or communication symptoms. It is also possible that dementia may be overdiagnosed in persons with hearing loss.

Peripheral auditory system function Persons with a neurodegenerative disease (with the diagnoses discussed above) are generally thought to have an intact peripheral auditory system and are only affected by typical, age-related changes. That is, most neurodegenerative diseases do not directly damage the peripheral auditory system. Autopsy studies have not detected neuropathologic changes associated with AD in the peripheral auditory system (Sinha et al., 1993). However, only a few studies have been done, and the majority of these autopsy studies focus on AD. The peripheral auditory system is just beginning to be studied in non-AD dementias. Early studies documented normal peripheral hearing function in AD patients (Grimes et al., 1985; Eustache et al., 1995; Gates et al., 1995). For example, Kurylo and colleagues (1993) investigated a comprehensive battery of auditory function, including pure-tone thresholds, sound localization, pitch perception of complex tones, phoneme perception, timbre discrimination, and tonal memory (from the Seashore Tests of Musical Abilities). There were no differences between patients with AD and matched older adults on the majority of these tests. Another study (Strouse et al., 1995) administered immittance tests (e.g., tympanograms, acoustic reflex

669

thresholds), pure-tone and speech audiometric testing, word recognition, and distortion product otoacoustic emissions testing to 10 mild to moderate patients with AD and matched controls. They found that the AD patients had only slightly worse low-frequency thresholds compared to the controls. Another study involving 33 patients with a diagnosis of AD, progressive nonfluent aphasia, or logopenic aphasia found only small differences on sound detection thresholds in the patient groups compared to controls (Goll et al., 2011). Mahoney and colleagues (2011) reported that 32% of patients with semantic dementia complained of tinnitus or hyperacusis, but peripheral hearing function was not examined. A few other less common adult-onset neurodegenerative diseases occasionally involve the peripheral auditory system. For example, one study documented a 71-year-old man who developed a rapidly progressive dementia with features of DLB and also inflammation of the cartilage of the pinna (Head et al., 2006). An autopsy revealed inflammation-induced neurodegeneration caused by relapsing polychondritis, an autoimmune inflammatory disorder of cartilaginous tissues. There are also a few other rare neurodegenerative diseases or genetic mutations that can cause a dementia and sensorineural hearing loss (e.g., mitochondrial disease syndromes, adult-onset Friedreich’s ataxia). A few recent studies have focused on cases of autosomal-dominant hereditary sensory and autonomic neuropathy with dementia and hearing loss (HSAN1) (Wright and Dyck, 1995). Klein and colleagues (2011, 2013; U.S. Congress, Office of Technology Assessment, 1992) described a primarily adult-onset hearing loss and neuropathy followed by memory decline or personality changes typical of FTD in the 30s and 40s with a mutation in DNA methyltransferase 1 (DNMT1). Autopsies in persons with a DNMT1 mutation in a case series from Japan revealed diffuse non-specific degeneration and glial activation especially in the frontal, temporal, parietal, and occipital cortex, hippocampus, and thalamus, but the auditory system was not mentioned (Hojo et al., 2004).

Central auditory system Because neurodegenerative diseases primarily affect the central nervous system, the majority of studies have focused on the central auditory system. The changes to the central auditory system are thought to occur as a result of the neurodegenerative diseases, in addition to age-related changes in the central auditory system. Histopathologic and morphometric studies have found a number of neuropathologic changes in the central auditory system in different neurodegenerative diseases. The auditory system has been most extensively studied in persons with AD. Neuron loss, neuritic plaques, and

670 J.K. JOHNSON AND M.L. CHOW neurofibrillary tangles, the classic neuropathologic impairment performed worse than matched controls lesions of AD, have been identified in auditory system but better than the demented patients, even after controlbrainstem and midbrain nuclei, including the olivary ling for age, hearing threshold, and word recognition nucleus, inferior colliculus, and medial geniculate body scores. However, the underlying diagnoses of the (Ohm and Braak, 1989; Dugger et al., 2011). In addition, demented participants were not reported. Another study plaques and tangles are also common in primary audialso found that persons with MCI had an impairment on tory and auditory association cortex in persons with a dichotic listening task that was intermediate between AD (Sinha et al., 1993; Chance et al., 2011). Neuropathohealthy adults and AD patients (Idrizbegovic et al., logic studies of the central auditory system are less com2011), again suggesting that deficits in central auditory mon in non-AD dementias. A few studies suggest that an processing occur before the onset of dementia and get accumulation of tau neuropathology in auditory brainworse after the onset of dementia symptoms. stem nuclei in persons with progressive supranuclear Impairments in central auditory function may also be palsy (Dugger et al., 2011) and severe neuronal loss a risk for developing dementia. For example, one study has been documented in the auditory cortex of persons recently found that older adults with severe central audiwith FTD and primary progressive aphasia (Baloyannis tory dysfunction, particularly as measured by the et al., 2011). These neuropathologic changes of the cenDichotic Sentence Identification test, were at increased tral auditory system are thought to be related to the prorisk for developing incident AD after 3 years (Gates cessing of sounds. et al., 2011). The majority of those who developed AD The majority of studies focus on the processing of also had lower memory scores, as measured by the memverbal information, while studies about the processing ory subscale of the Cognitive Abilities Screening Instruof non-verbal information, including music and environment. As discussed above, another recent study found mental sounds, are less commonly done. This section will that hearing loss (pure-tone average >25 dB) was indeprovide a brief overview of central auditory system dyspendently associated with increased rate of cognitive function in neurodegenerative diseases, and additional decline and incident cognitive impairment in a large saminformation about the processing of music and other ple of community-dwelling older adults (Lin et al., 2013). non-verbal sounds will be discussed in the following Some authors propose to frame auditory cognition two sections. deficits in terms of “auditory objects” or “auditory scene Early studies in the 1980s used dichotic listening paranalysis,” the ability to parse sound sources in the audiadigms (simultaneous presentation of different acoustic tory environment (Goll et al., 2010b). For example, Goll signals to the right and left ears) and other basic auditory and colleagues (2012a) recently assessed auditory scene perceptual tasks to study central auditory function in analysis of both verbal and non-verbal sounds in a cohort persons with AD. For example, Grimes and colleagues of 21 persons with AD. The persons with AD performed (1985) found that 81% of the patients with AD had abnormuch worse than matched controls on both auditory mal scores on dichotic listening tasks. The dichotic listenscene analysis tasks, but their performance was someing scores correlated with performance on tests of what attenuated after accounting for visuospatial workcognition, volume of the temporal lobes on brain coming memory. They also found that performance puted tomography imaging, and metabolism of the left correlated with brain volume in several posterior cortical temporal lobe using positron emission tomography areas, using voxel-based morphometry of brain magimaging. That is, lower scores on dichotic listening tasks netic resonance imaging (MRI). correlated with lower cognitive scores, less brain volCentral auditory processing deficits have also been ume, and lower metabolism in the left temporal lobe. studied in a few non-AD dementias. For example, Goll Other early studies using dichotic listening methods also and colleagues (2010a) found significant difficulties in documented auditory processing impairments in AD the processing of complex non-verbal sounds in patients (Grady et al., 1989; Mohr et al., 1990). 12 patients with progressive non-fluent aphasia and Persons with MCI may also have central auditory 8 patients with semantic dementia. The authors used function impairments. For example, Gates and colseveral newly designed auditory tasks to assess early perleagues (2008) examined central auditory processing ceptual, apperceptive, and semantic levels of non-verbal using a comprehensive battery (synthetic sentence idenauditory processing. While patients with progressive tification with ipsilateral competing message, dichotic non-fluent aphasia were particularly impaired on the sentence identification, and dichotic digits) in a large early perceptual tasks, the semantic dementia patients cohort of older adults who had mild memory impairment had particular difficulty with the processing of semantic (but not demented) or dementia based on a cognitive aspects of non-verbal sounds. screening test (Cognitive Ability Screening Instrument). In conclusion, impairments in the central auditory The authors found that the persons with mild memory system are common in persons with various

HEARING AND MUSIC IN DEMENTIA neurodegenerative diseases. However, the majority of studies have focused on AD, while an interest in studying central auditory function in non-AD dementias is increasing. Additional consideration of the central auditory system processing of music and non-verbal sounds can be found in the next two sections.

PROCESSING OF MUSIC IN NEURODEGENERATIVE DISEASES As discussed in the introduction, persons with neurodegenerative diseases rarely present with significant deficits in the processing of music, compared with persons who have an auditory agnosia or amusia, an acquired impairment in the ability to process music (see Chapters 32 and 34). In contrast, there are numerous anecdotal reports suggesting that the appreciation (and perception) of music often remains preserved in persons with AD and possibly other neurodegenerative diseases. How do persons with a neurodegenerative disease process and comprehend music? Do persons with different neurodegenerative diseases perceive and process music differently? How is music used as a tool to better understand both the auditory system and neurodegenerative diseases?

671 Acoustic Input

Acoustic analysis

Temporal organization

Pitch organization Tonal encoding

Interval analysis

Contour analysis

Rhythm analysis

Meter analysis

Musical lexicon

Emotion expression analysis

Vocal plan formation

Singing

Acoustic to phonological conversion

Phonological lexicon

Associative memories

Tapping

Speaking

Framework for examining music perception in neurodegenerative diseases

Fig. 37.1. Cognitive model of music processing. Each box represents a processing component, and arrows represent pathways of information flow or communication between processing components. A neurologic anomaly may either damage a processing component (box) or interfere with the flow of information between two boxes. All components whose domains appear to be specific to music are in green; others are in blue. There are three neurally individuated components in italics – rhythm analysis, meter analysis, and emotion expression analysis – whose specificity to music is currently unknown. They are represented here in blue, but future work may provide evidence for representing them in green. (Reproduced from Peretz and Coltheart, 2003, with permission.)

As discussed in Chapter 11, there are both perceptual and associative aspects involved in the perception of music. Basic-level perceptual hearing processes extract pitch, rhythm, timbre, and timing information, while higherorder cognitive processes help store and associate music sequences with long-term memories. All of these processes facilitate recognition of a musical sequence as meaningful or familiar. One of the early music psychologists, Carl Seashore (1866–1949), provided a useful framework for understanding how the physical aspects of sound (frequency, intensity, duration, and waveform) are mapped on to the perceptual qualities of music (pitch, loudness, time, timbre). That is, the acoustic aspect of frequency (number of waves per second) is associated with the perception of pitch; intensity (decibels) is associated with loudness; duration (time intervals) is associated with time/meter; and wave form (tone quality from pure tone to noise) is associated with the perception of timbre. These basic physical components of musical sounds can be combined to create music intervals, scales, harmonies, melodies, and musical compositions. Figure 37.1 depicts a commonly used contemporary cognitive model of music recognition, as proposed by Peretz and Coltheart (2003). Each box represents a music-processing component, while the lines between boxes designate the path of

information processing between components. The acoustic signal enters from the top of the model. In addition, Stewart and colleagues (2006) identified the most important brain areas implicated in disorders of music listening. The schematic of the brain at the top provides the anatomic areas involved in music listening, while the four schematics below identify specific aspects of music processing. The authors argue that this framework can be applied to both acquired and congenital disorders of music listening. It is important to keep in mind that this framework was developed from studies of patients with focal brain lesions (e.g., stroke); however, there are no compelling reasons to think that the deficits in music processing observed in persons with dementia would not follow this framework (Fig. 37.2). The melody is often the most conspicuous aspect of music, and many studies focus on the processing of familiar and unfamiliar melodies. For familiar melodies in western cultures, healthy adults store relatively precise knowledge about the notes and timing that comprise the melody. Recognition of a melody as familiar depends on the ability to match the mental representation/percept of the melody with a “musical lexicon,” which includes all melodies known to the listener (Peretz and Coltheart, 2003). Recognition of familiar

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Fig. 37.2. Brain areas implicated in disorders of music listening. Critical brain substrates for musical-listening disorders across studies. Five cartoons are shown, each depicting the brain in a schematic axial section that includes all key anatomic areas involved in music listening (identified on the top cartoon); the corpus callosum (black), superior temporal plane (light gray), and middle/ inferior temporal gyri (dark gray areas, in exploded view) are colored for ease of identification. Musical functions analyzed in Supplementary Table 1 (http://brain.oxfordjournals.org/content/129/10/2533.figures-only) have been grouped as follows: pitch processing (pitch interval, pitch pattern, tonal structure, timbre); temporal processing (time interval, rhythm); musical memory (familiar and novel material); and emotional response to music. Each group of functions is assigned to a separate cartoon; individual functions are identified to the right of the corresponding cartoon. Raw data from Supplementary Table 1 have been thresholded; the presence of a colored circle corresponding to a particular function in a region indicates that at least 50% of studies of the function implicate that region. The size of each circle is scaled according to the proportion of studies of the function implicating that region (see text). Meter is not represented as no brain area was implicated in 50% or more of cases. amyg, amygdala; aSTG, anterior superior temporal gyrus; bg, basal ganglia; cc, corpus callosum; r, frontal; hc, hippocampal; HG, Heschl’s gyrus; ic, inferior colliculi; i, inferior; ins, insula; l, lateral; m, medial; thal, thalamus; PT, planum temporale; TG, temporal gyrus. (Reproduced from Stewart et al., 2006, with permission.)

HEARING AND MUSIC IN DEMENTIA 673 music can be assessed using a variety of methods. Seva 71-year-old amateur trombone player who continued eral studies asked participants to judge the familiarity of to play in a Dixieland jazz band after he developed a melody to determine if the listener can discriminate dementia (later confirmed to be AD by autopsy) familiar and novel melodies. Another method is to ask (Beatty et al., 1994, 1997). When patient T was in the mild participants to listen to a melody and determine if the stages of dementia (with a Mini-Mental State Examinamelody is correctly played or has an error (e.g., pitch, tion score of 20 out of 30), the authors made videotaped rhythm). The Distorted Tunes Test (Drayna et al., recordings of his playing during a band performance and 2001) is one example of a pitch error detection task. asked raters to compare the quality of his playing at that Brattico and colleagues (2006) suggest that the identifitime with recordings of him playing from approximately cation of errors in melodies occurs rapidly and automat30 years prior. The raters judged these two playing examically, even with unfamiliar melodies. Several studies ples as equivalent, suggesting that there had not been any also ask participants to generate a title for a familiar melsignificant decline in his playing ability after the onset of ody, but this type of task requires different cognitive dementia. Patient T was also asked to listen to 20 familiar processes (e.g., verbal recall) compared with recognizing holiday songs and generate the titles. He recalled 80% of melodies with errors. The processing of unfamiliar melthe song titles, but his performance was slightly below a odies can be assessed using a number of different paragroup of healthy controls who recalled 95% of the titles. digms. For example, both the explicit and implicit In another early case report, Crystal and colleagues memory of unfamiliar melodies can be examined. The (Beatty and Greiner, 1998) described an 82-year-old Montreal Battery for Evaluation of Amusia (Peretz music editor and pianist who was evaluated during the et al., 2003) includes several tasks that require comparMCI stage of AD. At that time, he was able to play, from isons of unfamiliar melodies that may differ by notes, memory, 13 popular classic music compositions. Howcontour, or rhythmic patterns. ever, 3 years later, he was only able to play a few bars The next sections will review the current literature of the same pieces. Several more recent case studies have about how music, and melodies in particular, is proexamined both music perception and production in more cessed in persons who have a neurodegenerative disease. detail, including comparisons with non-AD dementias It is important to keep in mind that performance on var(Cuddy and Duffin, 2005; Hailstone et al., 2009; ious music tasks can be affected by the type and severity Vanstone et al., 2009; Omar et al., 2010; Weinstein of dementia. This often makes comparisons across studet al., 2011). Polk and Kertesz (1993) studied two persons ies difficult. Performance on music tasks can also be with atypical presentations of AD (i.e., progressive aphaaffected by the amount of prior music training. The sia and posterior cortical atrophy). majority of case studies reviewed below focus on perAfter the early case studies in the 1980s, the examinasons who are either professional or amateur musicians, tion of music skills in persons with dementia eventually while many of the group studies include persons with expanded. Subsequent research aimed to better underdifferent levels of music background. Not all studies stand how music is processed by persons with AD, report the music background of the participants. Similar and eventually, other types of neurodegenerative disto the studies reviewed above, the majority of studies eases. In addition, a number of group studies were about music have been done with persons with AD. Howconducted. ever, recent studies focus more on the processing of Several studies have focused on the ability of persons music in non-AD dementias. with AD to process both familiar and unfamiliar melodies. Persons with AD are generally able to distinguish melodies as familiar or unfamiliar (familiarity decision). Alzheimer disease This is often assessed by asking participants to listen to a As mentioned in the introduction of this chapter, there melodic excerpt and decide if the excerpt is familiar or are several case reports in the literature that document novel (new) or old. The findings with AD patients, howa relative preservation of music abilities in persons with ever, are somewhat mixed. In one study, the persons with AD. These reports primarily focus on the preserved abilAD performed slightly lower than healthy controls ity to continue playing a musical instrument after the (Bartlett et al., 1995) when asked to discriminate familiar onset of dementia. Table 37.1 summarizes these case and unfamiliar melodies, while other studies found no studies and provides a short summary of the findings. differences between AD patients and controls (Cuddy In several of the early case studies, Beatty and coland Duffin, 2005; Hsieh et al., 2011). However, persons leagues described the preserved music abilities of perwith AD may have difficulty with the explicit recognition sons with AD who had music training (Beatty, 1988, of familiar melodies. One study presented eight familiar 1999; Beatty et al., 1994, 1999; Beatty and Greiner, melodies and then asked 15 persons with mild to moder1998; Cowles et al., 2003). For example, patient T was ately severe AD to if the melodies in the next set were old

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Table 37.1 Summary of case studies investigating music in persons with dementia Study

Case

Background

Diagnosis

Main findings

Beatty et al. (1988)

GW

AD

Crystal et al. (1989)

–

Polk and Kertesz (1993)

CW

Music teacher and pianist 82-year-old music editor and pianist 58-year-old guitar teacher

Polk and Kertesz, (1993)

MA

53-year-old piano teacher

Posterior cortical atrophy due to AD

Beatty et al. (1994) Beatty et al. (1997) Johnson and Ulatowska (1996)

T

71-year-old amateur trombonist 76-year-old nonmusician

AD (pathologically confirmed) AD

Beatty et al. (1999)

ML

79-year-old amateur pianist

AD

Miller et al. (2000)

4

Primary progressive aphasia

Miller et al. (2000)

5

Miller et al. (2000)

6

49-year-old nonmusician 78-year-old nonmusician 71-year-old musician

Preserved ability to play piano; impaired ability to name familiar music Preserved ability to play piano; unable to name title or composers Preserved ability to play guitar and recognize familiar melodies; unable to reproduce rhythms Preserved ability to name familiar tunes, discriminate melodies, identify pitch errors, and reproduce rhythmic patterns; impaired ability to play piano Preserved ability to play trombone and name familiar tunes Preserved ability to reproduce melodies and rhythmic patterns and sing familiar songs, which declined over 2 years Preserved ability to play piano; difficulty learning new song and impaired naming of familiar tunes and rhythm recognition Compulsive whistling; composed songs about his bird New skill in composing classic music

Tzortzis et al. (2000)

MM

74-year-old pianist and composer

Primary progressive aphasia

Cowles et al. (2003)

CL

80-year-old amateur violinist and pianist

AD

Cuddy and Duffin (2005) Vanstone et al. (2009) Fornazzari et al. (2006)

EN

84-year-old amateur pianist

AD (pathologically confirmed)

–

AD

Preserved ability to read, interpret, and learn new musical pieces

Hailstone et al. (2009)

–

63-year-old professional pianist 56-year-old nonmusician

Semantic dementia

Matthews et al. (2009)

JS

30-year-old nonmusician

Auditory agnosia due to neurodegenerative disease

Vanstone et al. (2009)

VC

83-year-old amateur pianist

AD

Barquero et al. (2010)

–

53-year-old music critic

Frontotemporal dementia (pathologically confirmed)

Correctly sang 63% of familiar melodies; increased interest in music listening and singing along Preserved affective response when listening to personal music; impaired performance on majority of music-processing tasks administered Preserved ability to recognize and sing familiar tunes; diminished ability to play piano Preserved ability to recognize familiar tunes and process rhythm and music emotions;

DN

MCI due to AD Primary progressive aphasia due to AD

Primary progressive aphasia Primary progressive aphasia

Composed songs that captured personalities of his acquaintances Preserved ability to compose and play piano. Impaired naming of nonmusical stimuli, but preserved naming of musical instrument sounds Learned to play new song on violin; preserved ability to play previously known tunes on violin and piano, recognize familiar songs, and reproduce rhythmic patterns Generally preserved ability to recognize familiar music

HEARING AND MUSIC IN DEMENTIA

675

Table 37.1 Continued Study

Case

Background

Diagnosis

Main findings

Omar et al. (2010)

BR

56-year-old professional trumpet player

Semantic dementia

Omar et al. (2010)

WW

AD

Weinstein et al. (2011)

–

67-year-old music librarian and oboist 59-year-old harpsichordist

Semantic dementia

impaired ability to judge quality of music performance Preserved recognition of music and music symbols; impaired recognition of music emotions and recognition of musical instruments Preserved recognition of music emotions and musical instruments; impaired recognition of music and music symbols Preserved ability to play harpsichord and learn new complex pieces

AD, Alzheimer disease; MCI, mild cognitive impairment.

or new (Bartlett et al., 1995) AD patients performed worse than matched controls, suggesting that the explicit memory for familiar melodies may not remain preserved in AD. Hsieh and colleagues (2011) found that the recognition of familiar tunes correlated with the volume of the right anterior temporal lobe. Persons with AD appear to retain the ability to recognize pitch or rhythmic errors in familiar tunes (e.g., wrong notes). For example, patient EN, who was in the severe stages of AD (Mini-Mental State Examination score of 8), was able to correctly identify familiar melodies with wrong notes (pitch errors) for 25 out of 26 tunes (Cuddy and Duffin, 2005). In another group study, Johnson and colleagues (2011) examined the ability of mildly demented patients with AD to detect pitch errors in highly familiar melodies. The AD patients performed similarly to matched controls, and, as expected, the key-violating pitch errors were easier to detect than key-preserving pitch errors for both groups. Performance on this familiar melody pitch detection task correlated with gray-matter volume in the right temporal cortex, as measured by voxel-based morphometry analysis of brain MRI. Another recent study found variability (ranging from 35% to 100% correct) in the ability of moderate to severely impaired AD patients to detect errors in familiar tunes (Vanstone and Cuddy, 2010). Several studies have evaluated the ability of persons with AD to generate a title for familiar tune (i.e., name that tune) as another way to assess knowledge about familiar melodies. As discussed above, generating a title for a familiar melody requires a different type of cognitive process (e.g., verbal recall) compared with recognizing melodies with errors. After listening to an excerpt from a familiar melody, participants are asked to generate the title or select the correct title in a multiple-choice

format. While some studies found that AD patients were able to generate a similar number of titles as controls (Hsieh et al., 2012), the majority of studies found that AD patients generated fewer song titles for familiar tunes than healthy controls (Crystal et al., 1989; Bartlett et al., 1995; Cuddy and Duffin, 2005), including several case studies of musicians with AD (Beatty et al., 1994; Cowles et al., 2003; Omar et al., 2010). However, when given a multiple-choice format, the AD patients may be able to improve their score to the level of the controls (Cowles et al., 2003; Johnson et al., 2011), suggesting that the knowledge about the tunes may be intact but the ability to access the verbal labels (titles) may be impaired. It also appears that AD patients are generally able to discriminate two short, unfamiliar melodic excerpts that may differ in a number of melodic aspects, such as pitch or rhythm. For example, two studies used the Scale subtest from the Montreal Battery for the Evaluation of Amusia, which asks participants to listen to two unfamiliar melodies and determine if the second melody was the same as or different from the first melody. Half of the second melodies in the Scale subtest have an alteration of one pitch (note). Both studies found that mildly demented AD patients performed similarly to healthy controls, suggesting that AD patients are able to process novel melodic information that is presented in relatively brief formats (Hsieh et al., 2011; Johnson et al., 2011). Omar and colleagues (2010) examined other aspects of unfamiliar melody processing in their case report of WW, who scored below controls on tasks that required the processing of interval and timbre in unfamiliar melodies. In contrast, WW was able to discriminate unfamiliar melodies that differed by alterations in scale, contour, and rhythm.

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In several other studies, the explicit short-term memory for unfamiliar melodies was examined in persons with AD. One study required participants to listen to eight unfamiliar melodies (presented twice) and then make old/new judgments about a new set of melodies (half of which were novel) (Halpern and O’Connor, 2000). Persons with AD performed similarly to controls, but worse than younger adults, on the explicit music memory task. However, both AD and age-matched controls performed near chance. Two other studies found that AD patients scored lower than controls on a task requiring explicit memory for unfamiliar melodies (Bartlett et al., 1995; Quoniam et al., 2003). Implicit memory for unfamiliar melodies may also be impaired in persons with AD. Implicit memory for unfamiliar music was examined by asking persons with AD to listen to unfamiliar melodies over several trials and rate their preference, with the idea that preference ratings increase after more exposure to the melodies (“mere exposure effect”). One study found that the preference ratings increased with the number of presentations for AD patients (Quoniam et al., 2003), while another study did not find this pattern (Halpern and O’Connor, 2000). The studies included patients with different dementia severity, and the tasks were slightly different, so it is difficult to make comparisons. Other aspects of music processing, such as pitch discrimination, recognition of major versus minor tonality (e.g., scale, chords), timbre and meter perception, are rarely examined in detail. However, a few studies suggest that the the processing of basic music components may remain relatively intact in persons with AD. For example, several studies report intact pitch discrimination (Johnson et al., 2011; Goll et al., 2012a), meter perception (Cowles et al., 2003), tonality discrimination (Mohr et al., 1990), and timbre perception (Goll et al., 2010b). Only a few studies have examined the auditory processing of rhythmic information in music with persons with AD. Two case studies administered a modified version of the Seashore Rhythm subtest from the Seashore Test of Musical Talent. Both ML and SL were able to complete this task, which requires participants to judge whether two rhythmic patterns are the same or different (Beatty et al., 1999; Cowles et al., 2003). The recognition of meter (waltz vs march) was intact in patient SL (Cowles et al., 2003). However, additional studies are needed to make more general conclusions about rhythm perception in persons with AD. There are a few case reports documenting the ability of persons with AD to learn new music. One case report described an 80-year-old amateur violinist (SL) with moderately severe AD who was able to learn a new, moderately difficult violin composition over six sessions over

2 months (Cowles et al., 2003). Raters judged the quality of his violin playing as “slightly better than that of a good high school violinist.” Another reported that a professional pianist in the severe stages of AD was able to learn and recall a new eight-bar composition (Fornazzari et al., 2006). However, reports like these are quite rare, and it is not yet known if the ability to learn a new musical composition is common in more than just a few exceptional cases of AD. There has been a recent interest in studying “auditory objects” in persons with dementia. Auditory objects can be defined as a “collection of acoustic data bound in a common perceptual representation an disambiguated from the auditory scene” (p. 617) (Goll et al., 2010b) These studies often consider basic levels of musical sound processing in addition to higher levels of sound conceptualization. For example, Goll and colleagues (2011) completed a systematic study of non-verbal sound processing, including music, in 21 persons with AD (and other neurodegenerative diseases, also discussed below). They found that AD patients scored lower than controls on timbre and pitch perception; however, after adjusting for performance on a spatial working-memory task, the AD patients performed similarly to controls. As discussed below, patients with progressive non-fluent aphasia and logopenic aphasia had difficulty with timbre perception. In contrast, the AD patients had a disproportionate impairment on a task that required recognition of degraded sounds based on perceptual rather than semantic information, even after adjustment for spatial working-memory performance. On this task, participants were asked to decide whether a degraded sound was more like an animal calling or a tool being used.

Frontotemporal dementia Although the initial studies about music and dementia focused on persons with AD, more recent studies have examined music abilities in persons with non-AD dementias, including the variants of FTD. Several case studies of persons with semantic dementia have recently been published. For example, a 56-year-old professional trumpet player and music teacher (BR) completed an extensive battery of tests to examine his music abilities after developing semantic dementia (Omar et al., 2010). On tests of music perception (from the Montreal Battery for the Evaluation of Amusia), he scored lower than controls on the recognition of melodic contour (shape of the melody), intervals, and timbre. He also had difficulty recognizing emotions in music and identifying the sounds of musical instruments. He was, however, able to play familiar pieces from memory after music cueing and continued to play his trumpet (non-professionally). As another example, a 64-year-old semiprofessional

HEARING AND MUSIC IN DEMENTIA harpsichordist diagnosed with semantic dementia was able to perform technically demanding compositions and generate appropriate stylistic embellishments 5 years after the onset of semantic dementia (Weinstein et al., 2011). However, additional tests of music perception were not administered with the harpsichordist. There have also been a few group studies involving patients with semantic dementia (who are mostly nonmusicians). These studies suggest that, while several aspects of music knowledge can remain preserved in semantic dementia, they may have difficulty processing familiar melodies. When examining the recognition of familiar melodies, two studies found that patients with semantic dementia had difficulty in either detecting “wrong notes” (pitch errors) in familiar tunes or judging if a tune was familiar or novel (Hsieh et al., 2011; Johnson et al., 2011). Patients with semantic dementia also had significant difficulty generating titles for familiar melodies or selecting the famous title from a four-item multiple-choice format. However, Omar and colleagues (2010) found that their 56-year-old trumpet player with semantic dementia could match titles to several famous melodies. It is important to keep in mind, however, that the majority of case studies involve persons who have a background in music, while most of the group studies involve non-musicians with varying degrees of involvement in music. Several other studies have documented an increased interest in music after developing semantic dementia (Miller et al., 2000; Boeve and Geda, 2001; Hailstone et al., 2009) and a change in music taste (new interest in pop music) in a person with FTD (Geroldi et al., 2000). Barquero and colleagues (2010) studied a 53-year-old music critic whose first symptom was a complaint about trouble evaluating the “quality of a musical performance.” Although her neurologic and neuropsychologic examinations were normal, she had difficulty differentiating renditions of music performed by either a professional or a beginner music student. It appears that her ability to recognize various music elements (e.g., melodies, pitch errors, rhythm, and meter) was preserved at that time, although the specific tasks and results are not available. She later developed a progressive dementia syndrome and was diagnosed with FTD caused by a novel progranulin mutation. An autopsy revealed ubiquitin-positive inclusions, particularly in the frontal, temporal, and parietal cortices. A few studies have focused on persons with progressive aphasia. For example, Miller and colleagues (2000) studied three individuals with progressive language symptoms (variants of primary progressive aphasia). One non-musician developed compulsive whistling and composed songs about a bird, and the other nonmusician began composing classic music that was

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performed in public (despite the lack of prior training in music composition). The third patient was a skilled musician who also composed songs. Tzortzis and colleagues (2000) performed a comprehensive examination of music abilities of a professional pianist and composer with a 9-year history of progressive aphasia. They administered a series of tests that focused on receptive music skills (e.g., pitch error detection, identification of chords and musical styles) and expressive music skills (e.g., playing music from memory, reading an unfamiliar musical score). They found a consistent preservation of both receptive and expressive music skills, and the patient continued to compose music. The famous French composer, Maurice Ravel, is another example of a musician who developed a progressive aphasia and apraxia but was able to compose for a time after the onset of symptoms (Amaducci et al., 2002). The progression symptoms, however, eventually affected his ability to compose, although Ravel reported that he could “hear” the music in his head. Additional studies are needed to better understand the effect of progressive aphasia on music skills.

Parkinson’s disease Only a few studies to date have focused on the perception of music in persons with Parkinson’s disease. Most studies have focused on rhythmic auditory cueing (using music) to improve gait in Parkinson’s disease (e.g., Thaut et al., 2001). One study examined rhythm discrimination in 15 persons with Parkinson’s disease (with Hoehn and Yahr stages 1 or 2) (Grahn and Brett, 2009). The authors administered a series of rhythm recognition tasks with and without a clear beat. The results suggested that the patients with Parkinson’s disease had difficulty perceiving the beat structure, compared with matched controls. However, the patients performed similarly to controls in the non-beat conditions. Another study found that patients with Parkinson’s disease had difficulty recognizing fear and anger in music (van Tricht et al., 2010). In this study, participants were asked to listen to 32 music excerpts and determine whether they expressed happiness, sadness, fear, or anger. Interestingly, the persons with Parkinson’s disease were able to correctly identify happiness and sadness in the music but had more difficulty identifying anger and fear (Fig. 37.3). The authors argued that the patients did not have deficits in the processing of music, as they performed similarly to controls on two subtests from the Montreal Battery for the Evaluation of Amusia (i.e., melodies, rhythm). The difficulty identifying fear and anger in music was consistent with other studies suggesting that persons with Parkinson’s disease have difficulty recognizing emotions.

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J.K. JOHNSON AND M.L. CHOW Emotion recognition in PD patients and healthy controls

8 +

Number correct

7

+

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4 3 2 1 Anger

Fear

Happiness

Sadness

Fig. 37.3. Identification of emotions in music by persons with Parkinson’s disease (PD). Box plot of the scores on the four subtests of the emotion recognition task in PD patients (black lines, gray boxes) and controls (gray lines, white boxes). On the happiness subtest all subjects obtained the maximum score, except two subjects (+). For the fear recognition subtask, none of the controls scored below 5, therefore the downward error bar is absent. (Reproduced from van Tricht et al., 2010, with permission.)

Huntington’s disease Woodie Guthrie (1912–1967) is perhaps the most famous musician to have developed Huntington’s disease. Guthrie performed during the early stages of the disease, but it eventually affected his music career and ability to sing and play (Arevalo et al., 2001; Innes and Chudley, 2002). His impact on the genre of folk music resulted in his induction into the Rock and Roll Hall of Fame in 1988. The impact of Huntington’s disease on the music abilities of Guthrie was never formally studied, but a few studies have examined the processing of music in persons with Huntington’s disease. For example, Beste and colleagues (2011) examined the brain response (using functional MRI) to three types of auditory stimulation (music, tones, and syllables) in persons with either premanifest Huntington’s disease or manifest Huntington’s disease. The music condition included listening to a piano piece by French composer Charles-Valentin Alkan (“Barcarole”). Compared to controls, the persons with Huntington’s disease had increased activation in the cerebellum and medial prefrontal cortex and reduced activity in the left parahippocampal gyrus and right fusiform gyrus when listening to a musical composition. In addition, the authors found that the processing of music was correlated with the severity of the movement disorder. Another study used an auditory stimulation paradigm (sequence of tones) and functional MRI methods to examine the basal ganglia-thalamic brain circuits in

persons with either premanifest or manifest Huntington’s disease (Saft et al., 2008). The authors found reduced activation of basal ganglia-thalamic circuits in premanifest Huntington’s disease, but persons with clinically evident Huntington’s disease had hyperactivation of the same structures when listening to a sequence of tones. The authors suggested that this pattern reflected functional reorganization of brain areas in an attempt to maintain auditory function. The basal ganglia has been an area of interest in investigations of sound processing because of its role in attention-dependent temporal processing (Buhusi and Meck, 2005; Langers and Melcher, 2011). In particular, this region interacts with the supplementary motor area and the cerebellum for the temporal processing of sounds Macar et al., 2006; Ivry and Schlerf, 2008; Coull et al., 2011). Apart from these few studies, there does not appear to be any further systematic studies of music processing in persons with Huntington’s disease.

Recognition of emotions in music The link between music and emotions has been debated for centuries. An interest in how humans perceive the emotional content in music or how an emotional response to music is generated has increased in recent years (Juslin and Sloboda, 2010). There are a number of cues that convey emotions in music. For example, a listener may visually perceive the gestures of a performer that reflect emotions. Listeners might also hear musical cues, such as tempo or tonality of a piece, that convey emotional information. For the purposes of this chapter, we will focus on the recognition of emotions while listening to music in persons with dementia. Several recent studies have examined the recognition of emotions in music in persons with both AD and nonAD dementias. Hsieh and colleagues (2011) studied the recognition of emotions in music with 11 persons with semantic dementia, 12 with AD, and 20 healthy controls. They administered 40 unfamiliar music excerpts that represented four emotions (happy, peaceful, sad, or scary). The participants were asked to listen to the excerpt and select the emotion that best represented the music. Both semantic dementia and AD patients scored lower than controls in identifying the emotions associated with the music, but the semantic dementia patients performed substantially worse than the AD patients. The authors also found that the semantic dementia patients had particular difficulty when identifying negative (sad or scary) compared to positive emotions (happy or peaceful) in the music. In addition, both AD and semantic dementia patients had more difficulty identifying emotions in music than emotions in faces.

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Fig. 37.4. Correlation between performance on music emotions task and brain atrophy. Voxel-based morphometry analyses showing brain regions that correlate with recognition of musical emotions (top left: Montreal Neurological Institute (MNI), x ¼ 46, y ¼ 12, z ¼ 46; top right: MNI, x ¼ 40, y ¼ 6, z ¼ 48). Colored voxels are significant at P < 0.001 uncorrected. (Reproduced from Hsieh et al., 2012, with permission.)

A similar pattern was observed in two case studies, one with AD and the other with semantic dementia (Omar et al., 2010). These initial studies suggest that persons with AD and semantic dementia have deficits in recognizing emotions in music when it is just presented as an auditory stimulus. Hsieh and colleagues (2012) also examined the correlation between the performance on the music emotions task with the amount of atrophy on the brain MRI using voxel-based morphometry. They found that performance on this task was correlated with brain atrophy in the right anterior temporal pole, insula, and amygdala (Fig. 37.4). That is, the patients who had the most difficulty identifying the emotions in the music excerpts had the most atrophy in these areas. Interestingly, there was some overlap between the brain areas involved in perceiving emotions in music and those involved in perceiving emotions in faces. Apart from these few studies with AD and semantic dementia, the recognition of emotions in other types of neurodegenerative disorders is largely unexplored.

PROCESSING OF NON-VERBAL SOUNDS IN NEURODEGENERATIVE DISEASES In addition to the studies involving music reviewed above, there are a number of other studies that have examined the processing of non-verbal (non-musical) sounds in persons with neurodegenerative diseases. Several authors have provided a framework for categorizing non-verbal sounds that occur in the environment. Taken broadly, there are sounds produced by both living (biologic) and non-living (non-biologic) agents. Within the living category, there are sounds produced by both humans and animals; within the non-living category,

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there are mechanic and environmental sources of sounds (Griffiths and Warren, 2004; Engel et al., 2009). There have been a number of studies that examine how nonverbal (non-musical) sounds are processed in neurodegenerative diseases. In one of the early studies about non-verbal sound processing in AD, Rapcsak and colleagues (1989) used a sound–picture-matching task to evaluate the processing of non-verbal sounds in AD. The authors found that patients with mild to severe AD had considerable difficulty selecting the correct picture that corresponded to the non-verbal sound. In contrast, the AD patients had no difficulty selecting the correct picture when the examiner verbalized the names. Other studies have also documented difficulty with selecting pictures to match non-verbal sounds in persons with AD (Eustache et al., 1995; Brandt et al., 2010). A few studies have examined the processing of environmental sounds in non-AD dementias. For example, Bozeat and colleagues (2000) used 48 sounds from six categories (domestic animals, foreign animals, human sounds, household items, vehicles, and musical instruments) to study non-verbal sound processing in 10 patients with semantic dementia. They asked the patients to match sounds to pictures, sounds to written words, and spoken words to pictures using an array with 10 within-category items. They also administered a neuropsychologic battery of general semantic knowledge. The semantic dementia patients performed below controls on all the tasks involving the environmental sounds. They also found significant correlations between the environmental sounds tasks and verbal tests of semantic knowledge, suggesting that the semantic breakdown in patients with semantic dementia extends to both verbal and non-verbal information. In another study involving patients with two atypical parkinsonian disorders (corticobasal degeneration, progressive supranuclear palsy), AD, and FTD, Chow and colleagues (2010) examined the naming sounds generated from both manipulable (e.g., hammer) and nonmanipulable objects (e.g., train). An item was considered manipulable if the action required to make the sound required manual manipulation by the hand. They found that the patients with corticobasal degeneration or progressive supranuclear palsy named significantly fewer sounds than controls or patients with AD or FTD, who typically do not have prominent motor symptoms. In addition, the corticobasal degeneration and progressive supranuclear palsy patients had a disproportionate impairment in the ability to name the sounds from manipulable objects. Interestingly, action naming and verb production are often impaired in patients with corticobasal degeneration and progressive supranuclear palsy (Bak et al., 2006; Cotelli et al., 2006). These

J.K. JOHNSON AND M.L. CHOW Left hemisphere

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findings suggest that the ability to physically manipulate an object is related to the ability to name an object and suggest a link between the auditory system, cognition, and the motor system. Chow and colleagues (2010) also found a correlation between performance on naming sounds of manipulable objects and gray-matter volume on MRI in the left, premotor areas and left dorsolateral prefrontal cortex. As discussed above, Goll and colleagues (2012a) recently assessed auditory scene analysis, the ability to parse sound sources in the auditory environment, of both verbal and non-verbal sounds in a cohort of 21 persons with AD. The persons with AD performed much worse than matched controls on both auditory scene analysis tasks, but the performance was somewhat attenuated after accounting for visuospatial working memory. They also found that performance correlated with brain volume in several posterior cortical areas, using voxelbased morphometry of brain MRI. The temporal lobe has also been implicated in the central auditory dysfunction of patients with other neurodegenerative diseases. Patients with semantic dementia showed differential activation of the temporal lobe when listening to animal and tool sounds in a functional MRI paradigm (Goll et al., 2012b) (Figs 37.5 and 37.6). The paradigm involved the perceptual processing of spectrotemporally complex but meaningless sounds and for the semantic processing of environmental sound category (animal sounds versus tool sounds). Thus, anterolateral temporal cortical mechanisms may be necessary for the representation and differentiation of sound categories. The processing of non-verbal auditory signals has also been studied using electrophysiology and other brain-imaging methods in persons with neurodegenerative diseases. For example, event-related potentials (ERPs) can be measured on the scalp (after stimulus onset) and can provide estimates of the activity of specific brain areas involved in the processing of sensory information. With auditory stimuli, electrical potentials can be measured beginning in the brainstem (as with brainstem auditory evoked potential) up to brain networks involved in both primary and secondary auditory cortices (P50, N100, N200) as well as association cortex (N200, P300). These scalp recordings are often recorded (using electroencephalograph (EEG) electrodes) when participants perform a behavioral task. The oddball task is commonly used in electrophysiologic studies of neurodegenerative diseases. The oddball task requires subjects to listen to a sequence of repeating tones (e.g., 1000 Hz) with a constant speed and press a button when they hear an oddball or deviant tone (e.g., 2000 Hz). In this oddball paradigm, the deviant tones elicit a series of electric potentials that can be measured over time using EEG methods.

% signal change

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1 0 −1

Fig. 37.5. Category-specific contrast effects sampled at previously specified foci of category-specific semantic sound processing. Bars show mean effect sizes (proportionate to percent blood oxygen level-dependent (BOLD) signal change) for the control and semantic dementia (SD) patient groups separately for the category-specific semantic contrast at prespecified foci of category-specific auditory processing (based on Lewis et al., 2005); 95% confidence intervals are also displayed. The upper panels show effects at foci previously associated with animal sound processing in the contrast assessing category-specific semantic processing favoring animal sounds, [(mful_a – mless_a) – (mful_t – mless_t)]; whilst the lower panels show effects at foci previously associated with tool sound processing in the reverse contrast assessing category-specific semantic processing favoring tool sounds, [(mful_t – mless_t) – (mful_a – mless_a)]. Asterisks above bars indicate significance levels for the control and SD groups separately; asterisks above brackets indicate significance levels for between-group comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; mSTG, middle superior temporal gyrus; pLaS, posterior lateral sulcus; pMTG, posterior middle temporal gyrus; SD, semantic dementia. (Reproduced from Goll et al., 2012b, with permission.)

Although the various potentials have been studied in persons with dementia, the P300 brain potential is thought to be important in the study of AD, particularly in the early stages. Again, the majority of studies have been done in persons with AD. Persons with AD have long been known to exhibit prolonged peak P300 latency and decreased P300 amplitude (Polich et al., 1990; Holt et al., 1995; Polich and Pitzer, 1999) compared with healthy controls. The differences in amplitude and latency may be used to help differentiate between healthy individuals and those with preclinical or early

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Fig. 37.6. Statistical parametric maps showing activation profiles for perceptual and semantic processing of environmental sounds in healthy controls and patients with semantic dementia. Statistical parametric maps show clusters (formed at whole-brain uncorrected height threshold P < 0.001) that are significant at extent threshold P < 0.05, family-wise error-corrected for multiple comparisons over the whole brain. Maps are rendered on a composite mean normalized structural brain image; the left hemisphere is shown on the left for all coronal and axial sections. For sagittal and coronal sections the plane is indicated using Montreal Neurological Institute (MNI) coordinates. All axial slices are tilted parallel to the superior temporal plane to show key auditory regions; the anatomic plane of view is indicated. SD, semantic dementia; STP, superior temporal plane; STS, superior temporal sulcus. Panels a and b: the color bar (left) codes voxel-wise T scores for contrast (meaningless sounds > silence). Panel c: all clusters showing a significant interaction with group (patient > control) for the contrast (all meaningless sounds > silence) are depicted in either magenta or cyan. Magenta codes voxels in which controls alone showed greater activation in the reverse contrast (silence > meaningful sounds) than the forwards (meaningless sounds > silence) contrast, indicating that the group interaction within these voxels may be driven by greater activation for controls compared to patients in the reverse contrast. However, remaining voxels, coded in cyan, are likely to be driven by greater activation for patients compared to controls in the forwards contrast. Panels d and e: green codes significant clusters in the contrast assessing the category-specific semantic processing favoring animal sounds, [(mful_a–mless_a) – (mful_t–mless_t)]; blue codes significant clusters in the contrast assessing category-specific semantic processing favoring tool sounds, [(mful_t – mless_t) – (mful_a – mless_a)]. Panel f: all clusters showing a significant interaction with group (patient > control) for the contrast assessing category-specific semantic processing favoring animal sounds are depicted in either magenta or cyan. Magenta codes voxels in which controls alone showed greater activation in the reverse contrast (categoryspecific semantic processing favoring tool sounds) than the forwards (category-specific semantic processing favoring animal sounds) contrast, indicating that the group interaction within these voxels may be driven by greater activation for controls compared to patients in the reverse contrast; however, remaining voxels, coded in cyan, are likely to be driven by greater activation for patients compared to controls in the forwards contrast. (Reproduced from Goll et al., 2012b, with permission.)

AD (Polich and Pitzer, 1999; Golob et al., 2002, 2007). In another study, Golob and colleagues (2007) found significantly larger P50 and N100 amplitudes (using an auditory oddball task) in amnestic MCI patients who eventually converted to AD, compared with those who remained stable. The P50 and N100 amplitudes were also larger in the MCI converters than those with mild AD, suggesting that these potentials may reflect the neural activity during the transition from MCI to AD. Figure 37.7 shows the P50 and N100 results for each of the groups studied (young adults, older adults, MCI stable, MCI converters, and mild AD). P300 latency was also increased in MCI converters, but the P300 did not differentiate the MCI converters from the mild AD patients.

ERP measures may also be helpful in differentiating dementia etiologies. For example, the P300 latency, amplitude, and topography may differ between individuals with DLB and AD (Bonanni et al., 2010). These measures may also help distinguish between patients with Parkinson’s disease with and without cognitive impairment (Nojszewska et al., 2009). Although few in number, ERP methods have also been used to study non-verbal auditory processing and attention in other non-AD dementias, such as Huntington’s disease (Uc et al., 2003; Beste et al., 2008), vascular cognitive impairment (Muscoso et al., 2006), and primary progressive aphasia (Onofrjet al., 1994). Thus, auditory potentials may differ according to the degree of cognitive impairment and also help distinguish dementia etiologies.

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Fig. 37.7. P50 and N100 results for five subject groups. Eventrelated potentials to non-targets during the baseline session in all older subjects (A), mild cognitive impairment (MCI) subtypes (B), and young and older controls (C). (D) P50 amplitudes from individual MCI subjects (MCI single domain (MCI-SD) and MCI multiple domain (MCI-MD)). Mean  1 SD from controls are also shown for comparison. Group comparisons of P50 (E) and N100 (F) amplitudes. Note that in panel F negative potentials are plotted upwards because the N100 is negative in polarity. Vertical lines indicate stimulus onset. Asterisks show post hoc tests indicating significant differences between pairs of groups, shown by insert (*P < 0.05, **P < 0.01). (Reprinted from Golob et al., 2007, with permission.)

MUSIC AS THERAPY FOR DEMENTIA Music has also been used as a therapeutic intervention for persons with dementia. The music activities range from informal (e.g., background music in assisted-living environments) to more formal approaches, such as with music therapy – defined as the use of music to accomplish specific therapeutic goals within a therapeutic relationship with a board-certified music therapist. Additional information about the use of music with dementia can be found in Clair and Memmott (2008).

The early evidence for the positive impact of music on persons with dementia came out of the music therapy and nursing literature in the 1980s. These studies focused on using music activities to manage behavioral symptoms and increase alertness in persons who were in the severe stages of dementia (Norberg et al., 1986; Millard and Smith, 1989). Since these early studies, the number of studies examining the effect of music interventions on persons with dementia has increased steadily. However, it is important to keep in mind that there are concerns about the methodologic quality of many of these studies, as articulated in the most recent Cochrane Collaboration review (Vink et al., 2004), which was updated in 2011 again with the statement, “There is no substantial evidence to support nor discourage the use of music therapy in the care of older people with dementia” (Vink et al., 2011). The studies have been criticized with regard to the research design, small sample sizes, short length of interventions, and presentation of results. Keeping these limitations in mind, however, the section below will review the primary areas of research and promising leads about the effects of music interventions for persons with dementia. There is clearly a need for higher-quality studies about the therapeutic effects of music on persons with dementia, particularly because non-pharmacologic interventions, like music, can be relatively low-cost to implement and easily translated in many different settings. There is also a need to improve the tools for assessing the effect of music on persons with dementia. This area of inquiry remains of high interest, which can be inferred by the publication of several recent reviews (Wall and Duffy, 2010; McDermott et al., 2012; Raglio et al., 2012). The majority of research about the therapeutic effects of music for persons with dementia has focused on using music to help reduce behavioral and psychologic symptoms, such as agitation, aggression, anxiety, and depression. A number of studies have concluded that music interventions, such as music listening or group music therapy sessions, were associated with reduced agitation in persons with dementia (Groene, 1993; Clark et al., 1998; Gerdner, 2000; Sung et al., 2006; Janata, 2012). It is important to note that the majority of these studies enrolled persons who met criteria for dementia, but most studies did not stipulate specific dementia diagnoses. It is likely that the effect of music on behavioral symptoms will differ depending on the dementia diagnosis. In a recent study with an improved study design, Vink and colleagues (2012) randomly assigned 77 persons with dementia (34% AD, 21% vascular dementia, 35% other or missing) to either 4 months of music therapy (twice weekly) or recreational activities (active control). Both interventions were associated with a reduction in agitation from before to after the sessions (as measured by a

HEARING AND MUSIC IN DEMENTIA modified version of the Cohen-Mansfield Agitation Inventory), but there were no significant differences between the effects of music or recreational activities on agitation. Several studies have also found a reduction in symptoms of anxiety and depression after various music interventions. For example, Guetin and colleagues (2009) randomly assigned 30 mild to moderately severe patients with AD in assisted living to either 4 months of weekly music therapy sessions or a control group. The patients with AD who completed the music therapy sessions had significantly lower scores on Hamilton Anxiety Scale scores. This effect persisted another 2 months after the music therapy sessions ended. Other studies also report a reduction in anxiety and depression after various music interventions (Ashida, 2000; Han et al., 2010; Sung et al., 2010, 2012). Several studies have also attempted to examine the possible effect of music interventions on cognitive function in persons with dementia. For example, one study found improved spontaneous speech content and language fluency (as measured by the Western Aphasia Battery speech subscale) in a group of mild to severely impaired persons with dementia following 2 months of music therapy, compared to conversation sessions. Another study examined the effect of a 12-week Sound Training for Attention and Memory and Dementia (STAM-Dem) program on persons with mild to severe dementia compared to a usual-care group (Ceccato et al., 2012). The authors found that the group with STAM-Dem training had significantly better pre–posttest scores on attention and prose memory but not the test of global cognition (Mini-Mental State Examination). Other studies also document a lack of improvement on the MiniMental State Examination after various music interventions (Groene, 1993; Raglio et al., 2008; Guetin et al., 2009). This is not surprising because it is unlikely that global tests of cognition are sensitive enough to detect possible effects of music on cognition. It is difficult to know at this stage whether or not music interventions are an effective tool for managing behavioral symptoms of dementia, in particular, AD. Despite the limitations of the studies, there appear to be promising trends that suggest that music may be an effective therapeutic tool, and additional studies are needed. Music-based movement therapy (Thaut et al., 1996) has also been used to help improve gait and balance in persons with Parkinson’s disease. This type of intervention is based on the premise that the temporal structure in music helps provide meaningful auditory cues that facilitate synchronization of movement, such as gait (Madison et al., 2011). A recent meta-analysis of six randomized controlled trials involving persons with Parkinson’s disease concluded that music-based movement

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therapy had positive effects on several motor outcomes (i.e., Berg Balance Scale, Timed Up and Go, and stride length) but not the Unified Parkinson’s Disease rating motor scale (de Dreu et al., 2012). These results suggest that additional research is needed to explore the possible benefit of music-based movement therapy for persons with Parkinson’s disease.

SUMMARY This chapter provided a broad overview of hearing in persons with neurodegenerative diseases, with a particular focus on the auditory processing of music as one type of auditory stimulus. The literature suggests that the processing of music information differs by dementia etiology. Impairments in the central auditory system are common in persons with various neurodegenerative diseases. A number of case reports document a relative preservation of music abilities in persons with AD, particularly for playing a musical instrument, processing of basic aspects of music, and making judgments about familiar melodies. However, persons with AD have difficulty with the short-term memory for music excerpts. Studies with persons with semantic dementia suggest that aspects of music knowledge may remain preserved, although they may have difficulty processing familiar melodies. These studies are few and most include only musically trained individuals. Music-based movement therapy may improve some motor function for persons with Parkinson’s disease, while it appears that they have difficulty with rhythm perception or recognizing some emotions in music. The processing of auditory stimuli in persons with Huntington’s disease appears to engage brain circuits involved in movement. The evidence for the positive effect of music on managing behavioral symptoms in AD is encouraging, but higher-quality studies are needed. It is important to keep in mind that performance on various music tasks can be affected by the type and severity of dementia. This often makes comparisons across studies difficult. Performance on music tasks can also be affected by the amount of prior music training. The majority of case studies focus on persons who are either professional or amateur musicians, while many of the group studies include persons with different levels of music background. The studies about music processing in neurodegenerative diseases are also helping improve the understanding about how the brain processes music information.

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Handbook of Clinical Neurology, Vol. 129 (3rd series) The Human Auditory System G.G. Celesia and G. Hickok, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 38

Future advances GASTONE G. CELESIA1* AND GREGORY HICKOK2 Department of Neurology, Loyola University of Chicago; Chicago Council for Science and Technology, Chicago, IL, USA

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Department of Cognitive Sciences, Center for Language Science and Center for Cognitive Neuroscience, University of California, Irvine, CA, USA

INTRODUCTION Advances in knowledge of the function of the auditory system have been particularly astounding in the last 30 years, fueled by technical advances that have allowed us to probe the functioning brain in vivo. Neuroimaging technologies (e.g., positron emission tomography, magnetic resonance imaging (MRI), functional MRI (fMRI)) have increased our understanding of brain function, particularly in humans, and allowed detailed diagnosis of neurologic disorders. Technology, from cochlear implants to robot surgery, from molecular biology to neuropharmacology, has improved our ability to alleviate human suffering. But what will the future hold? Making predictions about the future is a tricky business. As Eliot points out, “among all form of mistakes, prophecy is the most gratuitous” (Eliot, 1852). Nevertheless, some educated guesses may be formulated based on the current state of the art.

NEWAND DEVELOPING TECHNOLOGIES Technologic development is one of the biggest stories in the last 20 years of research in neuroscience and there is every reason to believe that continued development of existing methods and the invention of new technologies will drive the field in the next decade or two. Refinement of fMRI will improve the resolution of cortical mapping while diffusion MRI will allow us to push forward our knowledge of structural connectivity of the whole brain. New techniques, such as Optogenetics (Aston-Jones and Deisseroth, 2013), Brainbow, and CLARITY (Ducros et al., 2011; Chung et al., 2013) will “provide unprecedented images of neural architecture” (Livet et al., 2007; Aston-Jones and Deisseroth, 2013; Chung et al.,

2013; Deisseroth, 2014). CLARITY refers to the development of see-through brains (Chung et al., 2013; Shen, 2013; Deisseroth, 2014), making tissue transparent. It offers a three-dimensional view of neural networks, which can be combined with genetically labeling neurons with multiple, distinct color information from a complex system (Chung et al., 2013) (Fig. 38.1) and the ability to probe the “structural and molecular underpinnings of physiological function and disease” (Livet et al., 2007; Ducros et al., 2011; Deisseroth, 2014). As stated by Chung et al. (2013), “CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and diseases.” Molecular fMRI is another promising technique that allows the study of neurotransmitters detectable by MRI. For example, dopaminergic signaling has been studied in rats and it demonstrated the “participation of hypothalamic circuitry in modulating dopamine response” (Lee et al., 2014). These exciting technologies will improve our understanding of the auditory system.

NEW TECHNOLOGIES ENABLE NEW LARGE-SCALE RESEARCH PROJECTS Similar to the human genome project of the 1990s, new methods in neuroscience have sparked several largescale projects aimed at mapping the brain. The National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative is aimed at getting “a dynamic picture of the brain in

*Correspondence to: Gastone G. Celesia, MD, FAAN, 3016 Heritage Oak Lane, Oakbrook, IL 60523, USA. E-mail: [email protected]

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Fig. 38.1. Neurons in an intact mouse hippocampus visualized using CLARITY and fluorescent labeling. Kwanghun Chung and Karl Deisseroth, HHMI/Stanford University. (Reproduced from Shen, 2013.)

action” (Insel et al., 2013). BRAIN promises to expand the Brain Activity Map (BAM) (Alivisatos et al., 2013; Bonilha et al., 2014; Striedter et al., 2014). Another project, the Big Brain, is an ultrahigh-resolution threedimensional model of a “human brain at nearly cellular resolution of 20 micrometers, based on the reconstruction of 7404 histological sections” (Amunts et al., 2013; Caspers et al., 2014). According to Amunts et al., it “provides a basis for addressing stereotaxic and topological positions in the brain at micrometer range” (Amunts et al., 2013). The Human Connectome project or Connectomics (Irimia et al., 2012; Toga et al., 2012; Petrella and Doraiswamy, 2013) refers to the mapping of all neuronal connections in the live human brain. As stated by Goni et al. (2014), “Patterns of distributed brain activity are thought to underlie virtually all aspects of cognition and behavior” and, by mapping the connectivity patterns, it is hoped to achieve a better understanding of how these distributed patterns of activity give rise to human behavior. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) project is a consortium of many scientists looking at a large-scale collaborative analysis of neuroimaging and genetic data (Jahanshad et al., 2013). Its aim is to detect genetic variants that influence the brain. For example, Bakken et al. (2012) have shown that the common genetic variants in GPCPD1 gene “contribute to the proportional area of human visual cortex.” While large-scale neuroscience mapping studies are impressive and important, it is equally important to recognize that a detailed, high-resolution picture of brain structure and functional activity patterns does not, on its own, automatically reveal how the brain works, any more than the successful completion of the human genome project unraveled all the mysteries of how our genetic endowment builds a human. The key to a deeper

understanding of the brain generally, and the auditory system in particular, is uncovering the nature of the computations and information-processing systems that neural circuits support, how they evolve developmentally, and how they can be modified by learning or disease. For this we need a large-scale “Human Cognome” project (Horn, 2002) aimed at mapping the informationprocessing systems in the mind to parallel the large-scale neuroscience mapping projects. A combination of molecular genetics and advanced neuroimaging techniques will certainly be fruitful. Some programs, such as Connectome genetics attempts to discover how genetic factors affect brain connectivity,” are presently underway (Thompson et al., 2013).

APPLICATIONS TO DISEASE New developments in neuroscience are already having an impact on treatment. Research sparked by the Human Connectome project has been applied to Alzheimer disease and mild cognitive impairment (Reijmer et al., 2013), as well as autism spectrum disorders, in which Goch et al. (2014) report that “the network centrality of Wernicke’s area is significantly” reduced, suggesting that some brain disorders may be related to defective connectivity. Gene therapy is a particularly promising and potentially game-changing method for audition that could be facilitated by the ENIGMA project. For example, the discovery that Atoh1, a gene also known as Math1, is a “key regulator of hair cell development and induces regeneration of hair cells” (Izumikawa et al., 2005; Staecker et al., 2011) led to trials in guinea pigs and mice, showing that injection of Atoh1 into the cochlea improves hearing thresholds in the mature deaf inner ear (Fig. 38.2). A trial on humans is presently scheduled, with the hope of restoring “hearing to those that have lost it” (Thomson, 2014). Other potential strategies to repair inner-ear damage are stem-cell therapy and molecular therapy (Kesser and Lalwani, 2009; Geleoc and Holt, 2014). Other technologic advances have greatly improved digital hearing aids and recently nanotechnology has demonstrated the possibility of extracting energy from the biologic battery of the inner ear (Mercier et al., 2013). These authors have shown that the endochochlear potential can generate energy that can be utilized by a microchip (Fig. 38.3). It may be possible in the future to utilize this inner-ear “battery” for therapy of hearing disorders and specifically to energize “cochlear implants and stapes prosthesis” (Mercier et al., 2013). This is an exciting period for neuroscience, and the next decades will certainly result in stunning improvements in our understanding and treatment of hearing disorders.

FUTURE ADVANCES

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Fig. 38.2. Hair cells reappear in deaf ears treated with Ad.Atoh1. Scanning electron micrograph view of deafened cochlea 2 months after Atoh1 inoculation (A–C), contralateral cochlea (D), Ad.empty-inoculated ear (E), and higher magnification of inner hair cell (IHC) (F) and outer hair cell (OHC) (G) 2 months after Atoh1 inoculation. (A) The site of inoculation in the second cochlear turn (asterisk) is shown along with numerous stereocilia bundles at the normal sites of IHCs (I) and OHCs (rows 1–3). Pillar cells (P) are present between IHCs and OHCs. Ectopic bundles (arrowheads) are seen lateral to the third row of OHCs. (B) In some Atoh1-treated ears the morphology of IHCs (I) and OHCs (O) is less well differentiated. (C) In other Atoh1-treated ears, air cell reappearance is incomplete and third-row OHCs are missing. (D, E) Second cochlear turns of right (D, contralateral to A) or Ad. empty-inoculated left cochlea (E), showing complete absence of hair cells. (F, G) Stereocilia bundle organization is relatively normal in IHCs (F) and OHCs (G) but supporting cells between neighboring air cells are narrow and not well defined. Scale bar, 25 mm in (A); 50 mm in (B), (C), and (E);10 mm in (D), and 5 mm in (F) and (G). (Reproduced from Izumikawa et al., 2005.)

Fig. 38.3. Anatomy and physiology of inner ear. (A) Schematic of a mammalian ear, including the external, middle, and inner ear, which contains the cochlea and vestibular end organs. The endoelectronic chip is illustrated in one possible location, although the experiments were done with the chip located outside the middle-ear cavity. (B) Cross-section of a typical cochlear half-turn, showing the endolymphatic space (yellow) bordered by tight junctions (red), the stria vascularis (green), and hair cells (blue), which are contacted by primary auditory neurons (orange). (Reproduced from Mercier et al., 2013.)

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Irimia A, Chambers MC, Torgerson CM et al. (2012). Circular representation of human cortical networks for subject and population-level connectomic visualization. Neuroimage 60: 1340–1351. Izumikawa M, Minoda R, Kawamoto K et al. (2005). Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11 (3): 271–276. Jahanshad N, Kochunov PV, Sprooten E et al. (2013). Multisite genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA-DTI working group. Neuroimage 81: 455–469. Kesser BW, Lalwani AK (2009). Gene therapy and stem cell transplantation: strategies for hearing restoration. Adv Otorhinolaryngol 66: 64–86. Lee T, Cai LX, Lelyveld VS et al. (2014). Molecular-level functional magnetic resonance imaging of dopaminergic signaling. Science 344 (6183): 533–535. Livet J, Weissman TA, Kang H et al. (2007). Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450 (7166): 56–62. Mercier PP, Lysaght AC, Bandyopadhyay S et al. (2013). Energy extraction from the biologic battery in the inner ear. Nat Biotechnol 30 (12): 1240–1243. Petrella JR, Doraiswamy PM (2013). From the bridges of Konigsberg to the fields of Alzheimer: connecting the dots. Neurology 80 (15): 1360–1362. Reijmer YD, Leemans A, Caeyenberghs K et al. (2013). Disruption of cerebral networks and cognitive impairment in Alzheimer disease. Neurology 80 (15): 1370–1377. Shen H (2013). See-through brains clarify connections. Technique to make tissue transparent offers threedimensional view of neural networks. Nature News 496: 7444. Staecker H, Praetorius M, Brough DE (2011). Development of gene therapy for inner ear disease: using bilateral vestibular hypofunction as a vehicle for translational research. Hear Res 276 (1–2): 44–51. Striedter GF, Belgard TG, Chen CC et al. (2014). NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species. Brain Behav Evol 83 (1): 1–8. Thompson PM, Ge T, Glahn DC et al. (2013). Genetics of the connectome. Neuroimage 80: 475–488. Thomson H (2014). Deaf people get gene tweak to restore natural hearing. In: NewScientist, Reed Business Information, New York, pp. 8–9. Toga AW, Clark KA, Thompson PM et al. (2012). Mapping the human connectome. Neurosurgery 71 (1): 1–5.

Index NB: Page numbers in italics refer to figures and tables.

A Absolute threshold, outer/middle ear 3–4 Acamprosate 420 Acetylcholine associative behavioral memory 135–136, 135, 136 representational plasticity (RP) 134 Acoustic contour training 551 Acoustic reflex (AR) tests 314–315, 314 Acoustic stimulus parameters 125–126 Acoustic trauma acute 410, 417–418 auditory nerve damage 501 Acquired amusia 607–632 cognitive framework, assessment 610–613, 610, 611, 612 vs congenital amusias 589 future trends 609, 610, 611, 612, 625–626 musical emotion processing 611, 622–625, 623 musical object perception 611, 619–620, 620 musical object recognition 611, 620–622 melody 612, 620–622, 621 musical instruments 622 musical property encoding 611, 613–619 pitch perception 612, 613–616 temporal perception 616–617, 617 timbre perception 618–619, 618 musical scene analysis 611, 613, 613, 625 overview 607–608 scope 608–610, 609, 610, 611, 612 Acquired auditory synesthesias 390, 399–403 auditory-gustatory 403 auditory-tactile 403 auditory-visual 390, 399 lesional 399–401, 400 neurophysiologic studies 400 non-lesional 401 mechanisms 401–403 Acquisitions, signal-to-noise ratio (SNR) 262–263 Activation likelihood estimation (ALE) 188 Acute acoustic trauma 410, 417–418 Acute experiments 228 Adaptation designs 267–268, 268 Adaptive auditory analyzer 122

Adaptive Test of Temporal Resolution (ATTR) 320 Adaptive tracking algorithm 57 Affective agnosia, auditory 581–582 Age factors auditory development 68–69 auditory neuropathy (AN) 501 Age-related hearing loss (ARHL) 357–373 central auditory system 369–370 auditory cortex 369 calcium homeostasis 369–370 cortical disconnection, theory of 369 consequences 371 definitions/terminology 358 diagnosis/clinical manifestation 360, 361, 370 epidemiology 358–360, 359 general aspects 357 peripheral auditory system 364–369, 364 endocochlear potential 360, 366–367, 368 fibrocytes/fibroblast growth factor 362, 367–368 gender/hormones 368–369 genetics 365 mitochondria 365–366 oxidative stress 364–365, 364, 365 rehabilitation 370–371 Schuknecht’s classification 360–364 cochlear conductive presbycusis 360, 361, 363–364 indeterminant presbycusis 362 mixed presbycusis 362–363 neural presbycusis 360–361, 361 sensory presbycusis 360, 360 strial presbycusis 361, 361, 362 spiral ligament, atrophy 361, 363 Agnosia see Auditory agnosia Air conduction audiometry test 484 Alloacusis 563 Alzheimer disease (AD) see Dementia American Academy of Audiology 539, 545–546 American National Standards Institute (ANSI) 650–651 American Speech-Language-Hearing Association 538, 540, 545–546 Amisulpride 445 Amplification see Hearing aids

Amplitude modulation detection 503 Amusia 581 see also Acquired amusia; Congenital amusias Amygdala, anatomy 36, 39 Anhedonia see Musical emotion processing Anterior auditory field (AAF) 14, 16, 17–18, 19, 20, 74, 110 Anterior ectosylvian sulcus (AES), 19, 74 Anterior inferior cerebellar artery (AICA) 510, 516, 530, 530 stroke 633, 634, 635–636, 642–643 Anterior optic pathways 399–400 Anterior parietal cortex, anatomy 29, 38 Anterior temporal lobe (ATL) 152, 153 Anteroventral cochlear nucleus (AVCN) 102, 103 sound localization 8–10, 8, 9 Anticonvulsant drugs 446 Antidepressant drugs 446 Antipsychotic drugs 445–446 Aphasia 157, 459–460, 577 Apparent diffusion coefficient (ADC) 278 Apperceptive auditory agnosia 574–575 verbal (word deafness) 578–579, 579 see also Musical object perception Arousal, representational plasticity (RP) 132 Art, synesthesias 404–405 Associative auditory agnosia 574–575 verbal (word deafness) 579–580 see also Musical object perception Asymmetric sampling in time (AST) theory 94–95, 94 Attack dimension 191, 192 Attention deficit hyperactivity disorder (ADHD) 544–545 Attractor network models 449–450 Attractor state 450 Audiometry 293, 511–512, 512, 527–528 Auditory agnosia 573–588 affective 581–582 amusia 581 definitions 573–576, 575, 576 environmental sounds 580–581 general 576 overview 573 phonagnosia 580, 580 treatment 579, 582–583, 583

694 Auditory agnosia (Continued) verbal (word deafness) 574, 576–580, 577, 578 apperceptive 578–579, 579 associative 579–580 Auditory brainstem responses (ABRs) 484 see also Auditory neuropathy (AN) Auditory coding development 59–60 sensorineural hearing loss (SNHL) 484–486 sound, encoding behavioral importance 130, 131 temporal see Temporal coding Auditory comprehension 140–141 Auditory cortex age-related hearing loss (ARHL) 369 imaging see Functional magnetic resonance imaging (fMRI) loudness see Loudness music see Music perception primary see Primary auditory cortex (PAC) studies see Electrocorticography (ECoG) research temporal coding see Temporal coding Auditory cortex, anatomy 15–20, 16, 27–54, 458 definitions 28, 28 frequency-band strips 17, 18 hierarchical tiers 225 human vs non-human 41–44 location 41–42 regions/areas 42–44, 42 organization, principles of 28–41 regions, principle 1 28, 29–30, 29, 30 areas, principle 2 30–31, 31 tonotopy, principle 3 17–18, 17, 31–32, 31 thalamic inputs, principle 4 32–33, 32 connection features, principle 5 33–35, 34 topography, principle 6 32, 35–41 single neuron responses 18–19 sound localization 19, 65–66, 110–111 spatial representation 109, 110–111 stimulus complexity 19–20 Auditory development 55–72 age factors 68–69 behavioral testing/psychoacoustics 56–58, 58 coding, features 59–60 frequency/intensity 59 loudness 60 sound detection 59 ear 56 masking/segregation 60–64 backward masking 63–64 co-modulation masking release (CMR) 61–62 energetic masking 61 grouping/segregation 60–61 informational masking 62–63

INDEX Auditory development (Continued) overview 55–56 spatial/binaural hearing 64–68 binaural unmasking 66–67, 66 cues 64, 64 precedence effect 67–68, 67 sound localization 64–66, 65 Auditory discrimination tests 543, 545 Auditory edges 250, 250 Auditory evoked potentials (AEPs) 326 Auditory feedback control 162, 165–167, 166 Auditory Figure Ground subtest (SCAN:3A/3C) 323–324 Auditory hallucinations (AHs) 433–456 brainstem-related hearing disorders 521–525, 522, 525 classification 434, 435 conceptualization/demarcation 434 definition 433–434 etiology 437–439, 438 pathology, absence of 438–439, 439 metatheoretic considerations 447–450 network science 449–450, 449, 451 philosophy of science 447–449 non-verbal, stereotyped, repetitive 410, 411 overview 433 pathophysiology 439–445, 440 functional auditory network 440–443, 441, 442 processes 444–445 structural auditory network 443–444 phenomenologic characteristics 434–437, 435 non-verbal auditory hallucinations 436 perceived location 434–437 verbal auditory hallucinations 435–436, 435 psychotic illness 461–463, 463 stroke 642–644 treatment 445–447 pharmacotherapy 445–446 non-pharmacologic methods 446–447 Auditory memory 460 Auditory neglect 557–571 alloacusis 563 behavioral deficits 558–565 clinical presentation 557–558 defined 567 extinction 558–559, 558 dichotic speech tests 559–561, 560 temporal order 561 neural basis 565–567 functional imaging 565–567, 566 lesion sites 565, 565 models of neglect 565 spatial hearing deficits 564–565 non-spatial auditory deficits 562, 569 open questions 568–569 sound lateralization 563–564, 563 target detection tasks 561–562, 562 treatment 568 workups 567–568

Auditory neuropathy (AN) 495–508 auditory processing 503–504 brainstem-related hearing disorders 514, 516, 517 clinical expression 501–502 diagnosis 496–500 audiology/psychoacoustics 499–500 electrophysiologic tests 293, 496–499, 497 neuroimaging 499 etiology 500 future trends 505 hearing disorders, associated 502–503 auditory dyssynchrony 496 sound detection thresholds 502 speech perception 502–503, 502, 503 overview 495–496, 496 pathologies 500–501 auditory nerve 500–501, 500 treatment 504–505 cochlear implants 505 electric stimulation 420 hearing aids 504–505 signal clarity 504 see also under Sensorineural hearing loss (SNHL) Auditory neuropathy spectrum disorder (ANSD) 337 Auditory objects 670 Auditory pathways 1–26 auditory cortex see Auditory cortex, anatomy brainstem, dorsal auditory stream 11–12 dorsal cochlear nucleus (DCN) 8, 8, 9, 11, 13 posteroventral cochlear nucleus (PVCN) 8, 8, 9, 11–12 ventral nucleus of lateral lemniscus (VNLL) 10, 11, 12, 21 brainstem, ventral auditory stream 8–11 anteroventral cochlear nucleus (AVCN) 8–10, 8, 9 lateral superior olive (LSO) 8–9, 10–11, 12, 21 medial superior olive (MSO) 9–11, 9, 12, 13, 21 outputs 10–11, 10 central auditory nervous system (CANS) 7–8, 8 centrifugal system 21–22, 21 cochlea 4–7 anatomy, overall 4, 5 anatomy, relative to function 4–6, 5, 6 output 6–7, 7 inferior colliculus (IC) 12–13, 12, 14–15 central (ICC) 12–13, 12 external/dorsal cortex nucleus (DCN) 13 medial geniculate body (MGB) 10, 13–15, 21 anatomy/inputs 14, 14 medial/dorsal nuclei 15 ventral nucleus 14–15

INDEX Auditory pathways (Continued) outer/middle ear 3–4 absolute threshold 3–4 overview 3 Auditory perception perceived loudness, defined 75 perceptual learning 122 perceptual release theory 442–443 timescales 85–86, 86 Auditory scene 111–112, 187 analysis (ASA) 60–61, 670 Auditory steady-state responses (aSSR) 251 Auditory task classes 124, 129, 130 Auditory-motor integration 151, 153–154, 154, 155, 155, 156 Aura model, auditory hallucinations (AHs) 440 Autoimmune inner-ear disease 410, 415 Autophony (voice echo) 410–411, 410, 460–461, 463 Average evoked potential (AEP) waveforms 237 Ayahuasca 404

B Backward masking 63–64 Bastian, Henry Charlton 161 Bayesian random-effect modeling 280 Behavioral matters habituation/dishabituation 56–57 sound 130, 131 stimulus generalization gradient 120 techniques 420 testing 56–58, 58 central auditory 542–547, 545 training 57–58 Benzodiazepines 418–420 Big Brain model 689–690 Bilingualism 214, 215 Binaural hearing discrimination tasks 653, 660–663, 661 interaction tests 314, 316–319, 317, 543 masking level differences (BMLD) 66–67, 655 multiple sclerosis (MS) 652 unmasking 66–67, 66, 489 Bioelectric signal averaging techniques 227 Bipolar disorders 438 Blood oxygenation level-dependent (BOLD) contrast 259, 260, 261, 262, 265, 270–271 response 264, 264, 267, 271, 272, 273–274 Blood supply, auditory system 633–634 Blowing tinnitus 410–411, 410 Bone conduction audiometry test 484 Borderline personality disorder 438 Brain Activity Map (BAM) 689–690 Brain regions comparisons 272, 273 pitch perception 616 speech processing 178–179, 178 speech production 163, 163

Brain Research through Advancing Innovative Neurotechnologies (BRAIN) 689–690 Brainstem auditory hallucinosis model 440 auditory pathway, lesions 649–650, 650, 651 dorsal auditory stream 10–11 music and language 213, 213 ventral auditory stream 8–11 Brainstem auditory evoked potentials (BAEPs) 293, 397, 400, 401, 515–516, 515 intraoperative monitoring 300–301, 301, 302 multiple sclerosis (MS) 653, 657–658, 658, 660–663, 661 see also under Electrophysiologic tests Brainstem strokes 526, 529–531 hearing loss 636 internal auditory artery, occlusion 511, 526, 529, 530 lateral inferior pontine syndrome 526, 530–531, 530 lateral superior pontine syndrome 526, 530, 531 sound lateralization 513, 513 Brainstem-related hearing disorders 509–536 anatomy 509–510, 510, 511 auditory hallucinations (AHs) 521–525, 522, 525 clinical disorders 525–531, 526, 527 evaluation 511–521, 512 brainstem auditory evoked potentials (BAEPs) 515–516, 515 neuroimaging 514–515, 514, 515 psychoacoustic tests 512–513, 512, 514 isolated lesions auditory nerve 514, 516, 517 cochlear nuclei, unilateral lesions 516, 517 inferior colliculus (IC), bilateral lesion 520–521 inferior colliculus (IC), unilateral lesions 518–519, 519 lateral lemniscus, unilateral lesions 516–518, 517 pontomedullary region, bilateral lesion 521 superior olivary complex, unilateral lesions 516, 517 trapezoid body, unilateral lesions 518 management 531 multiple sclerosis (MS), hearing abnormalities 526, 531 prevalence 510–511, 512 British Society of Audiology 538

C Calcium homeostasis 369–370 Canadian Guidelines on Auditory Processing in Children and Adults (CISGSLPA) 538–539

695 Canadian Inter-organizational Steering Group for Speech-Language Pathology and Audiology (CISGSLPA) 538–539 Cannabis 404 Carbamazepine 411–412, 420, 427 Carboplatin 483 Cardiac gating 264–265, 265 Categoric designs 265–266, 266 Caudal-rostral axis 34, 35 Caudolateral area (CL) 110–111 Caudomedial area (CM) 110–111 Central auditory nervous system (CANS) age-related hearing loss 369–370 dementia 669–671 see also Central auditory processing disorder (CAPD) Central auditory processing disorder (CAPD) 313–332, 537–556 case study 551–552, 552, 553 central auditory tests 314, 315–325 binaural interaction procedures 314, 316–319 listening see Dichotic listening, test speech see Monaural lowredundancy speech tests temporal see Temporal processing tests cost-effectiveness 326 definitions/conceptualizations 537–542 behavioral central auditory tests 542–547, 545 electrophysiologic tests 547–548, 547 language/learning/communication 540–542, 541 diagnosis 542–548 differential diagnosis 327, 327 intervention 548–551, 549 central resources training 548–550 direct remediation 550–551 environmental modifications 548, 549 overview 313, 537, 538 peripheral tests 313–315, 314 acoustic reflex (AR) 314–315, 314 otoacoustic emissions (OAEs) 314, 314 pure-tone thresholds/speech recognition 313–314, 314 psychophysical tests 326 Central deafness, stroke 637–641, 638, 639, 640 Central inferior colliculus (ICC) 12–13, 12 Central nervous system (CNS) 401 tinnitus 410, 415, 417 see also Central auditory nervous system (CANS); Central auditory processing disorder (CAPD) Central resources training 548–550 Centripetal model, auditory hallucinations (AHs) 440 Cerebellopontine angle tumors 410, 417 see also Vestibular schwannomas Cerebral cortex, new model 141

696 Change response 249–251 Characteristic frequency (CF) 123 Charcot–Marie–Tooth (CMT) disease 497, 498, 505 Charles Bonnet syndrome 437 Children auditory neuropathy (AN) 498, 501 deaf 68–69 see also Congenital hearing loss language 216 music 207–208, 209, 212, 589–590 Cholinergic implantation of specific memory 139–140 Chromatic scale 194–195, 197 Chronic acoustic trauma 410, 415 Chronic experiments 228–232, 230, 231, 232 Chronic progressive symmetric hearing loss 410, 415 Circle of fifths 195 Cisplatin 483 Citalopram 445–446 CLARITY (Clear, Lipid-exchanged, Acrylamide-hybridized Rigid, Imaging/immunostaining compatible, Tissue hYdrogel) 689 Clicking 410, 411–412 click trains 236, 236 Clogged ear 460 Clomipramine 446 Closed-field conditions 99–100 Clozapine 445–446 Coarse intermittent sounds coincident with jaw/head movements 410, 410 Cochlea, anatomy see under Auditory pathways Cochlear battery 360 Cochlear development 56 Cochlear disorders conductive presbycusis 360, 361, 363–364 nuclei, unilateral lesions 516, 517 see also Sensorineural hearing loss (SNHL) Cochlear implants (CI) 61, 87 auditory neuropathy (AN) 505 cognition/learning 350–351 congenital hearing loss 342, 347–348, 348 sensorineural hearing loss (SNHL) 491 Cochlear microphonics (CMs) 290–291, 291, 495 Cochlear summating potential 291–292, 292 Cochrane Collaboration review, dementia 682 Cocktail-party effect 63 Coding see Auditory coding Cognitive ability age and 370 congenital hearing loss 349–352 Cognitive Ability Screening Instrument 670 Cognitive behavioral therapy 420, 446 Cognitive conjunctions 266–267

INDEX Cognitive model of music processing 610 Cognitive subtraction 265 Communication 207–208, 211, 540–542, 541 Co-modulation masking release (CMR) 61–62 Competing Sentences test 513, 551 Complex musical objects 192–199 Compound action potential (CAP), eighthnerve 289 Computer-based auditory skills training 551 Concept center 610 Conduction aphasia 169–170 Conductive hearing loss 410, 416 Conductive presbycusis, cochlear 360, 361, 363–364 Congenital amusias 589–605 implicit pitch processing 600–601 neural correlates 593–596 anatomic 593–595, 594 functional investigations 595–596 overview 589–591, 590 pitch dimension, deficit 591–593 memory for pitch 590, 592–593, 593 pitch perception 591–592, 591 pitch/music production disorders 598–599 processing deficits 596–598 spatial processing 598 speech processing 596–597, 597, 598 temporal processing 596 tests 596 Congenital hearing loss 333–356 audition/speech 344–349 cochlear implants 347–348, 348 literacy development 349 mild bilateral/unilateral conditions 346–347, 347 mild to severe conditions 344–346, 345 cognition/learning 349–352 cochlear implants 350–351 theory of mind (ToM)/social development 351–352 current context 342–343 cochlear implants 342 expectations 342–343 neonatal screening 342 effects on child/family 338–342 auditory plasticity 338–339, 338, 339 child family experience, impact 340–342, 341 language learning, sensitive period 339–340 neurocognitive development 343–344, 343 neurodevelopmental rehabilitation 344 overview 335 prevalence/epidemiology 335–338, 336 additional disabilities 337–338, 337 onset 335–336, 336 progressive 336 severity 337

Congenital hearing loss (Continued) types 336, 337 Conjunction analysis 266–267 Connectomics 690 Consonance 193–194, 207–208 -dissonance judgments 613–614 Contour 191, 193–197, 195 Contralateral hemifield spatial tuning 108 Coping-with-voices protocols 446–447 Core-belt-parabelt hierarchic model 34–35, 34, 225 Co-registration 270 Corollary discharge model 440 Cortical cooling 239–240, 240 Cortical deafness 637–641, 638, 639, 640 Cortical disconnection theory 369 Cortical oscillations 91 Cortical potentials 496, 497–498, 497, 497, 498, 499, 499 Cost-effectiveness, diagnostic tests 326 Critical bands (CBs) 76, 77, 79–80 Cross-activation model 397 /hyperbinding model 398–399

D Data analysis 232–234, 233 Data quality 263–265 Deafferentiation model 440 Deaf-hearing 637 Deafness central 637–641, 638, 639, 640 children 68–69 word see Verbal auditory agnosia; see also Age-related hearing loss (ARHL); Congenital hearing loss; Sensorineural hearing loss (SNHL) Decreased sound tolerance 375–388 definitions 375–377 diagnosis 378–380, 379 mechanisms 380–383, 382 neurophysiologic model 383, 383 overview 375 prevalence/epidemiology 380 problems 377–378, 378 treatment 383–385 tinnitus retraining therapy (TRT) 383, 384–385 Dementia 667–688 hearing function 668–671 central auditory system 669–671 impairment 668–669 non-verbal sounds, processing 679–681, 680, 681 peripheral auditory system 669 music, processing 671–679 Alzheimer disease (AD) 673–676, 674 emotion, recognition 678–679, 679 frontotemporal dementia 676–677 Huntington’s disease 678 Parkinson’s disease 677, 678 perception, framework for examining 671–673, 671, 672 musical therapy 682–683 overview 667–668

INDEX Dementia with Lewy bodies (DLB) 667–668, 669 Depressive disorder 438 Desensitization 384 Development see Auditory development Developmental auditory synesthesias 390–399, 390, 391, 392, 393 with auditory concurrent 393, 394 with auditory stimuli as inducer 390–393, 391, 392 auditory-olfactory/auditorygustatory 393–394 auditory-visual 390–393 bidirectional 394 drugs, effect of 404 neural models 397, 398–399, 398, 399 neurobiologic investigations 394 functional studies 395, 395, 396 neurophysiologic studies 395–397, 396 structural studies 394–395 prevalence/genetics 394 Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association) 438–439 Dichotic auditory target detection tasks 561–562, 562 Dichotic CVs (consonant-vowels) test 315 Dichotic Digits (DD) test 315, 370, 513, 544, 551 Dichotic listening 99–100, 550, 551 test 314, 315–316 findings 316, 316 methodology 315–316 Dichotic Rhyme test 551 Dichotic Sentences test 315, 370 Dichotic speech tests 541, 543, 544, 545 Dichotic Words test 315 Diffusion imaging tractography 277–288 applications 280–282, 281, 282 auditory pathways, reconstructions 282–285, 283, 284, 285, 286 deterministic vs probabilistic 282 diffusion tensor imaging (DTI) 279–280, 279 future directions 285 magnetic resonance imaging (MRI) 278, 278 non-tensorial models 279, 280 overview 277 Diffusion orientation distribution function (dODF) 280 Diffusion spectrum imaging 280 Diffusion tensor imaging (DTI) 177, 279–280, 279 Digital signal processing hearing aids 504–505 Diotic presentation 99–100 Diplacusis (diplacousis) see Decreased sound tolerance

Directions Into Velocities of Articulators (DIVA) model 163–169, 163, 164, 166, 167, 170–171, 170, 172 Disabilities 337–338, 337 Disconnection syndrome 577–578 Discretization 89–90 Discrimination auditory tests 543, 545 frequency/intensity 59 suppression 107 tasks 196 binaural 653, 660–663, 661 interaural (ITD) tests 652–655, 653, 654 temporal processing tests 320–321 Disinhibited feedback model 397 Disjunctivism 448 Dissociative disorder 438 Dissonance 193–194, 207–208 Distance localization 104–105 Distorted Tunes Test 671–673 Distortion product otoacoustic emissions (DPOAES) 495 Dopamine (DA) 136–137 Dorsal cochlear nucleus (DCN) auditory pathways 13 sound localization 104 stimulus analysis 8, 8, 9, 11, 13 Dorsal cochlear nucleus (DCN) hypothesis 420–426 implications 424–426, 425, 425 non-lateralized tinnitus 424 tinnitus pathway 426 Dorsal nucleus of lateral lemniscus (DNLL) 10, 11, 12, 12, 21 of medial geniculate body (MGB) 15 Down syndrome 337 Dual-stream model see under Speech perception Duplex theory 100–101 Duration Pattern Test (DPT) 319–320 Dynamic attending theory 209 Dyslexia 209 Dyssynchrony 496

E Ear development 56 ‘effect’ 551–552 mind’s 169–170 Early Hearing Detection and Intervention programs 345–346 Early-right anterior negativity (ERAN) 198 Earworms 436–437, 437 Echo heard/unheard 68 precedence effect (PE) 67–68, 67, 107 threshold 107 voice 410–411, 410, 460–461, 463 Echolalia 463–464 Eighth-nerve compound action potential (CAP) 289, 290–293, 292, 293, 294, 295, 296–297

697 Eighth-nerve disorders 526 vascular compression 410, 411, 413–414, 416 Einstein, A. 278 Electric stimulation 226–227 auditory neuropathy (AN) 420 brainstem 296 focal 238 mapping 226, 239–240, 239 tract tracing 238 transcranial magnetic stimulation (TMS) 426 Electrocochleography (ECochG) 498–499 see also under Electrophysiologic tests Electroconvulsive therapy (ECT) 446, 447 Electrocorticography (ECoG) research 223–244, 246 acute experiments 228 chronic experiments 228–232, 230, 231, 232 data analysis 232–234, 233 functional connectivity 238, 238 functional lesioning 239–240, 239, 240 overview 225–226 spectrotemporal processing 234–238, 235, 236, 237 subjects 227–228, 229 validity 240–241 Electrode fabrication 227 Electroencephalography (EEG) 246 musicogenic epilepsy 472–474, 472 Electromagnetic recording 245–256 overview 245–246 techniques 246 see also Magnetoencephalography (MEG) Electrophysical recording 226 Electrophysiologic responses, reduced 541 Electrophysiologic tests 289–312 brainstem auditory evoked potentials (BAEPs) 289, 294–302, 294 frequency-following responses 301–302, 302 generators 294–296, 295 interpretation 297, 298–301 recording techniques 292, 296–298, 297 brainstem disorders 512 electrocochleography (ECochG) 289–293 clinical applications 292–293 components 290–292 middle-latency auditory evoked potentials (MLAEPs) 289, 290, 302–304, 302, 303, 304, 305 clinical utility 304 components/generators 302–304 long-latency auditory evoked potentials (LLAEPs) 289, 290, 304–307, 304 clinical/research applications 307 mismatch negativity (MMN) 305–306, 306, 307

698 Electrophysiologic tests (Continued) P1-N1-P2-N2 complex 304–305 P3/P300 component 292, 293, 306–307, 307 overview 289, 290, 291 Emotion see Musical emotion processing Endocochlear potential 360, 366–367, 368 Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) project 690 Environmental modifications 548, 549 Environmental sounds 580–581 Epilepsy non-lesional auditory-visual synesthesia 401 research 227, 228–232 see also Musicogenic epilepsy Equal-temperament tuning 190 European First Episode Schizophrenia Trial (EUFEST) 445 Event-related band power (ERBP) 233, 236, 237 Event-related potential (ERP) 600–601 Evoked potentials, auditory 370 Experiential responses 458 Experimental design 265–268 Expertise, musical 199–202, 200, 201, 213–214, 214 Exploding-head syndrome 410, 410 Extended speech signal 87 External auditory hallucinations (AHs) 434–435 Extinction see under Auditory neglect Extraoperative diagnostic studies 299–300, 299, 300, 302

F Factorial designs 266–267, 266 False discovery rate (FDR) 272 Family, effects of childhood hearing loss 338–342 Family-centered practice 341 Family-wise error rate (FWE) 272 Far-field conditions 99–100 Far-field potentials 289 Fear, representational plasticity (RP) 132 FEAT (fMRI Expert Analysis Tool) 473 Feedforward control 164, 167–169 Fiber orientation distribution function (fODF) 280 Fibroblast growth factor 367–368 Fibrocytes 362, 367–368 Field strength 261–262 Fixed lateralization 106 Flashbacks 139, 458 Flutter percept 235–236 Fluttering 410, 410 FM-listening systems 504 Focal cooling 226 Focal electric stimulation 238 Food and Drug Administration (FDA) 348 Forced-choice methods 57 Forward transduction 6

INDEX Fractional anisotropy (FA) 279–280, 281–282 Free-field conditions 99–100 Frequency discrimination 59 Pattern, Test, (FPT) 319–320, 513, 544, 551 perception 487–488, 487 poor selectivity 488 resolution 4, 503 Frequency-band strips 17, 18 Frequency-following responses 301–302, 302 recording technique 193–194 Front/back localization 103–104 Frontotemporal dementia (FTD) 667–668, 669–670, 676–677, 679–680 Functional auditory network 440–443, 441, 442 Functional connectivity 238, 238 Functional lesion 226 Functional magnetic resonance imaging (fMRI) 257–276 analysis 268–272 spatial preprocessing 269–270, 269 statistical 269, 270–272 applications 257–258 data quality 263–265 cardiac gating 264–265, 265 scanner acoustic noise 263–264, 264 experimental design 265–268 adaptation designs 267–268, 268 categoric designs 265–266, 266 factorial designs 266–267, 266 parametric designs 266, 267 key principles 258–261, 258 definitions 258–259, 258 scanning parameters 259–261, 260, 260 musicogenic epilepsy 472–474, 473, 474 overview 257, 258 signal-to-noise ratio (SNR) 261–263 acquisitions, number of 262–263 field strength 261–262 radiofrequency coils 262 receiver bandwidth 258, 263 voxel size 262 Function-based tractography approach 177 Furosemide 483

G GABA (gamma-aminobutyric acid) 425, 449–450 GABAergic inhibition 450 Gamma-band oscillations 137, 138 assessment/treatment 139 Gap detection tasks 503 threshold (GDT) 320, 541 Gaps-in-Noise (GIN) measure 320–321 Gedankenlautwerden 435–436, 435 Gender age-related hearing loss (ARHL) 368–369 language organization 157

Gene therapy 690 General linear model (GLM) 270–272 Generalization gradients 129 Genetics 365, 394 GingerALE application 188 Goal-directed movement 162–163 Gradient order DIVA (GODIVA) model 163–164, 169 Guthrie, Woodie 678

H Habit vs memory 127 Hallucinations see Auditory hallucinations (AHs); see also Musical hallucinations Hallucinogens 403–404 Haloperidol 445 Harmony 189, 195, 197–198 harmonic expectancy violation 198 harmonic intervals 193–194 harmonic sequences 198 Hashish 404 Head trauma 410, 419 Head-orienting response 65 Head-related transfer functions (HRTFs) 100, 104 Heard echo 68 Hearing, measurement 292–293 Hearing aids 490–491, 504–505 Hearing in Noise Test (HINT) 324 Hearing loss chronic progressive symmetric 410, 415 cochlear/auditory nerve disorders see Sensorineural hearing loss (SNHL) stroke see under Stroke sudden, idiopathic 410, 417 tinnitus 420–421 see also Age-related hearing loss (ARHL); Congenital hearing loss; Deafness; Sensorineural hearing loss (SNHL) Hearing-motion synesthesia 394 Heisenberg’s uncertainty principle 95–96 Hemodynamic imaging see Functional magnetic resonance imaging (fMRI) Hemorrhagic lesions, stroke 636–637, 637 Hereditary hearing loss 410, 415 sensorineural (SNHL) 481 Hereditary sensory and autonomic neuropathy with dementia and hearing loss (HSAN1) 669 Herpes zoster oticus (Ramsay Hunt syndrome) 410, 417 Hierarchical State Feedback Control (HSFC) model 163–164, 169–171, 170 Hindrance-modulated orientation anisotropy (HMOA) 281–282 Histological Studies on the Localization of Cerebral Function (Campbell) 117 History, synesthesias 404–405 Horizontal localization 100–103

INDEX Hormones, age-related hearing loss (ARHL) 368–369 Hughlings-Jackson’s Darwinian thesis 442–443 Human Connectome project 690 Huntington’s disease 678 Hybrid depth electrodes (HDEs) 227, 229, 230, 234 Hybrid non-tensorial diffusion approach 280 Hyperacusis stroke 642–644 tinnitus 420 see also Decreased sound tolerance Hyperacusis Questionnaire (Khalfa’s) 379, 379 Hyperbinding model 398–399 Hypoxia 482

I Idiopathic conditions non-lesional auditory-visual synesthesia 401, 402 sudden hearing loss 410, 417 tinnitus 410, 419 Illusion 457–458 Implicit learning 211 Indeterminant presbycusis 362 Individual vs group level analysis 269, 271–272 Induced auditory synesthesia 390 Inducer-concurrent couplings 389, 391, 392, 393 Infarction 530 Inferior colliculus (IC) 245–246 auditory pathways 12–13, 12, 14–15 bilateral lesion 520–521 unilateral lesions 518–519, 519 Informational masking 62–63 Information-processing models 610–612 Inner hair cells (IHCs) 382 ribbon synapses 501 sensorineural hearing loss (SNHL) 479–480, 480 Inner-speech model, auditory hallucinations (AHs) 440 Intensity discrimination 59 Intensity theory 100–101 Interaural level differences (ILDs) 64 binaural hearing 652, 657 binaural unmasking 489 sound localization 101, 102–103, 105–106 spatial hearing 488–489 Interaural pitch difference (IPD) 377, 380 Interaural time differences (ITDs) 64 binaural hearing 652, 657 binaural unmasking 489 brainstem lesions 510–511, 513, 516–518 sound localization 100–102, 102, 103, 105–106, 107, 111–112 spatial hearing 488–489 tests 652–655, 653, 654 dichotic speech 559–560

Internal auditory artery (IAA) 511, 526, 529, 530, 633 Internal auditory hallucinations (AHs) 434–435 Internal synesthesia 401 International Classification of Functioning, Disability and Health (ICF) (WHO) 343–344, 538–539 Interval 191, 193–197, 195 harmonic 193–194 melodic 194, 195 Intraoperative BAEP monitoring 300–301, 301, 302 Intraoperative neurophysiologic monitoring (IONM) 293, 294, 297–298, 300 Invasive recordings see Electrocorticography (ECoG) research Ipsilateral Competing Message (ICM) test 323–324 Ischemic stroke see Stroke Isochronous sequence 198–199 Isofrequency lines (frequency-band strips) 17, 18 Isolated auditory objects 188–192 Isolated lesions see under Brainstemrelated hearing disorders

J Jaw proprioception 424 Jeffress ITD-versus-place model 102 Jervell and Lange-Nielsen syndrome 481 Just noticeable difference (JND) 652, 657

K Kant, I. 448 Key 195, 197–198 Klotho 365 Knowles electronics manikin for auditory research (KEMAR) 100

L Lamotrigine 445–446 Landmarks hypothesis (Stevens) 90 Language disturbance 459–460 see also Music and language; Speech perception; Speech processing; Speech production Lateral inferior pontine syndrome 526, 530–531, 530 Lateral lemniscus dorsal nucleus (DNLL) 10, 11, 12, 12, 21 ventral nucleus (VNLL) 10, 11, 12, 21 Lateral lemniscus, unilateral lesions 516–518, 517 Lateral nucleus of trapezoid body (LNTB) 102 Lateral superior olive (LSO) 103, 105 sound localization 8–9, 10–11, 12, 21

699 Lateral superior pontine syndrome 526, 530, 531 Lateralization discharge model 440 see also Sound lateralization Learning central auditory processing disorder (CAPD) 540–542, 541 congenital hearing loss 349–352 music and language 212 /plasticity, models 211–212 rule-based 211–212, 211 sensitive period 339–340 Learning and memory 117–148 contemporary approaches see Representational plasticity (RP) definitions 118 general implications 140–141 overview 117–118 perceptual learning 122 research 118–119 treatment implications 138–140 Left frontal cortex 178–179, 178 Left parietal cortex 179, 181 Left temporal cortex 179, 180, 181 Limbic mediation model 399 Listening in-noise 318–319, 504, 543 complaints 540 systems 504 tactics 504 Listening-in-noise 504 Listening in Spatialized Noise - Sentence (LISN-S) test 318–319, 543 Literacy development 349 LMNA gene 365 Local cooling of the cortex 226 Local field potentials (LFPs) 119, 226, 229 Localization of objects 245 see also Sound localization Long-latency auditory evoked potentials (LLAEPs) 397 see also under Electrophysiologic tests Loudness 73–84 animal physiology 75, 76–80, 78 auditory development 60 discomfort levels (LDLs) 375, 378–380, 385 exposure to 418–419 human cortical studies 78, 80–82, 81 perception 486, 487 psychophysics 75–76, 75, 77 sensory processing, overview 73–75, 74 Low-pass filtered speech tests (LPFS) 314, 323, 513 LSD (lysergic acid diethylamide) 404

M McGurk effect 208 Magnetic resonance imaging (MRI), diffusion 278, 278

700 Magnetoencephalography (MEG) 246–252, 247 auditory steady-state responses (aSSR) 251 neuronal oscillations 251–252, 252 transient evoked responses 248–249 transition responses 249–251, 250 Major key 198 Maskers 60 Masking 60–64 backward 63–64 co-modulation masking release (CMR) 61–62 energetic 61 informational 62–63 temporal 314, 321–322, 321 Masking level differences (MLDs) 317, 317, 503–504, 512–513 binaural (BMLD) 66–67, 655 Mean diffusivity (MD) 279–280, 281 Mean length of utterance (MLU) 345–346 Medialgeniculatebody (MGB)225,458–459 anatomy see under Auditory pathways auditory cortex 28, 32–33, 40, 41–42 connections 32, 33 dorsal nucleus 15 medial nucleus 15 ventral nucleus 14–15 Medial geniculate complex (MGC) 32 dorsal division (MGd), inputs 32, 33 magnocellular division (MGm), inputs 32, 33 ventral division (MGv), projection 33 Medial nucleus of medial geniculate body (MGB) 15 of trapezoid body (MNTB) 8–9, 10, 12, 21, 102, 103 Medial superior olive (MSO) 102 sound localization 9–11, 9, 12, 13, 21 Medial temporal-lobe epilepsy 475 Medical Research Council (UK), Institute of Hearing Research 264 Medication-related tinnitus 410, 415–416 Melody 189, 191, 193–197, 195 familiar 197 melodic intervals 194, 195 melodic intonation therapy 209 recognition 612, 620–622, 621 song and 197 Memory auditory 460 vs habit 127 for pitch 590, 592–593, 593 role of 442–443 strength substrate 131, 132, 139 see also Learning and memory Me´nie`re’s disease 293, 414–415, 416 formes frustes 416 Mescaline 404 Meter 191, 193, 195, 198–199 Midbrain stroke 636 Middle ear, auditory pathways 3–4 Middle-latency auditory evoked potentials (MLAEPs) see under Electrophysiologic tests

INDEX Middle-latency response (MLR) 547 Migraine 401 Mild cognitive impairment (MCI) 668, 670 Mind’s ear 169–170 Minimum audible angle (MAA) 64–65, 67–68, 105–106 thresholds 65, 65 Minimum audible movement angle (MAMA) 105–106 Minor key 198 Mismatch field/negativity (MMF/MMN) 199–202, 249–251, 397, 566–567, 595, 600–601 long-latency auditory evoked potentials (LLAEPs) 305–306, 306, 307 paradigm 196, 198 Misophonia see Decreased sound tolerance Mitochondria, age-related hearing loss (ARHL) 365–366 Mixed presbycusis 362–363 Modulations rates 87 sensitivity to 86, 88–89, 89 Monaural conditions sound localization 103 spectral cues 103 Monaural low-redundancy speech tests 314, 322–325, 541, 543, 545 classification 322–323 Montreal Battery for Evaluation of Amusia (MBEA) 581, 671–673 acquired amusia 612–613, 614 congenital amusias 589–590, 592, 595, 596 Montreal Battery for Evaluation of Musical Abilities (MBEMA) 589–590 Motion aftereffects 106 Motion perception 105–106 Motivation 211 Motivational states/tasks 126 Motor system 208–209 Motor-auditory integration 151, 153–154, 154, 155, 155, 156 Multidimensional scaling 191 Multiple rule tasks 126–130, 128, 129 Multiple sclerosis (MS) 649–666 brainstem lesions 513, 513, 526, 531 auditory pathway 649–650 overview 649 psychophysical assessment 650–658 binaural hearing 652 binaural masking level differences (BMLD) 655 brainstem auditory evoked potentials (BAEPs) 653, 657–658, 658, 660–663, 661 interaural discrimination (ITD) tests 652–655, 653, 654 lateralization experiments 655–657, 656, 657 pure-tone threshold 650–651

Multiple sclerosis (MS) (Continued) speech intelligibility 651–652, 652 theoretic explanations 658–663 binaural discrimination tasks 653, 660–663, 661 lateralization tasks, model 659–660, 659 tests, correlation 658–659 Multiple-Activity Scale for Hyperacusis (MASH) 379, 379 Multiple-compartment modeling 280 Multivoxel pattern analysis (MVPA) 196 Music and language 207–222 clinical implications 216, 216 language, ability/impairment 215–216, 215 learning/plasticity, models 211–212 rule-based learning 211–212, 211 neural plasticity 212–216 auditory brainstem 213, 213 selective enhancement 213–215 origins 207–208 communication 207–208, 211 structural 207–208 overview 207 temporal processing 208–211 oscillatory rhythms 210–211, 211 rhythm, as temporal map 209–210 Music perception 187–205 complex musical objects 192–199 harmonic sequences 198 harmony/key 189, 195, 197–198 interval/contour/melody 189, 191, 193–197, 195 rhythm/meter 189, 191, 193, 195, 198–199 dementia 671–673, 671, 672 disorders see Acquired amusia; see also Congenital amusias expertise/plasticity 199–202, 200, 201 future directions 191, 193, 202 isolated auditory objects 188–192 pitch chroma 188–190 timbre 189, 190–192, 193 overview 187–188 auditory scene 187 literature 187–188 neuroimaging 188, 189, 191, 193 Musical emotion processing 202, 209–210 acquired amusia 611, 622–625, 623 dementia 678–679, 679 Musical hallucinations 436–437, 437, 446 palinacousis 463, 466 pathophysiology 444–445 Musical instruments, recognition 622 Musical object perception 611, 619–620, 620 recognition 611, 620–622 Musical priming paradigm 600 Musical processing, dementia 671–679 Musical production disorder 598–599 Musical property encoding 611, 613–619 Musical scene analysis 611, 613, 613, 625

INDEX Musical sound analysis testing 581 Musical therapy, dementia 682–683 Musical training 551 Musicogenic epilepsy 469–478 clinical aspects 470 diagnostic evaluation, seizures 470–471, 471 epilepsy/music, relevance 474–476 functional imaging 472–474, 472, 473, 474 illustrative case 471–472, 472 seizures/reflex epilepsies 469–470 Myofascial disorders 428

N National Institutes of Health (NIH) 689–690 Near-field conditions 99–100 Near-field potentials 289 Neck proprioception 423–424 Neglect see Auditory neglect Neonatal screening 342 Network science 449–450, 449, 451 Neural circuitry of language model (Wernicke) 153 Neural excitability 86, 92 Neural oscillations see Oscillatory mechanisms Neural pitch salience 193–194 Neural plasticity learning models 211–212 music and language 212–216 musical expertise 199–202, 200, 201 Neural presbycusis 360–361, 361 Neural synchrony 137, 138 Neurocognitive development 343–344, 343 Neurodegenerative diseases see Dementia Neurodevelopmental rehabilitation 344 Neurofibromatosis type 2 (NF2) 529, 529 Neuron responses 18–19 Neuropathy see Auditory neuropathy (AN) N-methyl-D-aspartic-acid (NMDA) receptors 449–450 Noise listening in 318–319, 504, 543 pink noise therapy 384 sensorineural hearing loss (SNHL) 481–482 see also under Functional magnetic resonance imaging (fMRI) Non-verbal sounds, processing 679–681, 680, 681 Norepinephrine (NA) 137 Notched noise technique 485

O Observer-based psychophysical method (OBPM) 57 Occipital cortex, anatomy 36, 37–38 Octave equivalence 188 Octotoxic drugs 482, 483 Olanzapine 445 Open-field conditions 99–100 Optokinetic stimulation 568

Oral-expressive amusia 598–599 Ordering/sequencing tests 314, 319 Organ of Corti 4, 5, 6 Orientation distribution functions (ODFs) 280 Oscillatory mechanisms 86, 91–92 dysfunctional 95 gamma-band 137, 138 magnetoencephalography (MEG) 251–252, 252 rhythms 210–211, 211 Otoacoustic emissions (OAEs) 56, 289 age-related hearing loss (ARHL) 370 sensorineural hearing loss (SNHL) 484, 484 tests 314, 314 tinnitus 410, 416 Otoferlin (OTOF) 495, 501, 503 Outer ear, auditory pathways 3–4 Outer hair cells (OHCs) 380–382, 382, 479 Oxidative stress 364–365, 364, 365

P P1-N1-P2-N2 complex 304–305 P3/P300 component 292, 293, 296, 307, 307 Palilalia 464 Palinacousis 457–468 anatomy 458–460, 459 associated phenomena 466 musical hallucinations 466 palinopsia 466 auditory memory 460 clinical characteristics 460–461 content 460 latency 461 lesion location 461, 462 quality 460–461 sound lateralization 461 defining characteristics 457–458 illusion 457–458 perseveration 457 differential diagnosis 461–464 auditory hallucinations (AHs) 461–463, 463 echolalia 463–464 palilalia 464 postictal psychosis (PIP) 463 tinnitus 464 etiology 466 historical perspective 458, 458 overview 457 pathophysiology 464–466 ictal 462, 464, 465 postictal 465–466 stroke 642–644 Palinopsia 466 Panoramic location coding 108 Paradoxical extinction 560–561 Parallel processing 92–95, 93, 94 Parametric designs 266, 267 Parkinson’s disease 669, 677, 678 Pathways see Auditory pathways Pattern recognition models 488

701 Pediatric Speech Intelligibility with Ipsilateral Competing Message (PSI-ICM) test 323–324 Pediatric Speech Intelligibility (PSI) test 314, 324 Pendred syndrome 481 Perception see Auditory perception Peretz model 614, 615 Perilymphatic fistula 410, 416 Peripheral auditory nervous system aging 364–369, 364 dementia 669 tests 313–315, 314 Perseveration 457 Persistent angular structure MRI 280 Phantom sensations 82 Phase locking 484–485 Phasic alerting 568 Philosophy of science 447–449 Phonagnosia 580, 580 PING (pyramidal interneuron gamma network) model 92–93 Ping-pong interaction 91–92 Pink noise therapy 384 Pitch chroma 188–190 classes 187, 194–195, 195 constancy 196 dimension, deficit 591–593 errors 677 memory 590, 592–593, 593 onset response 249–251 production disorder 598–599 shift reflex 599 Pitch perception 487–488, 487 acquired amusia 612, 613–616 congenital amusias 591–592, 591 ‘pitch percept’ 235–236 Pitch processing 614 deficits 614–615 implicit 600–601 Place-frequency mapping 56 Plotting results 272 Polyacusis see Decreased sound tolerance Pontomedullary region, bilateral lesion 521 Posterior auditory field (PAF) 16, 17–18, 19, 20 sound localization 110 Posterior inferior cerebellar artery (PICA) 633, 634, 635–636, 642–643 Posterior parietal cortex, anatomy 36, 37 Posteroventral cochlear nucleus (PVCN) 8, 8, 9, 11–12 Postictal psychosis (PIP) 463 Postinfectious tinnitus 410, 419 Post-traumatic stress disorder (PTSD) 139 Precedence effect (PE) 67–68, 67, 107 Prefrontal and cingulate cortex, anatomy 36, 37 Presbycusis 410, 415 see also Age-relatedhearingloss(ARHL) Prestin 4–6 Primary auditory cortex (PAC) 16, 88 anatomy 459, 459 see also Learning and memory

702 Principal diffusion direction (PDD) 280–281 Prism adaptation 568 Production-preserved (congenital) amusics 599 Progressive non-fluent aphasia 615 Pseudohallucination 434–435 Psychedelics 403–404 Psychical responses 226–227 Psychoacoustics 56–58, 58, 499–500 tests 512–513, 512, 513, 514 pattern discrimination (PPDT) 561–562 Psychometric functions, measurement 57 Psychophysics 75–76, 75, 77 tests 326 Psychosis (PIP), postictal 463 Psychotherapy 446 Psychotic disorders 438, 461–463, 463 PSYRATS questionnaire 451 Pulsatile (cardiac synchronous) tinnitus 410, 411, 412–414, 413 Pure insertion 265 Pure-tone audiogram 512, 512 Pure-tone threshold, assessment 313–314, 314, 650–651

Q Q-ball imaging 280 Quasi-hallucination 434–435 Quetiapine 445

R Radial diffusivity (RD) 279–280, 281 Radiofrequency coils 262 Ramsay Hunt syndrome 410, 417 Random Gap Detection Test (RGDT) 320 Rate place coding 484–485, 485 Rate-level function (RLF) 78 Rayleigh, Lord 100–101 Receiver bandwidth 258, 263 Receptive field analysis 120 shift 117 Re-entrant feedback model 397 Reflex epilepsies 469–470 Region of interest (ROI) analysis 272 Rehabilitation age-related hearing loss (ARHL) 370–371 neurodevelopmental 344 Reinforcement outcome prediction 118–119 Renormalization 127 Reorientation 269 Reperception model 440 Representational plasticity (RP) 117, 119–122 acoustic stimulus parameters 125–126 across species 120–122 auditory cortical dynamics, specificity 120, 121 auditory task classes 124, 129, 130

INDEX Representational plasticity (RP) (Continued) characteristics 124, 125, 126 findings, challenges to 131–134 cortical lesions 133–134 fear/increased arousal 132 tuning shifts 132–133 forms of 122–123, 123 functions, primary auditory cortex (PAC) 130–131 individual vs group analysis 127–129, 130 mechanisms 134–138 circuit/synaptic processes 137–138 gamma-band oscillations 137, 138 neuromodulators 134–137 motivational states/tasks 126 multiple rule tasks/learning strategy 126–130, 128, 129 representational gain, reversal/loss 127 specific memory traces (SMTs) 122, 123–126 treatment implications 138–140 two discipline synthesis 119–120 Resolution, temporal processing tests 320–321 Responses to sound, ventral nucleus 15 Resting-state networks (RSNs) 273–274 Reverse transduction 4–6 Rhythm 189, 191, 193, 195, 198–199 oscillatory 210–211, 211 perception 208 as temporal map 209–210 Right-ear advantage (REA) 315 Root-mean-square (RMS) error 64, 65, 65, 67, 68 Rule-based learning 211–212, 211

S Salicylic acid 483 Salvia divinorum 404 SBUTT (sudden, brief, unilateral, tapering tinnitus) 409–410, 410, 414, 426 SCAN:3A (Auditory Processing Disorders in Adolescents and Adults) screening test 323–324 SCAN:3C (Auditory Processing Disorders in Children) screening test 323–324 Scanner acoustic noise 263–264, 264 Schuknecht’s classification 360–364 Seashore Tests of Musical Ability 669 Seashore Rhythm subtest 676 Segregation 60–64 grouping 60–61 Seizures diagnostic evaluation 470–471, 471 palinacousis 462, 464, 465 reflex epilepsies 469–470 Semantic specificity 208 Sensitive periods 212 auditory development 338–339 language learning 339–340

Sensorineural hearing loss (SNHL) 479–494 auditory coding 484–486 auditory nerve damage 486 cochlear damage 485–486 brainstem lesions 514, 515, 520–521, 527–528 defined 358 diagnosis 483–484, 484 auditory nerve dysfunction 484 cochlear damage 484 otoacoustic emissions 484, 484 threshold measurement 483–484 etiology 481–483, 482 aging 482–483, 483 hereditary causes 481 hypoxia 482 noise 481–482 octotoxic drugs 482, 483 perceptual consequences 486–490 cochlear damage 486–490, 487 structures affected by 479–481 auditory nerve 480–481 inner hair cells 479–480, 480 outer hair cells 479 stria vascularis 480, 481 treatment 490–491 cochlear implants 491 hearing aids 490–491 Sensory gating 307 Sensory hearing loss, defined 358 Sensory presbycusis 360, 360 Sensory processing 73–75, 74 Sequencing tests 314, 319 Serotonin (5HT) 137, 381 Sex differences age-related hearing loss (ARHL) 368–369 language organization 157 Short-latency auditory evoked potentials see Brainstem auditory evoked potentials (BAEPs) Sign language 338–339 Signal clarity, auditory neuropathy (AN) 504 Signal-to-noise ratio (SNR) 63, 261–263 Singing, poor 589 Single-sided deafness 69 Slice timing 269–270 Social development 351–352 Somatic modulation (SM) 418–419, 421, 423, 426–427 Somatic tinnitus 410, 418–419, 418 Somatosensory feedback control 167, 167 Somatosensory pulsatile tinnitus syndrome 410, 411, 412, 413 Somatosensory system 421, 422, 422, 423, 423 Sound encoding behavioral importance 130, 131 -field amplification systems 504 identification 245 pressure level (SPL) 75

INDEX Sound (Continued) recognition 641 tolerance, decreased see Decreased sound tolerance Sound detection 59 thresholds 502 Sound lateralization auditory neglect 563–564, 563 brainstem strokes 513, 513 multiple sclerosis (MS) 513, 513, 655–657 palinacousis 461 tasks, model 659–660, 659 tests 314, 317–318 Sound localization 99–116 auditory cortex 19 auditory development 65–66, 65 auditory neuropathy (AN) 504 brainstem 8–11 central representation 107–111 auditory cortex 108–110 specialized cortical areas 110–111 superior colliculus (SC) 107–108 defined 488–489 distance localization 104–105 dominance localization 67–68, 107 horizontal localization 100–103 duplex theory 100–101 interaural level differences (ILDs) 101, 102–103, 105–106 interaural time differences (ITDs) 100–102, 102, 103, 105–106, 107, 111–112 monaural conditions 103 measuring 64–65 motion perception 105–106 overview 99 precedence effect (PE) 67–68, 67, 107 spatial hearing mechanisms 111–112 stroke 641 terms/techniques 99–100 tests 314, 317–318 vertical and front/back 103–104 Sound Training for Attention and Memory and Dementia (STARDem) 683 Sparse scanning method 264, 264 Spatial hearing 99, 488–489, 489 Spatial listening, test 314, 318–319 Spatial normalization 270 Spatial preprocessing 269–270, 269 Spatial processing 598 Spatial release from masking (SRM) 66, 66 Spatial smoothing 270 Specific memory traces (SMTs) 122–130 Spectogram, speech sounds 86–87, 86 Spectral centroid dimension 192 defined 191 Spectral flux 191 Spectrotemporal features 88–89, 190–192 Spectrotemporal processing 234–238, 235, 236, 237 Spectrotemporal receptive fields (STRFs) 234

Speech audition and 344–349 error, correction 169–170 intelligibility 651–652, 652 reception threshold (SRT) 318, 651 recognition test 313–314, 314 sounds, temporal structure 85, 86–87, 86 Speech perception 149–160 auditory neuropathy (AN) 502–503, 502, 503 dual-stream model 149–156, 150 auditory-motor integration 151, 153–154, 154, 155, 155, 156 bilateral organization/parallel computation 149–150, 151 clinical correlates 156–157 computational asymmetries 150–151 dorsal stream 153–156 lexical-semantic access 152 phonological processing/superior temporal sulcus (STS) 151–152 ventral stream 149–153 hallucinations 442 overview 149 sensitive period 339–340 sensorineural hearing loss (SNHL) 489–490, 490 sex differences 157 Speech Perception in Noise (SPIN) test 324 Speech processing 177–186 brain regions 178–179, 178 left frontal cortex 178–179, 178 left parietal cortex 179, 181 left temporal cortex 179, 180, 181 central auditory processing disorder (CAPD) 540–542, 541 congenital amusias 596–597, 597, 598 language pathways 179–184 dorsal 180–182, 181, 182, 183 ventral 182–184 overview 177–178 Speech production 161–176 brain regions 163, 163 future directions 171–172 goal-directed movements, planning 162–163, 163 hallucinations 442 neurocomputational models 163–171 Directions Into Velocities of Articulators (DIVA) model 163–169, 163, 164, 166, 167, 170–171, 170, 172 gradient order DIVA (GODIVA) model 169 Hierarchical State Feedback Control (HSFC) model 163–164, 169–171, 170 overview 161–162 Speech-in-noise 540, 641 perception 211, 211 tests 314, 323–325 Speech-to-noise ratio 491 Spherical deconvolution 280 Spiral ligament, atrophy 361, 363

703 Spontaneous otoacoustic emissions (SPOAE) 382–383, 384 S-segment 10 Staggered Spondaic Word test 315 Statistical analysis 269, 270–272 Statistical inference 272 Stevens, K.N. 90 Stimulation optokinetic 568 see also Electric stimulation Stimulus-specific adaptation (SSA) 13 Streaming, auditory development 61 Stress, tinnitus and 418–419 Stria vascularis 480, 481 Strial presbycusis 361, 361, 362 Striatum, anatomy 38 Stroke 633–648 assessment protocol 643, 645 brainstem see Brainstem strokes current practice 644–645 hearing loss 634–641 central/cortical deafness 637–641, 638, 639, 640 hemorrhagic lesions 636–637, 637 population studies 634–635, 634 upper brainstem/midbrain 636 vertebrobasilar area 635–637, 637 overview 633–634 blood supply, auditory system 633–634 hearing disorders 634 processing deficits 641–642, 641, 642 tinnitus/hallucinations/hyperacusis/ palinacousis 642–644 Structural auditory network 443–444 Sudden, brief, unilateral, tapering tinnitus (SBUTT) 409–410, 410, 414, 426 Sudden idiopathic hearing loss 410, 417 Sulpiride 445–446 Superconducting quantum interference devices (SQUIDS) 246 Superior cerebellar artery (SCA) 510, 531 Superior colliculus (SC) 107–108 Superior olivary complex, unilateral lesions 516, 517 Superior semicircular canal dehiscence (SSCD) 410, 416–417 Superior temporal cortex, anatomy 36–37 Superior temporal sulcus (STS) 151–152 The Synesthesia List 394 Synesthesias 389–408 history/art 404–405 terminology 389 types 389–404 acquired see Acquired auditory synesthesias affectivity 390, 390 automaticity 389–390 consistency 389 developmental see Developmental auditory synesthesias dynamicity 390 induced 403–404 drug-induced 403–404 mechanisms 404 sensory deprivation 403

704 Synthetic Sentence Identification with Ipsilateral Competing Message (SSI-ICM) test 314, 323–324

T T1 recovery 259 T2 decay 259 Tapping tasks 598 Target detection tasks 561–562, 562 Technical advances 689–692 applications 690–691 new/developing technologies 689, 690 research projects, large-scale 689–690 Telomeres 365 Temporal coding 85–98 continuous sound stream 89–95 discretization 89–90 dysfunctional oscillatory sampling 95 multiple timescales, analysis 86, 90–91 neural excitability 86, 92 neural oscillations 86, 91–92 parallel processing 92–95, 93, 94 overview 85–87 auditory perception, timescales 85–86, 86 speech sounds, temporal structure 85, 86–87, 86 poor 488 sensorineural hearing loss (SNHL) 484–485, 486 spectrotemporal features 88–89 modulations, sensitivity to 86, 88–89, 89 temporal modulations, sensitivity 88 Temporal dimension 187 Temporal modulations 235–236 sensitivity 88 Temporal patterning tests 541 Temporal perception 612, 616–617, 617 Temporal processing 617 age and 370 congenital amusias 596 improving 582 music and language 208–211 Temporal processing, tests 314, 319–322, 543, 545 integration 314, 321 masking 314, 321–322, 321 ordering/sequencing 314, 319 resolution/discrimination 314, 320–321 Temporal structure, regularity/variability 209–210 Temporal-lobe association areas 459 Temporal-lobe epilepsy 226–227 Theory of mind (ToM) 351–352 Thresholds absolute 3–4 -based testing 592 gap detection (GDT) 320, 541 measurement 483–484 minimum audible angle (MAA) 65, 65

INDEX Thresholds (Continued) phenomenon 415, 426–427, 427, 483–484 pure-tone tests 313–314, 314 sound detection 502 tinnitus 424–425 Timbral dimension 187 Timbre perception 618–619, 618 Time-compressed speech tests 314, 325 Time-Compressed Speech with and without Reverberation test 551 Timescales 85–86, 86, 90–91, 92 Tinnitus 82, 377–378, 378, 409–432 characteristics 410 non-specific quality 414–419, 414 specific quality 410 etiology 409–419 hyperacusis 420 neurology 420–427 dorsal cochlear nucleus (DCN) hypothesis 420–426 threshold phenomenon 415, 426–427, 427 typewriter tinnitus 411, 427 vs palinacousis 464 stroke 642–644 treatment 419–420, 446 retraining therapy (TRT) 383, 384–385 Tonal dimension 187 Tone audiogram 370 duration 126–127 onset to error (TOTE) strategy 126–127, 129 Tonotopic maps 17–18, 17, 31–32, 31, 123 Tractometry 281–282 Training 550–551, 550 behavioral 57–58 central resources 548–550 Transcortical sensory aphasia 157 Transcranial magnetic stimulation (TMS) 426 Transformation between sounds and actions 245 Transient evoked responses 248–249 Transition responses 249–251, 250 Trapezoid body (TB) lateral nucleus (LNTB) 102 medial nucleus (MNTB) 8–9, 10, 12, 21, 102, 103 Trapezoid body, unilateral lesions 518 Travelling wave 75–76 Triggering factors, tinnitus 415 Tufted neurons 14 Tuning shifts 132–133 Turkeltaub non-additive algorithm 188 Typewriter tinnitus 410, 411–412, 411

U Uncertainty principle, Heisenberg’s 95–96 Unheard echo 68 Unilateral tonal/noise tinnitus 414

Universal newborn hearing screening (UNHS) programs 335–336, 337, 342 Usher syndrome 481

V Ventral nucleus of lateral lemniscus (VNLL) 10, 11, 12, 21 of medial geniculate body (MGB) 14–15 Ventral posterior field (VP) 16 Verbal auditory agnosia (word deafness) 156–157, 574, 576–580, 577, 578 apperceptive 578–579, 579 associative 579–580 Veridical perceptions 447, 448 Vertebrobasilar ischemic stroke 635–637, 637 Vertical localization 103–104 Vestibular schwannomas 514, 525–529, 526 diagnostic testing 527–528 neurofibromatosis type 2 (NF2) 529, 529 neuroimaging 528, 528 physiopathology 528, 528 symptomatology 525–527, 527 treatment 529 Vestibular symptoms 410, 416 Virtual auditory space 100 Visual reinforcement audiometry 56–57 Vocal amusia 598–599 Vocal performance studies 599 Vocoded speech 87 Voice echo (autophony) 410–411, 410, 460–461, 463 Voice onset time (VOT) 236–238, 237 Voxel comparisons, multiple 258, 272 Voxel size 262 Voxel-based-morphometry (VBM) 593–595

W Waterfall illusion 106 Waveform components 297, 298 speech sounds 86–87, 86 Wernicke–Lichtheim model 156 Wernicke’s aphasia 157 Wernicke-type aphasia 459–460 White-matter pathways see Diffusion imaging tractography; see also Speech processing Williams syndrome 381 Within-subject realignment 269 Word deafness see Verbal auditory agnosia World Health Organization (WHO) 343–344, 358–359, 538–539 Wrong notes (pitch errors) 677

Z Ziprasidone 445