Brain Evolution, Language and Psychopathology in Schizophrenia [1 ed.] 0415537649, 9780415537643

Table of contents :
Contents
List of illustrations
About the editors
List of contributors
Introduction
Part I: Brain evolution and language phylogenesis
1 Genes and the evolution of language • Philip Lieberman
2 Navigation, discourse and the origin of language • Francesco Ferretti
3 Phylogenetic aspects of world- and self-representation in humans • Franco Fabbro and Massimo Bergamasco
Part II: Brain abnormalities in schizophrenia
4 Auditory cortex asymmetry and language processing in schizophrenia • Steven A. Chance and Manuel F. Casanova
5 Disordered brain network function in adolescence: Impact on thought, language and vulnerability for schizophrenia • Vaibhav A. Diwadkar and Noa Ofen
6 Corpus callosum, inter-hemispheric communication and language disturbances in schizophrenia • Cinzia Perlini, Marcella Bellani and Paolo Brambilla
7 Structural and functional brain imaging of thought disorder • Andrew Watson and Stephen Lawrie
8 Brain structural abnormalities, social function and psychopathology in schizophrenia • Jaya Padmanabhan, Christine I. Hooker and Matcheri S. Keshavan
Part III: Psychopathology and schizophrenia
9 Thought, hallucinations and schizophrenia • Gemma Modinos and Philip McGuire
10 Neural correlates of cognitive control and language processing in schizophrenia • Katherine Scangos and Cameron S. Carter
11 Narrative language production in schizophrenia • Andrea Marini and Cinzia Perlini
12 Social premorbid adjustment and linguistic abilities in first-episode schizophrenia • Paula Suárez-Pinilla, Nicholas Chadi, Rosa Ayesa-Arriola and Benedicto Crespo-Facorro
13 Symptoms, thought disorders and cognitive remediation treatment in schizophrenia • Antonio Vita and Luca De Peri
Part IV: Conclusion
14 Concluding remarks • Paolo Brambilla and Andrea Marini
Glossary and abbreviations
Index

Citation preview

Brain Evolution, Language and Psychopathology in Schizophrenia

This book provides a comprehensive review of new developments in the study of language processing and related neural networks in schizophrenia by addressing the complex link between psychopathology, language and evolution at different levels of analysis. Psychopathological symptoms in schizophrenia are mainly characterized by thought and language disorders, which are strictly intertwined. In particular, language is the distinctive dimension of human beings and is ontologically related to brain development. Although normal at the levels of segmental phonology and morphological organization, the speech of patients suffering from schizophrenia is often characterized by flattened intonation and word-finding difficulties. Furthermore, research suggests that the superior temporal gyrus and specific prefrontal areas which support language in humans are altered in people with schizophrenia. Brambilla and Marini bring together international contributors to explore the link between brain evolution and the psychopathological features of schizophrenia, with a focus on language and its neural underpinnings. Divided into three sections, the book covers: • • •

brain evolution and language phylogenesis brain abnormalities in schizophrenia psychopathology and schizophrenia.

This theoretical approach will appeal to professionals including clinical psychologists, cognitive neuroscientists, neuropsychiatrists, neuropsychologists, neurolinguists and researchers considering the links between brain evolution, language and psychopathology in schizophrenia. Paolo Brambilla is Assistant Professor of Psychiatry at the University of Udine, Italy. Andrea Marini is Assistant Professor of Cognitive Psychology at the University of Udine, Italy.

Explorations in Mental Health series

Books in this series: New Law and Ethics in Mental Health Advance Directives The Convention on the Rights of Persons with Disabilities and the Right to Choose Penelope Weller The Clinician, the Brain, and I Neuroscientific findings and the subjective self in clinical practice Tony Schneider A Psychological Perspective on Joy and Emotional Fulfillment Chris M. Meadows Brain Evolution, Language and Psychopathology in Schizophrenia Edited by Paolo Brambilla and Andrea Marini

Brain Evolution, Language and Psychopathology in Schizophrenia

Edited by Paolo Brambilla and Andrea Marini

First published 2014 by Routledge 27 Church Road, Hove, East Sussex, BN3 2FA and by Routledge 711 Third Avenue, New York, NY 10017 Routledge is an imprint of the Taylor & Francis Group, an informa business © 2014 P. Brambilla and A. Marini The right of the editors to be identified as the authors of the editorial material, and of the authors for their individual chapters, has been asserted in accordance with sections 77 and 78 of the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. 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 Brain evolution, language, and psychopathology in schizophrenia / edited by Paolo Brambilla, Andrea Marini. pages cm. – (Explorations in mental health) Includes index. 1. Schizophrenia. 2. Schizophrenics–Language. 3. Psychology, Pathological. 4. Developmental neurobiology. I. Brambilla, Paolo, editor of compilation. II. Marini, Andrea, editor of compilation. RC514.B672 2014 616.89'8--dc23 2013017664

ISBN: 978-0-415-53764-3 (hbk) ISBN: 978-1-315-88258-1 (ebk) Typeset in Baskerville by FiSH Books Ltd, Enfield

Contents

List of illustrations About the editors List of contributors Introduction

vii viii ix 1

PART I

Brain evolution and language phylogenesis

5

1

7

Genes and the evolution of language PHILIP LIEBERMAN

2

Navigation, discourse and the origin of language

22

FRANCESCO FERRETTI

3

Phylogenetic aspects of world- and self-representation in humans

33

FRANCO FABBRO AND MASSIMO BERGAMASCO

PART II

Brain abnormalities in schizophrenia 4

Auditory cortex asymmetry and language processing in schizophrenia

51

53

STEVEN A. CHANCE AND MANUEL F. CASANOVA

5

Disordered brain network function in adolescence: Impact on thought, language and vulnerability for schizophrenia

73

VAIBHAV A. DIWADKAR AND NOA OFEN

6

Corpus callosum, inter-hemispheric communication and language disturbances in schizophrenia 96 CINZIA PERLINI, MARCELLA BELLANI AND PAOLO BRAMBILLA

vi

Contents

7

Structural and functional brain imaging of thought disorder

118

ANDREW WATSON AND STEPHEN LAWRIE

8

Brain structural abnormalities, social function and psychopathology in schizophrenia

135

JAYA PADMANABHAN, CHRISTINE I. HOOKER AND MATCHERI S. KESHAVAN

PART III

Psychopathology and schizophrenia

151

9

153

Thought, hallucinations and schizophrenia GEMMA MODINOS AND PHILIP MCGUIRE

10 Neural correlates of cognitive control and language processing in schizophrenia 168 KATHERINE SCANGOS AND CAMERON S. CARTER

11 Narrative language production in schizophrenia

181

ANDREA MARINI AND CINZIA PERLINI

12 Social premorbid adjustment and linguistic abilities in first-episode schizophrenia

194

PAULA SUÁREZ-PINILLA, NICHOLAS CHADI, ROSA AYESA-ARRIOLA AND BENEDICTO CRESPO-FACORRO

13 Symptoms, thought disorders and cognitive remediation treatment in schizophrenia

212

ANTONIO VITA AND LUCA DE PERI

PART IV

Conclusion

229

14 Concluding remarks

231

PAOLO BRAMBILLA AND ANDREA MARINI

Glossary and abbreviations Index

233 243

Illustrations

Figures 6.1 Intra- and inter-hemispheric major white matter connections represented in a magnetic resonance image of a human brain 97 7.1 Cortical areas related to aspects of thought disorder: the superior temporal gyrus 129 7.2 Cortical areas related to aspects of thought disorder: the fusiform gyrus 129 8.1 Confounding factors affecting correlations between brain structure and psychopathology 144 9.1 The most consistently reported areas of abnormalities in studies of auditory hallucinations in schizophrenia comprise the left superior temporal gyrus and the left middle temporal gyrus. The images depict the anatomical landmarks of these regions on the axial (left), and rendered views (right) 156 9.2 Areas of convergent findings in functional and structural studies of auditory hallucinations in schizophrenia 158 10.1 Illustration of the context model whereby a dysfunctional dorsolateral prefrontal cortex (DLPFC) and poor connections with the parietal cortex and anterior cingulate cortex (ACC) lead to a faulty representation of context 175 11.1 Representation of the epicenter in the left inferior frontal gyrus (LIFG) found involved in the selection of informative words in individuals with schizophrenia and healthy individuals 188 12.1 Interaction between social skill deficits and linguistic disabilities in psychosis 195

Table 12.1 Some of the most common alterations found in the language of patients presenting with a first psychotic episode 203

About the editors

Paolo Brambilla is Assistant Professor of Psychiatry at the University of Udine, Udine, Italy, Senior Researcher at the IRCCS scientific institutes “E. Medea”, Udine, Adjunct Associate Professor of Psychiatry at the University of Texas Medical School at Houston, USA, and Head of the Research Unit on Brain Imaging and Neuropsychology at the InterUniversity Center for Behavioral Neurosciences of the Universities of Udine and of Verona, Italy. He has been leading imaging and cognitive studies in major psychoses, mood disorders and developmental psychiatry. His research has resulted in over 150 publications to date in international peer-reviewed journals. Andrea Marini is Assistant Professor of Cognitive Psychology at the University of Udine, Italy, where he leads the Language Laboratory at the Department of Human Sciences. He is Senior Researcher at the Scientific Institutes “E. Medea” in Udine, and “Santa Lucia” in Rome, and member of the board of the School of Specialization in Psychiatry at the University of Udine and of the PhD school of Cognitive Neuroscience at the University of Trieste. His research interests include the study of the neural correlates of language, neuropsychology of language in both adults and children, procedures of discourse analysis and the phylogenetic evolution of language. He is author of books, book chapters and several articles in peer-reviewed international journals.

Contributors

Rosa Ayesa-Arriola is Psychologist Researcher for CIBERSAM (Center for Biomedical and Health Sciences Research in Psychiatry) at the Psychiatry Research Unit of Cantabria, University Hospital ‘Marqués de Valdecilla’, Santander, Spain. Assistant Teacher in the degree in Psychology for the UNED (National University of Distant Education), Bergara, Spain. Marcella Bellani is Senior Registrar in Psychiatry at AOUI Azienda Ospedaliera Universitaria Integrata of Verona and Senior Researcher at the InterUniversity Centre for Behavioral Neurosciences, University of Verona, Verona, Italy. Her main research interests include white matter pathology and neuroimmunology, new brain imaging techniques applied to psychiatry. Massimo Bergamasco is Full Professor of Theory of Mechanisms and Machines at the Faculty of Engineering of the Scuola Superiore Sant’Anna, Pisa, Italy. He is the founder of the PERCRO Laboratory (PERCeptual RObotics) which performs research activities in virtual environments, simulators, telemedicine, teleoperation, virtual prototyping and cultural heritage. He is author of more than 200 scientific papers published on journals and/or international conferences proceedings. Cameron S. Carter is Professor of Psychiatry and Psychology and Directs the Early Diagnosis and Preventive Treatment (EDAPT) Clinic as well as the Imaging Research Center and the UC Davis Center for Neuroscience, USA. He has been studying the neural basis of higher cognition as well as cognitive dysfunction in schizophrenia and other mental disorders using behavioral methods and functional neuroimaging for over 20 years. Manuel F. Casanova is the Gottfried and Gisela Kolb Endowed Chair in Psychiatry at the University of Louisville, USA, He spent three years doing a fellowship in neuropathology at the Johns Hopkins Hospital. At present Dr Casanova has over 200 peer reviewed publications and 70 book chapters.

x

Contributors

Nicholas Chadi is General Pediatrician at Sainte-Justine University Hospital Centre, Montreal, Canada. Steven A. Chance is University Research Lecturer in clinical neurosciences at the University of Oxford, UK. He undertook his doctoral thesis on the neuropathology of schizophrenia at Queen’s College, University of Oxford. Subsequently he has continued to work in Oxford on additional topics including comparative evolutionary neuroscience, dementia and, most recently, autism. Benedicto Crespo-Facorro is Associate Professor of Psychiatry at the University of Cantabria and Director of the First Episode of Psychosis Clinic at the University Hospital Marqués de Valdecilla, Santander, Spain. Luca De Peri is a postdoctoral Clinical Research Fellow at the University of Brescia, School of Medicine, Italy. Currently, he is leading neuropsychological and cognitive remediation studies in schizophrenia aimed at assessing the efficacy and correlates of treatment response to cognitive remediation interventions in schizophrenia. Vaibhav A. Diwadkar is Associate Professor of Psychiatry and Behavioral Neurosciences in the School of Medicine at Wayne State University, USA. His main research consists of the use of functional magnetic resonance imaging to identify developmental dysmaturation of functioning brain networks in psychiatric illnesses, with a particular focus on the schizophrenia diathesis. Franco Fabbro is Full Professor of Developmental Neuropsychiatry at the University of Udine, Udine, Italy, and Scientific Director of the IRCCS E. Medea Research Institute, Polo Regionale Friuli Venezia Giulia, Italy. He has been Chief of the Aphasia Committee of the International Association of Logopedics and Phoniatrics (IALP) and associate/consulting Editor of several scientific journals, such as the Journal of Neurolinguistics and Folia Phoniatrica and Logopaedica. He is also author of a number of books and articles in peer-reviewed journals. Francesco Ferretti is Associate Professor in Philosophy of Language at University of Rome “Roma Tre”, Italy. His research interests primarily concern the following topics: the evolution of language and mind; the functioning of language from a pragmatic perspective; the role of spatial navigation in discourse processing; the analysis of the relationship between animal communication and human language. On these topics he has published several monographs and articles on international journals. Christine I. Hooker is Associate Professor of Psychology at Harvard University, USA, and Director of the Social Neuroscience and

Contributors

xi

Psychopathology laboratory. Her research uses functional Magnetic Resonance Imaging (fMRI) to investigate neural mechanisms that facilitate social functioning in healthy adults and individuals at risk for or suffering from schizophrenia. Matcheri S. Keshavan is Professor of Psychiatry at the Beth Israel Deaconess Medical Center; Harvard Medical School, USA. He is also Vice-Chair for the department’s Public Psychiatry Division, and a senior psychiatric advisor for the Massachusetts Mental Health Center. He is closely involved in research in neurobiology of psychosis, especially as it pertains to first episode psychotic disorders. His research has resulted in over 350 publications to date, including over 270 peer-reviewed papers, three books, 20 book chapters, and over 140 abstracts. He is a distinguished Fellow of the American Psychiatric Association, a Fellow of the Royal College of Physicians, Canada, and a Fellow of the Royal College of Psychiatrists, UK. He is also the Editor-in-Chief of the Asian Journal of Psychiatry. Stephen Lawrie is Head of Psychiatry at the University of Edinburgh, Scotland, Director of the Scottish Mental Health Research Network, and Director of the MRF/MRC CRTF Programme for Mental Health in the UK (PsySTAR). Philip Lieberman is George Hazard Crooker University Professor, Emeritus at Brown University. He has focused on the biological bases and evolution of human language and cognition. His papers and books span from 1960 to 2013. His 2013 book, The Unpredictable Species: What Makes Humans Unique, provides an overview of his studies on human speech anatomy, neural circuits, cues to emotion, schizophrenia, Parkinson’s disease, epilepsy, and hypoxia, as well as a critique of theories such as that of Noam Chomsky, which posits innate brain mechanisms without taking into account biological evidence. Philip McGuire is Head of the Department of Psychosis Studies at the Institute of Psychiatry, London, UK, and the Academic Director and joint Leader of the Psychosis Clinical Academic Group, King’s Health Partners. He is also Director of OASIS, and of the Voices Clinic. He is a Fellow of the Academy of Medical Sciences, the Royal College of Psychiatrists, the European Psychiatric Association, and the International College of Neuropsychopharmacology, and Associate Editor of the British Journal of Psychiatry. He leads a clinical academic research group focused on determining the neurocognitive basis of psychosis and developing new treatments for psychosis. Gemma Modinos is a psychologist and neuroscientist. She is now Senior Postdoctoral Researcher at the Institute of Psychiatry in London, UK, where she coordinates a multicenter and multimodal brain imaging project on the neurobiology of psychosis onset.

xii

Contributors

Noa Ofen is Assistant Professor in the Institute of Gerontology and Department of Pediatrics in the School of Medicine at Wayne State University, USA. She studies the development of memory systems in the brain using behavioral and neuroimaging approaches in typical and atypical development. Jaya Padmanabhan is a resident at the Harvard Longwood Psychiatry training program in Boston, Massachusetts, USA. She is working on a study of correlations between regional brain structure and symptom severity in psychosis. Cinzia Perlini is a Senior Researcher Psychologist at the Department of Public Health and Community Medicine, Section of Clinical Psychology and at the InterUniversity Centre for Behavioral Neurosciences, University of Verona, Verona, Italy. Her main research interests include biological correlates and neurocognitive profiles of major psychosis. Katherine Scangos is a Postdoctoral Scholar at the UC Davis Center for Neuroscience, USA, where she is studying cognitive dysfunction in schizophrenia using functional neuroimaging. She recently completed MD/PhD training at The Johns Hopkins University School of Medicine, USA. Her thesis work in systems neuroscience focused on understanding the higher order control of movement using single unit recording. Paula Suárez-Pinilla is Psychiatrist Researcher for IFIMAV (Educational and Research Institute Marqués de Valdecilla) and CIBERSAM (Center for Biomedical and Health Sciences Research in Psychiatry) at First Episode of Psychosis Clinic, University Hospital Marqués de Valdecilla, Santander, Spain. Antonio Vita is Director of a Psychiatric Unit at the Department of Mental Health of the Hospital Spedali Civili of Brescia and Full Professor of Psychiatry at the University of Brescia, Brescia, Italy. He is Past Chair of the Section of Neuroimaging of the World Psychiatric Association, and President of the Italian Society for Neuroimaging in Psychiatry, member of the Scientific Advisory Board of the Schizophrenia International Research Society and of the Italian Society of Biological Psychiatry. He has studied brain morphological and functional correlates of psychoses and is now involved in research and clinical application of cognitive remediation techniques to various psychiatric disorders. He is author or co-author of more than 300 scientific papers in national and international journals. Andrew Watson is a Clinical Research Fellow in Psychiatry at the University of Edinburgh, Scotland.

Introduction

Psychopathological symptoms in schizophrenia are mainly characterized by thought and language disorders, which are deeply intertwined. This book addresses the issue of the complex link between psychopathology, language and evolution at different levels of analysis. The book is structured in three major sections. The first part, dedicated to the issue of the interplay between brain evolution and the origins of language, is opened by the chapter by Philip Lieberman on genes and the evolution of language. The author warns from looking at the neural correlates of language from a naïve localizationist perspective. Rather, language processing is subserved by a complex set of neural networks linking activity in different parts of the brain. The author then focuses on the similarities between human and non-human primate neural networks and cortical structures. Finally, the attention is shifted on the role potentially played by the FOXP2human gene and other genes that appear to be candidates for conferring the linguistic, cognitive and motor capacities that distinguish humans from other living species. In Chapter 2, Francesco Ferretti explores the intriguing issue of a potential interconnection between navigation, discourse and the origin of language. Namely, the chapter explores the hypothesis that language processing is deeply connected to the ability to navigate and that, as such, its origins can be explained when considering that human communication took advantage of the spatial navigation processing systems capable of interpreting the limited set of signals in terms of appropriateness. The fascinating issue of language phylogenesis is further explored by Franco Fabbro and Massimo Bergamasco in their third chapter. Here, the authors discuss the phylogenetic aspects of world- and self-representation in humans focusing on the cognitive and anatomo-functional correlates of the narrative self and its connections with the neural networks underpinning language, episodic memory and mental mind travel. The second part of the book focuses on brain abnormalities in schizophrenia. This section is opened by Steven A. Chance and Manuel F. Casanova with their chapter on auditory cortex asymmetry and language processing in schizophrenia. Reviewing the literature, the authors show that gray matter in primary auditory cortex is thinned out and that reductions in

2

Introduction

size are correlated with the degree of though disorder observed in patients with schizophrenia. They come to the conclusion that minicolumnar abnormalities in their brains help explain the putative link between described abnormalities of cerebral dominance and language in these individuals. This delicate issue is further discussed in Chapter 5 on disordered brain network function in adolescence: impact on thought, language and vulnerability for schizophrenia. In this chapter, Vaibhav A. Diwadkar and Noa Ofen provide a comprehensive overview of intra-hemispheric dysconnection, focusing on neurodevelopmental dysmaturation taking place during adolescence in subjects at risk for the disease. This is further debated in Chapter 6 by Cinzia Perlini, Marcella Bellani and Paolo Brambilla entitled “Corpus callosum, inter-hemispheric communication and language disturbances in schizophrenia”, which deals with the interplay between inter-hemispheric connectivity and language dimension in schizophrenia. In this chapter the authors focus on the role of intra-hemispheric networks in sustaining language deficits in patients with schizophrenia, which are mainly mediated by the corpus callosum. Successively, in Chapter 7 on structural and functional brain imaging correlates of thought disorder, Andrew Watson and Stephen Lawrie debate the studies examining the neural correlates of thought disorder, focusing on the way it might relate to language processing in schizophrenia. Finally, in Chapter 8 on brain structural abnormalities, social function and psychopathology in schizophrenia, Jaya Padmanabhan, Christine I. Hooker and Matcheri S. Keshavan discuss the associations between brain anatomy, social function and language in schizophrenia, in light of the current literature limitations, which are mainly due to variations in methodology and subject populations. The third part of the book is dedicated to psychopathology and schizophrenia. It is opened by Chapter 9 on thought, hallucinations and schizophrenia by Gemma Modinos and Philip McGuire. In this chapter, the authors provide a state-of-the-art overview of recent developments on auditory hallucinations, providing a cognitive and linguistic account for these symptoms. Chapter 10 is dedicated to the neural correlates of cognitive control and language processing in schizophrenia. Katherine Scangos and Cameron S. Carter discuss evidence from behavioral and imaging research across cognitive tasks, suggesting that faulty context processing underlies cognitive difficulties in general, leading to disorganized behavior and disorganized speech. In a similar vein, Chapter 11 by Andrea Marini and Cinzia Perlini on narrative language production in schizophrenia reviews the literature on narrative language processing deficits in schizophrenia. Starting from the outline of the static and dynamic properties of the language production system, this chapter describes the technique of narrative analysis as a useful tool to comprehensively assess linguistic deficits in schizophrenia. Indeed, both micro- and macrolinguistic impairments have been described in people with schizophrenia using this approach, with the latter being more impaired, possibly relying on a dysfunctional cognitive

Introduction

3

control due to attentive, executive functions and working memory deficits. In Chapter 12, Suárez-Pinilla, Chadi, Ayesa-Arriola and Crespo-Facorro focus on the social premorbid adjustment and linguistic abilities in first episode schizophrenia. The authors claim that at least developmental deficits of social adjustment and linguistic abilities may be prodromal symptoms in patients who subsequently develop psychosis. Finally, Chapter 13 on symptoms, thought disorder and cognitive remediation treatment in schizophrenia, by Antonio Vita and Luca de Peri, focuses on the efficacy of cognitive remediation in schizophrenia. They discuss indirect yet interesting evidence of a significant positive impact of cognitive remediation interventions on the neuropsychological dimensions related to language and formal thought disorders. The book ends with a conclusive chapter where Andrea Marini and Paolo Brambilla draw the conclusions from the issues raised in the book.

Acknowledgement The Editors wish to thank Dr Cinzia Perlini for her insightful help in the revision of the proofs of this book.

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Part I

Brain evolution and language phylogenesis

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1

Genes and the evolution of language Philip Lieberman

It is clear that the traditional theory developed in the nineteenth century that localized speech production to a discrete frontal region of the cortex, Broca’s area, is wrong. Wernicke’s area, located in the posterior cortex, likewise does not appear to be the speech perception “organ” of the human brain. Current research instead points to neural circuits that link “local” activity in different cortical and subcortical structures as the agents involved in learning and carrying out the motor acts involved in talking. Similar neural circuits play a role in language and cognitive acts. Consistent with the fact that 99 percent of our genes are shared with chimpanzees, our closest living “cousins”, we share similar neural circuits. Claims for humans having unique neural circuits linking cortex to the larynx that somehow confer linguistic ability (Deacon 1997; Fitch 2010) do not hold up. This leads to an apparent mystery, since no chimpanzee, or other living species, can talk or command the complexities of human language. Fortunately, recent independent studies have provided a starting point in understanding some of the genetic events that confer human linguistic and cognitive capabilities. The assessment of the motor, syntactic and some of the cognitive deficits of a large extended family led to the discovery of the FOXP2human transcriptional factor. Further studies identified the neural structures affected by the anomalous form of FOXP2 present in this family. Genetic studies show that the human form of this gene spread throughout the extent human population some 260,000 years ago (Enard et al. 2002), and that its neural sequelae, which appear to enhance the efficiency of the subcortical basal ganglia and other structures, are linked in the neural circuits that regulate speech motor control and cognition, including language. Ongoing research has identified other transcriptional factors unique to humans that also act on the brain. Thus, what follows is an account of work in progress.

The Broca-Wernicke theory is wrong In light of almost ubiquitous references to two discrete areas of the human cortex constituting “organs” that confer human language, a brief discussion

8

Philip Lieberman

of why this is not the case is in order. Paul Broca published in 1861 the study that relocated the “seat” of language to the lower left side of the frontal cortex (the left inferior frontal gyrus). Broca’s theoretical framework was phrenological. Phrenology is often described as an exercise in “quack” science. However, in the early decades of the nineteenth century, it was a plausible explanation of why some people are more capable at music, others at mathematics, why some people are pious, and so on. The phrenological solution was that some particular part of our brain is the “faculty” of mathematics, morality, piousness, language, and so on. Johann Spurzsheim published his treatise in 1815; it divided the surface of the brain into areas – “seats” that each yielded a particular aspect of behavior. Larger areas conferred greater capabilities or behavioral tendencies. It was not unreasonable to suppose that discrete regions of the neocortex, the outermost region of the brain that seemed to differ most when apes and humans were compared, were conferring these complex human capabilities and behavior. The heart, for example, is a discrete organ whose primary function is pumping blood, although subsequent studies showed that it also contains sensors that monitor the level of CO2 in the bloodstream and produces hormones. The external ear enhances localizing sounds, and so on. Phrenology was not a crank theory. But Broca thought that Spurzsheim had erroneously located the language organ between the eyes. If you accept the phrenological model, excising the cortical area that is the “seat” of talking should preclude or at least impede talking. This was ethically impossible, so Broca instead studied two patients who had extreme difficulty talking after suffering brain damage from strokes. The study of patient “Tan” is Broca’s better-known case. Tan was a 51-yearold man who could not produce any recognizable words other than the syllable “tan”. Tan died soon after Broca saw him. The autopsy showed damage to the surface of the left frontal lobe of the patient’s brain, but Broca never examined the subcortical structures of Tan’s brain. A few months later, Broca examined a second patient, who could only say five words after suffering a stroke. An autopsy showed brain damage at approximately the same part of the surface of the brain, and so thereafter that part of the neocortex, Broca’s area, became the seat of expressive vocal language. Fortunately, the brains of both patients were carefully preserved in alcohol, and more than a century later, high-resolution magnetic resonance imaging (MRI) were performed (Dronkers et al. 2007). The MRI scans showed that in both patients massive damage had occurred to the neural circuits that link cortex with other parts of the human brain. The basal ganglia, structures deep within the brain that date back to species that lived before the age of the dinosaurs, other subcortical structures, and the pathways that connect cortical and subcortical neural structures were damaged. Moreover, the cortical area commonly labeled “Broca’s area” – the left inferior frontal gyrus, was not damaged in Paul Broca’s first two patients. Instead, anterior prefrontal areas (to the front of Broca’s area) were damaged.

Genes and the evolution of language

9

In 1874, Carl Wernicke studied a patient who had difficulty comprehending speech after a stroke damaged part of the posterior temporal region of his cortex. Following the phrenological model, Wernicke decided that language comprehension was located in this area. Since language entails both talking1 and comprehending speech, Lichtheim thus claimed in 1885 that a cortical pathway must link Broca’s and Wernicke’s areas. Thus, you can still read that Broca’s and Wernicke’s cortical areas are the neural bases of human language, as well as attempts to decide whether the skull of an extinct hominin (a primate thought to be in or related to species ancestral to present day humans) shows that its brain may have had Broca’s area. Doubts had been expressed early in the twentieth century concerning the Broca-Wernicke theory, but in the closing decades of the twentieth century independent studies (e.g. Naeser et al. 1982) using computer-augmented tomography scans and MRI to examine the brains of stroke patients had already shown that permanent language loss does not occur unless subcortical structures, primarily the basal ganglia and/or pathways to them, are damaged. Patients having brain damage limited to the cortex typically recovered after a period of months. Dronkers and her colleagues (2007) demonstrated that the Broca-Wernicke theory was flawed from the start.

Neural circuits linking cortex and the basal ganglia Around the same period as doubts were being raised concerning Broca’s and Wernicke’s areas being the human brain’s language organs, studies using highly invasive “tracer” techniques were mapping out neural circuits that regulated various aspects of behavior in animals. Clinical studies of neurological diseases such as Parkinson’s disease were coming to the same conclusion. Tracer techniques generally involve injecting a substance into a particular part of an animal’s brain. The animal is left alive for a period of time while the tracer moves up for certain substances, or down the pathways that link different neural structures. The animal is then sacrificed, its brain is suffused with a dye that attaches itself to the tracer, sliced up and microscopically examined. Alexander et al. (1986) mapped out a class of parallel, segregated neural circuits, some of which linked areas of the motor cortex with the basal ganglia. Other circuits linked prefrontal regions of the cortex with the basal ganglia and other subcortical structures. Other invasive experiments in which microelectrodes that directly recorded neural activity were inserted into an animal’s brain showed that these structures were active when some motor act was performed or when animals performed cognitive tasks such as keeping the location of an object in short-term memory.

1 Writing dates back to at most 10,000 years ago and complex sign language a few hundred years.

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Philip Lieberman

Studies of Parkinson’s disease established in broad terms some of the operations that the basal ganglia perform in these circuits. In Parkinson’s disease, basal ganglia functions deteriorate owing to a decrease in output of the neurotransmitter dopamine (Jellinger 1990). The behavioral deficits that are first noted usually involve motor control. Tremor, rigidity and problems executing internally guided acts occur. Neurosurgery once was the only way to mitigate the disease’s effects and still is employed. Marsden and Obeso, in their 1994 review, noted that the basal ganglia carry out several “local operations”. The basal ganglia call out and link the sub-movements, stored in motor cortex, that constitute a willed, internally guided action such as walking or picking up a glass of water. Through a set of complex neural links the linked sub-movements ultimately activate the muscles that enable a person to walk or pick up the glass of water. The basal ganglia, in effect, act as sequencing “engine” that enables an animal or human to carry out routine motor acts. The basal ganglia complex (it consists of a number of structures, including the caudate nucleus, putamen, and globus pallidus) receives a flow of sensory information, and acting on contingencies that are either innate or learned can shift to different action. For example, frogs that lack a cortex will abort attempting to catch flies when they sense a predator approaching, and initiate a different action – jumping into the nearest pond. Marsden and Obeso (1994) presciently suggested that, in humans, the basal ganglia may be a critical element of the neural machinery that confers cognitive flexibility – shifting thought processes. They took into account the cognitive inflexibility that often marks Parkinson’s disease – the “subcortical dementia” observed by Flowers and Robertson (1985). My research group noted similar effects in Parkinson’s disease, as well as deficits in comprehending the meaning of English sentences that have even moderately complex syntax (Lieberman et al. 1990, 1992). Our findings were replicated in subsequent studies (e.g. Natsopoulos 1993; Grossman et al. 2001; Hochstadt et al. 2006). Similar effects occurred in a subject who had bilateral focal lesions in the caudate nucleus and putamen (Pickett et al. 1998), and to a lesser degree in mountain climbers ascending Mount Everest, where the low oxygen content of air at extreme altitudes degrades basal ganglia activity (Lieberman et al. 2005). Diffusion tensor imaging (DTI), a noninvasive technique based on MRI imaging that can map out neural circuits in humans, has revealed hundreds of circuits in the human brain, including circuits that connect different parts of the cortex. They show that humans have cortical-basal ganglia circuits similar to those found in monkeys discerned using traditional tracer techniques (Lehericy et al. 2004). DTI analyses support the finding reported by Cummings (1993) in his review article based on clinical findings and animal tracer studies. Human neural circuits channel the flow of information from dorsolateral prefrontal cortex, lateral orbitofrontal cortex, and the anterior cingulate cortex, as well as from the motor cortex. Cummings

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noted that the anterior cingulate circuit regulates attention and also controls laryngeal phonation. Patients become mute and apathic when the circuit is damaged. Clinical evidence suggested that the orbitofrontal circuit was implicated in emotional regulation – patients became disinhibited.

Neuroimaging studies Neuroimaging studies have added to our knowledge of the operations performed in circuits linking cortex and the basal ganglia when humans perform cognitive tasks. Functional magnetic resonance imaging (fMRI) is a variant of MRI imaging that tracks the level of deoxygenated blood flow, reflecting metabolic activity in specific neural structures. Data from independent fMRI studies (e.g. Postle 2006; Badre and Wagner, 2006; Miller and Wallis 2009) indicate that ventrolateral, dorsolateral and other prefrontal cortical areas, in circuits involving the basal ganglia, direct attention to information used to carry out seemingly different tasks such as comprehending the meaning of a sentence (Kotz et al. 2003), mental arithmetics (Wang et al. 2005), or when selecting words according to their meaning or sound structure (Simard et al. 2011). The fMRI studies of Monchi and his colleagues have monitored the local operations carried in specific parts of the basal ganglia in tasks that entail cognitive flexibility and language. The Wisconsin card sorting test (WCST), which has been in use since the 1960s, is a standard instrument for assessing cognitive flexibility. Subjects are presented with a sequence of cards that each have images that vary according to shape, number and color. The task is to sort out the cards as the sorting criterion shifts arbitrarily from time to time. The subject, for example, may start by sorting out cards according to color, and then having to change to sorting by shape and then number, and then back to color, and so on. The Monchi research group adapted the WCST so that it could be used in fMRI studies. Monchi et al. (2001) reported the involvement of a cortical-basal ganglia loop involving the ventrolateral prefrontal cortex, the caudate nucleus, and the thalamus when a subject was told to change his or her sorting criterion. The posterior prefrontal cortex and putamen were active when applying the new sorting criterion for the first time. Dorsolateral prefrontal cortex was involved whenever subjects received any information as they performed the task, apparently monitoring whether their responses adhered to the chosen criterion. In another fMRI study, Monchi et al. (2006) showed that ventrolateral prefrontal cortex is active in planning ahead when a subject has to compare the card that is to be selected and the criterion. The basal ganglia’s caudate nucleus uses this information when any novel action needs to be planned. The Monchi fMRI studies point to the caudate nucleus being involved in the selection and planning, and the putamen in the execution of a self-generated action among different alternatives. The subthalamic nucleus (another basal ganglia structure) was only involved when a new motor action was required,

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whether planned or not. Other neuroimaging studies confirm the role of dopamine and the basal ganglia in cognitive flexibility (Monchi et al. 2007). Contrary to the claims of widely cited books such as Pinker (1994), the operations performed in particular neural structures and circuits are not necessarily domain specific. Humans do not, as Noam Chomsky claims, have neural organs devoted to language and language alone. Independent neuroimaging studies show that is the case for specific prefrontal cortical areas and basal ganglia. Cools et al. (2001) showed that working memory tasks involving recalling digits, words, images, reading, etc., all correlated with basal ganglia dopamine levels. Hazy et al. (2006) showed that corticalbasal ganglia circuits link activity in prefrontal cortex, basal ganglia and the subcortical hippocampus in these tasks. Wang et al. (2005) found increased activity in left ventrolateral prefrontal cortex and the basal ganglia as task difficulty increased during a mental arithmetic task. Kotz et al. (2003) found bilateral ventrolateral prefrontal cortical and basal ganglia activity in tasks that involved both comprehending the meaning of a spoken sentence or the speaker’s emotion. Duncan and Owen (2000), in their review of neuroimaging studies published before 2000, concluded that mid-ventrolateral and dorsolateral prefrontal cortex, as well as the anterior cingulate cortex, are active in a wide range of cognitive tasks involving executive control. The cognitive operations played by the thalamus, another subcortical structure linked to the basal ganglia and cortex, are not clear, but it has been apparent for decades that lesions in thalamus can result in speech motor, word-finding and comprehension deficits (Mateer and Ojemann 1983).

Learning anything Noam Chomsky (2012) holds to his view that children would be incapable of learning their native language unless every human brain contained a store of innate, “preloaded” knowledge that caused them to activate the salient aspects of syntax, phonetics, or semantic features of the language of their parents and siblings. Chomsky’s premises run counter to the established facts and principles that have guided biology since Charles Darwin’s time (discussed in detail in Lieberman 2013), but the question then arises – what are the neural mechanisms by which humans learn to talk or command complex syntax, or the range of activities that are absent in chimpanzees, our nearest living relations? The apparent answer is that neural circuits involving the cortex, basal ganglia and other subcortical structures are involved in learning these defining human capabilities. The basal ganglia facilitate reward-based associative learning process. Mirenowitz and Schultz (1996) monitored basal ganglia dopamineactivated neurons in the basal ganglia while monkeys learned to push a button to obtain a reward. Basal ganglia neurons were activated when the

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monkeys were rewarded. When MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a basal ganglia neurotoxin, was administered, the monkeys were unable to perform the task. When given dopamine agonists that enhance basal ganglia activity, the monkeys again pressed the buttons and received their juice rewards. Graybiel (1997) replicated these findings. Her studies show that the basal ganglia play an essential role in learning both motor and cognitive acts. Recent studies show that the basal ganglia network involved in learning involves neurons that code the expectations that guide associative learning, allowing animals to learn to perform complex linked sequences. In humans, similar processes would account for our learning to talk or the syntax of a language, or the rules that define a culture (Bar-Gad and Bergman 2001; Joshua et al. 2008; Assad and Eskandar 2011).

Do humans have a unique cortex or cortical circuits that confer language? When the human brain is compared with that of a chimpanzee, it is evident that it has about three times as many neurons, the basic computing elements of all brains (Herculano-Houzel 2009). This may account for our ability to store concepts. The ASPM gene might be responsible for the larger size of the human brain (Zhang 2003). Although some studies claim that the human prefrontal cortex is disproportionately larger than would be expected, this does not seem to be the case; the posterior temporal cortex is instead disproportionately larger in humans than would be expected (Semendeferi et al. 1997, 2002). Semendeferi and others also have suggested that the human cortex is more interconnected and may have faster information transfer than that of a chimpanzee. The posterior temporal cortex is involved in storing long-term memory traces. However, theories that assign information storage to posterior cortex and rulegoverned actions to frontal cortex are not in accord with the findings of neuroimaging studies. Independent studies have shown that many areas of the cortex are activated in both perception and imagery (e.g. Martin and Chao 2001; Kosslyn et al. 1999; O’Toole et al. 2005). The pattern of activation extends to cortical areas involved in perceiving motion when a movement is involved (Kourtzi et al. 2002). Activation in the frontal motor cortex occurs when people think of words such as hammer, which involves overt motor activity (Martin et al. 1995). Enhanced human cognitive capabilities might derive from there being something very distinctive about the structure of human frontal cortex. However, this does not appear to be the case. Petrides (2005), in his review of both classical and current studies, including his own contributions, concludes that the basic architectonic organization (the distribution of neurons in the frontal layers of the cortex) is the same in humans and monkeys. Deacon (1997) and Fitch (2010) both claim that humans have

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unique neural circuits linking the cortex to the larynx. These unique circuits hypothetically allow us to imitate sounds and talk. However, their supposition rests on flawed studies that attempted to adapt a highly invasive tracer technique used in animals to study human brains. The technique involves deliberately destroying part of an animal’s brain, letting it live for a while and then sacrificing it and determining the pattern of change in neurons that were connected to the structure that was destroyed. Iwatsubo et al. (1990) ethically attempted to use this technique when they studied the brain of a person who died after two massive strokes that destroyed large parts of the brain, including the basal ganglia and other subcortical structures. They found changes in brainstem neurons linked to the larynx and concluded that this might be linked to the cortical damage that the patient suffered. However, the general pattern of destruction makes it impossible to conclude that a destruction of any specific cortical structure was involved. A subsequent study (Terao et al. 1997) found similar changes in these neurons in patients who had died of non-neurological conditions, suggesting that the effects noted reflected necrosis after death. Moreover, as noted above, if a direct cortical pathway to the larynx existed, basal ganglia lesions (Pickett et al. 1998) and Parkinson’s disease would not degrade laryngeal control. The issue is discussed in detail in Lieberman (2012).

The FOXP2 transcriptional factor In the 1970s, a genetic anomaly was discovered in three generations of a family living in London. A series of studies by the Institute of Child Health (ICH), University College London, revealed a syndrome – a suite of severe movement disorders involving lip and tongue movements, cognitive deficits, and a general problem in comprehending distinctions in meaning conveyed by syntax (Vargha-Khadem et al. 1995). Subsequent studies found that the apparent neural locus of the syndrome was in the basal ganglia and neural structures linked to it (Vargha-Khadem et al. 1998, 2005; Watkins et al. 2002). Watkins and her colleagues (2002: 452) concluded that these “verbal and non-verbal deficits arise from a common impairment in the ability to sequence movement or in procedural learning”. In light of studies of the motor deficits and neural bases of Parkinson’s disease noted by Marsden and Obeso (1994) and many other studies, this pointed to disruption of the normal operations of the basal ganglia. This appeared to be probable because the putamen and globus pallidus of the basal ganglia were abnormal unilaterally in affected individuals in this family, as were the angular gyrus, cingulate cortex, and Broca’s area. The cortical plate (layer VI), the input level of the cortex, is also affected by the FOXP2 mutation. Genetic analysis found the affected members of this large family had an anomalous form of the FOXP2 gene, a transcriptional factor that affects the

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expression in the brain during embryonic development in mammals of the basal ganglia (Fisher et. al. 1998; Lai et al. 2001, 2003). The FOXP2 and Foxp2 genes (the lower-case spelling refers to the non-human form) encode a forkhead transcription factor, a protein that regulates the expression of other genes during the processes that occur during embryonic development. Mutations to other forkhead transcription factor genes have been implicated in a number of developmental disorders. In the case of the afflicted members of the London family, the mutation changes an amino acid in the DNA-binding region of the protein, resulting in protein dysfunction. Lai and her colleagues (2003) showed that the brain structures in which FOXP2human and Foxp2 were expressed in both the human and mouse brain are similar. They include the neural structures that form the human cortical-striatal-cortical circuits involved in motor control and cognition (the thalamus, caudate nucleus, and putamen, as well as the inferior olives and cerebellum). The cerebellum, which receives inputs from the inferior olives, is involved in motor coordination. FOXP2human is not a “language and speech” gene. It also affects the development of heart, muscle and lung tissues. Using techniques analogous to those employed to produce genetically modified plants and animals, mice were targeted. The mouse form of Foxp2 controls the embryonic development of the lungs, the intestinal system, heart, and other muscles, as well as the spinal column of mice (Shu et al. 2001). When the mouse pups’ “wild” version of Foxp2 is knocked out, they die after a few weeks. Enard et al. (2009) and Reimers-Kipping et al. (2011) knocked FOXP2human into mice pups. They found that synaptic plasticity was enhanced in their basal ganglia neurons and in the substantia nigra (another structure in corticalbasal circuits). Dendritic lengths were increased in the basal ganglia, thalamus and layer VI of the cortex. In particular, FOXP2human increased synaptic plasticity in medium spiny neurons in the basal ganglia that code the outcomes achieved in associative learning. Jin and Costa (2010) independently showed that increased synaptic plasticity enhanced associative motor learning in mice, which was not surprising. Hebb, in 1949, formulated the theory that has since guided research on the basic operations of the brain. Synaptic modification is the neural mechanism by which the relations that hold between seemingly unrelated phenomena are learned. The process by which we learn anything – walking, talking, playing the piano, syntax, concepts, etc. – involves modifying synaptic “weights”, the degree to which synapses transmits information to a neuron. The DNA sequence of the avian form of Foxp2, for example, is 98 percent identical to the human version and appears to be involved in the neural circuits in birds that are homologous to the basal ganglia when birds learn new songs (Brainard and Doupe 2000; Doupe et al. 2005). The evolution of the human form of FOXP2 appears to have occurred in stages. In the millions of years of evolution that separates humans and

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chimpanzees FOXP2human underwent two substitutions in its DNA sequences, causing two amino acid changes in FOXP2 protein. The two amino acid changes have been found in Neanderthal bones (Krause et al. 2007) which pushes its date back at least 370,000–450,000 years, when human and Neanderthal lineages diverged (Green et al. 2010). However, Coop and his colleagues, in 2008, pointed out that the selective sweep that spread the completely human form of FOXP2human occurred about 260,000 years ago, concurring with the original date noted by Enard and colleagues in 2002. If the selective sweep had occurred 500,000 or so years ago, we would expect to find much more variation in FOXP2human, which, as the Enard study showed, is not the case. An additional change, that still is the subject of ongoing research, seems to have occurred in the period in which anatomically modern human beings appeared some 260,000 years ago. Ongoing research projects point to other transcriptional factors that may have enhanced human cognitive ability, including language, which, as the studies noted above demonstrate, is not disjoint from other aspects of cognition. Konopka et al. (2009) confirmed that FOXP2 “upregulated” genes that, in turn, affect the caudate nucleus of the basal ganglia. The caudate nucleus, as the studies discussed earlier show, is involved in a range of cognitive and linguistic tasks. Konopka and her colleagues found 61 other human genes whose expression was upregulated by the human form of FOXP2. Five of these genes, expressed in the brain, were under positive selection in the human lineage. Preuss and his colleagues, in their 2004 Nature Genetics review paper, surveyed the several hundred genes that are known to differ in humans and chimpanzees. They pointed out that virtually all of these genes that were expressed in the human brain are upregulated. In another study, Green et al. (2010) identified “highly accelerated regions” (HARs) of the human genome that differ from the Neanderthal genome. These genes appear to be associated with cognition. Their “cost” is that they seem to be associated with schizophrenia, autism, and other mental illnesses. Pal et al. (2010), for example, identified a gene involved in seizures and speech motor control. In contrast to FOXP2human, the role played in neural development and the behavioral consequences of most of these genes are as yet unknown. But as research continues, we can expect to find other genes that enhance the attributes that we think of as distinctively human, but in light of present knowledge concerning the neural bases of motor control, and cognition, it is unlikely that any genes specific to language will be discovered.

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Navigation, discourse and the origin of language Francesco Ferretti

Investigating the origin of language corresponds to investigating the essential characteristics (the properties that allow the origin and which govern the actual functioning) of human communication. According to the common view in cognitive science, the trait that mainly distinguishes language from other systems of communication is the recursive nature of universal grammar proposed by Noam Chomsky in the 1950s. Recursion is in fact the process at the foundation of combinatorial creativity (i.e. the ability to generate an unlimited number of utterances from a finite number of components and combination rules), unanimously considered one of the most typical characteristics of human language (Corballis 2011; Hauser et al. 2002). Considering the relevance of the universal grammar model in the contemporary debate, Chomsky’s (1988) criticism of analyzing language in evolutionary terms is a must for anyone interested in the birth of our verbal skills. Chomsky’s skepticism over language as a biological adaptation is dependent on universal grammar’s incompatibility with natural selection. It is the language model, therefore, that leads Chomsky to criticize evolution. In this chapter, it is argued that a model of language that is not in accord with the theory of evolution is not a good model of our verbal skills. If universal grammar fails the test of evolutionary plausibility, the best thing to do is abandon it (Christiansen and Chater 2008; Tomasello 1995). Our idea is that, to conform to evolutionary theory, the investigation on the origin of language has to shift focus from grammar to pragmatics. The shift from “linguistic competence” to “communicative competence”, then, implies that the priority usually given to recursion gives way to the question of appropriateness (the ability to use language coherently and in ways that are consonant with the situation). Chomsky himself admitted that the issue of speaking appropriately is critical to the investigation of the nature of language. In referring to Descartes, he argued that coherence and consonance with the situation are the essential characteristics of the creative use of language. That said, however, Chomsky (1988) did not add anything more; in his view, the ability of human beings to speak appropriately within a context is a mystery (the “Descartes’ problem”) that the human mind

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cannot solve in principle. In our opinion, the Descartes problem is unsolvable from the frame of reference of universal grammar. Since syntax explains how the symbols fit together (combinatorial creativity) but not how the symbols are grounded in the situation (creative use of language), we must not look to recursion to explain the creative use of language. In cognitive science, theoretical considerations about the essential properties of language must converge with considerations about its processing systems. Chomsky also argued that the problem of Descartes is a mystery without solutions because, in his opinion, we have no idea what kind of mental device would have to be the basis of communicative competence. The only thing that can be said, according to Chomsky, is that such a device, by analogy with other cognitive devices, must respect the domain specificity (Tooby and Cosmides 1992; Fodor 1983). If the mechanisms at the basis of the creative use of language are general purpose devices, in fact, “the ‘communicative competence’ that enables to use language coherently and in ways that are appropriate to situations” should show strong similarity, for example, to capacities such as “finding our way home when we come upon a detour” (Chomsky, in Stemmer 1999: 395). From our point of view, the example that Chomsky uses to argue against language as the product of domain-general devices could not have been more emblematic. Our main idea in this chapter is that verbal expressions’ coherence and consonance with the situation are the product of processing mechanisms strongly related to those that govern spatial navigation. Before presenting the details of the pars costruens of our argument, however, some more general considerations are necessary. The first is an explanation why the analysis of language should be assigned to pragmatics rather than grammar.

It is a matter of clues The conceptions of language that, like universal grammar, consider comprehension-production processes in the constituent analysis are strictly dependent on the “code model” inspired by the mathematical theory of information proposed by Shannon and Weaver (1949). According to this model, which Fodor (1975: 106) considered “not only natural, but inevitable”, the communicative act is the process by which the speaker’s thought (the message) is encoded in a succession of sounds that the listener decodes in order to share the thought (the message) that the speaker intended to communicate. The code model, however, is not a good conception of human communication both from an evolutionary point of view and from the point of view of the actual functioning of language. From an evolutionary point of view, the idea of communication in terms of encoding-decoding triggers a vicious circle. Universal grammar requires a code in order to operate; the existence of a code, however, strongly depends on the existence of universal grammar.

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The device at the basis of language operates, in fact, only assuming the appropriate environmental input: without a common code (the languages used by communities of speakers), universal grammar would be like a system for viewing a room without light since it is a device innately specialized for language. If we exclude the reference to the preformism hypothesis, the relationship between linguistic code and universal grammar is highly problematic. On the one hand, it is not possible to analyze the origin of language assuming the existence of a linguistic code (a code is exactly what it is missing in the early stages of language); on the other hand, it makes little sense to assume that brains are predisposed to language before humans are able to exploit the symbolic code used by the community of speakers in which they live. That said, the code model is unconvincing, especially in terms of the actual functioning of language. Such a model only works assuming that all that matters in the relationship between thought and language is contained in the sentence that expresses the thought it conveys. Sperber and Wilson (1986) launched a harsh attack on the idea of communication as a process that translates thoughts into linguistic expressions (in the production of the speaker) and as a process that transforms linguistic expressions into thoughts (in the understanding of the listener). The essential point is the difference between what the speaker says and what he/she means. With reference to Grice (1957), Sperber and Wilson have shown that human communication is supported by information processing governed by the intention of the speaker. In such a perspective, rather than providing detailed expressions that encode his thoughts exactly, the speaker provides the listener with only expressive clues that help him to rebuild his communicative intentions. The key is that, to work correctly, the clues must be appropriate. The hypothesis that communication takes place through clues rather than fully coded expressions has important consequences for understanding the nature of language. Because constituent analysis is a necessary but not sufficient condition to communicate correctly, the sentence can no longer be regarded as the essential structure of the processes of verbal processing. Specifically, our opinion is that the ability to speak appropriately involves the relationship between sentences rather than the relation between the constituent elements of the sentence. The level of discourse (the flow of speech), in other words, is the right level of analysis to understand the role of coherence and consonance with the situation in the creative use of language. These conceptual arguments are supported by empirical considerations. Increasing evidence shows that the processing of internal constituents of the sentence (microanalysis) and the relationship between sentences in the flow of speech (macroanalysis) can be analyzed separately (Davis et al. 1997; Marini et al. 2005). For example, the analysis of the language of individuals with schizophrenia supports the existence of a dissociation between these levels, showing that linguistic production is

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impaired mainly at the macrolinguistic level of processing (Marini et al. 2008). A typical example is the phenomenon of “derailment”, a pattern of speech in which incomprehensible, disconnected, and unrelated ideas replace logical and logical thought (Andreasen 1979). Another example, more interesting for our purpose, is that of Williams syndrome. People with Williams syndrome have adequate phonological, lexical, and syntactic skills but a relative weakness in the domain of discourse processing (Marini et al. 2010). Albeit in different ways, derailment and Williams syndrome share a common problem: these individuals are unable to keep to the route of their discourses. For this reason, they cannot produce a coherent discourse. If the primacy accorded to the phrase gives way to the primacy assigned to the flow of speech, communication has the character of a path dotted with clues in which speaker and listener are committed to building and maintaining the route of the flow of speech in order to achieve the goal (the mental content that the speaker intends to convey to the listener). It is in this context that the idea of combining the processes of spatial navigation and comprehension of speech leaps to the forefront.

Navigating the space of discourse Navigation represents, even intuitively, a good metaphor for thinking about the processes at the foundation of the flow of discourse (e.g. Ferretti et al. 2013). Jonsson (2002: 27) defined navigation as “knowing where you are and how to get to where you want to go”. Gallistel (1990: 34) defined navigation as “the process of determining and maintaining a course or trajectory from one place to another”. What happens in real navigation, indeed, is never equivalent to the straight path drawn on a map (such as that calculated from the identification of the azimuth on a topographic map to get from point A to destination B). The actual movement in space requires a continuous realignment of the goal because of the difficulties posed by environmental harshness. Similarly, the process of discourse construction relies on the ability to identify a goal (the communicative intention or content that the speaker wishes to convey to the listener), to constantly monitor the step where we are in the flow of speech, and to overcome several difficulties that may alter the intended route. As in spatial navigation, the achievement of the communicative goal in discourse depends on the speakers’ constant realignments to continuously rebuild the route, such as those after a digression or derailment caused by the different points of view typical of verbal communication. The tight relationship between spatial navigation and discourse production also appears when we consider the distinction between the processes involved in route planning and actual navigation. Planning mainly concerns the generation of mental representations that represent space and spatial relationships between objects in an allocentric way

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(independently from the position of the observer). The construction of a “mental map” – which includes a destination, a specific direction, and a sequence of intermediate steps – is the prerequisite of any form of intentional movement in space (O’Keefe and Nadel 1978). Pertinent to our point here, mental map construction is a process that precedes navigation in the actual route. Analyzing the case of London taxi drivers, Spiers and Maguire (2006) and Maguire et al. (1998) recorded the functioning of the hippocampus and retrosplenial and frontal cortices “only at the beginning of the trip when one plans the route to a desired goal” (Dudchenko 2010: 182). Even if the construction of allocentric maps is essential to the mental (internal) process before real navigation, a key role in actual navigation is played by egocentric (observer-centered) processes. The internal sense of direction, a kind of neural compass, allows us to identify and maintain the correct direction toward the goal even in absence of external references (Dudchenko 2010; Ellard 2009; Jonsson 2002). The key aspect of actual routing, however, is the identification and recognition of landmarks in the external world: Salient spatial positions signaled by a recognizable object (e.g. a church, a building). Route-based representations are dependent on brain structures (i.e. lingual gyrus, calcarine cortex, fusiform gyrus, parahippocampal cortex) that are different from those implicated in the use of mental maps (Epstein 2008). Jonnson (2002) emphasized the magnetic power of landmarks, and Nemmi et al. (2013) considered the reference points in the external world as “beacons” that attract the attention of the traveler. Our idea is that landmarks are not only “poles of attraction” acting as guides to navigation, but they can be conceived also as “landing points”; that is, places where one stops to rest, to determine if he/she is at the expected position, and, if in a wrong location, to plan a new route before returning to the road. The idea of landmarks as beacons and landing points exemplifies the function of anchoring to the context provided by these important (external) points of reference. In our opinion, the landmarks (intended as the clues on the ground through which the traveler “finds confirmation” of the planned route in mental maps) are the tools that allow speakers to assess the consonance between the chosen route and the actual walking. The overall picture that emerges from these considerations is summarized very effectively by Jonsson: When we want to go a faraway familiar place, we first see the direction to it in our cognitive map. We see it from where we are without any detail; it is just an awareness of a direction and distance. Later when we think about how to go there, we picture the route we have to follow. Usually we cannot visualize this route as one picture all the way from our starting point to our destination with sufficient detail to be useful; instead a cognitive route map is a series of pictures seen from points along the route and in the direction in which we are travelling. It is as if we, when we encoded the map of this route earlier, had a camera and

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snapped a picture every time something interesting appeared ahead. This means that a monotonous boring part is neglected in our map, whereas a stretch with many outstanding landmarks is well covered. And since our most important tasks is to reach our destination without fail, all the places along the route where we could possibly take the wrong road (like forks and intersections) are shown with enough detail to prevent mistakes. (Jonsson 2002: 33–5) In extending the metaphor of navigation to language, landmarks work the same way both when we recognize and localize points of reference in the real world (through the actual perception) and when we imagine them mentally (through the simulation of actual perception). It therefore seems plausible that speakers’ realignments and continuous revisions in expressing their communicative intentions in the flow of speech rely on points of support characterized by a strong magnetic power, analogous to what happens in route-based navigation. The construction of scenes (Hassabis and Maguire 2007) in the critical points of the flow of speech fulfills the same function of landmarks in actual navigation. It is not surprising, then, that scene construction and the ability to locate and identify landmarks on the ground is attributable to the same processing system – the parahippocampal area (Epstein 2008) – crucial for the construction of visual egocentric mental representations. In The Art of Memory, Yates (1966) described the loci method used by ancient Greek and Roman orators to maintain the route of discourse in public debates. This method makes extensive use of the metaphor of navigation and, in particular, of the construction of (the mental representation of) specific spaces along the route whose attractiveness plays a central role in the construction of the flow of discourse. We posit that the ancient rhetoricians offer us extraordinarily effective insights to investigate the role of landmarks in the mental processes of comprehension and production of language. It is thus possible to maintain that speaking appropriately (a property typical of the flow of speech) exploits two of the major systems governing navigation in space: the construction of mental maps and the localization and identification of landmarks on the ground. More specifically, our idea is that, while the processes that govern the construction of the mental map (which include the goal to be achieved, the direction to be taken, and the stages of the path to touch) control the construction of the coherence of the discourse, the representations of landmarks (through the scene construction) ensure consonance with the situation of the flow of speech. Coherence and consonance with the situation, as we have said, are at the foundation of our ability to speak appropriately and, therefore, at the basis of the creative use of language. As the creative use of language is the hallmark of human communication, then, the navigation systems can be placed at the base of one of the essential features of the language.

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Getting lost in space and in discourse The difficulties that our navigation systems must constantly handle to orient us in the world are obvious to anyone who has been lost in a forest or has experienced disorientation in the mountains due to fog or snow. Analysis of specific brain-orientation deficits is significant to investigating the cognitive systems involved in navigation. In addition to being a useful test of the ability to represent space, such analysis is a way to empirically verify the theoretical foundation of the ideas portrayed in this chapter: if the flow of speech exploits spatial navigation systems, then navigation deficits should have effects on discourse processing. Since the most interesting phenomenon for our purpose is linguistic derailment, the question to be tested is whether difficulties in keeping to the route that are typical of discourse could be due to pathological phenomena of spatial navigation. At the moment, we have no experimental evidence of a direct causal link between the deficits of navigation and discourse. That said, we have very encouraging data about the co-occurrence of disorders of spatial navigation and the inability to keep to the route in the construction of the flow of speech. Our hypothesis is that deficits relating to discourse derailment are the effects of different kinds of spatial derailment. Empirical data seem to corroborate the relationship between spatial language and spatial navigation (Denis et al. 1999; Tenbrink and Wiener 2007). The more documented case is that of Williams syndrome, a pathology characterized principally by visuo-spatial representation deficits (Atkinson et al. 2001; Farran and Jarrold 2003). Even if the relationship between Williams syndrome and spatial language is analyzed mainly at the microanalysis level (Karmiloff-Smith 2007; Landau 2002; Landau and Zukowsky 2003), we have good reasons to believe that it largely concerns the macroanalysis level. The narrative deficits of individuals with Williams syndrome substantiate this hypothesis. According to Marini et al. (2010), Williams syndrome affects the narrative aspects of language. Our interpretation of the empirical data is that the difficulties of these persons are caused by their reorientation deficits (Lakusta et al. 2010) rather than to their visuo-spatial representation deficits (Ferretti et al. 2013). We believe that individuals with Williams syndrome have an impaired mental space travel (Ciaramelli et al. 2010), a network of processing systems that allows a person to orient himself and to navigate the space correctly. Turning to the aspects of navigation more closely related to the characteristics of verbal communication that we consider to be at the foundation of language (the ability to speak appropriately), the most interesting case concerns the lack of coherence of the discourse produced by persons with traumatic brain injury. In our hypothesis, these deficits are related to the role of executive functions of action planning and monitoring exploited in spatial navigation (Ferretti and Adornetti 2011). The important finding in this regard concerns the inability of individuals with traumatic brain injury

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to build (at the macroanalysis level) the global coherence of discourse, despite the fact that it does not meet difficulty in the construction of local coherence (at the microanalysis level; Biddle et al. 1996; Hough and Barrow 2003). Because of their inability to formulate and to pursue a communicative goal in terms of coherence, the discourse of patients with traumatic brain injury appears pragmatically inappropriate (see also Chapter 11 for a discussion of these issues in relation to schizophrenia). Although the analysis of discourse production in persons with Williams syndrome and traumatic brain injury is a good way to investigate the relationship between the flow of discourse and spatial navigation, the case par excellence should include individuals who are topographically disoriented, a specific disorder of navigation in space (Aguirre and D’Esposito 1999). Although the relationship between this kind of deficit and the level of discourse appears still largely unexplored, the few available empirical data are very encouraging. Ciaramelli (2008) reported the case of LG, a person with brain lesions at the ventromedial prefrontal and rostral anterior cingulate cortices, who invariably lost his way whenever asked to go somewhere on his own. Interpreting LG’s spatial difficulties, Ciaramelli maintained that “when travelling along routes that included a location he had attended frequently in the past, LG was ‘attracted’ to the familiar location, and failed to reach the goal location” (Ciaramelli 2008: 2103). The hypothesis of landmarks as a magnet and beacon that we mentioned in the previous section is empirically confirmed by this study. More interesting for us is that Ciaramelli established a direct connection between becoming lost in space and becoming lost in thought and language. Specifically, she suggested that LG’s spatial disorientation (because of the attractive power of landmarks) involved a form of linguistic disorientation interpretable in terms of confabulation (a disorder characterized by a form of derailment that in our opinion is possible to interpret as the other side of the moon of the deficits exhibited by individuals with either traumatic brain injury or Williams syndrome). With confabulation, consonance with the situation is compromised more than coherence. The fact that confabulation is mentioned as a symptom of a disorder of disorientation shows the role of landmarks in the construction of discourse; when landmarks are not recognized correctly, the subject cannot link with reality and constructs discourses that, even if coherent in terms of the flow of speech, are inappropriate because they are totally ungrounded from the contextual situation. What emerges, then, is that the ability to navigate space and the ability to build the flow of speech in a coherent and consonant way with the situation share a number of structural and functional similarities. The empirical cases available, indeed, indicate that the same specific processing systems at the base of spatial navigation can be interpreted as the systems at the base of discourse processing. The idea that the ability to orient and move in space can be the basis of the creative use of language is therefore something more than just a metaphor.

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Spatial navigation and the origin of language With the creative use of language as the hallmark of human verbal skills, what distinguishes human language from animal communication has important implications for the origin of language. The shift of the focus from grammar to pragmatics (from the combinatorial creativity to the creative use of language) overcomes the difficulty of the code model – an interpretive model, as we have seen, highly problematic in investigating the origins of language. Even intuitively, it is clear that the dawn of language needs to be analyzed by excluding the preexistence of a common code between speakers and listeners. How do we explain the advent of language in the absence of a code? It is legitimate to assume that our ancestors’ communicative exchanges were governed by a limited set of expressive signals probably similar to the signals used by vervet monkeys (Cheney and Seyfarth 1990; Seyfarth et al. 1980). Without adequate cognitive resources, however, signals of this kind would not have ensured the transition from animal communication (mechanical and determined) to human language (free and creative). Our idea is that the emerging forms of human communication strongly take advantage of the spatial navigation processing systems capable of interpreting the limited set of signals in terms of appropriateness. Exploiting the same devices used to construe the route to reach the goal, in effect, the mechanical signals are deployed in a sequence of clues characterized by coherence and consonance with the situation. Interpreting the passage from animal to human communication in terms of the bridge between the mechanical signals to the appropriate clues makes it possible to maintain that the navigation system may have played an important role in the origin of language. In contrast to the still-dominant universal grammar models, communication grounded in clues appears very promising both for investigating the effective functioning of language and for analyzing its evolutionary origins. Such a model of human communication, then, respects both evolutionary and cognitive plausibility. If, as we argued at the beginning of this chapter, the creative use of language is what distinguishes human verbal skills from animal communication, then appropriateness is an essential property in the origin of language. But if this is true, then the cognitive systems at the basis of language (both its actual functioning and its evolution) must be closely related to navigation systems. Chomsky could not have chosen a worse example to take into account language’s supposed autonomy from other cognitive systems.

References Aguirre, G. K. and D’Esposito, M. (1999) ‘Topographical disorientation: A synthesis and taxonomy’, Brain, 122: 1613–28. Andreasen, N. C. (1979) ‘Thought, language, and communication disorders: Clinical assessment, definition of terms, and assessment of their reliability’, Archives of General Psychiatry, 36: 1325–30.

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Atkinson, J., Anker, S., Braddick, O., Nokes, L., Mason, A. and Braddick, F. (2001) ‘Visual and visuospatial development in young children with Williams syndrome’, Developmental Medicine and Child Neurology, 43: 330–7. Biddle K., McCabe, A. and Bliss, L. (1996) ‘Narrative skills following traumatic brain injury in children and adults’, Journal of Communication Disorders, 29: 447–69. Cheney D. and Seyfarth, R. (1990) How Monkeys See the World: Inside the Mind of Another Species, Chicago: Chicago University Press. Chomsky, N. (1988) Language and Problems of Knowledge. The Managua Lectures, Cambridge, MA: MIT Press. Christiansen, M. H. and Chater, N. (2008) ‘Language as shaped by the brain’, Behavioral and Brain Sciences, 31: 489–508. Ciaramelli, E. (2008) ‘The role of ventromedial prefrontal cortex in navigation: A case of impaired wayfinding and rehabilitation’, Neuropsychologia, 46: 2099–3005. Ciaramelli, E., Rosenbaum, R. S., Solcz, S., Levine, B. and Moscovitch, M. (2010) ‘Mental space travel: Damage to posterior parietal cortex prevents egocentric navigation and reexperiencing of remote spatial memories’, Journal of Experimental Psychology, 36: 619–34. Corballis, M. (2011) The Recursive Mind, Princeton: Princeton University Press. Davis, G., O’Neil-Pirozzi, T. and Coon, M. (1997) ‘Referential cohesion and logical coherence of narration after right hemisphere stroke’, Brain and Language, 56: 183–210. Denis, M., Pazzaglia, F., Cornoldi, C. and Bertolo, L. (1999) ‘Spatial discourse and navigation: an analysis of route directions in the city of Venice’, Applied Cognitive Psychology, 13: 145–74. Dudchenko, P.A (2010) Why People Get Lost: The Psychology and Neuroscience of Spatial Cognition, Oxford: Oxford University Press. Ellard, C. (2009) Where Am I? Why We Can Find Our Way to the Moon but Get Lost in the Mall, Toronto: Harper Collins Canada. Epstein, R.A. (2008) ‘Parahippocampal and retrosplenial contributions to human spatial navigation’, Trends in Cognitive Sciences, 12: 388–96. Farran, E. K. and Jarrold, C. (2003) ‘Visuo-spatial cognition in Williams syndrome: Reviewing and accounting for the strengths and weaknesses in performance’, Developmental Neuropsychology, 23: 175–202. Ferretti, F. and Adornetti, I. (2011) ‘Discourse processing and spatial navigation’, in B. Kokinov, A. Karmiloff-Smith and N. J. Nersessian (eds) European Perspectives on Cognitive Science, Sofia: New Bulgarian University Press. Available online at http://nbu.bg/cogs/eurocogsci2011/proceedings/pdfs/EuroCogScipaper251.pdf (accessed 21 May 2013). Ferretti, F., Adornetti, I., Cosentino, E. and Marini, A. (2013) ‘Keeping the route and speaking coherently: The hidden link between spatial navigation and discourse processing’, Journal of Neurolinguistics, 26: 327–34. Fodor, J. (1975) The Language of Thought, New York: Thomas Y. Crowell. Fodor, J. (1983) The Modularity of Mind, Cambridge, MA: MIT Press. Gallistel, C. R. (1990) The Organization of Learning, Cambridge, MA: Bradford/MIT Press. Grice, P. (1957) ‘Meaning’, Philosophical Review, 66: 377–88. Hassabis, D. and Maguire, E. A. (2007) ‘Deconstructing episodic memory with construction’, Trends in Cognitive Sciences, 11: 299–306. Hauser, M., Chomsky, N. and Fitch, T. (2002) ‘The faculty of language: What is it,

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who has it, and how did it evolve?’, Science, 298: 1569–79. Hough, M. S. and Barrow, I. (2003) ‘Descriptive discourse abilities of traumatic brain-injured adults’, Aphasiology, 17: 183–91. Jonsson, E. (2002) Inner Navigation. Why We Get Lost and How We Find Our Way, New York: Scribner. Karmiloff-Smith, A. (2007) ‘Williams syndrome’, Current Biology, 17: R1035–6. Lakusta, L., Dessalegn, B. and Landau, B. (2010) ‘Impaired geometric reorientation caused by genetic defect’, Proceedings of the National Academy of Science of the USA, 107: 2813–17. Landau, B. (2002) ‘Spatial cognition’, in V. S. Ramachandran (ed.) Encyclopedia of the Human Brain, vol. 4, San Diego: Academic Press, pp. 395–418. Landau, B. and Zukowski, A. (2003) ‘Objects, motions, and paths: Spatial language in children with Williams Syndrome’, Developmental Neuropsychology, 23: 107–39. Maguire, E. A., Burgess, N., Donnett, J. G., Frackowiak, R. S., Frith, C. D. and O’Keefe J. (1998) ‘Knowing where and getting there: A human navigation network’, Science, 280: 921–4. Marini, A., Carlomagno, S., Caltagirone, C. and Nocentini, U. (2005) ‘The role played by the right hemisphere in the organization of complex textual structures’, Brain and Language, 93: 46–54. Marini, A., Spoletini, I., Rubino, I. A., Ciuffa, M., Banfi, G., Siracusano, A., Bria, P., Caltagirone, C. and Spalletta, G. (2008) ‘The language of schizophrenia: An analysis of micro- and macrolinguistic abilities and their neuropsychological correlates’, Schizophrenia Research, 105: 144–55. Marini, A., Martelli, S., Gagliardi, C., Fabbro, F. and Borgatti, R. (2010) ‘Narrative language in Williams syndrome and its neuropsychological correlates’, Journal of Neurolinguistics, 23: 97–111. Nemmi F., Piras, F., Péran, P., Incoccia, C., Sabatini, U. and Guariglia, C. (2013) ‘Landmark sequencing and route knowledge: An fMRI study’, Cortex, 49: 507–19. O’Keefe, J. and Nadel, L. (1978) The Hippocampus as a Cognitive Map, Cambridge: Oxford University Press. Seyfarth, R. M., Cheney, D. L. and Marler, P. (1980) ‘Monkey responses to three different alarm calls: Evidence of predator classification and semantic communication’, Science, 210: 801–3. Shannon, C. E. and Weaver, W. (1949) The Mathematical Theory of Communication, Urbana, IL: University of Illinois Press. Sperber, D. and Wilson, D. (1986) Relevance: Communication and Cognition, Cambridge, MA: Harvard University Press. Spiers, H. J. and Maguire, E. A. (2006) ‘Thoughts, behaviour, and brain dynamics during navigation in the real world’, NeuroImage, 31: 1826–40. Stemmer, B. (1999) ‘An on-line interview with Noam Chomsky: On the nature of pragmatics and related issues’, Brain and Language, 68: 393–401. Tenbrink, T. and Wiener, J. M. (2007) ‘Wayfinding strategies in behavior and language: A symmetric and interdisciplinary approach to cognitive processes’, Lecture Notes in Computer Science, 4387: 401–20. Tomasello, M. (1995) ‘Language is not an instinct’, Cognitive Development, 10: 131–56. Tooby, J. and Cosmides, L. (1992) ‘The psychological foundations of culture’, in J. H. Barkow, L. Cosmides and J. Tooby (eds) The Adapted Mind, Oxford: Oxford University Press, pp. 19–136. Yates, F. A. (1966) The Art of Memory, London/New York: Routledge and Kegan Paul.

3

Phylogenetic aspects of worldand self-representation in humans Franco Fabbro and Massimo Bergamasco

Considered logically this concept (the bodily object) is not identical with the totality of sense impressions referred to it; but it is an arbitrary creation of the human (or animal) mind. Albert Einstein (1936) Trying to reflect on the problem of world and self-representation is a very complex task. Difficulties depend on several factors: a) the role of consciousness in world and self-representation (consciousness is considered a “hard problem”; see Chalmers 1995); b) the need, for humans, to deal with both analysis according to a “third person” (objective) perspective and analysis in “first person” (subjective) perspective; c) the need to develop considerations on the mind of animals in terms of anatomical and physiological organization of their nervous system; d) the need to deal with philosophical reflections related to the different levels of analysis of the problems under investigation; e) the problem of rendering explicit the philosophical positions of the scientific investigator. First, an attempt is made to define the meaning of world and self-representation according to the following levels: phenomenological, cognitive and neurophysiological.

Consciousness in human beings Consciousness can be considered as the appearance of a world (Edelman 2004; Metzinger 2009). Individuals to whom a world appears during waking or dreaming states are conscious (Revonsuo 2010). Experiments in cognitive neuroscience suggest that the human brain continuously creates the conscious experience; i.e. that I am present in a world outside my brain (Metzinger 2009). Then both the Self and the world with its objects are a construction of our brain (Frith 2007; Libet 2006), which creates also the illusion that they are truly real (in philosophical terms this means that the models of world and of Self are “transparent”) (Revonsuo 2006; Metzinger 2009). For this reason, it may be useful to compare consciousness with virtual reality and the brain with a flight simulator, in which both the functioning of the airplane and the operation of the pilot are completely

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simulated (Metzinger 2009). In general, the images or representations of the Self and of the world created by the brain are effective. Indeed, they allow the individual to move in the world, to maintain homeostasis, and to develop a plan for self-fulfillment. However, sometimes the images of the world and of the Self are contradictory, as for visual illusions, rubber hand illusion, illusory shadow person or in out-of-the-body experiences (Botvinick and Cohen 1998; Arzy et al. 2006; Lenggenhager et al. 2007; Ehrsson 2007), or, as it happens during dreaming, even created by a brain fully de-afferentiated from the external world (Hobson 1989; 1999). It is thought that the nature of dreams and of the illusions mentioned above are of fundamental importance to understanding the problem of consciousness (Metzinger 2009; Revonsuo 2010). Human consciousness can be analyzed according to different organizational levels, of which the most significant are the phenomenological, the cognitive and the neurophysiological levels (Revonsuo 2006). Each level possesses specific properties and rules; the lower levels influence the higher levels and vice versa. Different epistemological perspectives foresee more or less constraining influences among the different levels, from models with hierarchical structures (Craver and Darden 2001; Neisser 2012) up to models in which the different levels can be considered relatively independent (Feyerabend 1987; Ayala and Arp 2010).

The phenomenological level At the phenomenological level, in addition to the classical third-person perspective analysis (a perspective in which the whole universe is given as existent independently from the observer) it is necessary to envisage a firstperson-perspective (in this perspective, the objects in space are necessarily related to an agent) (Revonsuo 2006, 2010). At this level, consciousness is an immediate, undeniable fact of experience; i.e. a “world-for-me” and, more generally, “a world-for-someone” (Metzinger 2009). Since the phenomenal world is perceived as “present-for-me”, it can be considered as composed by a phenomenal space and by a Self, which represents an egocentric frame of reference. The ego-center is single and located behind the bridge of the nose, inside our head (Bisiach and Luzzati 1978; Landau 2002). In the phenomenal space, which contemplates space-time dimensions, are located the objects belonging to the world (Revonsuo 2006). The phenomenal Self, as pointed out by William James, possesses the characteristics of being “partially known and partially knower, partly object and partly subject” (James 1892: 176). Already at the phenomenological level, the Self does not seem to be an object. Rather, it resembles a process (a continuous stream of thought): it disappears during sleep, and sometimes also during dreaming (Revonsuo 2005), to reappear when we wake up (Damasio 2010). It seems that it is made of different components, probably arranged in layers. One component that observes (defined by James as

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the “I” and only scarcely studied by Western psychology – that did not provide enough attention to introspection – but well practiced in the Far East, especially in the context of Buddhism; Horny 1950; Tsering 2006), and one component of the mind which is the object of observation (e.g. thoughts, sensations, emotions and after all perceived objects) (the “Me” or the empirical aggregates of things objectively known) (James 1890; Tagini and Raffone 2010).

The consciousness of the world At the cognitive level, the consciousness of the world and of the Self are typically separated and studied through the analysis of their different neuropsychological components. The world that surrounds us is made of a space where there are located objects considered interesting, dangerous or indifferent. This is a unified representation depending on the integration of sensory-motor information. The phenomenal space is an egocentric coordinate system (Revonsuo 2006; Metzinger 2009). In the human species, and generally in vertebrates, the sensory modality carrying out a fundamental role in the representation of the world and in the capability to orientate in it is sight (von Senden 1960). Aristotle sustained that the ability to know primarily depends on sight (Metaphysics, Book 1, Part 1; see also Blumenberg 1993). The sense of sight allows us to clarify the concept of “representation” or “image”. We often say that the eye is able to create an image of the external world: But, what is an image? An image is a simplification of reality. Our brain is making a simplification of reality. It is making a simplification of reality of the external world, but a very useful one. An image is a simplified representation of the external world written in a strange form . . . [The brain] makes representations of aspects of the external world, fractionalized aspects, by making a useful geometry, a geometry with internal meaning that has nothing to do with the ‘geometry’ of the external world that gave rise to it. (Llinás 2001: 108–9; see also Oatley 1978) Several studies of clinical and experimental neuroscience have clarified how the different structures of the brain decode, transmit and process visual information (Zeki 1999, 2009). The organization of vision in the human brain has been schematically divided into two large systems: a ventral and a dorsal stream, respectively. In the ventral stream visual information coming from the retina travels through the lateral geniculate nucleus in order to reach the primary visual cortex (V1). From V1, the information is transmitted to several other occipital-temporal areas, and eventually reaches the inferior temporal cortex, where we finally recognize what has been perceived (contours extraction, color and movement

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perception, comparison with previously memorized objects). Electrophysiological studies showed that the extrastriate temporal cortex is implicated in the production of a specific neural response pattern for each category of objects (Kupers et al. 2011). In the dorsal stream, visual information reaches the posterior parietal cortex through both subcortical (retina → superior colliculus → pulvinar → parietal cortex); and ii) and cortical (retina → lateral geniculate → primary visual cortex → posterior parietal cortex) routes. The dorsal stream seems to play a crucial role in the representation of space for orientation and for the organization of movements (Yarbus 1967; Goodale 1996; Goodale and Milner 2004; Kupers et al. 2011). Neuropsychological studies on patients with cerebral lesions allow us to pinpoint some of the critical cognitive processes that enable us to recognize what is perceived in the world. For example, individuals with apperceptive agnosia, a clinical condition generated by diffuse lesions in the ventrolateral regions, are no longer able to recognize forms and objects. Instead, they succeed in organizing manual movements to correctly grasp a specific object; moreover, they are able to avoid obstacles during walking (as their visual dorsal stream is unaffected) (Shelton et al. 1994; De Renzi 2000). The complete destruction of the visual cortical areas in a monkey initially generates a complete loss of vision. After few years she seems to be able to “see” again. In fact, she succeeds in grasping a fly in mid-air but not in recognizing forms and colors (Humphrey 1992) (note that the monkey can move efficiently in the world by means of the subcortical route of the dorsal stream). In associative agnosia, patients no longer recognize objects; even if they are able to recognize the single parts of an object, they do not succeed in integrating all the elements in a gestalt. These patients can meticulously copy a scene without being able to recognize what they have drawn. In associative agnosia, part binding fails (Goldberg 1990; De Renzi 2000). Acromatopsia is a disorder characterized by the loss of color perception and is caused by bilateral damage to the extrastriate visual cortex and to the lingual and fusiform gyri (area V4) (Cowey and Heywood 1997; Zeki et al. 1999). Other patients, with bilateral lesions to the middle temporal gyri and the adjacent portion of the occipital gyri, lose their ability to recognize movement and to make predictions of the future position of objects (akinetopsia) (Zeki 1991, 2009). Objects are always located in the space surrounding us. The brain is then able to generate a representation of space in which we have a central position. Human beings are able to recognize an object and to define its relative position with their body and other objects. This cognitive ability is affected in Balint’s syndrome (dorsal simultagnosia), a condition caused by bilateral lesions to the occipito-temporal lobes. In this syndrome, patients lose cognition of the space surrounding them. They can recognize a bird (e.g. a finch) but they are unable to specify where it is located in space. Moreover, they cannot recognize more than one object at a time (Farah

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1990; Jackson et al. 2006). The hemispatial neglect is a condition in which the patient is incapable of exploring the left hemispace. Generally, the patient is not aware of this problem and the deficit is present in both visual perception and visual imagery. This syndrome depends on a lesion in the infero-posterior parietal region of the right hemisphere (Robertson and Halligan 1999; Bartolomeo 2007). The angular gyrus, in particular in the right hemisphere, has a critical role for egocentric phenomenal space representation. Lesions in this structure can generate orientation disorders, out-of-body experiences, peak experiences, and an increase in Self-transcendence (Urgesi et al. 2010). Charles Bonnet syndrome is a condition in which patients (generally elderly people who become blind because of an eye disease) have complex visual hallucinations, of which they are aware. In this syndrome, their brain is able to generate a visual phenomenal world in which moving objects and animals are present (de Morsier 1967; Abbott et al. 2007). One of the most significant discoveries of contemporary neurophysiological research has been the correlation between neural activity of specific neuronal populations and conscious experience. It has been demonstrated that the conscious recognition of a visual stimulus correlates with synchronized discharge frequencies of neurons around 40 Hz (or in the gamma band: 20–80 Hz). In binocular rivalry experiments (Logothetis and Shall 1989), the gamma band is correlated with the neurons of the visual areas that are involved in the processing of the dominant (i.e. conscious) stimulus, while it decreases in neurons that are involved in the processing of the suppressed (i.e. unconscious) stimulus (Engel and Singer 2001; Fries 2009). The neural activity synchronized around 40 Hz has been correlated with the phenomenal content of visual awareness, and has been associated to the cortico-cortical connections and/or to specific and nonspecific thalamo-cortical loops (Llinás 2001; Edelman 2004). The neuronal activities in the gamma range have also been found at the subcortical level, in the superior colliculus, and have been referred to “binding” functions for consciousness; i.e. in the integration of diverse elements in a unitary conscious percept (Brecht et al. 2001; Merker 2007).

Consciousness of Self The specification of the psychological characteristics of the Self in human beings is a very complex problem. It is considered as a set of organizational tools for making the individual’s plans, decisions, and perceptions, coherent (Churchland 2002). Empirical studies and philosophical debates suggest that the Self, in human beings, is formed of different components (Stern 1985; Gallagher 2000; Gillihan and Farah 2005; Samsonovich and Ascoli 2005; Northoff et al. 2006). William James (1890), in “The Consciousness of Self”, Chapter 10 of his Principles of Psychology, proposed to distinguish between a physical Self, a mental Self, and a spiritual Self.

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These distinctions reappeared in several studies in neuroscience. Particularly important are those performed with different animal species, those assessing the features of complex human pathologies (e.g. epilepsy, disorders of consciousness, and the clinical conditions that generate Selfdisorders; Feinberg 2001, 2009; Feinberg and Keenan 2005; Fabbro and Marini 2012). Overall, these studies allowed the following components of the human Self to be distinguished: i) the primary Self; ii) the core Self; iii) the Self-consciousness; iv) the narrative Self. The primary Self (Merker 2007; defined as “proto-Self” by Damasio [1999]; the “ecological Self” by Neisser [1988]; and Panksepp [1998]; and “pre-reflective Self” by Zahavi [2005]), can be defined as the most ancient form of coherent world and Self-representation (Panksepp and Northoff 2009). It can be considered as an organizational unit coordinating all sensations (Humphrey 1992, 2006) and primordial emotions (Denton 2006). This organizational unit is responsible for co-perception of Self and environment, and is accompanied by a definite type of awareness (Neisser 1988: 41; see also Legrand 2007; de Preester 2007). In human beings, it is already present in the first weeks of life and allows infants to differentiate themselves from the environment (Rochat 1998; Stern 1985). The core Self (Damasio 1999; defined as “minimal Self” by Gallagher [2000]; “noetic consciousness” by Tulving 2002a) is a component of the mind of living beings who are conscious of their world. It is connected to the semantic memory system and also to affective systems (Panksepp and Northoff 2009). It is a form of consciousness of themselves and of the world that develops only at the present moment. Those endowed with this form of consciousness “recognize” themselves and objects of the world but are not able to “remember” (Tulving 2002b). “Many nonhuman animals, especially mammals and birds, possess well-developed knowledge-of-the-world (semantic memory) systems and are capable of acquiring vast amounts of flexibly expressible information” (Tulving 2002a: 6). Two characteristics of this component of the Self are the sense of Self-ownership and the sense of Self-agency (Christoph et al. 2011). In persons affected by schizophrenia, who experience thought insertions, delusions of control, auditory hallucinations, and conversion disorders (Voon et al. 2010), these two characteristics of the core Self dissociate, the sense of ownership remains, while the sense of agency is lost. This is due, according to Frith (1982), to problems in the systems of forward pre-action monitoring of movement that are correlated to dysfunctions in the premotor and prefrontal cortices and in the right temporo-parietal junction (Frith 1996; Voon et al. 2010). Thus, the psychopathological disorders typical of patients with schizophrenia may depend on a disorder in the representation of the core Self (Cermolacce et al. 2007; Kean 2009). Self-consciousness is the ability to Self-recognize. In developmental and comparative psychology, it is studied through mirror recognition tests. An organism is considered as Self-aware if it recognizes itself placed in front a

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mirror. Only at the age of 18 months do children become able to recognize themselves in a mirror. The same test has been proposed in several vertebrate species. Chimpanzees, orangutans, dolphins, elephants and corvid birds seem to be able of mirror Self-recognition; other animals either ignore the image or appear to think that a rival organism is present (Vallortigara 2000; Tannenbaum 2009; Devue and Brédart 2011). The narrative Self (Gallagher 2000; also defined as ”autonoetic consciousness” by Wheeler et al. [1997]; Tulving [2002a]; and the “narrative interpreter” by Gazzaniga [1987, 2002]) consists of the ability to process declarative episodic memories that unify the Self into a single story. Among the prerequisites for the development of the narrative Self, we may include the development of language (Baddeley et al. 2009) and the ability for mental time travel (Tulving 2002 a,b). The capability to mentally travel in time probably appeared more than one million years ago in Homo habilis and is at the basis of building lithic tools. In fact, in order to build and store tools it is necessary to imagine their possible use in the future (Fabbro and Tomasino 2012). This level of development of consciousness depends not only on specific neurobiological bases, connected to the neural networks underpinning language and episodic memory, but also on the ability to process significant affective relationships and on suitable educational and social experiences (Luria 1976; Stern 1985; Bowlby 1989).

Neurobiological correlates of consciousness At a very general level, the human brain can be conceived as being composed of two main anatomo-functional blocks: i) a basal block, (including the spinal cord, the brainstem, the cerebellum, the hypothalamus, and the oldest portions of the telencephalon; Nieuwenhuys et al. 1998; Northcutt 2002; Striedter 2005), and ii) a superior block (including the basal ganglia and the cerebral cortex, and subdivided in two components: medial and lateral, respectively). According to a fortunate metaphor proposed by MacLean (1990), it is possible to assume that, in the human brain, instead of three (reptilian, paleomammalian and neomammalian) only two types of brain are present: the brains of fish and of terrestrial animals (amphibians, reptiles, birds and mammals). On the basis of the studies present in the scientific literature, it is possible to advance the hypothesis that a form of primary consciousness is already present in the animals with a nervous system composed only of the basal block, e.g. in fish (Merker 2007; Damasio 2010). Neurobiology, neuropsychology and neuroimaging studies have pointed out that the two systems (the basal block and the superior block) are densely and reciprocally connected; both systems are involved in the representation of the Self and the world. In human beings, the structures involved in the representation of the Self are: i) for the basal block, the midline regions in midbrain and brainstem; and ii) for the medial superior

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block, the medial cortical regions, in particular the medial orbital prefrontal cortex; the ventromedial prefrontal cortex; the sub/pre- and supragenual anterior cingulate cortex; the dorsomedial prefrontal cortex; the medial parietal cortex; the posterior cingulate cortex, and the retrosplenial cortex (Parvizi and Damasio 2001; Mercker 2007; Northoff et al. 2006; Northoff and Panksepp 2008; Panksepp and Northoff 2009; Damasio 2010). On the other hand, the representation of the world depends on both structures of the first block and on lateral structures of the superior block (i.e. the cortical and subcortical structures associated to the functioning of the occipital, temporal, parietal, and frontal lobes; Frith 2007). The role played by the structures of the basal block in the representation of the Self and the world has been analyzed by Damasio (1999, 2010; Parvizi and Damasio 2001), Panksepp (1998, 2004); Northoff and Panksepp (2008); Panksepp and Northoff (2009), Solms and Pansksepp (2012), and Merker (2007). This component of the nervous system has already reached a strong development in fish and is present in all other classes of vertebrates. The main structures of the basal block represent a cephalic expansion of the nervous system and perform coordinating and control functions of both cephalic segment and the remaining parts of the body. The main structures of the brainstem are the nuclei of cranial nerves (and in particular the vestibular nuclei and the nuclei of the oculo-motor nerves); the catecholaminergic nuclei (noradrenergic, serotoninergic and dopaminergic nuclei); the cholinergic nuclei; the autonomic nuclei (in particular, the periacqueductal gray matter); the superior colliculus (optic tectum); the bundles of ascendant fibers of proprioception, tactile, thermal and pain senses; the bundles of descendent fibers; the reticular formation. According to Merker (2007), three structures of the midbrain and brainstem play a critical role for the development of the primary forms of consciousness: i) the hypothalamus, which is primarily involved in the regulation and integration of motivational states related to goal directed behaviors; ii) the roof of the midbrain (superior colliculus or tectum), which represents a multisensory integration station that generates a representation (simulation) of a “distal world”; and iii) the periacqueductal gray (PAG), a structure of fundamental importance for the emotional-motor integration. The roof of the mesencephalon of vertebrates (optic tectum), together with the hypothalamus (located in the floor of the diencephalon), forms the mesodiencephalon, a structure with major integrative functions observable in all vertebrates. Although a subcortical structure, the superior colliculus exhibits a considerable structural and functional complexity. It is a structure composed of different thin layers, similar to the layered organization of the cerebral cortex in mammals, in which different pieces of sensory information (i.e. visual, auditory and somatosensory) are integrated and provide a representation of the space allowing for an efficient motor control, in particular that of the eye, which is probably the most

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complex movement present in fish (Stein et al. 2002a,b). Moreover, the superior colliculus is the only structure outside the cerebral cortex in which fast oscillations in the gamma range that have been associated with the conscious perception of stimuli have been recorded (Brecht et al. 2001; Engel and Singer 2001; Fries 2009). The periacqueductal gray is a complex structure of the mesencephalon that surrounds the cerebral aqueduct, intimately related to the deeper collicular layers. It is an important structure in the emotional motor system. In mammals, it receives more than half of the ascendant fibers of the sense of pain (Parvizi and Damasio 2001; Damasio 2010), it is strongly connected with the other structures of the basal block (i.e. hypothalamus, amygdala, raphe nuclei, and superior colliculus) and with structures of the superior block (i.e. insula and cingulate cortex) (Vianna and Branda˘o 2003). The PAG is probably one of the most ancient structures devoted to the integration of emotions and coordinates an exceptional variety of emotion-related behaviors such as defensive, aggressive, reproductive, vocal and pain-related behaviors, from fish to human beings (Lovick and Adamec 2009). The importance of PAG in emotional integration is particularly evident in very rare cases of human beings with lesions to this structure. In one of these cases, the patient (GM) maintained herself immobile for hours, completely dumb, lacking in any motor initiative. However, she was able to understand complex sentences and execute complex orders (Esposito et al. 1999). According to Merker (2007), the neural structures of the basal block are predisposed to generate a representation of the world and of the Self in mobile animals. The two entities: the Self and the world, appear simultaneously. The Self that develops with the support of the basal block constitutes a primary consciousness, represents the ego-center place, centered on the colliculus extending into periacqueductal gray (Merker 2007; Stein et al. 2002b; Damasio 2010). Without a Self, an ego-center (eyecentered in vertebrates), a representation of the world cannot be generated, nor can objects appear (Merker 1997; Rosenfield 1993; Humphrey 1992, 2006). A conscious mind appears inside a relationship in which the subject (the Self) is in the presence of an object to be recognized (Revonsuo 2006; Merker 2007; Damasio 1999, 2010). According to Merker (1997), the conscious state has an internal structure in the sense that in it some “x” is in the presence of some “y”. Both the Self and the world, and also objects that surface to consciousness are probably a mere appearance (Metzinger 2009). For animals able to actively move, in which sight has a prevailing role in orientation, it is necessary to internally generate a stable spatial map, also integrating the other sensory modalities (i.e. smell, hearing, etc.), that does not modify as a consequence of body, head and eye movements. The brainstem and the cerebellum seem to perform the above stabilization functions of the representation of the world (Merker 2005, 2007).

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The idea that consciousness was related to the structures of the superior brainstem has been promoted by Penfield, who recognized that absence attacks were “a unique opportunity to study the neuronal substratum of consciousness” (Penfield and Jasper 1954: 480; Penfield 1975). Merker (2007) provides interesting data supporting the presence of consciousness in children affected by anencephaly, a condition in which children are born without cerebral hemispheres (they possess only the structures of the basal block). From a neurological point of view, these children are awake, they are able to interact with the environment by means of motor activities and emotional reactions (to express pleasure by smiling, laughter, and aversion by “fussing”; and emotion with facial expressions) that are different either with respect to relatives or strangers, or toys and videogames. Moreover these children often suffer of seizures of absence epilepsy. The fact that during episodes of absence epilepsy they loose the “contact” with the environment means that usually they are probably conscious (Shewmon et al. 1999).

Conclusions As far as we know, human beings are the only living species that presents a narrative Self. There are several reasons to explain this. From a neuroanatomical point of view, human beings show one of the most complex central nervous systems, with a very high brain-body scaling index (brain weight versus body weight), together with the presence of specific neuroanatomical structures, such as the extraordinary development of the prefrontal lobes and the development of a direct cortico-spinal bundle, that made it possible to execute the fine movements of eye muscles, of the vocal articulatory system and of the hands (Jerison 1973; Voogd 1998; Striedter 2005). The evolutionary thrust to develop brains even more extended, from Homo habilis to Homo sapiens, seems to be in relation with the strong tendency to socialization present in the Homo species. To succeed in surviving with other, often threatening, human beings, it is necessary to imagine what are their thoughts, projects and intentions (i.e. to generate a theory of mind; Goldsmith and Zimmerman 2001; Baron-Cohen 2011; Churchland 2011). Other characteristics that distinguish human beings from other animal species are the presence of language and the development of relevant technological and cultural abilities (Lieberman 1975, 2006; Dunbar 1998; Corballis 2002). Since consciousness is “the appearing of a world to myself”, it manifests in human beings in a quite particular way: it is an existential consciousness and shows temporal characteristics. Human beings are aware of living not only in the present moment but also along a time line. This means that they are aware that they own a subjective time. This awareness has been defined as autonoetic consciousness and corresponds to the human ability “to mentally represent and to become aware of their protracted existence across subjective time” (Wheeler et al. 1997: 335). Human beings have then

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“invented” a mental device not only to represent space and Self but also to represent time. Such a device has been called “mental time travel” and allows human beings to reconstruct events of their past and imagine their possible future. In the mid-80s, Tulving described an amnesic patient (KC) who could no longer memorize past events, recall them or even imagine his future. He lost the subjective experience of time, the autonoetic consciousness (Self-knowing), while his semantic memory (noetic consciousness) was unaffected. He lived in a permanent present, he knew the time (he could speak about physical time, its units, its structure, and its measurement by clocks and calendars), however, he had lost the subjective sense of time. “He thus exhibits a dissociation between knowing time and experiencing time, a dissociation that parallels one between knowing the facts of the world and remembering past experiences (Tulving 2002b: 317). Subsequent neuroimaging studies showed that the cerebral structures associated to processes of remembering the past and imaging the future (i.e. mental time travel) are probably the same and include: i) medial prefrontal regions; ii) medial (precuneus) and lateral parietal cortex; iii) medial and lateral temporal lobe (Schacter et al. 2007). In order to mentally travel in time, it is necessary to develop: i) a sense of subjective time; ii) the ability to be aware of subjective time (autonoesis); iii) a traveler, i.e. a “special Self” able to imagine to exist in time (Tulving 2002a). This special Self is not present in children, as it starts to develop around six months after the ability to mirror Self-recognition. At the age of 23 months, children begin to make use of temporal markers for the past and are able to foresee future activities on the basis of past experiences. It is possible that the autonoetic consciousness is already developed around age three; it is necessary but it seems not to be sufficient for the development of episodic memory (Wheeler et al. 1997; Buckner and Carroll 2007). The awareness of Self in time constitutes the typical existential dimension of human beings (Heidegger 1972). Such a dimension does not seem to be present in any other living species (Clayton et al. 2003; Suddendorf and Busby 2003). It probably played a crucial role in human cultural evolution (Tulving 2002b). The construction and conservation of tools (lithic) is probably possible only in light of their possible future utilization. Moreover, language, with the presence of verbal structures indicating past and future, cannot develop without a subjective awareness of time. In conclusion, the narrative Self, one of the most advanced forms of conscious representation of the Self and of the world, can probably develop only in individuals who have developed a subjective consciousness of time and a sufficient verbal communication.

Acknowledgments This chapter is dedicated to Dr Claudio Naranjo, MD. Franco Fabbro is supported with funding from the Mind and Life Institute (Mind and Life Contemplative Fellowship, 2012-04-001).

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Part II

Brain abnormalities in schizophrenia

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4

Auditory cortex asymmetry and language processing in schizophrenia Steven A. Chance and Manuel F. Casanova

The key auditory processing regions of the brain are found in the superior temporal cortex. The primary auditory cortex is approximately coincident with Heschl’s gyrus on the superior surface of the superior temporal gyrus (STG) lying within the Sylvian fissure (Da Costa et al. 2011). In humans, the STG also contains perhaps the most prominently asymmetrical brain area: the auditory association cortex of the planum temporale. This cortical area lies posterior and lateral to Heschl’s gyrus, thus contributing to the hemispheric asymmetry of the posterior Sylvian fissure. This region in the posterior STG plays a key role in phonological processing and forms part of the receptive language region often identified as Wernicke’s area. The anterior STG is also implicated in syntactic processing. With regards to psychosis, the auditory region offers one of the clearest associations between psychotic symptoms and brain structure, as it is activated during auditory hallucinations (Shergill et al. 2000; Ropohl et al. 2004). Electrophysiological (“mismatch”) responses to anomalous sounds in a series or words at the end of a sentence are also reduced in patients with schizophrenia. At a structural level, reduced gray matter in the STG is one of the most replicated structural changes in the disorder.

Language and asymmetry Among the earliest observations of localized cognitive functions in humans, Paul Broca and Carl Wernicke identified areas in the left hemisphere associated with linguistic aphasias (but see also Chapter 1 for a comprehensive discussion on this issue). The area whose lesion leads most often to receptive language deficits, in the region of the parietal-occipitaltemporal junction near the posterior Sylvian fissure, came to be called Wernicke’s area. Geschwind and Levitsky (1968) “rediscovered” the anatomical asymmetry of the brain when they studied part of this region on the dorsal surface of the posterior STG in post-mortem brains. They found leftwards asymmetry (greater size on the left than the right) of the planum temporale in two-thirds of individuals. It has been proposed that the hemisphere in which a given brain region is larger is also the dominant one for

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the associated function (Galaburda 1995). By the late 1960s, Juhn Wada’s test of alternately anesthetizing the cerebral hemispheres had also demonstrated the widespread left-hemisphere dominance for language. The implied association between leftward structural asymmetry and functional lateralization has led some authors to suggest that cerebral asymmetry is a defining feature of the human brain, central to the evolution of human cognition and language (e.g. Broca 1877; Corballis 1992; Crow 2000). In fact, there is uncertainty concerning the relationships between different measures of asymmetry and corresponding language lateralization. Approximately 67 percent of the modern human population have typical gross hemispheric asymmetry (a relative expansion of the right frontal region, described as rightward frontal petalia). This is similar to the proportion of leftward planum temporale observed by Geschwind and Levitsky (1968), and it has been reported that asymmetry at the macroscopic level is correlated with the local volume of the STG (Chance et al. 2005). However, individuals with situs inversus (reversal of the bodily organs) who also have reversed frontal petalia still show normal asymmetry of the planum temporale (Kennedy et al. 1999). This suggests dissociation between elements of structure, even while it supports the functional significance of localized asymmetry in the planum temporale, as these individuals also tend to have normal language dominance. The correspondence between language lateralization assessed by the Wada test and volumetric asymmetry of the planum temporale is sufficient to have led to the suggestion that structural magnetic resonance imaging (MRI) of the planum temporale could be used as an alternative to the Wada test (Oh and Koh 2009). However, other researchers have found that, although planum temporale asymmetry and language laterality are significantly left-hemisphere biased, they may not be correlated (Eckert et al. 2006) – although it is worth noting that these authors assessed language laterality at a single-word level and a stronger relationship may be found with more complex language presentation. Many subsequent psychological and neuroimaging studies have clarified which processes involve the STG and the degree to which they are lateralized. The anterior STG is sensitive to early syntactic processes in auditory sentence comprehension; for example, responding to syntactic word category violation in a sentence (Friederici et al. 1993). The posterior STG plays a greater role in processing spatial auditory information, as well as its left-hemisphere bias for phonological processing (e.g. Robson et al. 2012). Auditory cortex in both hemispheres has a tonotopic organization of stimulus sensitivity. The right hemisphere auditory areas are dominant for music perception in untrained listeners (Ono et al. 2011), although this functional asymmetry is modulated by degrees of expertise and ability. Local connectivity in perisylvian regions appears to be enhanced in musicians with perfect pitch compared with both non-musicians and musicians with relative pitch (Jäncke et al. 2012) and musical training may also alter functional lateralization.

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The left-hemisphere dominance for processing speech is thought to depend, partly, on a bias for processing short temporal transitions in the speech signal (Efron 1963; Tallal et al. 1993; Shtyrov et al. 2000; Zatorre et al. 2002). A right-ear (i.e. left-hemisphere) advantage is seen for some simple auditory tasks (Jerger and Martin 2004), whereas right auditory cortex advantages are seen for other aspects of complex acoustic signals. For example, music perception is dominant in the right hemisphere in untrained listeners (Ono et al. 2011), and this may result from the righthemisphere bias for spectral sound processing (Zatorre and Belin 2001). Zatorre and Belin (2001) have proposed that the different computational emphasis between the hemispheres emerges from the different neural organization in the left and right auditory regions, based on the columnar organization of cells. Current conceptions of the role of the posterior STG suggest it is not specifically involved in semantic processing (Eckert et al. 2006). A mismatch activation detected in the posterior STG in response to a semantically anomalous word appearing at the end of a sentence may not be dependent on semantic comprehension, which is likely to involve more of the middle temporal gyrus (Dronkers et al. 2004). Rather, it may be that lexico-semantic expectation drives the expectation of a phoneme or word form that is mismatched when the wrong word is presented. Nonetheless, evidence supports the speculation that in the generation of ‘meaning’ the left parieto-occipito-temporal junction (Wernicke’s area) is associated with the activation of more discrete, narrow, semantic associations, whereas the right hemisphere activates more distributed semantic fields appropriate to its greater sensitivity to context (Rodel et al. 1992). The hierarchical relationship between Heschl’s gyrus and secondary auditory regions such as the planum temporale, in which the planum temporale is the recipient of feed-forward projections from the primary auditory area of Heschl’s gyrus, has the consequence that the planum temporale plays a role in more integrative, associative processing than Heschl’s gyrus. The two regions differ in maturation (Guillery 2005; Chance et al. 2006a; Toga et al. 2006), dendritic arborization (Elston et al. 1999), asymmetry, and neuroplasticity (Arendt 2004). Recent analysis suggests that the planum temporale may be further subdivided into medial, lateral and caudal parts, each associated with different aspects of speech processing (Tremblay et al. 2013). The presence of asymmetry in the human cerebral hemispheres is detectable at both the macroscopic and microscopic scales. However, not all measures of the superior temporal plane identify hemispheric asymmetries. This is due to a combination of natural variation, anatomical definition, and the method of measurement. After the original observations by Geschwind and Levitsky (1968), Zetzsche et al. (2001) have shown that the definition of planum temporale borders influences the detection of cerebral asymmetry. Past MRI studies have been limited by imaging

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resolution and some studies indicate that both volume and surface area should be reported. Pearlson et al. (1997) suggested that measurements of surface area were more important than those of volume and Barta et al. (1997) detected asymmetries by surface area measurements that were not detected by volume measures. Both are consistent with the hypothesis of Harasty et al. (2003) that asymmetry of the planum temporale is due to lengthening of the cortex on the left side relative to the right. Some MRI studies have found leftwards asymmetry of Heschl’s gyrus (Penhune et al. 1996; Dorsaint-Pierre et al. 2006; Golestani et al. 2006), although a larger left Heschl’s gyrus surface area has not been reported by other studies (Chi et al. 1977; Rademacher et al. 2001).

Microstructure The horizontal expansion of cortical surface during development (within individual brains), and across evolutionary time (between species), is largely due to the proliferation and spacing of radial minicolumns of cells that form the cortex (Rakic 1995). These microscopic structures persist in the mature brain, where they span the 3–4 mm depth of the cortex with a horizontal width of approximately 50 µm. Minicolumns emerge by radial migration of cells towards the brain’s surface during embryonic formation of the cerebral cortex. Column-like radial organization is found for cell bodies, and their axonal and dendritic connections. Intra- and inter-cortical connections are organized according to these basic units of organization. Auditory cortex in the STG develops a clear columnar cell distribution by the third trimester of fetal life, which is established in early childhood, although axonal maturation continues up to at least 12 years of age (Moore and Guan 2001). In the human planum temporale, minicolumn width asymmetry is associated with surface area asymmetry (Chance et al. 2006b). Although the human minicolumn asymmetry is not large (Buxhoeveden et al. 2001; Hutsler 2003), it is estimated to account for a surface area asymmetry of eight to nine percent of the region’s size (Chance et al. 2006b). Critically, this asymmetry of minicolumn spacing is absent in the equivalent areas of the brains of other apes (Buxhoeveden et al. 2001). The microscopic asymmetry in humans appears to reflect a larger scale asymmetry of inter-connected fields because larger ‘macrocolumn’ patches (approximately 500 µm diameter) are also more widely spaced in the left than in the right auditory association cortex (Galuske et al. 2000). The functional role of columns is not fully understood, but they contribute to topographical functional organization across the brain’s surface. Cytoarchitectural columns have electrophysiological counterparts, identified by single unit recordings, in which cells within the same column share similar stimulus sensitivity. The combination of stimulus sensitive columns in a region presumably confers processing specialization.

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Topological mappings of stimulus features such as frequency and ear preference have been proposed to conform approximately to a macrocolumnar organization (Linden and Schreiner 2003). Minicolumn organization in the planum temporale has been found to correlate with cognitive scores (Chance et al. 2011); a relationship with cognition that was specific to minicolumn measures and was not found for neuron density. It has been suggested that greater spacing of minicolumns in human association cortex results in less-overlapping dendritic trees and allows more independent minicolumn function (Seldon 1981a,b). This is consistent with the association between the greater surface area and the wider spacing of evoked electrophysiological activity peaks in the superior temporal plane of the left hemisphere compared with the right (Yvert et al. 2001). It has been found that a wider cell dense core is associated with wider peripheral neuropil space (Chance et al. 2006a). Harasty et al. (2003) have developed the notion that widely spaced minicolumns function as discrete units facilitating computational processing of more independent components, whereas narrow minicolumns permit greater co-activation and therefore confer more holistic processing. Jung-Beeman (2005) has characterized the difference in terms of the density of synapses and the distribution of dendritic branches in relation to the cell body, whereby the basal dendrites of right hemisphere pyramidal neurons have longer initial branches and more synapses further from the soma than left-hemisphere neurons where the more widely spaced minicolumns have more dendritic branching within their territory. Wider minicolumn spacing is therefore associated with higher resolution processing across less-overlapping basal dendritic fields whereas narrow minicolumn spacing is associated with lower resolution, holistic processing due to relatively greater distal sampling of more overlapping fields (Jung-Beeman 2005).

Mechanistic models and connectivity It is plausible that wider minicolumn spacing in the left STG facilitates fine temporal discrimination because minicolumns function as more discrete computational elements, whereas narrow minicolumn spacing in the right STG supports broad spectral processing, due to the minicolumns’ greater computational overlap. It should be noted that primary auditory cortex might not share the leftward minicolumn spacing asymmetry that is present in the neighboring planum temporale (Chance et al. 2006b). Nonetheless, this concept refines the simple notion that a larger brain area is associated with dominance for a function and offers an alternative, mechanistic explanation associated with ‘processing type’ (Chance et al. 2012). The difference between hemispheres may also be seen in terms of processing speed, characterized as ‘asymmetric sampling in time’ (Poeppel 2003). Zatorre and Belin (2001) observed that hemisphere differences in the length of the acoustic sampling window might also partly depend on the

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asymmetric myelination of white matter tracts in the auditory region. The involvement of axonal connections recalls that language lateralization involves an interaction between the auditory cortices of the two hemispheres mediated by the corpus callosum. Thus, two streams of processing occur in parallel – global processing in broad-activation fields of the right hemisphere and local processing in focused fields of the left hemisphere. In isolation, these streams simply represent two separate levels of detail, but by cross-referencing the differences between the active fields of the two hemispheres the relationship of local features to global features may be encoded. The emergent hierarchy of features within features is a recursive structure that may functionally contribute to generativity – the ability to perceive and express layers of structure and their relations to each other. It is interesting to consider that the recursive generativity, an essential component of language, may reflect an interaction between processing biases that is traceable in the microstructure of the STG. Cytoarchitectural asymmetries have been found in normal auditory cortex that correlate with the number of axons passing through the connecting regions of the corpus callosum (see also Chapter 6 for a comprehensive discussion on callosal inter-hemispheric connections); the posterior mid-body contains the connections between the primary auditory regions of Heschl’s gyri and the isthmus contains the connections between the plana temporale (Chance et al. 2006b). An increase in the number of inter-hemispheric axons is associated with more minicolumns in the right hemisphere planum temporale and more minicolumns in the left-hemisphere Heschl’s gyrus. Therefore, an increase in computational units in the region and hemisphere associated with a functional bias is linked to more inter-hemispheric connections (auditory processing that varies in the temporal domain is processed preferentially by Heschl’s gyrus in the left hemisphere, whereas variation in the spectral domain is preferentially processed by the auditory belt areas in the right hemisphere [Jamison et al. 2006]). This indicates that the domain-sensitive processing bias for each region may depend on callosal interaction. However, intra-hemispheric connections are also asymmetrical. Gray matter volume asymmetry of the planum temporale relates to asymmetry in fractional anisotropy of the arcuate fasciculus (Takao et al. 2011) with a larger planum temporale correlated with greater fractional anisotropy.

Evolution It has been suggested by some (Annett 1985; McManus 1985) that hemispheric asymmetries are human-specific and offer a neural correlate of lateralized function, including language, in humans. Broca’s original contention was that humans have the most asymmetrical brain. A challenge to this thesis has emerged from comparative neuroanatomy indicating the

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presence of asymmetries in other primate species. Some comparative data suggest that gross brain asymmetries (“petalia”) are present in modern great apes (Holloway and De La Coste-Lareymondie 1982; see also Chapter 1 for additional considerations on the differences and similarities between the brains of humans and apes). Evolutionary continuity is sometimes claimed for macroscopic asymmetry. However, current evidence indicates evolutionary discontinuity for microscopic, cytoarchitectural asymmetry. Posteriorly, in the auditory receptive region, Gannon et al. (1998) have reported gross region size asymmetry of the planum temporale in chimpanzees, although two early studies reported the absence of planum temporale asymmetry in apes (von Economo and Horn 1930; Pfeifer 1936). However, the relationship between the extent of hemispheric asymmetry of the planum temporale and the inter-hemispheric connections through the corpus callosum connections appears to be similar in humans and chimpanzees, indicating consistent, proportionate, connectivity in the two species (Hopkins et al. 2012). Asymmetry of the Sylvian fissure has been variously reported as present in orangutans and gorillas (LeMay and Geschwind 1975), and chimpanzees (Yeni-Komshian and Benson 1976), but absent in lesser apes and inconsistent in Old World monkeys (Falk et al. 1986; Heilbroner and Holloway 1988), where the planum temporale itself may be absent (Pfeifer 1936). Perisylvian asymmetries have been identified in fossil endocasts attributed to Homo and Australopithecus (LeMay 1976; Holloway 1980; Tobias 1987), although the reliability of such measures are not certain, since fossil endocasts are prone to qualitative interpretation. Because Sylvian fissure measurements only indirectly reflect the size of auditory cortex, including the planum temporale, the implications of Sylvian fissure asymmetries for language capacity in fossil humans and apes are unclear.

Human differences By contrast with the macroscopic picture based on surface landmarks, cytoarchitecturally defined assessments have found that region size asymmetries are weaker in chimpanzees (Spocter et al. 2010), indicating that species differences may not be reliably detected at the level of gross region size. Hemispheric asymmetries at the neuronal level yield more consistent differences between humans and other primates (Chance and Crow 2007). Asymmetry in the spacing of minicolumnar units of neurons in the human planum temporale is absent in the brains of other primates (Buxhoeveden et al. 2001), and there is a preponderance of large layer III pyramidal neurons (Hutsler 2003) with wider dendritic arbors (Seldon 1981a,b) filling the space in the left hemisphere compared with the right in humans. Both Broca’s area and Wernicke’s area in humans have more connective neuropil in the left hemisphere compared with the right (Amunts et al. 1999; Anderson et al. 1999). In contrast, chimpanzees lack neuropil

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asymmetry in the equivalent areas (Sherwood et al. 2007). Neuron density in the posterior STG (area Tpt) in chimpanzees is not asymmetrical (Schenker et al. 2010). It is worth acknowledging, however, that symmetry of cytoarchitectural organization may not always be detected. Spocter et al. (2012) did not detect a significant asymmetry of neuropil fraction in the planum temporale or Heschl’s gyrus in chimpanzees or humans. Instead, they noted that, in chimpanzees, the neuropil fraction was especially low in the primary auditory area, and for both planum temporale and Heschl’s gyrus, the values in chimpanzees were significantly lower than the equivalent areas in humans. It may be that the characteristics of neuronal size, minicolumn width and neuropil space are more variable between brain regions in humans, contributing greater heterogeneity and more functional differentiation. It has been suggested that there are two phases in minicolumn development; first proliferation, and second, expansion, that contribute to cortical surface asymmetry to different degrees in different regions (Chance et al. 2006b). Hemispheric asymmetries are amplified in more recently evolved association cortex where the phase of expansion has greater influence on region size and asymmetry. Early-phase minicolumn proliferation is likely to be more tightly linked to primary sensory cortex size, with an older evolutionary origin, whereas the later phase of minicolumn expansion will play a greater role in the surface area expansion of association cortex (including language cortex), and will have a more recent human evolutionary origin (Chance and Crow 2007).

Schizophrenia and clinical correlates The planum temporale (particularly on the left) has been found to be smaller and even to reduce over time in schizophrenia (Kasai et al. 2003), and its reduced size has been correlated with the degree of thought disorder in patients (Shenton et al. 1992). The perception of auditory-verbal hallucinations – a well-known and relatively common symptom – is accompanied by increased blood flow seen in functional MRI (Shergill et al. 2000) and increased neural activity measured by magnetoencephalography (Ropohl et al. 2004) in the planum temporale and the primary auditory cortex in Heschl’s gyrus. In addition, patients who are prone to auditory–verbal hallucinations have been found with reduced connectivity between Wernicke’s and Broca’s area (C´urc˘ic´-Blake et al. 2012). Most notably, schizophrenia patients without hallucinations had a less severe reduction in connectivity that was intermediate between patients who had hallucinations and controls (see also Chapter 9). The most replicated structural change in schizophrenia, enlargement of the ventricles, has also been found to be correlated with reduced superior temporal gyrus volume (Chance et al. 2003). Alterations in schizophrenia

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may be greatest in the latest maturing, most asymmetric cortex and reductions or reversals of asymmetry of the planum temporale have been reported (Rossi et al. 1992; Petty et al. 1995; Barta et al. 1997). Meta-analyses (Shapleske et al. 1999; Sommer et al. 2001) confirm a loss of asymmetry in patients relative to controls in the literature as a whole, although it has not been found in a number of individual studies (e.g. Rossi et al. 1994; Kulynych et al. 1995; Frangou et al. 1997). A review of 34 structural MRI studies of sub-regions of the STG in schizophrenia (Chance et al. 2008) found that half of the studies reported a change in the planum temporale, 13 reported a decrease, nine of which were selective to the left hemisphere, and three reported an increase, two of which were selective to the right hemisphere. Barta et al. (1997) suggested that measurements of the surface area of the planum temporale were more important than those of volume, and reported reversal of surface area asymmetry but an absence of asymmetry of volume. Across studies, the male–female ratio among patients was approximately five to two. For the majority of studies, the numbers of female subjects were too small to be able to analyze sex differences. However, it is of interest that there are differences between the sexes in the normal trajectory of agerelated changes in the superior temporal gyrus (Chance et al. 2006b), and there are sex-dependent, asymmetric alterations in the evoked activation of auditory cortex in schizophrenia (Rojas et al. 1997). Structural changes in the STG are among the most frequent to be associated with functional deficits. Change in the size of Heschl’s gyrus has been associated with hallucinations, semantics, mismatch negativity, illness duration and auditory sensory memory. Asymmetry or left hemispheric size of the planum temporale has been correlated with delusions, positive symptoms, phonetic mismatch strength, hallucinatory behavior, social withdrawal, stereotyped thinking, memory deficits, P300 amplitude, suspiciousness, left-ear advantage, phonological processing, psychosis duration and thought disorder. Of this wide range, the most consistent relationship is that of planum temporale size with auditory mismatch responses (McCarley et al. 1993, 2002; Yamasue et al. 2004; Salisbury et al. 2007). Reduced electrophysiological auditory mismatch responses have been associated with altered lateralization in the planum temporale in schizophrenia (Kircher et al. 2004). Changes in Heschl’s gyrus may also relate to early auditory perceptual abnormalities in patients (Chance et al. 2008).

Pathological microstructure In general, neurochemical findings in schizophrenia indicate deficits in GABAergic markers (Torrey et al. 2005) A few immunohistochemical studies have used the global marker GAD (glutamic acid decarboxylase) to identify inhibitory interneurons, but most have used a mixture of markers for calcium binding proteins: parvalbumin, calretinin and calbindin.

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Parvalbumin-positive interneurons in the prefrontal cortex have been most strongly implicated, but in the superior temporal cortex a reduced density of calbindin positive cells (Chance et al. 2005) and reduced reelin, which is expressed by Cajal-Retzius cells in early life and GABAergic cells in adult life, have been found in schizophrenia patients (Eastwood and Harrison 2003). Additional indicators include reduced GAD67 mRNA levels in auditory association cortex (Impagnatiello et al. 1998) and reduced density of axon terminals immunoreactive for the GABA (gamma-amino-butyric acid) membrane transporter (GAT-1) in superior temporal cortex (Konopaske et al. 2004). All of these suggest reduced inhibition, which may relate to the anomalous activation of auditory regions during auditory hallucinations in schizophrenia. Although the evidence in general does not indicate an excess of gliosis in schizophrenia, recent microscopy has found reduced density of glia in the superior temporal gyrus (Beasley et al. 2009). The potential relationship between oligodendrocytes and the white matter changes identified in MRI studies, and the relationship between astrocytes and medication effects (see below), make the glial cell literature a topic of continuing interest.

Cell size, misconnectivity, and medication Reduced size of layer III pyramidal neurons has been found in both primary and association auditory cortices in schizophrenia (Sweet et al. 2003). Lewis and González-Burgos (2008) have suggested that smaller somal volume is associated with lower basilar dendritic spine density, particularly in deep layer III pyramidal neurons. The effect of pathology appears to be greater in the largest, magno-pyramidal neurons in the left hemisphere (Simper et al. 2011). Somal size has also been related to axon length and the number of magno-pyramidal neurons in the planum temporale correlates with the number of axons in the connecting sub-region of the corpus callosum (Simper et al. 2011). It has been suggested that cortical misconnections underlie the symptoms of schizophrenia (Friston and Frith 1995) and that the corpus callosum may be particularly vulnerable (Crow et al. 1998). Minicolumn asymmetry of both Heschl’s gyrus and the planum temporale has been found to relate to axon number in the wrong subregions of the corpus callosum in schizophrenia patients (Chance et al. 2008). Abnormal inter-hemispheric connections in the planum temporale and Heschl’s gyrus have also been implicated by alterations in callosal white matter in MRI (Diwadkar et al. 2004). Post-mortem studies in schizophrenia of mean cell spacing within minicolumns have shown abnormalities in both the lamina and cortical area (Casanova et al. 2005). Lamination arises after the formation of minicolumns and is concurrent with the innervation of mesocortical monoaminergic inputs. The time window for lamination during corticogenesis coincides with epidemiological studies that suggest a risk for schizophrenia during the second trimester

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of gestation (Limosin et al. 2003). This study suggests that schizophrenia may arise from abnormalities in the modulation of minicolumns by second messenger pathways of the monoaminergic system (Casanova et al. 2005). That said, a proportion of larger cells in the STG will also be the ipsilaterally projecting neurons with the longest connections (with prefrontal cortex, including the anterior motor language area, for example). Of those, some will contribute to the arcuate fasciculus connections identified as being asymmetrical in humans (Glasser and Rilling 2008). It is therefore plausible that larger neurons will be more sensitive indicators of asymmetric function and disruption, as they appear to be in the asymmetric STG in schizophrenia. The local connectivity between Heschl’s gyrus and the planum temporale also deserves attention. Most imaging studies have investigated Heschl’s gyrus as well as the planum temporale, and changes occur in both (Chance et al. 2008). Altered clustering (Beasley et al. 2005) and reduced volume of layer III pyramidal neurons in the planum temporale (Sweet et al. 2003) have been interpreted as impaired feed-forward connections from the primary auditory area in schizophrenia (Sweet et al. 2003). Few developmental processes continue into adult life, although myelination is a notable exception. Expansion of the corpus callosum continues through the third decade of life and it completes later in females than in males (Cowell et al. 1992; Pujol et al. 1993). This sex difference in maturation of the corpus callosum reflects the sex difference in the timing of illness onset in early adulthood (females later than males) and the coincidence may be meaningful (Crow et al. 2007). The maturation of myelinated tracts may mark a shift in the dominant form of neuroplasticity in the brain. Neuroplasticity is largely concerned with the development of brain networks before maturity, but beyond that point the emphasis shifts to the maintenance and modulation of those established networks, at which time the consequences of misconnected networks are exposed. Marked brain structural changes occurring early in the illness may reflect this shift. They may, in addition, be due to the effect of beginning medication. Several studies have reported reductions in cortical gray matter volume that may be related to antipsychotic medication (e.g. Lieberman et al. 2005; Ho et al. 2011). An attempt to model medication effects in primates has reported increased neuron density in the cortex without reduction of total neuron number, implicating neuropil loss but also identifying a reduction of glial cells as an effect of medication (Konopaske et al. 2007). In the process of retrieving a better inhibitory balance in brain networks, medication may facilitate the loss of neuropil around misconnected or misfiring neurons. Haloperidol, in particular, has been shown to cause reduced neurites,1 reduced cell somal size, and neuronal apoptosis (Ukai et al. 1 The term neurite refers to any projection from the cell body of a neuron (either an axon or a dendrite).

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2004), which would contribute to eventual cell loss. Furthermore, studies of white matter have found that antipsychotic treatment appears to inhibit the normal age-related white matter volume expansion during early to midadulthood (Bartzokis et al. 2003; Ho et al. 2011). This is the time when illness onsets and neuroplasticity may shift.

Conclusion “The question of question for mankind – the problem that underlies all” (Huxley 1919) is what characteristic of our brains makes us human? Notably, traditional views of comparative anatomy have emphasized brain size, more specifically encephalization, with its attendant increasing numbers of neurons, minicolumns, and connections. It has been hypothesized that, during brain development, the cortex grows by the supernumerary addition of radial aggregates called minicolumns. Numerous genes and environmental factors interplay to modulate minicolumnar morphometry. Studies on Brodmann area 22 (part of Wernicke’s region) in humans, chimpanzees, and rhesus monkeys have shown differences of minicolumnar lateralization restricted to humans. This minicolumnar phenotype may constitute a speciation event linking modularity to both cerebral dominance and language. It is therefore unsurprising that minicolumnopathies are involved in human conditions defined by abnormalities of language. Language disorder is a prominent manifestation of schizophrenia, where often it is disorganized, confused and characterized by the use of peculiar words and phrases. Multiple studies have now shown that language abnormalities in schizophrenia are a strong predictor of maladaptive social and vocational functioning. Neuroimaging (structural and functional) and post-mortem studies in schizophrenia suggest a breakdown of the anatomy for left-sided brain specialization for language. Numerous studies have now shown that the histological basis for this breakdown of hemispheric lateralization is reflected in the modular organization of the cortex.

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Disordered brain network function in adolescence Impact on thought, language and vulnerability for schizophrenia Vaibhav A. Diwadkar and Noa Ofen

The origins of schizophrenia, and indeed of most psychiatric illnesses, are presumed to lie in adolescence (Keshavan et al. 2005b; Paus et al. 2008). This framework is well expressed in extant neurodevelopmental models of schizophrenia (Weinberger 1987; Murray and Fearon 1999), almost all of which propose a complex interaction between genes and environmental factors, leading to neurodevelopmental dysmaturation (Lewis and Levitt 2002). Several proximate mechanisms have been proposed to explain the emergence of the illness. For example, disordered stress reactivity in adolescence has been suggested as a plausible mechanism (Walker et al. 1999). In this model, multiple risk factors converge to impact the brain’s response to stress as subjects enter early adulthood (a typically stressful life period). This disordered stress response may be expressed in the frank onset of symptoms, making early adulthood the modal age of onset for schizophrenia. The impact of susceptibility genes suggests a parallel mediating mechanism; for example, a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity appears to impact prefrontal dopamine (Weinberger et al. 2001). This in turn may affect prefrontal function during working memory, providing evidence of genetic effects on a domain of functioning that is of particular relevance to the schizophrenia spectrum (Goldman-Rakic 1999; Weinberger et al. 2001). Yet another genetic mediator involves the glutamatergic system, particularly, n-methyl-d-aspartate (NMDA)-mediated synaptic dysplasticity, which may be related to impaired mechanisms of hippocampal learning and memory in schizophrenia (Javitt 2004; Stephan et al. 2006; Brambilla et al. 2007). These sampled models are not exclusive, exhaustive, or comprehensive. Indeed, the pathophysiology of schizophrenia is perhaps too complex to be captured within a single model. Yet it is notable that each of these models predicts impairment in functioning brain networks in schizophrenia. Chronic stress (that is associated with schizophrenia) is proposed to have an adverse effect on prefrontal pyramidal cells. This results in a cascade of molecular event leading to the ultimate loss of prefrontal connectivity with other brain regions (Arnsten 2011). COMT variation in schizophrenia results in a loss of

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prefrontal efficiency for working memory related function, and altered prefrontal–parietal coupling (Tan et al. 2007). NMDA receptor hypo-function in schizophrenia results in synaptic dysplasticity. Dysplasticity in turn may particularly affect hippocampal interactions with cortical targets including the prefrontal cortex, and may result in impaired learning (Brambilla et al. 2007; Lau and Zukin 2007; Stephan et al. 2009a; Banyai et al. 2011). Thus, from the perspective of system neuroscience (Stephan 2004), these competing or overlapping mechanisms of schizophrenia are all proposed to impact the development and/or the behavior of functioning brain networks in the schizophrenia diathesis (Uhlhaas and Singer 2010). This convergence toward a single overarching theme is notable because it validates the historical conception of the presumed bases of schizophrenia (Bleuler 1908). Using the narrow focus of dysconnection between brain networks, this chapter provides the (re)motivation for analyzing this framework for schizophrenia, and more importantly, for looking at the risk of developing schizophrenia (Diwadkar 2012). The notion of dysconnection is not original, and dates in some form to over a century ago. Nevertheless, we attempt to capture how these ideas have progressed since Bleuler’s original conception of the illness as the “splitting of the mind”. We attempt this by emphasizing the sweep of neuroscience, the advent of sophisticated methods for monitoring brain activity, and more recently, techniques for modeling these brain signals. All of these advances have enhanced our ability to develop and test sophisticated theories about brain function and dysfunction (Uhlhaas and Singer 2011; Stephan and Roebroeck, 2012). We briefly review known aspects of the development of brain networks in health, why schizophrenia and the risk of schizophrenia might be associated with the disruption of normal brain development, and finally we discuss evidence of disordered network function associated with the domains of cognition, thought and language. We also provide details of analytic methods for inferring effective connectivity from imaging data. These methods provide a specific quantitative context, and therefore renewed impetus for understanding schizophrenia as a dysconnection syndrome.

Dysconnection in schizophrenia: From old to new The roots of the dysconnection hypothesis are reflected in the etymology of the schizophrenia label itself (Bleuler 1908). However, early neurology (and subsequently psychiatry) lacked a rich neuro-scientific framework to adequately operationalize the meaning of the term. In a more recent and influential characterization, Karl Friston (1998) proposed the “dysconnection hypothesis”, an idea that bridges the original clinical conception of the illness with a modern mechanistic framework consistent with emergent trends in clinical neuroscience. In this approach, he argued that the notion of dysconnection in schizophrenia was complicated by a relative absence of

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disrupted anatomical (and therefore functional) connections, and by the fact that the illness appeared to be associated with regional measures of brain dysfunction such as reduced volumetry in specific brain regions (McCarley et al. 1999). In this context, the distinction between two parallel principles of functional brain organization, specifically relative specialization of function, and the functional integration of information is relevant (Friston 2005). Relative specialization of function has roots in phrenology, emphasizing the study of regional function to understand how the brain works (or does not work). The functional integration of information emphasizes the network architecture of the brain, and an understanding of brain function in terms of system biology (von Bertalanffy 1968). Building on the distinction between relative regional specialization of brain function and the integration of information across brain regions, Friston argued that schizophrenia resulted from a lack of functional integration of information within brain networks; he hypothesized that this lack of integration might be related to, or independent of impaired relative specialization of regional function (Friston 2005). The modern version of the dysconnection hypothesis is clear and is based on a renewed understanding of system’s neuroscience. Brain regions with relatively specialized functions transact information across networks subserved by direct or higher-order anatomical connections (Mesulam 1998; Passingham et al. 2002). The ensuing pattern of “effective connectivities” or causal interactions between neuronal elements give rise to integrated function (Stephan 2004). The causal interactions are disrupted in schizophrenia. This modern conception of dysconnection is distinctly rooted in Bleuler’s original theses, yet the transition to a mechanistic systems model of schizophrenia is readily appreciated. The dysconnection hypothesis provides an explicit scientific context for testing biological theories of schizophrenia using multiple brain imaging modalities. We briefly refer to electrophysiology below, but subsequently expand on functional magnetic resonance imaging (fMRI) studies of dysconnection. Electrophysiological studies indicate that neural oscillations are a central mechanism for enabling coordinated activity (both bottom-up and topdown) across brain regions (Singer 1994). This coordinated activity is associated with the emergence of integrated percepts, attention and higher-order cognition (Engel et al. 2001). Therefore, extensive electrophysiological evidence of reduced neural oscillations in schizophrenia (Uhlhaas and Singer 2010) is highly suggestive of reduced network function. Notably, reduced neural synchrony has been associated with both lower-order perceptual tasks, such as perceptual grouping (Uhlhaas et al. 2006) and higher-order tasks including context processing and control (Cho et al. 2006). In vivo neuroimaging techniques, particularly fMRI, have provided a rich experimental framework for studying dysconnection in schizophrenia.

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fMRI provides a particularly useful balance between the spatial and temporal resolution of brain signals (Diwadkar and Keshavan 2002), allows both surface and deep tissue coverage, and thus in many ways exceeds the limits of positron emission tomography or magneto-encephalography (Harel et al. 2006). It is now possible to understand task-induced changes in brain signals dynamically over time (Friston et al. 2003), and leverage an understanding of these causal dynamics towards studying abnormal brain network function in schizophrenia (Stephan et al. 2009a). A consideration of these methods is useful because they post-date Friston’s paper on the dysconnection hypothesis, and provide evidence of how methods have advanced the theories underlying schizophrenia.

Effective connectivity approaches toward modeling fMRI data: Relevance for the dysconnection hypothesis The attempt to investigate causal dynamics in the brain has had a relatively short but densely active history (Stephan and Roebroeck 2012). Early attempts at understanding brain network interactions primarily rested on the mining of statistical and/or fixed temporal dependencies between regional interactions in the brain. It was possible to model the effects of a single (or multiple) brain region(s) (“sources”) on other regions (“targets”) by studying signal covariances between an anatomically constrained brain network using for example structural equation modeling (de Marco et al. 2009). Alternatively, it was also possible to investigate taskrelated effects of a single source region on multiple targets using general linear model based approaches (Friston et al. 1997). However, the reliance on fixed temporal dependencies is severely limiting. These approaches were unable to exploit the more complex temporal dynamics embedded across fMRI signals acquired through the brain (Lee et al. 2006). Methods limited to fixed temporal dependencies will not be sensitive to interactions that are mediated by the order of anatomical connections between them (e.g. direct connections having closest temporal dependencies, whereas indirect connections will have higher order dependencies). This is relevant to schizophrenia because sub-networks embedded within larger macronetworks may be impaired, but not the entire network itself (Érdi et al. 2007; Diwadkar et al. 2008; Gore et al. 2010; Banyai et al. 2011; PetterssonYeo et al. 2011). These limitations were partially resolved in a seminal paper on “dynamic causal modeling (DCM)” (Friston et al. 2003), a method since extensively extended and updated (Friston et al. 2012). DCM is a unique approach for assessing effective connectivity between brain regions, that is, the influence that one neural system exerts on another (Penny et al. 2004). DCM relies on a validated biophysical forward mapping of neural responses into brain hemodynamics (Buxton et al. 1998); by modeling interactions from the hemodynamic response, it is possible to infer neuronal coupling between

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brain regions. Another challenge in analyzing fMRI data is that the possible sets of network interactions that generate the observed data are large. Therefore, rather than using traditional goodness-of-fit metrics to assess the viability of an individual model, DCM relies on evaluating multiple neurobiological plausible competing network models (Stephan et al. 2010). Across competing models, specific network connections may be permuted, and these permuted connections serve as hypotheses. Across models, connections can be constrained or informed by known properties of neuroanatomy (Stephan et al. 2009b). Most importantly, the method provides an approach toward understanding how brain networks “work”, by corollary providing a compelling context for understanding cases (such as schizophrenia) in which the brain does “not work” (Seghier et al. 2010). In doing so, the method explicitly incorporates principles of both relative specialization and functional integration, by modeling three distinct contributions toward task-implementation in the brain. These are: •

•

•

driving inputs to brain regions; these incorporate sensorimotor inputs to regions (e.g. visual cortex driven by visual stimulation), and reflect the relatively high degree of specialization of function that is characteristic of sensorimotor cortex (Eickhoff et al. 2011); endogenous connections between brain regions; these connections reflect functional connections between brain regions that are informed by neuroanatomy; contextual modulation of brain regions; most intriguingly, it is possible to estimate the extent to which the endogenous couplings between brain regions are modulated by an induced task. For example, during a neuroimaging experiment, subjects may be required to alternate between periods of simply observing a flashing probe against periods of tapping in response to the probe. In such a case, we might expect to see contextual modulation of visual-motor pathways during tapping.

These multiple models are tested against each other in a fully competitive Bayesian framework, and the winning model(s) is/are one that appears the likeliest generative model across subjects. In this way, DCM closes the gap between the modeling and the hypotheses being tested. The winning model is the supported hypothesis. Why are these details relevant to the study of dysconnection and schizophrenia? Approaches such as DCM do overcome substantial challenges in understanding brain network dysfunction in the illness. Firstly, it is unclear whether the functional organization of the brain in schizophrenia is similar to or different from typical controls (Bassett et al. 2008). With DCM, it is possible using Bayesian model selection to determine whether the likely models of the task are different from typical controls. If model selection suggests different winning network models in patients, it indicates that the disease may result in the functional reorganization of the brain (Harrison

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and Weinberger 2005; Tan et al. 2009). Alternatively, it is plausible that the functional organization of the brain in schizophrenia is similar to typical controls, but the degree of coupling between brain regions is different (Pettersson-Yeo et al. 2011). In such cases, differences in estimated neuronal coupling between brain regions in the identical winning models provides a signature of dysconnection. Thus, the approach permits parallel and exclusive hypotheses testing on model structure and coupling parameters (Stephan et al. 2010), providing many empirical options toward understanding dysconnection in the illness. Salient applications of DCM and other methods will be considered later. Further explanatory power from dysconnection hypotheses comes from their ready integration with neurodevelopmental models of schizophrenia. Separate proposals by Murray and Lewis (1987) and Weinberger (1987) advanced the idea of schizophrenia being a disorder of neurodevelopment. The significant interest in imaging, genetics, and clinical characterization that ensued has led to this idea gaining acceptance as a leading framework for the disease (Lewis and Levitt 2002; Keshavan et al. 2004a). In this framework, genetic vulnerability for the illness (Harrison and Weinberger 2005; O’Tuathaigh et al. 2007) acts to impair interactions with the environment during critical stages of adolescent development. This leads to a multiplicity of dysmaturational processes, including exaggerated synaptic pruning (Feinberg 1997; Keshavan 1999; Selemon et al. 2003) with gray matter loss (Thompson et al. 2001; Gogtay 2008), and abnormal myelination (Davis et al. 2003; Flynn et al. 2003). The parallel dysmaturation of gray and white matter is functionally expressed as dysconnection in the schizophrenia diathesis. We next consider pathways of brain development, focusing on the idea that the critical dimension of interest in normative brain development is network organization (Arbib and Erdi 2000).

Development and connection Postnatal development is characterized by a rapid expansion in behavioral competence, particularly accelerated during adolescence (Case 1992). This acceleration in behavioral competence appears broadly correlated with parallel and complementary trends in the brain’s structural compartments. First, there is a heterochronous pattern of programmed gray matter loss, with frontal regions of the brain showing dynamic changes that extend into late adolescence (Gogtay et al. 2004; Giorgio et al. 2010). The heterochronicity observed in longitudinal in vivo structural MRI studies broadly corroborates studies on synaptic density (Huttenlocher and Dabholkar 1997). Gray matter loss appears to reflect mechanisms of synaptic pruning (Campbell et al. 2012), the elimination of exuberantly overproduced synapses (Rakic et al. 1986) in the service of shaping brain organization (Edelman 1993). These regional changes are also occurring concurrently with system-wide changes in the connective structure of the brain. Age-

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related changes in white matter density in the interior capsule (Paus et al. 1999) likely subserve the integration of inter-cortical signals between brain regions (Edin et al. 2007). The assessment of white matter changes using diffusion-based metrics have indicated increases in fractional anisotropy and/or decreases in diffusivity in multiple white matter pathways including the corpus callosum, the corona radiata and the longitudinal fasciculi (Barnea-Goraly et al. 2005; Giorgio et al. 2008; Qiu et al. 2010). The broad thrust of typical development results in increased efficiency in functional interactions within the brain (Uhlhaas et al. 2010). The complementary trends of gray and white matter change, result in a transition from short- to long-range connections in the brain (Meunier et al. 2009; Supekar et al. 2009), with increased hierarchical structure through development reflecting functionally and metabolically optimized functional neuro-architecture (Zhang and Sejnowski 2000). Changes in anatomical connectivity also predict brain activations in the fundamental domains of thought, language and memory (Durston et al. 2001). Regional activation studies with fMRI indicate increased recruitment of the prefrontal cortex during successful inhibition (a critical element of cognitive control) (Rubia et al. 2007). In addition, development results in increased anterior cingulate activation during inhibition errors (Rubia et al. 2007), activation that presumably reflects enhanced selfreflective thinking that underlies cognitive development (Kerns et al. 2004). Functional MRI patterns during memory tasks are broadly similar to those associated with cognitive control. For example, episodic memory, a medial temporal lobe centric memory system, is central to the emergence and the bases of thinking and the subjective sense of self (Squire and Zola 1996; Tulving 2001; for a comprehensive discussion on the issue related to the construction of the Self, see Chapter 3). Functional MRI studies of episodic memory indicate age-related increases in activation during episodic retrieval in frontal-parietal regions, but not the medial temporal lobe (Ofen et al. 2007, 2012). The literature on developmental changes in brain activations is vast, and very under-sampled in this chapter (Casey et al. 2005), and is now being complemented by studies assessing changes in brain functional connectivity through development. For example, during phonological processing, a basic sub-process in language, age-related increases in the effective connectivity between the inferior frontal gyrus and receptive language regions like the temporal cortex are observed in processing phonological mismatches (Cone et al. 2008; Bitan et al. 2009). These “top-down” effects reflect a language-specific sharpening of increases in cognitive control with adolescence reiterating the dynamic patterns of functional brain changes through adolescence (Luna 2009; Dahl 2004). These normative patterns of functional brain organization are precisely what have been hypothesized to be disrupted in risk for schizophrenia, and ultimately in schizophrenia itself (Diwadkar et al. 2004; Hirvonen and Hietala 2011; Diwadkar 2012).

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Emergent dysconnection in adolescence: The intersection between neurodevelopmental models and dysconnection hypotheses Why do “so many psychiatric disorders emerge during adolescence (Paus et al. 2008)?” This is certainly true of schizophrenia, hypothesized as a “lifelong” illness of the central nervous system characterized by a multiplicity of “hits”, beginning with the pre- and perinatal phase (obstetric complications; Pilowsky et al. 1993; Gilbert et al. 2003; Gilmore et al. 2010), abnormal neurodevelopment (Lewis 1997) and ultimately progressive neuro-degeneration (Ho et al. 2003). This three-hit related hypothesis emphasizes the pervasive lifespan-related effects of the illness (Keshavan 1999). That subthreshold symptoms present long before the onset of the illness has been intriguingly demonstrated in retrospective analyses of longitudinal cohorts. In a landmark analysis, Cannon and colleagues assessed mid-childhood reports of a large birth cohort collected in New Zealand (Cannon et al. 1997; Cannon et al. 2002a). Striking evidence of “pre-morbid” deficits in social and emotional functioning predated the onset of schizophrenia by over a decade. Moreover, impaired pre-morbid social functioning was reported in individuals with an eventual diagnosis of schizophrenia or bipolar disorder, with the degree of the impairment in part mediated by the nature of the eventual phenotype (schizophrenia worse than bipolar disorder). Thus, neurodevelopmental models predict that clinical symptoms presage the eventual onset of the illness, but recent studies indicate intriguing deficits in pre-morbid brain network function measured with fMRI. These studies can be divided into two broad classes; studies on late adolescents in the prodromal phase of the illness, and studies in adolescent relatives, or children of schizophrenic patients.

Dysconnection in the prodromal stage of schizophrenia The prodrome in schizophrenia (and in medicine in general) refers to the early non-specific state of illness symptoms that precede the more specific symptoms associated with the phenotype itself. Prodromal subjects (also called “clinical high risk”) present with a variety of symptoms, including paranoia, and impairment in social function, and in general have high rates of conversion to psychosis (Cannon et al. 2008). The prodromal phase of schizophrenia therefore assumes particular relevance for understanding vulnerabilities for the illness. Prodromal subjects show differences in fMRI-measured activation that constitute evidence of both dysfunction and compensation. For example, during tasks assessing Theory of Mind skills (e.g. inferring the mental states of protagonists in presented images), prodromal subjects hyperactivate (relative to both controls and schizophrenia patients) prefrontal and posterior cingulate brain regions that are typically associated with these tasks (Brune et al. 2011). Studies in more cognitive domains including language

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(indexed with verbal fluency) and executive function, and episodic memory provide expected evidence of intermediate deficits in prodromal subjects compared to controls and schizophrenia patients (Morey et al. 2005; Allen et al. 2011; Broome et al. 2009; Valli et al. 2011). These trends are supported by meta-analyses of the fMRI data (Fusar-Poli et al. 2007). Individuals in the prodromal stage show many alterations in fMRI-measured connectivity that characterizes the illness. Basic working memory tasks appear to result in disordered temporal-frontal coupling (i.e. effective connectivity) in prodromal subjects compared with controls, with prodromal subjects lying intermediately between patients and controls (Crossley et al. 2009). Using a delayed match-to-sample task, Benetti and colleagues employed DCM to investigate frontal-hippocampal effective connectivity between prodromal and control subjects. Notably, effective connectivity between the posterior hippocampus and the inferior frontal gyrus was reduced in prodromal subjects, similar to what was observed in schizophrenia patients (Benetti et al. 2009). Using the Hayling’s sentence completion task, studies have indicated a distinct loss of functional connectivity between prefrontal and cerebellar networks in the high genetic risk state (Whalley et al. 2005). Recent studies have shown reduced thalamocortical effective connectivity in prodromal subjects during the Hayling’s task (Dauvermann et al. 2013), suggesting that the prodromal state affects the gating mechanisms to the cortex that originate in the thalamus (Andreasen et al. 1994). Disordered fronto-striatal interactions also underlie prodromal subjects, providing convergence with the dopamine hypothesis of schizophrenia (Howes et al. 2007; Howes and Kapur 2009). Subcortical dopamine levels in the dorsal striatum are directly predictive of prefrontal and hippocampal activation in controls. However, they are inversely predictive of prefrontal activation during working memory in prodromal subjects, providing multimodal imaging evidence of disordered striatal-frontal interactions (Fusar-Poli et al. 2010; Roiser et al. 2012). Finally, recent evidence indicates aberrant increases in effective connectivity between the anterior cingulate cortex and the temporal lobe during a basic sentence completion task (Allen et al. 2010).

Dysconnection in the “pre-morbid” stage of schizophrenia What is the “pre-morbid’ stage of schizophrenia, and is it feasible to identify individuals in adolescence who conform to this characterization? Individuals in the pre-morbid stage must have a significantly elevated incidence of the illness in their lifetime, some evidence of an increase in sub-clinical symptoms, and evidence of biological alterations. Thus some of the endophenotypes associated with schizophrenia must be expressed in pre-morbid individuals as well (Gottesman and Gould 2003). In this context, adolescent children of a parent with schizophrenia form a

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compelling case for studying pre-morbid expressions of schizophrenia (Diwadkar et al. 2004). Estimates suggest that children of schizophrenia parents have a ten- to twenty-fold increase in the incidence of psychosis compared with global base rates (Erlenmeyer-Kimling and Cornblatt 1987; Murray and Lopez 1996; Schultz and Andreasen 1999). Thus, this “premorbid” phase has been used to refer to the developmental period that precedes the prodromal phase of the illness (Keshavan et al. 2004b). Although conversion rates to psychosis are lower than those observed in prodromal individuals, the pre-morbid stage nevertheless signifies a general period of genetic/developmental risk. Thus, these individuals are characterized by a sub-clinical phase associated with increased impairment in multiple neuro-behavioral and clinical domains. These include an increase in clinical characteristics such as schizotypy (Keshavan et al. 2004b; Diwadkar et al. 2006), increases in axis I psychopathology, increased incidence of conduct disorders and notably attention deficit hyperactivity disorder (Erlenmeyer-Kimling et al. 1995; Keshavan et al. 2004b; Keshavan et al. 2005a; Diwadkar et al. 2006; Keshavan et al. 2008). Many of the neurobehavioral impairments observed in adult patients are also observed in the pre-morbid phase. These include deficits in working memory (Diwadkar et al. 2001; Diwadkar et al. 2004) and social cognition (Dworkin et al. 1991, 1993; Eack et al. 2010). Thus, there is substantial construct validity to the idea of pre-morbid schizophrenia. Evidence of brain network alterations using task-based fMRI remains modest. Using DCM we have recently demonstrated substantive decreases in cortical-limbic endogenous effective connectivity in adolescent children of schizophrenia parents (Diwadkar et al. 2012). Subjects participated in an affective processing paradigm that engaged mechanisms of affective mentation and appraisal (Barbour et al. 2010). Effective connectivity analyses allowed us to investigate differences in endogenous connectivity, and the modulatory effects of affective valence on network pathways. Several notable results emerged. The brain in the risk or pre-morbid state was characterized by highly significant reductions in endogenous coupling between the frontal cortex (both dorsal and ventral) and the amygdala, signifying a latent and presumably dormant pattern of network dysfunction that may predispose the brain to emotional dysregulation (Phillips et al. 2003). This emergent connective dysfunction in a population under genetic risk, may reflect developmental dysmaturation of a critical brain circuit. Frontolimbic connections rapidly mature in adolescence (Tottenham and Sheridan 2009), enabling the development of face and emotion processing mechanisms, and social development (Herba and Phillips 2004; Insel and Fernald 2004). These reductions in endogenous coupling within corticallimbic circuits may impair the affective response and mediate the emergence of impairments in social behavior and adjustment in vulnerability for schizophrenia (Cannon et al. 1997). The conceptual convergence with the previously referenced analyses of longitudinal birth cohorts is

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notable (Cannon et al. 2002a). Other domains relevant to thought and language have also been carefully assessed. Deficits in sustained attention have been linked to the degree of expressed sub-clinical symptoms (Diwadkar et al. 2011) and have also been related to dysfunctional effective connectivity between frontal-striatal pathways (Diwadkar et al. 2010). Disordered intra-cortical network interactions also characterized this group. During basic working memory tasks, such as the verbal n-back, the degree of dorsal anterior cingulate cortex facilitation needed to subserve performance increases as a function of task demand (Bakshi et al. 2011). This pattern of presumed inefficiency is revealing for its consistency with what has been documented in adult schizophrenia patients (Callicott et al. 2000; Schneider et al. 2007) and indicates that dorsal anterior cingulate based mechanisms of cognitive control (Paus 2001) are impaired in the pre-morbid risk state.

Dysconnection in schizophrenia Techniques for effective connectivity have been most widely applied in the study of schizophrenia itself. For example, using DCM, we recently investigated mechanisms of frontal-hippocampal based learning (Banyai et al. 2011). Such hippocampal learning has been closely associated with mechanisms of synaptic plasticity (Silva 2003), and disordered synaptic plasticity is implicated in schizophrenia itself (Stephan et al. 2009a) linking it to failures in higher-order thinking. Two notable effects were observed. Firstly, across the network assessed, reduced endogenous connectivity was specific to the frontal-hippocampal pathway, consistent with hypothesized deficits in schizophrenia (Harrison 2004; Harrison and Weinberger 2005). Secondly, the time-related modulation of the frontal-hippocampal pathway was reduced in schizophrenia. This reduction in contextual modulation can be straightforwardly interpreted as a reduction in learning-related plasticity on this pathway, constituting relatively direct evidence of reduced frontal-hippocampal interactions that underlie memory consolidation (Eichenbaum 2001). These effects were consistent with independent simulations of associative learning behavior using multi-parameter computational models. Reduced values of model parameters representing synaptic plasticity resulted in schizophrenia-like performance (Diwadkar et al. 2008). Several other successful applications have noted disordered effective connectivity from the prefrontal cortex. During working memory, effective connectivity between the prefrontal and parietal (Deserno et al. 2012), and prefrontal and cerebellar regions is significantly reduced (Schlosser et al. 2003). Compelling reductions in effective connectivity are associated with patients with auditory hallucinations. When hearing their own spoken words, patients with hallucinations evinced reduced effective connectivity between the superior temporal gyrus (a primary language receptive region) and the anterior cingulate, suggesting a critical loss of

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connectivity within a pathway that underlies speech attribution (Mechelli et al. 2007). Furthermore, independent investigations have documented a loss in connectivity between Wernicke’s area and Broca’s area in patients with hallucinations (Curcic-Blake et al. 2012). Finally, reduced connectivity between the caudate and the inferior frontal gyrus in schizophrenia during semantic processing (Chen et al. 2013) further underlines the significant value of using dynamic causal modeling in identifying language-related network dysfunction in schizophrenia.

Disordered brain network function in adolescence and relevance for schizophrenia: Redux Understanding brain network function and dysfunction provides an extremely valuable framework for understanding the schizophrenia diathesis in the lifespan. Latent biological endowments in the form of birth complications and/or vulnerability genes may result in an aberrant developmental program from the “cradle” (Marenco and Weinberger 2001; Cannon et al. 2002b). A resultant impairment in gene-environment interactions during the postnatal developmental period further amplifies an already aberrant neurodevelopmental trajectory (Tsuang et al. 2001). Without corrective intervention during critical periods of adolescence (Lewis and Levitt 2002) this dysmaturation remains as a constant characteristic of risk for the illness, manifest in multiple ways in the pre-morbid and prodromal phases (Cannon et al. 1997; Cannon et al. 2002a; Diwadkar and Keshavan 2003; Keshavan et al. 2008) before the ultimate transition to the full-blown phenotype. Among the myriad neurobiological changes occurring in the span of the illness, brain network function provides a cardinal systems signature. It is unsurprising that genetic vulnerabilities have been hypothesized to impact brain networks (Harrison and Weinberger 2005) and that the genes that confer vulnerability to schizophrenia are also the genes that mediate neurodevelopment (Jones and Murray 1991). Several valuable approaches toward fMRI data have proved illuminating. Using resting state fMRI and graph-theoretic methods, studies have indicated reduced long-distance inter-cortical connections in schizophrenia, but increased intra-regional connections (Alexander-Bloch et al. 2010), suggesting a highly inefficient organization of brain networks in the illness (Bassett et al. 2008). These results are consistent with disordered anatomical connectivity revealed by diffusion imaging techniques in the groups within the diathesis we sample (Munoz Maniega et al. 2008; Karlsgodt et al. 2009; Ardekani et al. 2011). Our focus on methods of effective connectivity for task-based fMRI is motivated by the unique value in understanding how the healthy brain “works”, and by association, how it does not work in schizophrenia. Understanding dysconnection and its relevance for vulnerability in schizophrenia also offers the opportunity of discovering important network-based biomarkers for identifying

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particularly vulnerable individuals. An obvious implication is that in conjunction with targeted interventions, techniques for understanding effective connectivity may provide meaningful information on whether the interventions effect fundamental changes in brain network function. This is an important goal for schizophrenia research (Lewis 2012; Fisher et al. 2013), and is a frontier that is yet to be significantly breached.

Acknowledgements The ideas presented in this chapter were supported by the National Institute of Mental Health (MH68680), the National Alliance for Research on Schizophrenia, the Children’s Research Center of Michigan (CRCM), the Children’s Hospital Foundation and the Prechter Pediatric Bipolar Program World Heritage Foundation.

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Cortesi, M., Veggiotti, P., Politi, P., Barale, F. and McGuire, P. (2007) ‘Neurofunctional correlates of vulnerability to psychosis: A systematic review and meta-analysis’, Neuroscience and Biobehavioral Reviews, 31: 465–84. Gilbert, A. R., Montrose, D. M., Sahni, S. D., Diwadkar, V. A. and Keshavan, M. S. (2003) ‘Obstetric complications correlate with neurobehavioral and brain structural alterations in young relatives at risk for schizophrenia’, Annals of the New York Academy of Sciences, 1008: 269–75. Gilmore, J. H., Kang, C., Evans, D. D., Wolfe, H. M., Smith, J. K., Lieberman, J. A., Lin, W., Hamer, R. M., Styner, M. and Gerig, G. (2010) ‘Prenatal and neonatal brain structure and white matter maturation in children at high risk for schizophrenia’, American Journal of Psychiatry, 167: 1083–91. Giorgio, A., Watkins, K. E., Douaud, G., James, A. C., James, S., De Stefano, N., Matthews, P. M., Smith, S. M. and Johansen-Berg, H. (2008) ‘Changes in white matter microstructure during adolescence’, NeuroImage, 39: 52–61. Giorgio, A., Watkins, K. E., Chadwick, M., James, S., Winmill, L., Douaud, G., De Stefano, N., Matthews, P. M., Smith, S. M., Johansen-Berg, H. and James, A. C. (2010) ‘Longitudinal changes in grey and white matter during adolescence’, NeuroImage, 49: 94–103. Gogtay, N. (2008) ‘Cortical brain development in schizophrenia: Insights from neuroimaging studies in childhood-onset schizophrenia’, Schizophrenia Bulletin, 34: 30–6. Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., Nugent, T. F. 3rd, Herman, D. H., Clasen, L. S., Toga, A. W., Rapoport, J. L. and Thompson, P. M. (2004) ‘Dynamic mapping of human cortical development during childhood through early adulthood’, Proceedings of the National Academy of Sciences of the USA, 101: 8174–9. Goldman-Rakic, P. S. (1999) ‘The physiological approach: Functional architecture of working memory and disordered cognition in schizophrenia’, Biological Psychiatry, 46: 650–61. Gore, C. D., Banyai, M., Gray, P. J., Diwadkar, V. and Erdi, P. (2010) ‘Pathological effects of cortical architecture on working memory in schizophrenia’, Pharmacopsychiatry, 43, Suppl 1: S92–7. Gottesman, I. I. and Gould, T. D. (2003) ‘The endophenotype concept in psychiatry: Etymology and strategic intentions’, American Journal of Psychiatry, 160: 636–45. Harel, N., Ugurbil, K., Uludag, K. and Yacoub, E. (2006) ‘Frontiers of brain mapping using MRI’, Journal of Magnetic Resonance Imaging, 23: 945–57. Harrison, P. J. (2004) ‘The hippocampus in schizophrenia: A review of the neuropathological evidence and its pathophysiological implications’, Psychopharmacology, 174: 151–62. Harrison, P. J. and Weinberger, D. R. (2005) ‘Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence’, Molecular Psychiatry, 10: 40–68. Herba, C. and Phillips, M. (2004) ‘Annotation: Development of facial expression recognition from childhood to adolescence: Behavioural and neurological perspectives’, Journal of Child Psychology and Psychiatry and Allied Disciplines, 45: 1185–98. Hirvonen, J. and Hietala, J. (2011) ‘Dysfunctional brain networks and genetic risk for schizophrenia: Specific neurotransmitter systems’, CNS Neuroscience and Therapeutics, 17: 89–96.

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Corpus callosum, inter-hemispheric communication and language disturbances in schizophrenia Cinzia Perlini, Marcella Bellani and Paolo Brambilla

In the last decades, the study of the neural underpinnings of language has mainly focused on intra-hemispheric networks. However, more recently, there has been substantial research investigating the interplay between linguistic processes and inter-hemispheric communication, which is mainly mediated by the corpus callosum, in healthy subjects and in individuals with schizophrenia. In particular, the disordered callosal communication observed in schizophrenia may affect receptive and productive language processing.

Corpus callosum: anatomy, microstructure and functions The corpus callosum represents the major white matter tract in the human brain, allowing the transfer of information between left and right hemisphere by means of more than 200 million fibers (Figure 6.1; Aboitiz and Montiel 2003). From an anatomical point of view, the corpus callosum has traditionally been divided into five portions, based on Witelson’s (1989) histological studies: rostrum, genu, body, isthmus, splenium (Aboitiz 1992). In a rostro-caudal direction, these regions are organized in a topographic way (Aboitiz 1992), with the anterior corpus callosum connecting the anterior cortical brain areas, while posterior areas are connected through more posterior corpus callosum regions. Specifically, the genu, which represents the anterior part of the corpus callosum, connects bilateral prefrontal and premotor parietal regions. The splenium connects association areas of the parietal and temporal lobes (anterior splenium) and occipital lobes (posterior splenium). The body of the corpus callosum connects motor areas (posterior body) and premotor and supplementary motor areas (anterior body; Hofer and Frahm 2006; Paul 2011). Although callosal fibers mostly connect corresponding regions of the cerebral hemispheres, they also facilitate the communication between non-homologous areas (i.e. left frontal and right parietal cortices; see Jarbo et al. 2012). From a cito-architectonical perspective, callosal regions are nonhomogeneous. Indeed, callosal fibers can be divided into low myelinated and slow conduction fibers (especially composing genu and rostrum)

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Figure 6.1 Intra- and inter-hemispheric major white matter connections represented in a magnetic resonance image of a human brain

connecting high-order association areas, and highly myelinated and rapid conduction fibers (i.e. in posterior body and posterior splenium), which are responsible of the connection between visual, motor and second somatosensory areas (Doron and Gazzaniga 2008; Paul 2011). Human brain activities are based both on intra-hemispheric and interhemispheric processes. Although intra-hemispheric processes granted by cortico-cortical and cortico-subcortical projections pathways within each hemisphere (Mori et al. 2002) represent the majority of processes in the human brain (Nowicka and Tacikowski 2011), inter-hemispheric processes mediated by the corpus callosum play a crucial role in cerebral connectivity. The sum of intra- and inter-hemispheric processes allows a unified experience of the world and a coherent integration of cognition and behavior (Doron and Gazzaniga 2008). Some of the first insights on the structural and functional organization of the corpus callosum were drawn in the 1960s with the pioneering work of Roger Sperry (1913–1994) on patients who had received the surgical disconnection of the two hemispheres for treating epilepsy (Gazzaniga 2005). In the last decades, the advance of neuroimaging techniques has

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allowed to further examine the corpus callosum and the ways in which it relates to cognitive functioning and cerebral lateralization in both healthy and psychiatric conditions. Specifically, diffusion tensor imaging (DTI) is a relatively recent and very promising technique for the investigation of the microstructural organization of white matter and fiber tracking, which has especially been applied to schizophrenia (Catani 2006; Assaf and Pasternak 2008; Doron and Gazzaniga 2008; Hasan et al. 2009; Chao et al. 2009; Perlini et al. 2012). Despite the advances of imaging methodologies, the way in which the corpus callosum allows inter-hemispheric communication is still a matter of debate (van der Knaap and van der Ham 2011). However, it likely inhibits potential interferences from the contralateral hemisphere (this mechanism would be useful when one hemisphere is superior to the other in processing certain kinds of data in order to promote performance) and promotes cooperation between the two hemispheres in processing data (which is advantageous when both hemispheres are qualified to process the same information; Schulte and Müller-Oehring 2010; van der Knaap and van der Ham 2011). The corpus callosum is involved in both lower- and higher-level cognitive processes (Schulte and Müller-Oehring 2010). As for the lower-level processes, it is particularly involved in visuo-motor information transfer, as showed by several studies applying the Poffenberger paradigm (Poffenberger 1912; Marzi 1999; Bellani et al. 2010). This experimental task consists of the presentation of brief simple visual stimuli either to the left or the right visual hemifield. Subjects are asked to respond as quickly as they can after the presentation of the stimuli with either the hand on the same side of the stimulated hemifield (uncrossed condition) or with the hand on the opposite side (crossed condition). The difference between the time necessary to transfer the information in crossed (stimulus presented in the opposite visual field) and uncrossed (stimulus presented in the same visual field) conditions represents a measure known as Crossed-Uncrossed Difference (CUD). From CUD, it is possible to infer the Inter-Hemispheric Transfer Time (IHTT), which appears to be directly related to the structural integrity of the posterior corpus callosum (Westerhausen et al. 2006a). In healthy individuals, the IHTT is of about 4 milliseconds (Marzi et al. 1991). However, it is subject to considerable lengthening when the corpus callosum is sectioned (i.e. in so-called “split brain” patients who manifest an IHTT of about 30–60 milliseconds) or absent (i.e. in patients with callosal agenesis who show an IHTT of about 15–20 milliseconds) (see, for a brief review, Bellani et al. 2009). Interestingly, recent DTI studies have pointed to the functional relevance of microscopic properties of the corpus callosum in mediating changes in IHTT observed in normal aging and in some pathological conditions such as chronic alcoholism (Schulte et al. 2005; Westerhausen et al. 2006a). The corpus callosum is also implicated in higher-level cognitive

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processes such as attention, memory, and language (Zaidel 1995; Banich 1998; Schulte and Müller-Oehring 2010), likely because of its role in interfacing bilateral areas involved in these functions (i.e. the fronto-parietal attention system; Schulte and Müller-Oehring 2010). Also, recent studies have allowed better descriptions of specific populations of callosal projection neurons (CPN), which represent pyramidal neurons connecting the two hemispheres and whose myelinated axons make up the corpus callosum. Specifically, molecular genetic controls have been recently identified that specify different CPN subpopulations, thus allowing a better understanding of the role of such callosal neurons in high-level cognition and behavior and their involvement in pathological conditions (e.g. cognitive deficits, autism, complete or partial agenesis of the corpus callosum; Fame et al. 2011). The corpus callosum is indeed involved in a variety of developmental disorders such as dyslexia, attention-deficit hyperactive disorder, autism, Tourette syndrome, developmental language delay (Paul 2011). The role of the corpus callosum in cognition has been further explored investigating cognitive functions in people with agenesis of the corpus callosum (AgCC; Gazzaniga 2000; Hinkley et al. 2012). These studies have shown that, in contrast to simple visuo-motor information, which can still be transferred between hemispheres despite callosal section (even though at reduced speed), the corpus callosum is fundamental for the inter-hemispheric transfer of higher cognitive information (Gazzaniga 2000). Therefore, if hemispheres are disconnected (i.e. in patients with split brain), perceptions and memories generated in one hemisphere cannot be processed by the other. Also, it has been observed that the absence of CPN connectivity might be associated with deficits in problem solving, generalization, and abstract reasoning (Paul et al. 2007).

The neural substrates of language and the role of the corpus callosum Although language has been traditionally viewed as a left hemispheric function, in the last decades the advances in neuroimaging techniques (Small and Burton 2002; Lee et al. 2006), especially functional magnetic resonance imaging (fMRI) and DTI, have reshaped our knowledge about the neural substrates of language. More brain areas than the traditional Broca’s and Wernicke’s areas are indeed involved in both linguistic production and reception, each one subserving specific functions and contributing to the complexity and dynamicity of language (see also Chapter 1; Hickok and Poeppel 2000; Demonet et al. 2005; Vigneau et al. 2006; Poeppel et al. 2012). In spoken language comprehension, the left hemisphere mainly sustains segmental information such as phonetic, syntactic and semantic processes (Vigneau et al. 2006), which may share a fronto-temporal network. This is composed by the anterior portion of the superior temporal gyrus (STG), the frontal operculum and the inferior portion of Broca’s

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area (Brodmann area, BA 44) for the syntactic circuit and by the mid and posterior portion of the superior temporal gyrus, the middle temporal gyrus (MTG) and Brodmann area 45 in the inferior frontal gyrus for the semantic network (Hickok and Poeppel 2000; Friederici and Alter 2004; Marini and Urgesi 2012). At the early stage of linguistic process, speech sounds are processed by the bilateral auditory cortices (i.e. Heschl’s gyrus and planum temporale) located in the posterior superior temporal gyrus, which plays a crucial role in phonological aspects of both speech perception and production (Hickok and Poeppel 2000; Buchsbaum et al. 2001). As for intra-hemispheric connectivity, these language-related areas are topographically connected via white matter fiber bundles such as the superior longitudinal, uncinate and arcuate fasciculi in each hemisphere (Catani et al. 2005; Glasser and Rilling 2008). Together with other brain areas, the role of the right hemisphere in language has also been dramatically reconsidered (Jung-Beeman 2005; Mitchell and Crow 2005; Lindell 2006). Specifically, it has been suggested to be primarily involved in the comprehension of suprasegmental information of speech, such as prosody, accentuation (Gandour et al. 2000; Zatorre et al. 2002; Friederici and Alter 2004) and discourse level processing (i.e. coherence across sentences) (Ditman and Kuperberg 2010; Marini 2012). Since the late 1960s, it has been observed that patients with callosal transection may experience anomia (Paul 2011). Successively, further lines of evidence have suggested a relationship between corpus callosum morphology or functionality and linguistic functions. First, the corpus callosum has been involved in several common developmental disorders characterized by linguistic deficits such as speech language impairments (Fabbro et al. 2002), dyslexia (Elnakib et al. 2012), attention-deficit hyperactive disorder (Emond et al. 2009), autism spectrum disorder (Anderson et al. 2011) and stuttering (Choo et al. 2011). Also, the recent rethinking of language neural substrates has increased the interest for the role of the corpus callosum and inter-hemispheric communication in supporting the active interaction between the two hemispheres in the domain of language (Westerhausen et al. 2006b; Friederici and Alter 2004; Friederici et al. 2003, 2007; Friederici 2011; Josse et al. 2008; Fryer et al. 2008; Wood et al. 2008; Ibrahim 2009; Häberling et al. 2011; Elmer et al. 2011). Starting from the observation that the comprehension of segmental (phonemic, syntactic and semantic) information influences the comprehension of suprasegmental (linguistic and emotional prosody) components of speech and vice versa, Friederici and Alter (2004) proposed a dual pathway model where the corpus callosum would represent the crucial neuroanatomical structure for the integration of both segmental and suprasegmental information in speech comprehension. These processes are subserved by the dynamic interaction between the two hemispheres. To test whether anterior or posterior portions of the corpus callosum represent the crucial brain area involved in the interaction

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among these linguistic abilities, Friederici et al. (2007) used an eventrelated potential task that crossed prosodic and syntactic manipulations. The Event-Related Potential (ERP) technique allows the registration of transient changes in the brain’s electrical activity in response to the presentation of a stimulus. They are recorded from the scalp surface during electroencephalogram (EEG) and are extracted by means of filtering and signal averaging to eliminate background EEG rhythms and noise. Each event-related potential component is labeled with a ‘‘P’’ (positive) or ‘‘N’’(negative), and the latency from stimulus onset is always specified (i.e. N400 is a negative component that occurs approximately 400 milliseconds after the onset of the stimulus; Picton and Hillyard 1988; Banaschewski and Brandeis 2007). In 2010, Sammler et al. enrolled patients with lesions in the anterior part of the corpus callosum, persons with lesions in the posterior third of the corpus callosum, and a group of healthy participants. Interestingly, patients with posterior damages to the corpus callosum showed intact and independent prosodic and semantic processes, comparable with the performance of both healthy volunteers and subjects with anterior corpus callosal lesions. Nevertheless, compared with the latter groups, they did not show the frontal negativity (between 200 and 500 milliseconds after the stimulus onset) indicating a syntactic–prosodic interaction between the hemispheres (Friederici et al. 2007; Sammler et al. 2010; Friederici 2011). These findings thus support the hypothesis that the posterior portion of the corpus callosum is the critical area for interfacing these linguistic processes between left and right hemispheres. Other authors have suggested the involvement of other sections of the corpus callosum in linguistic functions, such as the anterior portion for the processing of affective and linguistic prosody (Klouda et al. 1988) and the posterior quarter for the inter-hemispheric transfer of auditory information (Rumsey et al. 1996; Pollmann et al. 2002) and for the development of verbal abilities (Nosarti et al. 2004). Conflicting findings, however, exist regarding the relationship between the corpus callosum and the lateralization of linguistic functions, which represents one of the well-established conditions in the normal brain (Broca 1865; Hécaen et al. 1981; Josse et al. 2008). Indeed, some authors sustain the hypothesis that the left-hemispheric specialization for language observed in the adult brain would be due to callosal inhibition of homologous speech areas in the other hemisphere during brain development (Moscovitch 1977; Corballis and Morgan 1978; Komaba et al. 1998), although other researchers support the idea that language lateralization would not involve the corpus callosum and is already present at birth (Pena et al. 2003; Pelletier et al. 2011). Although little work has been done so far on this field, some functional magnetic resonance imaging (fMRI) and DTI studies have specifically addressed the relationship between the corpus callosum and brain language lateralization. Westerhausen et al. (2006b) used a combined fMRI, structural

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MRI and DTI approach in healthy subjects with different degrees of functional language lateralization (previously determined with an fMRI task). The study did not find differences in corpus callosum size between groups (that is, no lateralization effects on corpus callosum macrostructure) but showed lower molecular diffusion in strongly left-lateralized individuals compared with all the other subjects. Generally speaking, water molecular diffusion in the brain tissue (measured in this study as mean diffusion [MD], and its complementary measure, relative anisotropy [RA]) reflects the integrity of white matter fibers and thus the integrity of intra- and inter-hemispheric connectivity in the brain. The lower is the movement of water molecules, the higher is the structural organization (that is integrity) of the tissue. This study suggests that corpus callosum microstructure, rather than size, would reflect callosal functionality in interfacing linguistic data between hemispheres, possibly because microstructure is more directly linked to myelination process than macrostructure. By contrast, a study with healthy participants by Josse and colleagues (2008) showed that the size of the corpus callosum is bigger in those individuals with stronger left fronto-temporal functional lateralization in a semantic decision fMRI single-word production task. This result suggests that not only corpus callosum microstructure but also macrostructure would contribute to the degree to which language is functionally lateralized, possibly because functional lateralization is supposed to be proportional to the number of fibers connecting the hemispheres (that is, corpus callosum size). A recent study by Häberling et al. (2011) suggested that an atypical representation of language may be associated to enhanced fractional anisotropy (FA) in the posterior segment of the corpus callosum. Specifically, fractional anisotropy represents another measure of white matter microstructure organization. Low fractional anisotropy values (corresponding to high mean diffusion values) indicate a disruption of brain tissue fibers, possibly related to damage in the axonal membrane (Bellani and Brambilla 2011). The high fractional anisotropy values observed by Häberling et al. (2011) may thus reflect enhanced inter-hemispheric connectivity in subject with atypical right hemispheric dominance. Other authors propose that the degree of language asymmetry activation, rather than the laterality (left versus right), correlates with the morphology of the corpus callosum. This seems to be especially the case in cerebral lesions, which require a change in the pattern of language representation after the damage. Wood et al. (2008), for example, showed that the laterality scores obtained by patients with focal epilepsy in a letter fluency fMRI task were positively correlated to callosal thickness (especially in the isthmus and the mid-body). Such correlation was not observable in the group of healthy participants, thus suggesting an important role of the corpus callosum for the transfer of language function after cerebral injury. Also, the left hemispheric dominance for speech production seems partly dependent on genetically driven processes of axonal pruning in the corpus callosum (Annett 1991), as suggested by a recent study of Häberling et al.

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(2012) on monozygotic twins concordant or discordant for functional language dominance. The authors proposed that genetic mechanisms involved in determining both hemispheric dominance for language and handedness would influence inter-hemispheric connectivity through the corpus callosum, and, finally, the degree of language lateralization in the brain. Interestingly, Pelletier et al. (2011) directly investigated the role of the corpus callosum in the establishment of language lateralization. If the corpus callosum had a crucial role, it would be expected that language representation would develop bilaterally in persons with agenesis of the corpus callosum. Pelletier and colleagues compared acallosal brain patients with healthy volunteers on syntactic decision and sub-vocal verbal fluency fMRI tasks, reporting no differences in language lateralization between groups, although patients showed a more bilateral pattern of frontal activation in the expressive task than controls. To sum up, although jeopardized because of the strong dependence of language activation on fMRI tasks, findings from these studies generally suggest the involvement of the corpus callosum in language processing and a possible relationship between the corpus callosum and linguistic lateralization. This finding is also supported by the correlation between splenium integrity and linguistic performance in adolescents (Fryer et al. 2008), by the more effective inter-hemispheric communication in response to task demand in bilingual subjects (Ibrahim 2009) and by the association between the degree of language expertize and plastic changes in the white matter architecture of the corpus callosum in samples of professional simultaneous interpreters (Elmer et al. 2011).

Inter-hemispheric communication in schizophrenia Together with abnormal fronto-parieto-temporal intra-hemispheric connectivity (Oh et al. 2009; Sussmann et al. 2009; Voineskos et al. 2010; Hanlon et al. 2012), electrophysiological, neuropsychological and histological studies support the hypothesis of altered inter-hemispheric communication of schizophrenia (Mohr et al. 2000; Hulshoff Pol et al. 2004; Bellani et al. 2009; Paul 2011). In this context, it has also been seen as a “dysconnection syndrome” (Friston and Frith 1995), with abnormal callosal connectivity between homologous brain areas (Park et al. 2011). Interestingly, some symptoms of the disease appear to be very similar to those affecting patients with agenesis of the corpus callosum, including affected abstract reasoning, insight, social functioning, and language (Paul et al. 2007). Two opposite pathogenic mechanisms have been proposed to explain these anomalies: (1) according to the hyper-connectivity hypothesis, redundant synapses have not been correctly eliminated during neurodevelopment (Feinberg 1982); (2) according to the hypo-connectivity hypothesis, too many synapses might have been eliminated because of abnormal interactions between neurons (Friston and Frith 1995). In this

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context, the corpus callosum has been hypothesized to play an important role in the neurobiology of schizophrenia. Recent advances of neuroimaging techniques have indeed allowed to finely examining white matter tracts in schizophrenia, showing alterations of shape (DeQuardo 1999; Downhill et al. 2000; Frumin et al. 2002), and of macro- (that is, size) and micro-structural properties (Woodruff et al. 1995; Diwadkar et al. 2004; Innocenti et al. 2003; Brambilla et al. 2005; Arnone et al. 2008) of the corpus callosum. A meta-analysis by Arnone et al. (2008) on 28 structural MRI studies showed that callosal size is significantly reduced in patients suffering from schizophrenia compared with healthy controls. Interestingly, this study suggests that such reduction would be most prominent in patients at first episode than in chronic phases, possibly because of the neuroprotective effect of prolonged medication. This finding is consistent with a postmortem study reporting density reduction of myelinated fibers and glial cells in all regions of the corpus callosum, except for the rostrum, in female patients with schizophrenia (Highley et al. 1999). Furthermore, in a prospective study by Keller et al. (2003) an abnormal developmental trajectory of the splenium was found in patients with childhood-onset schizophrenia during adolescence and early adulthood. In the last ten years, DTI has been extensively used to investigate the integrity of the corpus callosum in schizophrenia, supporting the presence of an abnormal corpus callosum (Whitford et al. 2011a, c; Kunimatsu et al. 2012; Sugranyes et al. 2012; Knöchel et al. 2012), also at early stages of the illness (Douaud et al. 2007; Gasparotti et al. 2009; Henze et al. 2012; Lee et al. 2013; Samartzis et al. 2013). Indeed, DTI investigations allow the detection of the microstructural properties of white matter tissue (i.e. axonal density and/or myelin content) that, if altered, may underlie the decrease in size of the corpus callosum observed in schizophrenia, and may be present even in the absence of detectable size alterations. Specifically, the splenium and the genu of the corpus callosum have been indicated as areas of crucial interest, both showing low fractional anisotropy values (that is disrupted fibers) in patients with schizophrenia compared to controls (Kitiş et al. 2011; Boos et al. 2013; Knöchel et al. 2012), although not in all studies (Friedman et al. 2008; Gasparotti et al. 2009; Kitiş et al. 2011). A recent meta-analysis by Patel et al. (2011) on seven DTI studies points to the splenium as a key area for schizophrenia, whose lesion might affect interhemispheric connectivity between heteromodal association cortices. Also, a meta-analysis of 15 voxel-based DTI studies by Ellison-Wright and Bullmore (2009) reported evidence of abnormalities (low fractional anisotropy) in inter-hemispheric fibers running through the genu and the splenium of the corpus callosum in patients with schizophrenia compared with controls. Such DTI findings are consistent with the decreased N-acetyl aspartate concentrations in the anterior part of the corpus callosum observed in a MRI spectroscopy study in both first episode patients and ultra high-risk subjects (Aydin et al. 2008).

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Other neuroimaging studies have further explored the relation between structural alterations in the corpus callosum and clinical symptoms in schizophrenia (Foong et al. 2000; Innocenti et al. 2003; Hubl et al. 2004; Brambilla et al. 2005; Gavrilescu et al. 2010; Nakamura et al. 2012). In particular, negative symptoms inversely correlate with corpus callosum size (Innocenti et al. 2003) or fractional anisotropy (Nakamura et al. 2012). Altered connectivity between auditory cortices (Gavrilescu et al. 2010; Mulert et al. 2012) and disrupted anterior callosal transfer have also been shown in patients with positive symptoms (Hubl et al. 2004; Brambilla et al. 2005). In general, conduction delays (i.e. delays in neural timing) arising from callosal fiber damage have been considered as a potential explanation for the dysconnectivity in schizophrenia (Andreasen et al. 1998; Bartzokis 2002; Kubicki et al. 2007, 2008; Stephan et al. 2009; Whitford et al. 2011a,b), as supported by a recent combined ERP-DTI study (Whitford et al. 2011a). Some studies have also investigated inter-hemispheric information transfer in schizophrenia using behavioral tasks, reporting conflicting findings (see Bellani et al. 2009 for a review; Bellani et al. 2010; Florio et al. 2002). Overall, there is robust evidence for the presence of structural alterations of the corpus callosum in schizophrenia, also relating to psychopathological symptoms. Conversely, there are still no conclusive results on the relationship between the corpus callosum and inter-hemispheric information transferring deficits.

Inter-hemispheric communication, language and schizophrenia To date, two major hypotheses have linked the corpus callosum, schizophrenia and language. The first one points to reduced or absent normal left>right cortical lateralization in patients suffering from schizophrenia (Sommer et al. 2001a,b; Renteria 2012), already present in the first phases of the illness (Bleich-Cohen et al. 2009). This reversal or reduced asymmetry specifically affects language-related neural networks, especially the superior temporal gyrus and the planum temporale (Barta et al. 1995; Pearlson 1997; Shapleske et al. 1999; Josse and Tzourio-Mazoyer 2004; Buchsbaum et al. 2005; Bleich-Cohen et al. 2009). In this context, Crow proposed a fascinating theory, combining linguistic deficits, reduced asymmetry and psychosis in an evolutionary scenario. In particular, he considered as critical factors for his hypothesis: (1) the survival of the illness across generations in the face of a fecundity disadvantage; and (2) the absence of variations over time of reduced left lateralization for language (Crow 1997, 2008; Mitchell and Crow 2005; Ceccherini-Nelli et al. 2007). Crow suggested that when left hemisphere dominance breaks down, language anomalies, considered the core symptoms of psychosis, are the outcome. In this regard, Bhojraj et al. (2009) showed a correlation between verbal fluency deficits and reversed or exaggerated structural asymmetry of

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language-related areas (i.e. pars triangularis and Heschl’s gyrus) in nonpsychotic first- and second-degree young relatives of patients with schizophrenia. This implicates genetic liability in the development of altered structural lateralization of language areas in schizophrenia, potentially accompanied by abnormal functional asymmetry (Sommer et al. 2001b; Josse et al. 2003; Josse and Tzourio-Mazoyer 2004; Jeong et al. 2009; Oertel-Knöchel et al. 2012; Bleich-Cohen et al. 2009, 2012b). The other hypothesis points to an altered cooperation between left and right hemispheres rather than to a change in laterality degree, thus assuming a crucial role of the corpus callosum during language processes (Mohr et al. 2000, 2008; Lohr et al. 2006). The above mentioned structural and microstructural alterations of the corpus callosum in schizophrenia strongly support this view. Interestingly, some studies have directly explored the relationship between the corpus callosum, language and inter-hemispheric communication in schizophrenia. Rushe et al. (2007) showed a correlation between the performance at the Crossed Finger Localization Test (CFLT), which is a measure of the inter-hemispheric transfer of somatosensory information, and language processing in schizophrenia, suggesting a relationship between language deficits and impaired callosal functioning. Mohr et al. (2000) investigated inter-hemispheric cooperation during a behavioral lexical decision task requiring subjects to decide whether a letter string was a real word or a nonsense word. In this combined behavioral-ERP study, participants with schizophrenia showed a lack of cooperation between the hemispheres in spite of a normal language lateralization patterns (left>right). Bleich-Cohen et al. (2009, 2012a,b) found an overall reduced functional brain asymmetry in inferior frontal gyrus, corresponding to Broca’s area, and superior temporal sulcus, representing the Wernicke’s region, in patients with schizophrenia compared with controls in a verb generation task. The same authors reported, during language processing, abnormal changes in functional connectivity between left and right inferior frontal gyri (decreased) and between inferior frontal gyrus and the medial prefrontal cortex (increased) in patients with schizophrenia, the latter also correlating with disruption of genu of the corpus callosum. Other fMRI studies also reported a decreased inter-hemispheric inferior frontal gyrus functional connectivity during semantic language tasks in schizophrenia (Jeong et al. 2009; Li et al. 2010). Furthermore, faster IHTT from the right to the left hemisphere (than from left to right) for verbal stimuli has been shown in controls but not in patients with schizophrenia (Endrass et al. 2002; Barnett and Kirk 2005), possibly resulting from callosal deficit in transferring linguistic information. To sum up, there is substantial evidence from behavioral, neurophysiological, and imaging investigations that callosal deficits, probably resulting in altered inter-hemispheric transmission, affect language functions in schizophrenia.

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Conclusions In the first two sections of this chapter we have shown that the corpus callosum is involved in high-level cognition, including human language. It has been observed that human language is a complex function supported by a fronto-parieto-temporal neural network and by connecting white matter tracts, together with the dynamic interplay between the two hemispheres anatomically sustained by the corpus callosum. This structure plays a major role for language processing in humans supporting the linguistic functional brain lateralization. Indeed, anatomical alterations to the corpus callosum relate to deviation from the normal (left>right) functional representation of language. We have shown that schizophrenia is characterized by both volumetric and microstructural callosal abnormalities, particularly in the genu and the splenium, which connect language-related areas of the two hemispheres (e.g. inferior frontal and superior temporal gyri). Such corpus callosum anomalies point to disrupted inter-hemispheric information transfer in schizophrenia, ultimately leading to impaired inter-hemispheric functional connectivity and language processing. In sum, there is robust evidence that corpus callosum and inter-hemispheric communication deficits are involved in linguistic performance in schizophrenia. Future neuroimaging research should further characterize fiber topography of the corpus callosum in relation to specific linguistic features (see also Chapter 11). The investigation of this relationship in high-risk and first-episode patients will be necessary to improve our understanding of the role of the corpus callosum in modulating language since the early stages and over the clinical course of the illness.

Acknowledgments This study was supported by grants from the Italian Ministry of Health to Dr Paolo Brambilla (GR-2010-2316745) and to Dr Marcella Bellani (GR 2010-2319022).

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7

Structural and functional brain imaging of thought disorder Andrew Watson and Stephen Lawrie

The production of jumbled and disorganized speech has been described and discussed right from the earliest clinical descriptions of psychotic illnesses. The importance placed on productive speech abnormalities in the diagnosis of schizophrenia has varied over the last 100 years, but these phenomena have continued to be researched throughout (McKenna and Oh 2005). Early attempts to elucidate the structures in the brain that were related to thought disorder were based on the examination of post-mortem brains, but these efforts were inconclusive. Since the development of techniques that can image brain structure and activity in life, there has been a surge of interest in looking at the neural correlates of thought disorder. In addition, over the last ten years it has become clear that higher levels of thought disorder, alone and in combination with other disorganization symptoms, contribute to a poorer outcome in schizophrenia (Bowie and Harvey 2008; Ventura et al. 2010) and therefore are of great interest in attempting to understand how this aspect of schizophrenia impacts on daily life. People with schizophrenia, and their relatives, demonstrate a range of difficulties in both understanding and producing language (Levy et al. 2010). The more subtle abnormalities are found using specific tasks to measure language use, but only a subset of patients demonstrate frank or formal thought disorder, where the abnormalities are clear during everyday speech. Whether all these language difficulties are caused by one common abnormality, but at differing levels of severity, or overt thought disorder has a different underlying basis remains uncertain. Even those patients who have periods of suffering from high levels of thought disorder demonstrate marked fluctuation in the level of disorganization in their speech. This variability has been a major challenge in designing and interpreting studies. While some studies do try to select patients with stable symptoms and/or assess them on the same day as the scan, the inherent variability of all psychotic symptoms does mean that this approach can only go so far in assessing whether the findings are related to the level of current thought disorder (state effects) or an underlying predisposition to these symptoms (trait effects). Functional brain imaging has allowed sophisticated paradigms to be used to try to tease these state-versus-trait effects

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apart, but general challenges in attempting to find neural structures associated with either schizophrenia as a whole or specific symptoms are also relevant to the issues raised in this chapter. The effects of the illness itself over time, changes in environmental exposures from having a diagnosis of schizophrenia, and the long-term use of medication, will all have an effect on the structure and function of the brain. All these factors serve to increase the difficulty in isolating a specific brain structure or network related to a specific symptom or cluster of symptoms. This chapter focuses on brain imaging, predominately positron emission tomography (PET) and magnetic resonance imaging (MRI) and does not cover the use of electrophysiology to examine language use in schizophrenia. This means that the emphasis is on the location of areas or networks in the brain to which thought disorder might be related. We have only included studies that directly measure thought disorder and relate it to brain function, and therefore the extensive literature on abnormalities in language understanding and subtle abnormalities on specific language tests is not covered, unless the imaging study specifically assessed thought disorder. While thought disorder is found in other psychiatric disorders, especially mania, we were unable to find any studies examining the imaging correlates of thought disorder in these patient groups.

The assessment of thought disorder From the early accounts of schizophrenia emphasizing disorder of thought as a key impairment in schizophrenia, various methods of assessing the abnormalities have been used. These have relied on the assessment of patients’ language, without assumptions being made about putative underlying neural networks subserving language functions. The most influential has been Andreasens’s (1986) thought, language and communication scale, which brought together 20 items to describe specific abnormalities in a patient’s speech. While the definitions of specific abnormalities marked a step change in clarity for assessing language in schizophrenia, it has not been widely used in studies attempting to examine the neuroanatomical basis of thought disorder. A number of other scales have been used, which include varying numbers of specific descriptors for abnormalities in speech. As the various scales were evaluated further, it became clear that disorganization in speech, or positive thought disorder, was distinct from reduced production of speech, or negative thought disorder (Kuperberg 2010a). Disorganization in speech encompasses what can be called formal thought disorder and is best summarized by Chaika (1974) as language productions organized “according to the semantic features of previously uttered words, rather than according to a topic”. An example of the phenomena included under this rubric comes from the thought, language and communication index, where looseness, peculiar word usage, peculiar

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sentence construction, peculiar logic and distractibility are grouped to form a measure of positive thought disorder (McGuire et al. 1998). Negative thought disorder usually has at its core reduced verbal output or poverty of speech, and its proposed thought equivalent, alogia. Poverty of the content of speech, where little is communicated to the listener despite the number of words used being appropriate, is usually grouped with negative thought disorder, but has also been included with positive thought disorder items in some studies. Neuroimaging studies have not evaluated negative thought disorder separately. As Kuperberg (2010a) and Covington et al. (2005) have stated, the precise levels of normal language processing have not been reflected in a consistent manner in the assessment of thought disorder (see also Chapter 8). A further complication reviewing the literature regarding the neuroanatomical basis of thought disorder is that many studies examine the neural correlates of Liddle’s (1987) three factor solution of the symptoms of schizophrenia. These three groups of symptoms, or syndromes, have been consistently found to separate from each other on factor analysis. Reality distortion consists of delusions and hallucinations, psychomotor poverty includes poverty of speech, flatness of affect and decreased spontaneous movement, while disorganization consists of disorders of the form of thought, inappropriate affect and non-goal-directed behavior (Liddle et al. 1992). While the disorganization factor contains the phenomena that are described as positive thought disorder, it includes other behaviors that could be assumed to be subserved by different functional networks in the brain. Positive thought disorder has been noted to comprise the largest component of the disorganization factor (Kircher et al. 2008; Ventura et al. 2010) and studies examining its neural basis do offer important extra information relevant to the issues raised in this chapter. With these caveats regarding the variability in assessment of thought disorder in mind, clear themes do emerge from the study of thought disorder using brain imaging.

Structural correlates of thought disorder Shenton et al. (1992) examined a group of 15 men with chronic schizophrenia. The neural correlates of a wide range of positive thought phenomena, as measured by the Thought Disorder Index (Solovay 1986), were assessed using structural MRI. They found that the hand-traced volume of the left superior temporal gyrus (STG) was negatively and significantly correlated with the level of thought disorder. As the authors commented, the area found to be smaller in size included the planum temporale, long associated with language processing and a part of Wernicke’s area. Alongside this, the size of the right temporal horn, a part of the lateral ventricle containing cerebrospinal fluid, increased in size as the severity of thought disorder symptoms increased. These changes in volume were highly correlated with reductions in other parts of the left

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temporal lobe (the STG as a whole and the parahippocampal gyrus) and the authors therefore suggested that thought disorder was associated with damage to a connected network of brain structures crucial in making associative links between perceptual representations: ‘an inability to maintain a proper gradient of strength of associated linkages, leading to thought disorder and, as described by Bleuler, “incidental linkages”’ (Shenton et al. 1992). Anderson et al. (2002) provided support for this, finding that a reduced gray matter volume in the left planum temporale was correlated with increased thought disorder. While Shenton et al. (1992) studied patients who had been diagnosed for over ten years, Vita et al. (1995) used structural MRI to examine 19 patients with an average duration of illness of only 1.6 years. They used the thought, language and communication scale to assess the level of thought disorder, and included both measures of disorganized speech and reduced speech output in the overall score. The regions of interest examined were the temporal lobes and the prefrontal cortex. While they found no relationship with volumes in the temporal lobes and thought disorder, a significant negative correlation between higher thought disorder scores and the volume of the bilateral prefrontal cortices was observed. They did attempt to look at individual items on the thought, language and communication scale, but no associations survived multiple testing corrections. Further evidence of a structural reduction in brain tissue associated with increased thought disorder was found by Nakamura et al. (2008). While the prefrontal lobes are known to be functionally subspecialized, direct imaging of frontal sub-regions is technically challenging. The large variation in sulcal and gyral folding has made group comparisons in this area difficult, and findings in schizophrenia have been mixed (Honea et al. 2005). Using a combined hand-traced and automated parcellation method to examine regions of interest in the prefrontal lobe, they found that the volume of the left middle orbitofrontal gyrus was negatively correlated with positive thought disorder items on the schedule of the assessment of positive symptoms (Andreasen 1984). The volume of this area was also positively correlated with verbal comprehension across the groups. This is in keeping with current theories of language comprehension in the brain; that it is a distributed across a number of areas, and not just related to STG and inferior parietal lobe functioning (Kuperberg 2010b). The authors “speculate that these features associated with left middle orbitofrontal volumes could reflect a milder form of suppression failure of evoked memory traces irrelevant to ongoing reality [which is] similar to ‘spontaneous confabulations’ found in orbitofrontal lesions” (Nakamura et al. 2008). They add that their findings may therefore reflect a deficit in “monitoring ongoing reality in speech”. This work suggests that abnormalities in two brain areas consistently associated with both schizophrenia and language processing are related to thought disorder. Abnormal linkages between frontal and temporal

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regions have been long viewed as underlying many aspects of psychotic symptomatology (Frith 1992; Leube et al. 2008). A reduction of the left posterior STG has been found in people experiencing their first episode of psychosis, specific to schizophreniform psychosis as compared with affective psychosis (Hirayasu et al. 1998). Voxel-based morphometry, an automated analysis tool, allows the amount of tissue in small areas of the brain (voxels) to be compared between groups without limiting the search region (Ashburner and Friston 2000). Regions of interest do not need to be specified in advance, and it therefore allows the structures across all the brain to be compared. Combining voxel-based morphometry studies in a meta-analysis, Honea et al. (2005) found significant reductions in volumes in the left STG and left-middle temporal gyrus in schizophrenia. Extending this work, a recent meta-analysis of studies in people at high risk of developing a psychotic episode found that the development of a full psychotic episode was related to lower right inferior frontal and right STG volumes (Fusar-Poli et al. 2011), suggesting that these are key areas associated with psychotic illnesses. The variability in the lateralization of cerebral hemisphere changes in structure and function that have been associated to thought disorder, and other manifestations of schizophrenia, is a recurrent theme throughout this chapter. Diffusion tensor imaging is an MRI method for examining the integrity of white matter tracts in the brain. Widespread reductions in this integrity have been found in schizophrenia (Kubiki et al. 2007), including in the main pathways that have been associated with normal language processing. This maybe related to the disruptions seen in these networks in schizophrenia. Unfortunately, these findings have not been examined in relation to specific thought disorder phenomena and this should be an important focus for future work. In summary, a reduction in gray matter in the left superior temporal lobe has been linked to increased levels of thought disorder. A smaller volume of this area has also been related to the diagnosis of schizophrenia, but reductions in gray matter related to the subsequent development of schizophrenia have been associated with the right hemisphere homologue. Reduced prefrontal volumes have also been reported to be related to thought disorder and it appears that the abnormalities extend much further than just the classical speech processing areas of Wernicke’s and Broca’s (see Chapter 1 for a discussion on this issue).

Functional correlates of thought disorder Functional neuroimaging studies attempting to examine thought disorder have taken two main approaches. The first clinically assesses the level of thought disorder during an interview and then looks to correlate the symptoms to patterns of inferred neural activity at rest using either blood flow (PET) or the blood oxygen level-dependent (BOLD) response (functional

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MRI [fMRI]). After some initial PET studies taking this approach, it is becoming popular again, as more evidence accumulates about organized, highly correlated, low-frequency patterns of brain activation evident even when the subject is instructed only to look at a cross. Various networks have been proposed to contribute to this but the default mode network is the most commonly examined (Fox et al. 2005). This approach suffers from the same limitation as structural scans in struggling to separate trait-versus-state effects. The second approach is to use a task, usually a language or working memory paradigm, to activate specific areas or networks within in the brain. Differences in the activations can then be related to thought disorder phenomena, either produced during the task or assessed outside the scanner. Increasing the processing demands on the brain by having the participant perform a task has the advantage of potentially demonstrating differences between groups that are not evident at a lower level of processing demand. This is may be particularly relevant in schizophrenia, as it has been repeatedly shown that greater demands placed on working memory paradigms increase the differences between patients and controls (Han and Wible 2010). One approach is to use tasks that have different levels of difficulty; the analysis can look at those areas that are more active with increasing processing demands. Other studies use two different conditions, such as passive reading compared with making a decision based on the text. These studies then examine the differences between the two tasks to pinpoint putatively specific aspects of the task. The baseline condition from which to compare is crucial in interpreting the results and there has been criticism of using tasks like this for language processing or production tasks (Han and Wible 2010). Using the example above, where the participant is asked to read a sentence against deciding on its plausibility, some of the common activations between the two conditions would not emerge in the analysis; for example, those related to the visual processing of word-like shapes. This may be specifically important in schizophrenia, as even very early perceptual processing has been found to be attenuated in schizophrenia that comparative PET and fMRI studies may miss (Ngan et al. 2003). The first study examining the functional correlates of thought disorder was by McGuire et al. (1998). They recruited six men with schizophrenia who demonstrated high levels of thought disorder but low levels of other symptoms. All were on antipsychotic medication and had been diagnosed for at least three years (mean 12 years). During PET scanning, the researchers asked participants to describe ambiguous scenes that included human figures. The words produced were recorded and then analyzed for specifically positive thought disorder phenomena. They found widespread blood flow changes related to higher levels of thought disorder. Blood flow was increased to the right caudate and bilateral fusiform gyri, and decreased to the left STG, bilateral inferior frontal gyri, left insula, both the anterior and posterior cingulate and the right middle frontal gyrus. When

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they examined the areas more active the greater the number of words were spoken, the left inferior frontal, left STG and left insula demonstrated increased blood flow. The authors interpreted these findings as indicating a widespread reduction in blood flow to language-related areas of the brain in thought-disordered patients, with increased activation of areas which relate to “subjects encountering unexpected stimuli, such as words anomalous to the preceding context” (McGuire et al. 1998). As the patients were not aware of the unusual use of the words they were demonstrating, and made no effort to correct them, the authors suggested that the some areas in the patients’ brains were noticing the anomalous words but that this was not entering consciousness awareness. A series of studies on a sample of six men with schizophrenia offers the most comprehensive effort to examine different aspects of language processing in patients exhibiting high levels of thought disorder (Kircher et al. 2001a, 2002, 2005). These patients were 34 years old on average (SD 11.5) and had had a diagnosis of schizophrenia for 13 years (SD 9.9). They were all on antipsychotic medication, with a mean dose of 1042mg of chlorpromazine equivalents. These studies (Kircher et al. 2001a, 2002, 2005) used fMRI to examine the neural correlates of the language produced when participants were asked to describe ambiguous stimuli: Rorschach plots. The initial analysis measured the amount of positive thought disorder phenomena per description, as measured by the Thought, Language and Communication Index, and co-varied for the number of words used (Kircher et al. 2001a). Increased thought disorder was correlated with increased BOLD response in the right caudate, right precentral gyrus and the cerebellar vermis. Decreased BOLD response was seen in the left STG and left middle temporal gyrus (MTG), and the findings overlap with McGuire et al.’s (1998) study. The number of words produced during this task was examined in a later paper (Kircher et al. 2002). This analysis found that an increase in the number of words produced per picture was associated with different activations in patients with thought disorder and controls. Enhancements of the BOLD response were found in the left STG and left supramarginal gyrus in controls. In patients with schizophrenia, the right STG, right MTG and bilateral fusiform gyri demonstrated the enhancement. Patients showed a reduced BOLD response in bilateral frontal regions, whereas in controls this was in the left precuneus and right superior occipital gyrus, with no significant changes in frontal areas. This is in contradiction to the reports above, which did find left STG activation to be associated with the number of words produced in the schizophrenia patients. The final analysis examined the complexity of the sentences used during the picture descriptions (Kircher et al. 2005). Simple sentences only included one clause, whereas complex sentences had at least one subordinate clause. Again, different enhancements were seen in the patient and the control groups. When comparing simple with complex sentences, the controls had

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greater activations in the left STG and left superior frontal regions. Patients did not show enhancement in these regions and instead only demonstrated an increased BOLD response in the right MTG. The authors suggest that the failure to recruit the left STG and instead activating the right STG (and MTG) in patients demonstrating high levels of thought disorder demonstrates an abnormal lateralization in the neural functions of men with schizophrenia. Unfortunately, network-based, effective connectivity analysis has not been reported on these data, so firm conclusions about the relative contributions of different brain regions are difficult to make. A further study by the same group examined six patients with high levels of thought disorder, six patients without thought disorder and seven controls (Kircher et al. 2001b). In this study, participants were asked to complete a sentence by either reading an appropriate word, generating a suitable word or deciding between two options as to which was more suitable to the context. The patients with thought disorder made more errors overall, and these errors were particularly semantic rather than pragmatic or syntactic. After co-varying for errors and reaction time, this time reduced right STG activation was found in the group who had high levels of thought disorder when generating a novel sentence ending. In all groups, the words generated that were classified as errors were associated with BOLD enhancements in the left inferior frontal, left inferior temporal and left fusiform/occipital gyrus. These findings could again be interpreted as indicative of patients with thought disorder brains’ registering the semantic incongruity in their speech, but that this is not leading to behavioral change (i.e. correcting the errors). Kircher et al. (2008) looked at phonological and semantic fluency alongside free association in a sample of 12 men with schizophrenia. While this sample was not specifically recruited to have high levels of thought disorder, these men were found to have a moderate level of abnormalities during the assessment interview. Overall, the patients demonstrated “less conventional associations” than healthy controls while performing the tasks. While there are a number of interesting findings from this study, the only contrast that demonstrated an effect of greater thought disorder symptoms was free association compared with reading. Greater thought disorder was associated with reduced activations in the right MTG and right lingual gyrus. There were no areas of increased activation and no differences observed on semantic verbal fluency or phonological verbal fluency. A combination of functional and structural approaches were taken using structural MRI and a measure of resting cerebral blood flow, arterial spin labeling, by Horn et al. (2009). They used the total score of the thought, language and communication scale, combining negative and positive thought-disorder phenomena, and found that higher scores were correlated with gray matter reduction across a wide range of brain regions: bilateral anterior cingulate, bilateral precuneus, left superior temporal structures and the left angular gyrus. Increased blood flow to the left STG,

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left insula and the left inferior frontal gyrus was correlated with an increased level of thought disorder. These findings contrast with the PET findings of McGuire et al. (1998), who studied the actual production of thought disorder in the scanner, and found reductions in blood flow in the similar regions. Kuperberg et al. (2008) have reported a differential effect in semantically associated brain regions between patients and controls. Semantic priming, where target words are processed faster when a semantically related word is presented first, in contrast to an unrelated word, has been studied extensively using behavioral tests and electrophysiology in schizophrenia. The findings are mixed (Kuperberg 2010a), but point to a pattern of people with schizophrenia, and especially those with thought disorder, as demonstrating increased priming effects on tasks where a response is required quickly. Kuperberg et al. (2008) used fMRI to attempt to elucidate the neural underpinnings of this effect. They found that, while controls demonstrated suppression in the BOLD response to both directly (e.g. stripes – tiger) and indirectly (lion – stripes) related words, patients showed an enhancement. This effect was significant in prefrontal regions (bilateral anterior, inferior prefrontal gyri and left lateral obito-frontal gyrus) for directly related words and temporal (left STG and bilateral fusiform gyrus) for indirectly related word pairs. A significant correlation with the conceptual disorganization item on the Positive and Negative Syndrome Scale was found with greater activation in the bilateral fusiform gyri while processing indirectly related words. Higher levels of activation, and for longer, in areas of the brain associated with processing semantic relationships match electrophysiology findings during the same task. The authors concluded that “this inappropriate activity maybe a neural correlate of the abnormal associative activity as conceived by Bleuler as being fundamental to the understanding of positive thought disorder and schizophrenic psychosis as a whole” (Kuperberg et al. 2008). In summary, thought disorder has been related to changes in blood flow in the areas found to be reduced in size using structural scanning: superior temporal structures and prefrontal regions, but both the lateralization of these findings and the direction of the correlation vary in different studies. The changes in blood flow also extend out to anterior parietal and midline structures and the disruption is again more widespread than the two regions classically associated with aphasic symptoms.

Structural and functional correlates of disorganization Liddle et al. (1992) looked at 30 patients with schizophrenia who were selected for having a stable set of symptoms. They found that lower resting blood flow on PET was significantly correlated with higher disorganization scores in the right ventral prefrontal cortex, left Broca’s area (left inferior frontal gyrus) and in the bilateral angular gyri (inferior parietal lobule).

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Higher blood flow was found in the anterior cingulate, medial prefrontal cortex (slightly right biased), thalamic nuclei and the left superior temporal sulcus. Kaplan et al. (1993) examined 20 patients with schizophrenia who had not taken any medication for at least four months. They also found that reduced blood flow in the left superior temporal gyrus and bilateral inferior parietal areas were related to higher levels of disorganization. Schroder et al. (1996) also did not replicate reduced blood flow in frontal areas, but instead found that disorganized symptoms were related to parietal and motor areas. Lahti et al. (2006) reported two cohorts of medication-free patients. They found disorganization to be related to higher blood flow to the left inferior frontal area and the anterior cingulate. Reduced flow was also demonstrated in the left hippocampus. Structural associations have also been reported between disorganization and specific brain areas. In the same sample as Liddle et al. (1992), Chua et al. (1997) found that higher disorganization within people with schizophrenia was related to an increase in the gray matter volume in the bilateral medial temporal area, especially in the hippocampus and the parahippocampal gyrus. A relative increase in gray matter may be a marker of abnormal neuronal development in that area. Lopez-Garcia et al. (2006) found that reduced dorsolateral prefrontal cortex (DLPFC) volumes correlated with a higher load of symptoms, although in patients with larger DLPFC volumes than controls. This was evident in patients with established schizophrenia, but not those experiencing their first episode of psychosis. Finally, Nenadic et al. (2010) recently reported prefrontal reductions in gray matter across all symptom groups, but found a specific effect of disorganization in the medial temporal lobe. In a recent review of fMRI correlates of symptom dimensions or factors, Goghari et al. (2010) commented that disorganization symptoms have been much less widely reported than other groupings of symptoms in schizophrenia. In tasks examining the ability of patients with schizophrenia to use context to determine the appropriate task-relevant responses, DLPFC activation has been found to be lower in patients with schizophrenia (Barch et al. 2003; MacDonald et al. 2005; Snitz et al. 2005). The degree of the failure to engage this area was strongly related to the level of disorganization exhibited by the patients, although on differing sides of the brain in different studies. Interestingly, Snitz et al. (2005) found that this effect was no longer significant after four weeks of treatment with antipsychotics. Goghari et al. (2010) commented that many of the studies they examined used a region-of-interest approach and may have missed other activations relevant to disorganization symptoms. From the studies they examined, they calculated an effect size of 0.43 (confidence interval 0.25 to 0.61) when relating higher disorganization scores with reductions in DLPFC activations. The review found few studies showing links between temporal lobe activations and disorganization. The functional connectivity of the DLPFC has also been related to

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disorganization. Yoon et al. (2008) used a continuous performance test and showed that patients experiencing their first episode of psychosis demonstrated reduced BOLD enhancements across all the task-related areas. Specifically, DLPFC connectivity with the right inferior parietal lobule and left premotor cortex was significantly reduced as disorganization scores increased. The authors commented that “the convergence of behavioral, functional neuroimaging and clinical findings in this present study supports the DLPFC dysfunction model of cognitive control deficits in schizophrenia” (Yoon et al. 2008; see also Chapters 7, 10 and 11). Recently, resting state functional connectivity has been found to be altered in schizophrenia (Rotarska-Jagiela et al. 2010). In this study, disorganization was measured by a single item in the Positive and Negative Syndrome Scale, and they found that increased connectivity of the superior motor area (superior frontal) as part of an “auditory cortex network” was related to higher disorganization. A “right fronto-parietal network” was also less coherent in patients with higher levels of disorganization. Wider findings related altered functional connectivity and temporal dynamics in the default mode network and fronto-temporal connectivity to positive symptoms in general but these were not significantly related to disorganization in this study. In summary, disorganization has been related to similar areas of the brain as thought disorder but, additionally, there has been a greater focus on the DLPFC and this area has been consistently found to be altered in patients with higher levels of disorganization.

Conclusions While there is variability in the findings presented in this chapter, certain themes do emerge. The structure and function of the superior temporal lobe (Figure 7.1) has been associated with positive thought disorder phenomena across a wide range of studies using different modalities. Other temporal structures have also been related to aspects of thought disorder including the bilateral fusiform gyri (Figure 7.2). Specific frontal areas associated with thought disorder have varied, but bilateral inferior frontal areas are the most commonly implicated. More general disorganization has been associated with a varied set of brain areas, but DLPFC changes have been the most consistently found. Two main models have been proposed to underlie thought disorder in schizophrenia (Kuperberg 2010a). The first places much emphasis on correlations between working memory measures and thought disorder phenomena, although these associations could be determined by a third, common factor. The second emphasizes the role of disrupted semantic processing: people with thought disorder rely too heavily on the links between words rather than on the overall goal of their communication. The imaging data reviewed here do not offer a clear answer as to which is

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(3)

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Figure 7.1 Cortical areas related to aspects of thought disorder: the superior temporal gyrus is represented in (1), the inferior frontal gyrus in (2) and the inferior parietal lobule in (3)

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(1) Figure 7.2 Cortical areas related to aspects of thought disorder: the fusiform gyrus is represented in (1), the anterior cingulate gyrus in (2) and the precuneus in (3)

correct, but they does suggest that changes in the areas involved in building up semantic meaning in language are consistently associated with thought disorder. How language is normally processed is crucial for attempting to understand how it may go awry in schizophrenia. Older models, which assumed

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that there was a specific store of semantic meaning in the brain that was subservient to the combinatorial rules of grammar or syntax, do not appear to reflect how people process language in real-life situations. In addition, the assumption that language has its own specific and separate network in the brain has been criticized (Kuperberg 2010b). Indeed, one persuasive theory of language development suggests that the structure of our communicative utterances is explained by constraints within a system of communication itself, and does not rely on any specific neural architecture beyond the ability to make the complex motor patterns needed to speak (Kirby et al. 2008). If this is the case, then the marked inter-individual variation often masked by group comparison in imaging studies becomes much more interesting: it suggests that individuals can use different neural architectures to complete the same broad task of successful communication. This line of work suggests that there will be no easy answer to the anatomical correlates of thought disorder in the brain, as the thought disorder construct does not need to have a specific brain area attached to it, nor do people with schizophrenia have a single disrupted language network. Instead, a number of overlapping networks that build up meaning from perception and decide on the appropriate behavioral response (be it speech or some other behavior) may have different relative impacts, leading to thought disorder phenomena. A disruption in one or more parts of the system, or the links between the different parts, may lead to a reduced reserve for increased processing demands or other environmental stresses. Ferreira (Ferreira et al. 2002; Ferreira and Patson 2007) suggests a model where, most of the time, our use of language utilizes a fast, heuristic system based on expected semantic relationships. This system of pattern recognition has developed as wider representations than single words and most of the time this allows us to handle the extreme time pressures that spoken language places on us. When it is noticed that this system is not working to meet communicative goals, a second approach is preferred. This uses grammar, or syntax, to resolve the ambiguities in speech. Kuperberg et al. (2008) suggests that thought disorder, and wider language abnormalities in schizophrenia, may arise from a mismatch between these two systems (i.e. an overreliance on the semantic system). Speculatively, this idea could be integrated with the finding that psychosis appears to be related to a state of attenuated prediction error (Corlett et al. 2011) where violations of expected associations lead to an attenuated neural response in people with schizophrenia. If the failure of a semantic processing stream is not noticed by key parts of the patient’s neural architecture then there would be no need to use other strategies to resolve that failure. The imaging findings do suggest that the brain areas most commonly associated with semantic processing are registering the anomaly in the patient’s own speech, but that it is not leading to any corrective strategies. Phenomenologically, patients will often acknowledge jumbled thoughts, but not the actual production of thought disorder phenomena.

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In summary, thought disorder is associated with functional and structural changes in areas of the brain strongly associated with both the development of schizophrenia and wider language processing. Whether the thought disorder phenomena are an extreme version of other language difficulties in schizophrenia, how they relate to normal language function and how improvements with treatment might relate to changes in brain function must be the focus for future work.

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Fusar-Poli, P., Borgwardt, S., Crescini, A., Deste, G., Kempton, M. J., Lawrie, S., McGuire, P. and Sacchetti, E. (2011) ‘Neuroanatomy of vulnerability to psychosis: A voxel-based meta-analysis’, Neuroscience and Biobehavioral Reviews, 35: 1175–85. Goghari, V. M., Sponheim, S. R. and MacDonald, A. W. 3rd (2010) ‘The functional neuroanatomy of symptom dimensions in schizophrenia: A qualitative and quantitative review of a persistent question’, Neuroscience and Biobehavioral Reviews, 34: 468–86. Han, S. D. and Wible, C. G. (2010) ‘Neuroimaging of semantic processing in schizophrenia: A parametric priming approach’, International Journal of Psychophysiology, 75: 100–6. Hirayasu, Y., Shenton, M. E., Salisbury, D. F., Dickey, C. C., Fischer, I. A., Mazzoni, P., Kisler, T., Arakaki, H., Kwon, J. S., Anderson, J. E., Yurgelun-Todd, D., Tohen, M. and McCarley, R. W. (1998) ‘Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects’, American Journal of Psychiatry, 155: 1384–91. Honea, R., Crow, T. J., Passingham, D. and Mackay, C. E. (2005) ‘Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies’, American Journal of Psychiatry, 162: 2233–45. Horn, H., Federspiel, A., Wirth, M., Muller, T. J., Wiest, R., Wang, J. and Strik, W. (2009) ‘Structural and metabolic changes in language areas linked to formal thought disorder’, British Journal of Psychiatry, 194: 130–8. Kaplan, R. D., Szechtman, H., Franco, S., Szechtman, B., Nahmias, C., Garnett, E. S., List, S. and Cleghorn, J. M. (1993) ‘Three clinical syndromes of schizophrenia in untreated subjects: Relation to brain glucose activity measured by positron emission tomography (PET)’, Schizophrenia Research, 11: 47–54. Kirby, S., Cornish, H. and Smith, K. (2008) ‘Cumulative cultural evolution in the laboratory. An experimental approach to the origins of structure in human language’, Proceedings of the National Academy of Sciences of the USA, 105: 10681–6. Kircher, T., Whitney, C., Krings, T., Huber, W. and Weis, S. (2008) ‘Hippocampal dysfunction during free word association in male patients with schizophrenia’, Schizophrenia Research, 101: 242–55. Kircher, T. T., Bulimore, E. T., Brammer, M. J., Williams, S. C., Broome, M. R., Murray, R. M. and McGuire, P. K. (2001a) ‘Differential activation of temporal cortex during sentence completion in schizophrenic patients with and without formal thought disorder’, Schizophrenia Research, 50: 27–40. Kircher, T. T., Liddle, P. F., Brammer, M. J., Williams, S. C., Murray, R. M. and McGuire, P. K. (2001b) ‘Neural correlates of formal thought disorder in schizophrenia: Preliminary findings from a functional magnetic resonance imaging study’, Archives of General Psychiatry, 58: 769–74. Kircher, T. T., Liddle, P. F., Brammer, M. J., Williams, S. C., Murray, R. M. and McGuire, P. K. (2002) ‘Reversed lateralization of temporal activation during speech production in thought disordered patients with schizophrenia’, Psychological Medicine, 32: 439–49. Kircher, T. T., Oh, T. M., Brammer, M. J. and McGuire, P. K. (2005) ‘Neural correlates of syntax production in schizophrenia’, British Journal of Psychiatry, 186: 209–14. Kubicki, M., McCarley, R., Westin, C. F., Park, H. J., Maier, S., Kikinis, R., Jolesz, F.

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A. and Shenton, M. E. (2007) ‘A review of diffusion tensor imaging studies in schizophrenia’, Journal of Psychiatric Research, 41: 15–30. Kuperberg, G. R. (2010a) ‘Language in schizophrenia Part 1: An introduction’, Language and Linguistics Compass, 4: 576–89. Kuperberg, G. R. (2010b) ‘Language in schizophrenia Part 2: What can psycholinguistics bring to the study of schizophrenia . . . and vice versa?’, Language and Linguistics Compass, 4: 590–604. Kuperberg, G. R., West, W. C., Lakshmanan, B. M. and Goff, D. (2008) ‘Functional magnetic resonance imaging reveals neuroanatomical dissociations during semantic integration in schizophrenia’, Biological Psychiatry, 64: 407–18. Lahti, A. C., Weiler, M. A., Holcomb, H. H., Tamminga, C. A., Carpenter, W. T. and McMahon, R. (2006) ‘Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia’, Neuropsychopharmacology, 31: 221–30. Leube, D., Whitney, C. and Kircher, T. (2008) ‘The neural correlates of egodisturbances (passivity phenomena) and formal thought disorder in schizophrenia’, European Archives of Psychiatry and Clinical Neuroscience, 258: 22–7. Levy, D. L., Coleman, J. E., Sung, H., Ji, F., Matthysse, S., Mendell, N. R. and Titone, D. (2010) ‘The genetic basis of thought disorder and language and communication disturbances in schizophrenia’, Journal of Neurolinguistics, 23: 176. Liddle, P. F. (1987) ‘The symptoms of chronic schizophrenia. A re-examination of the positive–negative dichotomy’, British Journal of Psychiatry, 151: 145–51. Liddle, P. F., Friston, K. J., Frith, C. D., Hirsch, S. R., Jones, T. and Frackowiak, R. S. (1992) ‘Patterns of cerebral blood flow in schizophrenia’, British Journal of Psychiatry, 160: 179–86. Lopez-Garcia, P., Aizenstein, H. J., Snitz, B. E., Walter, R. P. and Carter, C. S. (2006) ‘Automated ROI-based brain parcellation analysis of frontal and temporal brain volumes in schizophrenia’, Psychiatry Research, 147: 153–61. MacDonald, A. W. 3rd, Carter, C. S., Kerns, J. G., Ursu, S., Barch, D. M., Holmes, A. J., Stenger, V. A. and Cohen, J. D. (2005) ‘Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis’, American Journal of Psychiatry, 162: 475–84. McGuire, P. K., Quested, D. J., Spence, S. A., Murray, R. M., Frith, C. D. and Liddle, P. F. (1998) ‘Pathophysiology of ‘positive’ thought disorder in schizophrenia’, British Journal of Psychiatry, 173: 231–5. McKenna, P. J. and Oh, T. M. (2005) Schizophrenic Speech: Making Sense of Bathroots and Ponds that Fall in Doorways, Cambridge: Cambridge University Press. Nakamura, M., Nestor, P. G., Levitt, J. J., Cohen, A. S., Kawashima, T., Shenton, M. E. and McCarley, R. W. (2008) ‘Orbitofrontal volume deficit in schizophrenia and thought disorder’, Brain, 131: 180–95. Nenadic, I., Sauer, H. and Gaser, C. (2010) Distinct pattern of brain structural deficits in subsyndromes of schizophrenia delineated by psychopathology, NeuroImage, 49: 1153–60. Ngan, E. T., Vouloumanos, A., Cairo, T. A., Laurens, K. R., Bates, A. T., Anderson, C. M., Werker, J. F. and Liddle, P. F. (2003) ‘Abnormal processing of speech during oddball target detection in schizophrenia’, NeuroImage, 20: 889–97. Rotarska-Jagiela, A., van de Ven, V., Oertel-Knochel, V., Uhlhaas, P. J., Vogeley, K. and Linden, D. E. (2010) ‘Resting-state functional network correlates of psychotic symptoms in schizophrenia’, Schizophrenia Research, 117: 21–30.

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Schroder, J., Buchsbaum, M. S., Siegel, B. V., Geider, F. J., Lohr, J., Tang, C., Wu, J. and Potkin, S. G. (1996) ‘Cerebral metabolic activity correlates of subsyndromes in chronic schizophrenia’, Schizophrenia Research, 19: 41–53. Shenton, M. E., Kikinis, R., Jolesz, F. A., Pollak, S. D., LeMay, M., Wible, C. G., Hokama, H., Martin, J., Metcalf, D. and Coleman, M. (1992) ‘Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study’, New England Journal of Medicine, 327: 604–12. Snitz, B. E., MacDonald, A. 3rd, Cohen, J. D., Cho, R. Y., Becker, T. and Carter, C. S. (2005) ‘Lateral and medial hypofrontality in first-episode schizophrenia: Functional activity in a medication-naïve state and effects of short-term atypical antipsychotic treatment’, American Journal of Psychiatry, 162: 2322–9. Solovay, M. R., Shenton, M. E., Gasperetti, C., Coleman, M., Kestnbaum, E., Carpenter, J. T. and Holzman, P. S. (1986) ‘Scoring manual for the Thought Disorder Index’, Schizophrenia Bulletin, 12: 483–96. Ventura, J., Thames, A. D., Wood, R. C., Guzik, L. H. and Hellemann, G. S. (2010) ‘Disorganization and reality distortion in schizophrenia: A meta-analysis of the relationship between positive symptoms and neurocognitive deficits’, Schizophrenia Research, 121: 1–14. Vita, A., Dieci, M., Giobbio, G. M., Caputo, A., Ghiringhelli, L., Comazzi, M., Garbarini, M., Mendini, A. P., Morganti, C. and Tenconi, F. (1995) ‘Language and thought disorder in schizophrenia: Brain morphological correlates’, Schizophrenia Research, 15: 243–51. Yoon, J. H., Minzenberg, M. J., Ursu, S., Ryan Walter, B. S., Wendelken, C., Ragland, J. D. and Carter, C. S. (2008) ‘Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: Relationship with impaired cognition, behavioral disorganization, and global function’, American Journal of Psychiatry, 165: 1006–14.

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Brain structural abnormalities, social function and psychopathology in schizophrenia Jaya Padmanabhan, Christine I. Hooker and Matcheri S. Keshavan

Despite over a century of painstaking work, the pathophysiological substrate of schizophrenia remains poorly elucidated. The lack of progress in our understanding the neurobiological basis of this illness is partly related to uncertainty in its clinical boundaries; the question of what precisely constitutes schizophrenia has been a matter of debate, and different theorists have varied about its “core” disturbance. In the early twentieth century, Emil Kraepelin believed that the unifying aspects of this illness are its chronicity and declining course (Tandon et al. 2009). Eugene Bleuler (1911) argued that the central feature of this illness is the “splitting “ of mental functions, which leads to a tetrad of symptoms, including disturbance of association, disturbance of affect, autism (social withdrawal) and ambivalence. Kurt Schneider (1959), who considered the fundamental disturbance in schizophrenia to be one of ego boundaries, proposed a set of “first rank” symptoms, such as passivity phenomena, representing self–other boundary diffusion. The World Health Organization International Classification of Diseases (ICD; www.who.int/classifications/icd/en) and the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM; www.psychiatry.org/practice/dsm) used a combination of these cross-sectional and longitudinal clinical features to create a definition of schizophrenia for widespread use in clinical practice. While the DSM classification has improved diagnostic reliability, the validity of the schizophrenia construct remains poor, owing to heterogeneity within the illness, and substantive symptomatic and etiological overlap with related disorders (Tandon et al. 2009). A critical step in resolving the heterogeneity of schizophrenia is to understand the relationships between neurobiology and symptoms (Keshavan et al. 2011). This chapter reviews relationships between brain structural alterations and psychopathology in schizophrenia, including positive and negative symptom dimensions, hallucinations, delusions, and thought disorder. We also discuss associations between social function and brain structure. While multiple imaging modalities have offered insight into structure–symptom correlations, we focus on structural magnetic resonance imaging (MRI) and gray matter volume (GMV).

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Psychopathology and brain structure Meta-analyses have indicated a number of regional structural abnormalities in schizophrenia. These include enlargement in the ventricles and reductions in aspects of the frontal lobe, temporal lobe, hippocampus, insula, and cingulate gyrus (Shepherd et al. 2012). The relevance of these reductions to psychopathology has been frequently investigated, with various methodologies and results. Despite this heterogeneity, some notable patterns have emerged. Pos it ive s y mpt oms The positive symptom dimension includes hallucinations and delusions, and frequently incorporates thought disorder and bizarre behavior. Assessment of positive symptoms is done using the Scale for the Assessment of Positive Symptoms, the Positive and Negative Syndrome Scale positive subscale, or a positive symptom dimension derived from factor analysis of other scales. Meta-analyses have suggested the presence of small whole-brain volume reductions in schizophrenia (Shepherd et al. 2012). However, whole-brain volumes or total cortical GMV have generally not correlated with severity of the positive symptom dimension (Fannon et al. 2000; Sapara et al. 2007). Lateral ventricular enlargement, a well-replicated finding in schizophrenia (Shepherd et al. 2012), has not consistently correlated with positive symptom severity (Flaum et al. 1995; Fannon et al. 2000). The temporal lobe has been a focus of neuroimaging research in schizophrenia, owing to its involvement in language and auditory processing (see also Chapter 4). Volumetric reductions are seen in temporal lobe structures, particularly the superior temporal gyrus (STG) (Brodmann areas 22, 41, and 42; Shepherd et al. 2012; see Figure 7.1). The STG consists of the primary auditory cortex, which includes Heschl’s gyrus, the secondary auditory cortex, and the planum temporale. Positive symptoms as a dimension inversely correlate with the left STG (Sun et al. 2009; Nesvag et al. 2009) but less consistently with the right STG (Lui et al. 2009). The association between the positive symptom dimension and STG volume likely reflects the involvement of this region in hallucinations and thought disorder. The left-sided predominance of this association is consistent with the lateralization of language function. Medial temporal structures, such as the hippocampus and amygdala, are involved in memory consolidation, learning, and emotional processing. Reduction of the hippocampal–amygdalar complex in schizophrenia is consistently seen (Tamminga et al. 2010). In one compelling theory, hippocampal dysfunction could lead to false pattern completion, eventually giving rise to unusual thought content and impaired reality-testing (Tamminga et al. 2010). However, findings on hippocampal volume and positive symptom severity are inconsistent, with reports of no correlation and inverse correlations between the two (Kühn et al. 2012; Rajarethinam

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et al. 2001; Sallet et al. 2003; Molina et al. 2003). Most recently, Brambilla et al. (2013) found that hippocampal deflation, as measured by reduced hippocampal radial distance, correlated with increased positive symptom severity. Regional frontal lobe volume reductions in schizophrenia have also been identified frequently (Shepherd et al. 2012). Regions such as the inferior frontal gyrus, which includes Broca’s area, and the orbitofrontal cortex could contribute to psychopathology, given their role in emotional processing, language and social cognition. However, correlations between frontal subregions and the positive symptom dimension are heterogeneous. Several studies reported no correlation between severity of the positive symptom dimension and GMV of the orbitofrontal cortex and inferior frontal gyrus (Choi et al. 2005; Crespo-Facorro et al. 2000a; Lacerda et al. 2007). In contrast, other studies demonstrated inverse correlations between the positive symptom dimension and Brodmann area 45 within the inferior frontal gyrus (Suga et al. 2010), or the straight gyrus (Nesvag et al. 2009). The insula, a region located bilaterally in the lateral sulcus between the temporal and frontal lobes, is involved in somatosensory perception, interoceptive awareness of bodily states, salience detection (Kapur 2003) and emotional perception (Adolphs 2009). Dysfunction of the salience network, which consists of the insula and anterior cingulate, is believed to underlie referential thinking and other psychopathology. Multiple studies indicate insular reductions in schizophrenia (Palaniyappan et al. 2011). Individual studies have reported both inverse correlations and lack of correlation between the positive symptom dimension and insular GMV (Palaniyappan et al. 2011; Kasai et al. 2003; Kim et al. 2003; Crespo-Facorro et al. 2000b). However, as will be discussed, insular reductions correlate more strongly with hallucinations specifically (Palaniyappan et al. 2012). Reductions in anterior cingulate cortex, critically involved in executive function, emotional processing, and salience (Choi et al. 2005), have been observed in meta-analyses (Bora et al. 2011; Shepherd et al. 2012). In functional MRI and single-photon emission computed tomography (SPECT) studies of subjects at rest, altered blood flow and activation in the cingulate cortex correlate with positive symptoms (Choi et al. 2005). Again, however, both inverse volumetric correlations and lack of correlation with the positive symptom dimension have been reported (Lui et al. 2009; Choi et al. 2005; Palaniyappan et al. 2011; Crespo-Facorro et al. 2000b; Hazlett et al. 2008). Variability in subject characteristics and methodology may account for the diversity of findings. Thought disorder and disorganization The disorganized symptom dimension includes formal thought disorder, bizarre behavior, and inappropriate affect. Several studies have examined thought disorder, either with specialized assessment tools such as the

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Thought Disorder Index or items on general psychopathology scales (see also Chapter 7). Multiple studies on thought disorder have focused on the STG, owing to its presumed involvement in language. Overall, the literature supports an inverse association between left STG GMV and thought disorder, although the association is less consistent than it is for hallucinations (Sun et al. 2009; Horn et al. 2010). Additionally, electrophysiological and functional MRI studies have associated thought disorder with reduced P300 amplitude and altered activation in the temporal lobe (Sun et al. 2009; Weinstein et al. 2007). Volumetric reductions and loss of the normal asymmetry of the planum temporale have also been correlated with thought disorder (Weinstein et al. 2007). While the STG and planum temporale are known to be involved in language, it is unclear what specific aspects of thought disorder correlate with these brain regions (Weinstein et al. 2007; Allen et al. 2012). Results regarding the frontal lobe are varied. Thought disorder did not correlate with the prefrontal GMV as a whole (Wible et al. 2001), but inversely correlated with the orbitofrontal cortex in some studies (Horn et al. 2010). Studies examining the disorganized dimension have reported inverse correlations with the inferior frontal gyrus (Suga et al. 2010), or the straight gyrus (Nesvag et al. 2009). The limited data on the hippocampus, insula and anterior cingulate cortex have not yet indicated consistent correlations with thought disorder or disorganization (Molina et al. 2003; Crespo-Facorro et al. 2000b; Lui et al. 2009; Flaum et al. 1995). Some of the inconsistency in the structural literature may be due to the use of different clinical assessment methods. Studies that used more sensitive measures of thought disorder, such as the Thought Disorder Index, tended to find structural correlations more often than studies that used single items on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale. Hallucinations Numerous studies have reported an inverse correlation between hallucination severity and GMV of the left STG (Sun et al. 2009; Palaniyappan et al. 2012), or the left Heschl’s gyrus (Neckelmann et al. 2006; Modinos et al. 2012). The association of hallucinations with reductions in the left STG is one of the most consistent and well-substantiated findings in the literature on structure–symptom correlations. Even so, several studies found no correlation with this region (see Palaniyappan et al. 2012 for a review). Evidence for correlations with the right STG is more equivocal, with fewer studies observing inverse correlations (Sun et al. 2009; Matsumoto et al. 2001). Notably, two recent meta-analyses of voxel-based morphometry studies reported inverse correlations between hallucination severity and GMV of the right and left STG, respectively (Palaniyappan et al. 2012; Modinos et al. 2013).

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Structural studies on the STG corroborate findings from functional MRI and SPECT studies showing increased activity and blood flow in this region during hallucinations (Allen et al. 2012). The reductions in STG volume may reflect neuropathological alterations such as reduced dendritic spine density, which in turn impact synaptic connectivity (Neckelmann et al. 2006). Indeed, there is evidence of decreased synapse density in Brodmann area 41 in post-mortem brains of schizophrenia patients (Sweet et al. 2007). These neuropathological changes may underlie functional alterations in auditory processing. For instance, aberrant activation of these regions could lead to the generation of auditory perceptions in the absence of stimuli (Allen et al. 2012). The insula also shows a fairly consistent inverse correlation with severity of auditory hallucinations (Palaniyappan et al. 2012). In combination with altered auditory processing, insular dysfunction could result in the misattribution of internally generated thoughts to external sources. As suggested by the self-monitoring hypothesis, this misattribution may form the core basis of the experience of hallucinations (Frith and Done 1988). Evidence is weak for correlations between hallucinations and volumes of the hippocampus, amygdala, or lateral prefrontal cortex (Rajarethinam et al. 2001). However, both inverse and direct correlations have been reported with the inferior frontal gyrus, which includes Broca’s region (Palaniyappan et al. 2012; Modinos et al. 2009). Structural MRI studies on hallucinations are limited by the fluctuation in hallucinations over time. Rather than assessing hallucinations at one time point, it may be more informative to compare subjects with severe chronic hallucinations to those without them (Allen et al. 2012). As with thought disorder, more research is needed to elucidate what phenomenological components of hallucinations correlate with brain structure. Delusions Delusions have been investigated less extensively than hallucinations, and findings are contradictory. Volumes of the STG and the planum temporale have not shown consistent relationships with delusions (Sun et al. 2009; Menon et al. 1995; Sumich et al. 2005). However, a longitudinal study of subjects at high risk of psychosis found that GMV loss in the STG correlated with conversion to psychosis and increased severity of delusions (Takahashi et al. 2009). Inverse, direct, and lack of correlation with frontal regions have been reported (Suga et al. 2010; Whitford et al. 2009; Lacerda et al. 2007). Inverse correlations with the insula and hippocampus have also been observed (Cascella et al. 2011; Sallet et al. 2003). Inconsistencies in results may be due to variability of fine-grained assessment of delusions in the clinical assessment tools.

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Summary Reductions in STG GMV are correlated with positive symptom severity. Evidence is most robust for inverse correlations between STG GMV and severity of hallucinations and thought disorder. Insular GMV also appears inversely correlated with hallucination severity. Evidence is inconsistent regarding correlations with frontal subregions, the cingulate cortex, or hippocampus. Further investigation may integrate structural findings with data from other modalities, such as functional imaging and neuropathology, to achieve a clearer understanding of the pathophysiology of positive symptoms. Negat ive s y mpt oms Negative symptoms, which include alogia (poverty of speech), anhedonia/asociality, attentional impairment, affective flattening, and avolition/apathy (Andreasen 1985), account for much of the psychosocial morbidity of schizophrenia. While many studies have taken a dimensional correlation approach, other studies divided patients into “deficit syndrome” and “non-deficit syndrome” groups based on presence of enduring negative symptoms, and then contrasted the two groups. The frontal lobe has been a focus of research on the negative symptom dimension, owing to its role in goal-directed behavior and executive function. Reductions of the prefrontal cortex have been associated with increased negative symptom severity (Wible et al. 2001; Baare et al. 1999). More specifically, reductions in GMV of the orbitofrontal cortex and inferior frontal gyrus have correlated with negative symptom severity (Benoit et al. 2012; Baare et al. 1999; Bora et al. 2011). A meta-analysis of 79 voxelbased morphometry studies of schizophrenia found that negative symptom severity correlated inversely with GMV in the bilateral medial frontal gyrus (Brodmann’s areas 6, 8, 9) (Bora et al. 2011). Additionally, several studies observed correlations between negative symptom severity and reductions in GMV of the dorsolateral prefrontal cortex or superior frontal gyrus (Hazlett et al. 2008; Venkatasubramanian 2010; Cascella et al. 2010). However, other studies found direct correlations or no correlation with volumes of these regions (Volpe et al. 2012; Crespo-Facorro et al. 2000a; Galderisi et al. 2008). Several studies reported inverse volumetric relationships between anterior cingulate cortex GMV and negative symptoms, while others found no correlation (Hazlett et al. 2008; Choi et al. 2005; Galderisi et al. 2008; Crespo-Facorro et al. 2000a; Venkatasubramanian 2010; Cascella et al. 2010). The meta-analysis by Bora et al. (2011) reported an inverse correlation between negative symptom severity and left insula GMV, but most individual studies did not find such a correlation (Kasai et al. 2003, Kim et al. 2003, Crespo-Facorro et al. 2000b; Cascella et al. 2010).

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Whole-brain volume, ventricles and substructures generally are not correlated with negative symptom severity, with the exception of some studies reporting direct relationships with ventricular volumes (Fannon et al. 2000; Sapara et al. 2007; Benoit et al. 2012; Galderisi et al. 2008; Flaum et al. 1995). Most studies found no correlation between the STG and negative symptom severity (Lui et al. 2009; Onitsuka et al. 2004; Hazlett et al. 2008). These results suggest a specificity of the STG for positive symptoms. Hippocampal volumes have not correlated with the negative symptom dimension in most studies (Molina et al. 2003; Galderisi et al. 2008; Volpe et al. 2012; Kühn et al. 2012), with some exceptions (Brambilla et al. 2013). Summary Evidence favors an association between negative symptom severity and reductions in frontal subregions, particularly the orbitofrontal cortex and inferior frontal gyrus. Studies splitting subjects into “deficit” and “nondeficit” groups found structural relationships more often than studies pursuing a correlational approach, perhaps due to increased symptom stability among subjects across time. Findings are less robust for this symptom dimension than for positive symptoms, and should be corroborated via meta-analysis or larger-scale studies.

Neural structure and social function Functional disability is a diagnostic criteria of schizophrenia and yet little is known about its underlying neural substrates. Progress has been hindered by ill-defined criteria for disability, assessments that cover multiple domains of functioning, and measures of functional attainment (such as employment) that are influenced by environmental factors unrelated to the disease process. To gain traction on structure–function relationships, it is crucial to isolate and accurately measure the aspects of functioning that are most connected to the biologically based vulnerability and development of schizophrenia. Research indicates that deficits in social functioning are a core aspect of schizophrenia pathology and have the largest impact on functional outcome (Addington and Addington 2008). Interacting successfully with others depends on multiple social cognitive skills, including emotion recognition, emotion regulation, and theory of mind. These skills are supported by well-characterized networks of brain regions. One such network includes the dorsomedial and ventromedial prefrontal cortex, posterior superior temporal cortex, anterior cingulate cortex, and posterior cingulate cortex (Carrington and Bailey 2009). Another network is involved in emotion processing and includes the amygdala, insula, inferior parietal cortex, and orbitofrontal cortex (Adolphs 2009). Although neural regions that support cognition, such as the dorsolateral prefrontal cortex,

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are not considered crucial components of social brain networks, deficits in these regions can impact the processing of social and emotional information. The characterization of these networks in healthy adults provides the foundation for targeted hypotheses and informed interpretation regarding the neural basis of social dysfunction in schizophrenia. Recent research emphasizes neural regions that predict clinically based outcome measures as well as neural substrates related to the social–cognitive skills supporting long-term outcomes. The Global Assessment of Functioning (GAF) scale is a common clinically based tool for characterizing functioning. The scale reflects social and occupational functioning as well as symptom severity, and can be easily administered by clinicians. However, the inclusion of multiple domains of functioning creates a noisy, imprecise measure, decreasing ability to find relationships with specific brain regions. Nonetheless, cross-sectional and longitudinal studies indicate that schizophrenia patients with lower GAF scores have less GMV in regions associated with social and emotional processing, including the medial prefrontal cortex, superior temporal cortex, posterior cingulate cortex, insula, and dorsolateral prefrontal cortex (Mané et al. 2009; Mitelman et al. 2005; Prasad et al. 2005). Recent longitudinal studies highlight the role of the medial prefrontal cortex and superior temporal cortex. Five years after first episode, schizophrenia patients with low GAF compared with high GAF scores had less cortical thickness in the superior temporal cortex (including the STG and Heschl’s gyrus). Cortical thickness in the STG was also correlated to a composite measure of functioning across all subjects (van Haren et al. 2011). Another study found that, one year after the first episode of psychosis, schizophrenia patients with low functioning had less ventromedial prefrontal cortex GMV (including the orbitofrontal cortex and frontal pole; Brodmann areas 10, 11) compared with those with high functioning. The poor outcome group also had less ventromedial prefrontal cortex GMV at baseline even though there were no group differences on baseline clinical and functional measures (Kasparek et al. 2009). Thus, structural deficits may more sensitively predict outcome than clinical/behavioral measures. Studies on neural correlates of specific social deficits measured by clinician-ratings, self-report, or laboratory-based social cognition tasks, confirm the importance of ventromedial prefrontal cortex and superior temporal cortex in supporting successful social behavior. In a region-of-interest study, GMV in the ventromedial prefrontal cortex (including the orbitofrontal cortex and straight gyrus) predicted clinician-rated premorbid social adjustment and post-onset quality and quantity of interpersonal relationships (Chemerinski et al. 2002). Another study found a correlation (looking across the whole brain) between left superior temporal sulcus GMV and self-reported ability to read social cues during conversations (Sasamoto et al. 2011). Hooker et al. (2011) found that, among schizophrenia patients, ventromedial prefrontal cortex GMV was related to three

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different measures of theory of mind: 1) ability to recognize and understand social faux pas; 2) self-reported perspective-taking in daily life; and 3) clinician-rated capacity to understand different perspectives and affective states in social relationships. Several studies have also shown a relationship between volume of the ventromedial prefrontal cortex, including the anterior cingulate cortex, and ability to label emotional states as well as to infer a person’s emotional response from a description of a social situation (Fujiwara et al. 2007; Yamada et al. 2007). Lower GMV in the superior temporal cortex is also related to poor theory of mind skills (Benedetti et al. 2009; Hooker et al. 2011). Medial temporal lobe structures are also involved in emotion processing, especially emotion recognition. Schizophrenia is associated with reduced GMV in the medial temporal lobes, as well as poor emotion recognition. Accordingly, abnormally low amygdala volume in schizophrenia patients is associated with worse facial emotion recognition (Namiki et al. 2007). Among people in early-course schizophrenia, those with worse performance on the Mayer-Salovery-Caruso Emotional Intelligence Test, a measure of emotion processing, had reduced gray matter density in the left parahippocampal gyrus, and lower gray matter density in both the parahippocampal gyrus and posterior cingulate was related to worse performance (Wojtalik et al. 2013). Summary Collectively, these studies indicate that investigating the relationship between neural structure and specific social processes provides insight into core components of social functioning. Thus far, evidence supports an association between social cognition in schizophrenia and GMV of the ventromedial prefrontal cortex, anterior cingulate cortex and superior temporal cortex. Additional longitudinal studies are necessary to confirm which social cognition skills mediate the relationship between neural structure and long-term functional outcome.

Conclusions and future directions The findings on structure–symptom correlations are heterogeneous for multiple reasons. First, studies varied widely in the demographic and clinical characteristics of subject populations. Factors such as age, duration of illness, gender, and medication status could all independently affect brain structure or psychopathology, thus influencing structure–symptom correlations (Figure 8.1). Second, studies used different imaging methodologies. Region-of-interest approaches involve hypothesis-driven selection of regions, while voxel-based morphometry can uncover unexpected associations. Imaging techniques, such as slice thickness and resolution, could also affect detection of structural changes. In addition,

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~ :~:::? illness duration

Figure 8.1 Confounding factors affecting correlations between brain structure and psychopathology

choice of clinical assessment tools could impact sensitivity to symptoms, with fine-grained symptom-specific tools detecting more psychopathology than single items on general assessment scales. Studies also differed in analytic design. Some chose a correlational approach between structure and symptom severity, while others divided subjects into groups based on psychopathology and compared structure between groups. Lastly, the current literature is limited by small sample sizes, with most studies using fewer than 50 subjects. Despite such variability, some findings emerge repeatedly in this literature. These include associations between STG and positive symptoms, between frontal subregions and negative symptoms, and between the ventromedial prefrontal cortex and social cognition. These results suggest that the psychopathology of schizophrenia may be related to abnormalities in a network of brain regions involving primarily the STG, ventromedial and orbital prefrontal cortex, and other areas (e.g. insula, cingulate cortex). Functional, electrophysiological, and neuropathological data are consistent with structural findings, further implicating this network of regions in the core psychopathology and social deficits of schizophrenia. The literature on structure–symptom and structure–function correlations will be relevant to the development of biologically based nosology systems (Keshavan et al. 2011). Future studies could explore whether structure–symptom correlations are generalizable to the spectrum of psychosis. Specific associations, such as the correlation between hallucinations and the STG, could potentially be mapped to genes to derive diagnostic subgroups. These groups could then be linked to clinical measures such as outcome and treatment response, thus developing predictive biomarkers. This line of investigation is important considering that the present diagnostic system is limited by classifications that do not consider the biological

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etiology of symptoms, leading to overlap across diagnoses and the heterogeneity within diagnoses. Potential biomarkers show a lack of specificity when correlated with current diagnostic categories, because the symptombased categories lack biological validity. To move towards a biologically based classification system, it will be crucial to investigate symptom–biology correlations in large data sets of phenotypically diverse subjects. Using data-driven techniques agnostic to diagnosis, correlated biological features can be clustered together and then validated against other clinical measures. Such an approach will enable the development of a classification system that will be more clinically effective for the diagnosis and treatment of psychotic disorders.

Acknowledgements This work was supported in part by NIMH grant MH 78113 (MSK).

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Part III

Psychopathology and schizophrenia

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9

Thought, hallucinations and schizophrenia Gemma Modinos and Philip McGuire

Hallucinations are a hallmark symptom of schizophrenia. Although they can occur in the auditory, visual, olfactory, gustatory and somatosensory modalities, approximately 70% of individuals diagnosed with schizophrenia report hallucinations in the auditory modality (Andreasen and Flaum 1991). Auditory hallucinations can occur in the context of a wide range of psychiatric disorders, but their prevalence is highest in patients with schizophrenia (American Psychiatric Association 2000). The present chapter focuses on auditory hallucinations in schizophrenia. Research findings on hallucinatory experiences in other disorders and in healthy individuals have been recently synthesized elsewhere and will not be covered here (Jardri et al. 2013; Blom and Sommer 2012).

Cognition Auditory hallucinations are defined as auditory perceptions that resemble a veridical perception but are experienced in the absence of a corresponding external stimulation. Different explanations have been proposed to account for the different phenomenological features of auditory hallucinations, each potentially representing a particular circuitry of brain structures and functions. The most recent model of auditory hallucinations in schizophrenia (Waters et al. 2012) postulates that they arise from abnormal activation in brain networks involved in auditory processing (see Chapter 4), and disrupted interactions between these networks and cognitive processes that include deficits in signal detection and inhibition, top-down influences, and emotional processing. An overview of brain abnormalities associated with auditory hallucinations is provided later in this chapter. The model proposed by Waters et al. (2012) focuses on the idea that auditory hallucinations are essentially perceptions induced by an interaction between information arising from neural activity and top-down activity. It is proposed that auditory hallucinations are formed at different stages, instantiated at different neuroanatomical locations: (i) abnormal signals in sensory regions; (ii) top-down cognitive deficits in self-/source monitoring,

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signal detection and inhibitory control; (iii) and a contribution of emotions. A bnormal s ignals in s ens ory regions Salient auditory stimuli are thought to provide the basic signal for auditory hallucinations (the source). This is thought to arise from hyperactivation in functional networks involving the auditory cortex that generate aberrant auditory signals, possibly due to a deviant trigger of activations in languagerelated areas responsible for auditory hallucinations. Anomalous activations might be determined by environmental factors and/or internal (e.g. emotional) conditions. These anomalous neural activations may induce auditory signals that exceed the perceptual threshold, thereby causing unexpectedly salient sensory information. Specific forms of inner speech, or intrusive memories, may be particularly more likely to become an auditory hallucination and may account for some of its verbal and phenomenological properties. Top- dow n cognit ive deficit s in s elf- /s ource monit oring, s ignal det ect ion and inhibit ory cont rol Signal detection deficits increase the detection of ambiguous or salient signals and suppose an increased tendency to accept the salient signal as veridical. Deficient intentional inhibition cognitive mechanisms fail to suppress such information, which becomes functionally autonomous. This would contribute to the failure to control the onset and frequency of these salient auditory signals. Over time, expectations and hypervigilance over these experiences would increase the likelihood of them being repeated, increasing cognitive/perceptual biases and reducing the threshold to accepting the signal as veridical. Cont ribut ion of emot ions The meaning of auditory hallucinations is determined by state and trait characteristics that influence how these experiences are interpreted. The presence of reduced insight, delusional beliefs, negative beliefs about the self and about the world, and negative emotion, can all combine to produce a complex and elaborate system of beliefs around the hallucination. Emotion may play a particularly prominent role at all levels of hallucination formation (source, form, content, and meaning), and it may also provide the first traumatic insult in this ontogeny (Varese et al. 2012). The source of auditory hallucinations may be influenced by emotional content associated to trauma, and other intense negative emotions, increasing neural response and resulting in aberrant auditory signals. In addition,

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auditory hallucinations may play a role in determining the content of the auditory signals, as emotional and personally salient material is preferentially processed over neutral information. At this level, as proposed by Waters et al. (2012), emotion may produce attentional biases toward negative information, hypervigilance, and negative schemas that may further reinforce the processing and recall of emotionally charged material. Over time, this can influence higher-order aspects such as the beliefs attributed to the voices (e.g. benevolence or malevolence). In summary, auditory hallucinations are conceptualized as arising from interactions between hypersalient auditory sensory signals and top-down cognitive processing deficits involving error processing, cognitive control, and prior knowledge/experience, which may shape the form and content of the voices. Emotional processing plays a prominent role in this chain of events, with an impact at all levels of processing (e.g. an initial traumatic insult can create a vulnerability for experiencing auditory hallucinations, as well as determining the meaning attributed to the voices by influencing insight and belief systems). Finally, individual differences in the severity and localization of abnormal neural activity may determine the observed phenomenological variations, such that different combinations result in the many subtypes of auditory hallucinations (Jones 2010).

Neurobiology Significant strides have been made in recent years in hallucination research, with the neuroscientific contribution to psychopathology being fuelled by brain imaging techniques such as magnetic resonance imaging (MRI). Brain imaging methods provided exciting opportunities such as imaging patients with schizophrenia while they were experiencing hallucinations inside the scanner (e.g. McGuire et al. 1993), and investigating more fine-grained features such as the neural correlates of the loudness or vividness of the voices (e.g. Vercammen et al. 2011). Especially in the 1990s–2000s, neuroimaging techniques have been intensively applied with the aim to uncover the neural underpinning of hallucinations in schizophrenia. This section elaborates on the findings produced by these studies, covering structural and functional imaging studies of auditory hallucinations in schizophrenia. We show that, although early studies established the subsequently extensively replicated finding of auditory hallucinations being associated with differences in cortical areas responsible for auditory perception (i.e. primary and secondary auditory cortex, portrayed in Figure 9.1) and speech output (i.e. inferior frontal gyrus, anterior insular cortex; Allen et al. 2008), additional changes in a range of other cortical and subcortical regions have also been reported, with abnormalities currently being conceptualized as occurring at a network level.

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(2) (1) (2)

(1)

Figure 9.1 The most consistently reported areas of abnormalities in studies of auditory hallucinations in schizophrenia comprise the left superior temporal gyrus (1) and the left middle temporal gyrus (2). The images depict the anatomical landmarks of these regions on the axial (left), and rendered views (right). Images have been prepared with anatomically predefined masks using the WFU_PickAtlas Software in SPM8, overlaid on a standard brain template with MRICron

Structural MRI In neurological diseases, hallucinations are commonly associated with evident anatomic lesions, typically located in the brain pathway of the sensory modality involved in the hallucination (Allen et al. 2008; Braun et al. 2003). In schizophrenia patients with hallucinations, no gross structural deficit can be distinctively observed at the individual level. Nevertheless, group-level analyses comparing patients with and without hallucinations, or correlation analyses between severity of hallucinations and brain structure, show subtle but robust variations in association with auditory hallucinations in this group. Of particular relevance are volume reductions in the superior (STG) and middle temporal gyri, predominantly on the left hemisphere, which have been repeatedly implicated in auditory hallucinations in schizophrenia across different imaging modalities. Group-level analysis of structural brain images was initially performed with a region-of-interest approach. These early studies mainly reported volume reductions in the STG and increased lateral ventricles. More recently, voxel-based morphometry (VBM), a whole-brain, unbiased, semiautomated technique for characterizing regional cerebral differences with structural MRI (Ashburner and Friston 2000; Mechelli et al., 2005) has been applied to investigate structural abnormalities associated with

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auditory hallucinations at the whole-brain level. A recent meta-analysis was conducted on the nine studies available to date, which had used VBM to specifically examine gray matter abnormalities in patients with schizophrenia (Modinos et al. 2013). The “severity” of auditory hallucinations was found to be associated with gray matter reductions in the STG bilaterally, including Heschl’s gyrus, which is primary auditory cortex (Figure 9.2, lower panel). Left superior temporal areas are known to be involved in speech perception, particularly in the comprehension of the phonological and semantic characteristics of speech. A subthreshold effect was also reported in the right STG, thought to be involved in auditory and language processing, particularly of the emotional and prosodic aspect of speech stimuli (Downar et al. 2000). These findings suggest that structural aberrations within neural systems involved at different levels of language processing are critical to auditory hallucinations in patients with schizophrenia. Aside from the meta-analytical results, single VBM studies have also documented significant effects of auditory hallucinations in nonsensory regions, including the insula, anterior cingulate, posterior cingulate, and inferior frontal gyrus, thalamus, cerebellum, and precuneus (Allen et al. 2008). These studies demonstrate that volumetric changes in regions within a wider network than that involved in speech and language processing are also associated with auditory hallucinations.

Functional MRI Functional imaging procedures developed to examine neural correlates of auditory hallucinations can be conceptually classified into two main study categories. Firstly, cognitive “trait” studies are designed to investigate the neural bases of the susceptibility to hallucinate, independent of the subjects’ experience during scanning, by comparing hallucinators and non-hallucinators during a specific functional MRI paradigm. Secondly, “state” studies are designed to directly measure brain activation associated with the occurrence of auditory hallucinations. “State” studies have widely implicated the recruitment of the secondary auditory cortex during auditory hallucinations, which has been recently supported by a coordinate-based meta-analysis of functional MRI studies in auditory hallucinations (Jardri et al. 2011). This meta-analysis included ten functional imaging studies investigating state activation during auditory hallucinations, and evidenced that hallucinators showed increased activation likelihoods in a distributed bilateral frontotemporal network, including Broca’s area, anterior insula, precentral gyrus, frontal operculum, middle and STGs, inferior parietal lobule, hippocampus, and parahippocampal region (Figure 9.2, upper panel). These findings emphasize the involvement of a disrupted network of frontal language production and temporo-parietal language perception areas in auditory hallucination occurrence. Jardri et al. (2011) argued that the results from their meta-analysis would support two main hypotheses:

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Figure 9.2 Areas of convergent findings in functional (white circles) and structural (black circles) studies of auditory hallucinations in schizophrenia. Coordinates, as reported in Jardri et al. (2011) and Modinos et al. (2013), are overlaid on a standard brain template using MRICron. Functional studies converged on five loci of activation (cluster A: left Broca’s convolution, anterior insula, precentral gyrus; cluster B: hippocampus/parahippocampus; cluster C: anterior insula, frontal operculum; cluster D: left STG and MTG; cluster E: supramarginal gyrus), and structural studies in two loci (cluster A: left STG and MTG, and cluster B: right STG and MTG)

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(i) aberrant activations within frontotemporal language areas during auditory hallucinations; and (ii) dysfunction of verbal memory systems which could lead to the occurrence of auditory hallucinations. Further to the findings described above, neuroimaging studies in auditory hallucinations in schizophrenia have also examined abnormalities in white matter structure and connectivity, gyrification (cortical folding), and neurochemistry, recently reviewed by Allen et al. (2012). In summary, the main findings to date are: (i) impaired white matter connectivity between frontal and temporal brain regions, as measured with diffusion tensor imaging (which assesses the directionality of water diffusion within white matter fiber tracts, or fractional anisotropy); (ii) abnormal frontotemporal functional connectivity during task performance, and temporo-parietal connectivity during resting state; (iii) subtle gyrification deviations; and (iv) neurochemical abnormalities (decreased N-acetyl-aspartate concentrations in hippocampus and thalamus; no significant effects on dopamine synthesis capacity have been reported). In summary, abnormalities in the auditory cortex and language-related brain regions in patients with auditory hallucinations seem to be the most replicated finding across a range of imaging modalities. However, it should be noted that these areas also tend to be widely reported in schizophrenia regardless of specific symptoms (Honea et al. 2005). The main contributions with relative consistency across studies refer to decreases in gray matter volume, while increases in brain activation during auditory hallucinations and in white matter connectivity are commonly reported. More recent investigations have suggested aberrant neurochemical function and gyrification deviations. In order for this field to move forward, future studies should aim to address the number of methodological issues often associated with this body of work, mainly relating to sample sizes, choice of study design for functional MRI studies (state or trait studies), medication confounds, and the specificity of the findings to auditory hallucinations.

Etiology Auditory hallucinations have a heritability of 0.43 (McGrath et al. 2009). Although no genes are known to code for complex clinical phenotypes, some allelic variants in certain genes may contribute to auditory hallucination formation (e.g. by exceeding the threshold for abnormal sensory processing). From the viewpoint of genetic studies, hallucinations are considered among the most reliable endophenotypes for genetic research in psychosis because they seem to be consistently associated with specific physiological (P50/P300) and neuroanatomical (left STG abnormalities) features (Allen et al. 2009). Sanjuán et al. (2013) recently proposed an integrative etiological model of auditory hallucinations, which differentiates between three etiopathogenic

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pathways: (i) vulnerability to hallucinate; (ii) vulnerability to abnormal emotional responding; and (iii) vulnerability to language disorder. •

•

•

The first pathway refers to an individual’s general vulnerability to experience hallucinations, in any perceptual modality. Different genotypes might code for differences in the threshold for sensory gating, thereby inducing proneness to hallucinations in any sensory modality. This general vulnerability is proposed to be related to genes that modulate all perceptual input (in the glutamatergic, GABAergic, or cholinergic systems), through thalamo-cortical pathways. The second pathway refers to the vulnerability to produce an abnormal emotional response to stimuli. This would be partially regulated by genes related to serotoninergic and dopaminergic neurotransmission. The third pathway refers to the vulnerability to express abnormalities in language processing, which would increase the probability of hearing voices. This vulnerability could be the result of changes or abnormal expression in the POXP2 gene (which is involved in central nervous system development), among others.

Besides the three pathways described above, genetic variants may also influence the vulnerability to hallucinations indirectly by predisposing the individual to expressing specific temperament and personality traits. For instance, it has been shown that some temperament and personality traits are important predisposing factors for hallucinations (Read et al. 2009), which are thought to result from complex gene–environment interactions (Ivorra et al. 2010). Many genes of small effects may thus be involved in these pathways predisposing the patient to experience hallucinations. On the other hand, cultural and environmental factors are vastly regarded to exert a clear influence on auditory hallucinations, particularly on the content and the social adjustments of the experiences (Johns et al. 2002a,b). In summary, the current view lies with an etiological model of auditory hallucinations, that integrates genetic and environmental factors in their origin. At this point, the question arises of how would these vulnerabilities induce in the individual the neurobiological, cognitive, and ultimately behavioral expression that characterize what we call an auditory hallucination. The developmental neuroscience of hallucinations has been intensively researched in children and adolescents, since hallucinations are a hallmark symptom of early onset schizophrenia. This research has been centered on the neurodevelopmental theory of schizophrenia. As formulated by Weinberger (1987), this theory postulates increased risk associated with early abnormalities in brain development. This has been supported by evidence that harmful effects on fetal brain development (just prior to, or during, birth) in combination with subsequent brain changes later on in adolescence can result in the onset of psychotic symptoms (Cannon et al. 2003). The notion is currently still held that early developmental deficits,

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such as famine (St Clair et al. 2005), lower birth weight and lower intelligence quotient (Polanczyk et al. 2010), may signal the starting point for risk pathways that may lead to any expression in between non-affective (mild) psychotic experiences and full-blown schizophrenia. The clinical or nonclinical result for each person is thus thought to depend on a complex combination of perinatal, genetic and environmental factors that have yet to be well understood. In this context, developmental studies of psychotic children have shown marked abnormal brain trajectories. Childhood-onset schizophrenia (COS) is a rare, severe form of the disorder with more marked neurodevelopmental impairments (Rapoport et al. 2005), thought to be neurobiologically, diagnostically and physiologically continuous with the adult disorder (Nicolson et al. 1999; Addington et al. 2005). In COS, progressive decreases in cortical gray matter volume in frontal (11%), parietal (8.5%), and temporal lobes (7%) have been reported, as well as a progressive increase in ventricular volume (Rapoport et al. 1999; Sporn et al. 2003). The imaging data overall portray a fourfold greater reduction in cortical volume than in scans of healthy adolescent subjects. This imaging evidence taken as a whole has led to the idea that schizophrenia is a progressive neurodevelopmental disorder, with an emphasis on neuroanatomical change as a result of excessive synaptic elimination, which produces aberrant neural connectivity. Although these data are extremely interesting, whether any of these aberrant progressive changes are specific to auditory hallucinations still remains to be tested.

Treatment Treatment for auditory hallucination typically consists of medication, psychoeducation, psychosocial interventions, psychotherapy and, in some refractory cases, transcranial magnetic stimulation (TMS) or electroconvulsive therapy (ECT). Sommer et al. (2012) noted that there had been no clinical trials aimed at comparing the efficacy of various antipsychotic drugs prescribed uniquely for hallucinations. They then used existing data from the European First-Episode Schizophrenia Trial (EUFEST) to assess the potential of five different antipsychotic agents to reduce the severity of hallucinations. The EUFEST study (Kahn et al. 2008) included 498 patients with first-episode psychosis, who were randomized to receive haloperidol, olanzapine, amisulpride, quetiapine, or ziprasidone. Among these patients, 362 presented auditory hallucinations at baseline. Severity of auditory hallucinations showed a mean reduction from “marked/severe” to “minimal/mild” after four weeks, and the decline continued with prolonged treatment to ratings of “absent/minimal” hallucinations after six months of treatment. The proportion of patients with at least mild levels of hallucinations decreased strongly over time from 100% at baseline to 8% after 12

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months of treatment. These results suggest that auditory hallucinations respond to anti-psychotic treatment in patients with psychosis, and that there is a marked reduction in auditory hallucination severity within the first four weeks. In some cases, the drug of first choice is inefficient. It is then recommended to switch to another drug with a different receptor profile after a period of about two to four weeks. However, there will be patients who will not respond to a second anti-psychotic. In those cases, clozapine is considered the drug of choice. In fact, clozapine is nowadays still considered as having the most effective profile for patients with treatment-resistant auditory hallucinations (Kane et al. 1988). For patients with schizophrenia, it is recommended that, if successful, anti-psychotic treatment should be maintained in an unaltered dose for at least one year. In light of the evidence that the predisposition to auditory hallucinations is in part genetically influenced, the vulnerability to experiencing auditory hallucinations may be lifelong, and in fact continuous maintenance treatment with the initial dose used for symptom remission has been associated with lowest relapse rates (Sommer et al. 2012). There are cases in which clozapine also fails to reduce hallucinations. A number of treatment options may still be offered to these patients with refractory hallucinations, including psychotherapy, pharmacological augmentation, repetitive TMS (rTMS), and ECT. Cognitive behavioral therapy (CBT) can be applied as an augmentation to antipsychotic medication, thus not only in refractory cases. CBT aims at reducing the emotional distress associated with auditory hallucinations, and to develop new coping strategies. Overall, CBT has been found to provide beneficial effects, positive symptoms, negative symptoms, general functioning, mood, and social anxiety, with effect sizes ranging from 0.35 to 0.44, as reported by a recent meta-analysis (Wykes et al. 2008). TMS involves the application of a strong pulse of electrical current, which sent through a coil placed over a person’s skull, inducing a magnetic field pulse in a small brain area, depolarizing local neurones up to a depth of 2 cm. TMS is proposed as a non-invasive technique with only few side effects, and studies applying TMS for the treatment of auditory hallucinations have generally reported significant symptom reduction for TMS-treated groups compared with placebo groups (Aleman et al. 2007). TMS is currently being offered as treatment option to reduce the frequency and severity of auditory hallucinations in centers worldwide, combined with anti-psychotic treatment. Finally, ECT may also be offered in some cases of treatment-resistant psychosis. ECT involves placing electrodes attached to the scalp by which an electrical current is passed to induce a generalized seizure; it is performed under general anesthesia and muscle relaxants are administered to prevent body spasms. A number of neuropsychological deficits, mainly affecting memory, have been associated with the administration of ECT, although

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pretreatment functioning levels tend to be reached within the first months after treatment (Semkovska and McLoughlin 2010). Several studies have demonstrated clinical improvement after ECT in patients with schizophrenia, but a specific reduction in hallucination severity has not been demonstrated. The clinical improvement may thus be attributable to improving other symptoms (mood, motor retardation, agitation, and catatonia), rather than to core psychotic symptoms such as auditory hallucinations (Sommer et al. 2012).

Conclusions From the point of view of cognitive science, the evidence to date suggests that auditory hallucinations arise from interactions between hypersalient auditory sensory signals and top-down cognitive processing deficits, which may shape the form and content of the voices. Emotional processing is thought to play an important role at all levels of processing. Finally, individual differences in neural activation may determine the observed variability in phenomenological presentations, resulting in the many subtypes of auditory hallucinations (Jones 2010). Research into the neurobiological correlates of auditory hallucinations seems to converge in showing abnormalities in the auditory cortex and language-related brain regions in patients with auditory hallucinations. The most consistent findings across studies refer to decreases in gray matter volume, while increases in brain activation during auditory hallucinations and in white matter connectivity are commonly reported (Modinos et al. 2013; Allen et al. 2012; Jardri et al. 2011). In order for this field to move forward, future work should aim to overcome methodological issues such as reduced sample sizes, choice of study design for functional MRI studies (state or trait studies), medication confounds, and the specificity of the findings to auditory hallucination as a specific symptom. In terms of the etiology of auditory hallucinations, the current etiological model integrates genetic and environmental factors in the origin of auditory hallucinations. How genetic and environmental vulnerabilities induce in the individual the neurobiological, cognitive, and ultimately the behavioral expression that characterizes auditory hallucinations is currently framed within the neurodevelopmental theory of schizophrenia. Thus, the notion is currently still held that early developmental insults may signal the starting point for risk pathways that may lead to any expression in between subclinical psychotic experiences and full-blown schizophrenia. Finally, with regard to treatment options for auditory hallucinations in schizophrenia, there is vast evidence to suggest that auditory hallucinations respond to anti-psychotic treatment in patients with psychosis, and that there is a marked reduction in severity of hallucinations within the first four weeks (Sommer et al. 2012). In cases in which the drug of first choice is inefficient, patients are changed to another drug with a different

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receptor profile within a period of about two weeks. Nevertheless, some patients do not respond to a second anti-psychotic either, and then clozapine is considered the drug of choice. For patients with schizophrenia, it is recommended that, if successful, anti-psychotic treatment should be maintained in an unaltered dose for at least one year, and continuous maintenance treatment with the initial dose used for symptom remission has been associated with lowest relapse rates. In addition to pharmacological options, other approaches such as CBT provides beneficial effects for positive symptoms, negative symptoms, general functioning, mood, and social anxiety (Wykes et al. 2008). Studies applying another approach, TMS, for the treatment of auditory hallucinations have generally reported significant symptom reduction for TMS-treated groups compared with placebo groups (Aleman et al. 2007). TMS is currently being offered as treatment option combined with anti-psychotics. Finally, ECT is offered in some cases of treatment-resistant psychosis, and although several studies have demonstrated clinical improvement after ECT in patients with schizophrenia, a specific reduction in hallucination severity has not been demonstrated. In conclusion, the recent years have witnessed important progress in discerning the mechanisms underlying the emergence of hallucinatory experiences in patients with schizophrenia. This progress has been largely aided by the availability of advanced brain imaging acquisition and analysis techniques, together with rapid progress in genetic research. Challenges to be addressed in future research relate to the need to collect important clinical, environmental and genetic information on auditory hallucinations, so that their contribution to the underlying deficits may be assessed. Another issue concerns the boundaries between auditory hallucinations and other positive symptoms associated with schizophrenia such as delusions, so that shared and unique contributing processes may be identified. An additional challenge relates to the role of medications in neurobiological and cognitive measurements of auditory hallucinations. Further research addressing these issues can lead to refined evidence-based models of the processes underlying hallucinations and ultimately provide an integrative understanding of these intriguing subjective phenomena.

References Addington, A. M., Gornick, M., Duckworth, J., Sporn, A., Gogtay, N., Bobb, A., Greenstein, D., Lenane, M., Gochman, P., Baker, N., Balkissoon, R., Vakkalanka, R. K., Weinberger, D. R., Rapoport, J. L. and Straub, R. E. (2005) ‘GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss’, Molecular Psychiatry, 10: 581–8. Aleman, A., Sommer, I. E. and Kahn, R. S. (2007) ‘Efficacy of slow repetitive transcranial magnetic stimulation in the treatment of resistant auditory hallucinations in schizophrenia: A meta-analysis’, Journal of Clinical Psychiatry, 68: 416–21.

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Allen, A. J., Griss, M. E., Folley, B. S., Hawkins, K. A. and Pearlson, G. D. (2009) ‘Endophenotypes in schizophrenia: A selective review’, Schizophrenia Research, 109: 24–37. Allen, P., Laroi, F., McGuire, P. K. and Aleman, A. (2008) ‘The hallucinating brain: A review of structural and functional neuroimaging studies of hallucinations’, Neuroscience and Biobehavioral Reviews, 32: 175–91. Allen, P., Modinos, G., Hubl, D., Shields, G., Cachia, A., Jardri, R., Thomas, P., Woodward, T., Shotbolt, P., Plaze, M. and Hoffman, R. (2012), ‘Neuroimaging auditory hallucinations in schizophrenia: From neuroanatomy to neurochemistry and beyond’, Schizophrenia Bulletin, 38: 695–703. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, Washington, DC: American Psychiatric Association. Andreasen, N. C. and Flaum, M. (1991) ‘Schizophrenia: The characteristic symptoms’, Schizophrenia Bulletin, 17: 27–49. Ashburner, J. and Friston, K. J. (2000) ‘Voxel-based morphometry–the methods’, NeuroImage, 11: 805–21. Blom, J. D. and Sommer, I. E. C. (2012) Hallucinations: Research and Practice, New York: Springer. Braun, C. M., Dumont, M., Duval, J., Hamel-Hebert, I. and Godbout, L. (2003) ‘Brain modules of hallucination: An analysis of multiple patients with brain lesions’, Journal of Psychiatry and Neuroscience, 28: 432–49. Cannon, T. D., van Erp, T. G., Bearden, C. E., Loewy, R., Thompson, P., Toga, A. W., Huttunen, M. O., Keshavan, M. S., Seidman, L. J. and Tsuang, M. T. (2003), ‘Early and late neurodevelopmental influences in the prodrome to schizophrenia: Contributions of genes, environment, and their interactions’, Schizophrenia Bulletin, 29: 653–69. Downar, J., Crawley, A. P., Mikulis, D. J. and Davis, K. D. (2000) ‘A multimodal cortical network for the detection of changes in the sensory environment’, Nature Neuroscience, 3: 277–83. Honea, R., Crow, T. J., Passingham, D. and Mackay, C. E. (2005) ‘Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies’, American Journal of Psychiatry, 162: 2233–45. Ivorra, J. L., Sanjuan, J., Jover, M., Carot, J. M., Frutos, R. and Molto, M. D. (2010) ‘Gene–environment interaction of child temperament’, Journal of Developmental and Behavioral Pediatrics, 31: 545–54. Jardri, R., Cachia, A., Thomas, P. and Pins, D. (2013), The Neuroscience of Hallucinations, New York: Springer. Jardri, R., Pouchet, A., Pins, D. and Thomas, P. (2011) ‘Cortical activations during auditory verbal hallucinations in schizophrenia: A coordinate-based meta-analysis’, American Journal of Psychiatry, 168: 73–81. Johns, L. C., Hemsley, D. and Kuipers, E. (2002a) ‘A comparison of auditory hallucinations in a psychiatric and non-psychiatric group’, British Journal of Clinical Psychology, 41: 81–6. Johns, L. C., Nazroo, J. Y., Bebbington, P. and Kuipers, E. (2002b) ‘Occurrence of hallucinatory experiences in a community sample and ethnic variations’, British Journal of Psychiatry, 180: 174–8. Jones, S. R. (2010) ‘Do we need multiple models of auditory verbal hallucinations? Examining the phenomenological fit of cognitive and neurological models’, Schizophrenia Bulletin, 36: 566–75.

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Kahn, R. S., Fleischhacker, W. W., Boter, H., Davidson, M., Vergouwe, Y., Keet, I. P., Gheorghe, M. D., Rybakowski, J. K., Galderisi, S., Libiger, J., Hummer, M., Dollfus, S., Lopez-ibor, J. J., Hranov, L. G., Gaebel, W., Peuskens, J., Lindefors, N., Riecher-Rossler, A. and Grobbee, D. E. (2008) ‘Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: An open randomised clinical trial’, Lancet, 371: 1085–97. Kane, J., Honigfeld, G., Singer, J. and Meltzer, H. (1988) ‘Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine’, Archives of General Psychiatry, 45: 789–96. McGrath, J. A., Avramopoulos, D., Lasseter, V. K., Wolyniec, P. S., Fallin, M. D., Liang, K. Y., Nestadt, G., Thornquist, M. H., Luke, J. R., Chen, P. L., Valle, D. and Pulver, A. E. (2009) ‘Familiarity of novel factorial dimensions of schizophrenia’, Archives of General Psychiatry, 66: 591–600. McGuire, P. K., Shah, G. M. and Murray, R. M. (1993) ‘Increased blood flow in Broca’s area during auditory hallucinations in schizophrenia’, Lancet, 342: 703–6. Mechelli, A., Price, C. J., Friston, K. J. and Ashburner, J. (2005) ‘Voxel-based morphometry of the human brain: Methods and applications’, Current Medical Imaging Reviews, 1: 105–13. Modinos, G., Costafreda, S. G., van Tol, M. J., McGuire, P. K., Aleman, A. and Allen, P. (2013) ‘Neuroanatomy of auditory verbal hallucinations in schizophrenia: A quantitative meta-analysis of voxel-based morphometry studies’, Cortex, 49: 1046–55. Nicolson, R., Giedd, J. N., Lenane, M., Hamburger, S., Singaracharlu, S., Bedwell, J., Fernandez, T., Thaker, G. K., Malaspina, D. and Rapoport, J. L. (1999) ‘Clinical and neurobiological correlates of cytogenetic abnormalities in childhood-onset schizophrenia’, American Journal of Psychiatry, 156: 1575–9. Polanczyk, G., Moffitt, T. E., Arseneault, L., Cannon, M., Ambler, A., Keefe, R. S., Houts, R., Odgers, C. L. and Caspi, A. (2010) ‘Etiological and clinical features of childhood psychotic symptoms: Results from a birth cohort’, Archives of General Psychiatry, 67: 328–38. Rapoport, J. L., Addington, A. and Frangou, S. (2005) ‘The neurodevelopmental model of schizophrenia: What can very early onset cases tell us?’, Current Psychiatry Reports, 7: 81–2. Rapoport, J. L., Giedd, J. N., Blumenthal, J., Hamburger, S., Jeffries, N., Fernandez, T., Nicolson, R., Bedwell, J., Lenane, M., Zijdenbos, A., Paus, T. and Evans, A. (1999) ‘Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study’, Archives of General Psychiatry, 56: 649–54. Read, J., Bentall, R. P. and Fosse, R. (2009) ‘Time to abandon the bio-bio-bio model of psychosis: Exploring the epigenetic and psychological mechanisms by which adverse life events lead to psychotic symptoms’, Epidemiologia e Psichiatria Sociale, 18: 299–310. Sanjuán, J., Molto, M. D. and Tolosa, A. (2013) ‘Candidate genes involved in the expression of psychotic symptoms: A focus on hallucinations’, in R. Jardri, A. Cachia, P. Thomas and D. Pins (eds) The Neuroscience of Hallucinations, New York: Springer, pp. 231–52. Semkovska, M. and McLoughlin, D. M. (2010) ‘Objective cognitive performance associated with electroconvulsive therapy for depression: A systematic review and meta-analysis’, Biological Psychiatry, 68: 568–77.

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Sommer, I. E., Slotema, C. W., Daskalakis, Z. J., Derks, E. M., Blom, J. D. and van der Gaag, M. (2012) ‘The treatment of hallucinations in schizophrenia spectrum disorders’, Schizophrenia Bulletin, 38: 704–14. Sporn, A. L., Greenstein, D. K., Gogtay, N., Jeffries, N. O., Lenane, M., Gochman, P., Clasen, L. S., Blumenthal, J., Giedd, J. N. and Rapoport, J. L. (2003) ‘Progressive brain volume loss during adolescence in childhood-onset schizophrenia’, American Journal of Psychiatry, 160: 2181–9. St Clair, D., Xu, M., Wang, P., Yu, Y., Fang, Y., Zhang, F., Zheng, X., Gu, N., Feng, G., Sham, P. and He, L. (2005) ‘Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961’, Journal of the American Medical Association, 294: 557–62. Varese, F., Barkus, E. and Bentall, R. P. (2012) ‘Dissociation mediates the relationship between childhood trauma and hallucination-proneness’, Psychological Medicine, 42: 1025–36. Vercammen, A., Knegtering, H., Bruggeman, R. and Aleman, A. (2011) ‘Subjective loudness and reality of auditory verbal hallucinations and activation of the inner speech processing network’, Schizophrenia Bulletin, 37: 1009–16. Waters, F., Allen, P., Aleman, A., Fernyhough, C., Woodward, T. S., Badcock, J. C., Barkus, E., Johns, L., Varese, F., Menon, M., Vercammen, A. and Laroi, F. (2012) ‘Auditory hallucinations in schizophrenia and nonschizophrenia populations: A review and integrated model of cognitive mechanisms’, Schizophrenia Bulletin, 38: 683–93. Weinberger, D. R. (1987) ‘Implications of normal brain development for the pathogenesis of schizophrenia’, Archives of General Psychiatry, 44: 660–9. Wykes, T., Steel, C., Everitt, B. and Tarrier, N. (2008) ‘Cognitive behavior therapy for schizophrenia: Effect sizes, clinical models, and methodological rigor’, Schizophrenia Bulletin, 34: 523–37.

10 Neural correlates of cognitive control and language processing in schizophrenia Katherine Scangos and Cameron S. Carter

Cognitive control describes the ability to flexibly adapt to a changing environment by updating internal goals and carrying out goal-directed behavior based on the situational context. It encompasses a broad range of cognitive domains including attention, working memory, rule generation, inhibition, language, and emotional and social processing. Abnormalities in cognition in schizophrenia were first noted by Bleuler (1911) and Kraepelin (1919) near the time of the first description of the disease, and are now considered one of the most disabling deficits in schizophrenia. Cognitive deficits have been repeatedly associated with negative symptoms, disorganization (Dibben et al. 2009), thought disorder (Kerns and Berenbaum, 2003), and poor functional outcome (Green et al. 2000). Furthermore, cognitive deficits show evidence of arising prior to or during the prodromal phase, before a diagnosis of schizophrenia has been made (Cannon et al. 2002). Current therapies, however, have only modest impact on cognition (Minzenberg and Carter 2012). Thus, understanding the nature of deficits in cognitive control, and how such diverse domains of dysfunction are linked to pathophysiology, is of central importance to the improvement of the function and care of patients with schizophrenia. It has often been thought that many dissociable deficits with distinct pathophysiology are responsible for the observed impairments in schizophrenia. However, an alternative theory proposes that the range of deficits observed can be understood as a single disorder of context processing (Cohen et al. 1996; Lesh et al. 2011). Context refers to information that is maintained in working memory that can be used to guide task-relevant behavior. This information includes the behavioral goal, instructions to carry out that goal, and feedback information from previous experiences related to that goal. Thus, context influences behavior across effector systems, guiding movement, language, decision making, and understanding those same actions in others. A deficit in representing context would therefore lead to problems across multiple cognitive domains, which is precisely what is observed in schizophrenia. The connection between schizophrenia and language arises from the first description of the disease, and like cognitive dysfunction and

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psychosis, is considered a central symptom. Patients have difficulty in both speech production and in language comprehension (Boudewyn et al. 2012). The link between cognitive deficits and language disturbances in schizophrenia has only recently been a focus of investigation. Disorganized behavior is thought to arise from problems in maintaining an appropriate task goal due to problems in working memory, context processing, and attention. It is not a large leap to think that disorganized language may arise from disruptions in these same processes. In this chapter, we first discuss the current understanding of the neural correlates of cognitive control. The relationship between language and cognitive dysfunction is then addressed, focusing on the interaction of context, working memory, and control of thought and speech. We propose a model that links deficits in language comprehension and discourse to deficits in context processing (see also Chapter 11). Finally, we discuss the clinical relevance of understanding cognition and language in schizophrenia.

Cognitive control network and the prefrontal cortex Patients with damage to the prefrontal cortex provide some of the first accounts of executive dysfunction syndromes (Petrides and Milner 1982). It was thus expected that problems with the prefrontal cortex might explain the cognitive defects in schizophrenia. Initial positron emission tomography indicated reduced activity in the frontal cortex (Ingvar and Franzen 1974), and this hypofrontality was found most consistently across studies that used functional tasks employing complex behavior (Weinberger et al. 1986). This suggested the existence of faulty connectivity between a network of brain areas that rely on the prefrontal cortex (Liddle et al. 1992). Since these initial findings and the wider availability of functional neuroimaging, there has been an explosion of research seeking to understand the nature of the prefrontal cortex and its relationship to schizophrenia. Numerous imaging studies have implicated that one area of the prefrontal cortex, the dorsolateral prefrontal cortex (DLPFC), is especially disrupted in schizophrenia. Decreased activity in the DLPFC is seen across a range of tasks tapping cognitive control (Glahn et al. 2005; MacDonald and Carter 2003; Rubia et al. 2001), irrespective of medication status (MacDonald et al. 2005). Furthermore, the decrease in DLPFC activity is correlated with behavioral disorganization (MacDonald et al. 2005). The cognitive deficits and altered brain activity patterns are also present in those at risk for developing the disease (Callicott et al. 2003; Snitz et al. 2006). The finding of DLPFC deficits across a range of studies suggests that the area supports a wide range of functions, and may be understood in providing context information, an idea first put forward by Cohen et al. (1996). A version of the continuous performance task (CPT), known as the AX-CPT, was designed to test context processing, and in accordance with Cohen’s

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prediction, worse performance of both medicated and unmedicated subjects over controls was observed (Servan-Schreiber et al. 1996). It is now believed that cognitive control utilizes a network of brain regions including the DLPFC, anterior cingulate cortex (ACC), and parietal regions (Lesh et al. 2011). The DLPFC represents and maintains context, the ACC is involved in detecting conflict and the need for enhanced control, and the parietal cortex is involved in working memory storage and attentional shifting. Reciprocal connections from many other areas, including the striatum and thalamus, help provide feedback information, and sensory and perceptual information respectively (Miller and Cohen 2001).

Self-monitoring and reactive control The dual mechanism of control theory proposes that proactive and reactive cognitive control mechanisms work together to implement goal-directed behavior in a complex environment (Braver 2012). The DLPFC supports proactive control by actively maintaining context. Reactive control is mobilized only when additional top-down control is needed, such as during high-conflict situations where interference and errors occur. Reactive control is governed by the ACC and reciprocal connections with the DLPFC and striatum. The conflict hypothesis states that the ACC detects conflict, and recruits additional control by activating the DLPFC (Botvinick et al. 2001). The ACC is active during tasks such as the Stroop Go No Go test and verbal fluency tasks during errors and conflict (Braver et al. 2001; Kerns 2006; Kerns et al. 2005). Furthermore, the degree of ACC activity on error trials was associated with performance adjustments on subsequent trials (Kerns et al. 2004). The DLPFC follows a similar pattern, being more active following conflict trials. The degree of ACC activity on high-conflict trials predicts the degree to which the DLPFC is activated on subsequent trials. These findings suggest that the DLPFC and ACC work together to improve behavior in the face of conflict or error. People with schizophrenia have been shown to have deficits in performance monitoring. While healthy controls slow reaction time after making an error (Rabbitt 1966), patients make more errors and show less errorrelated reaction-time slowing, and these behavioral findings are associated with less ACC activation on functional magnetic resonance imaging (Carter et al. 2001) and electroencephalographic studies (Mathalon et al. 2002).

Impact of cognitive dysfunction on language Abnormalities in both speech production and in receptive language have been observed for patients and their relatives (DeLisi 2001; Kuperberg 2010). Furthermore, language deficits have been observed prior to illness

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onset (Reichenberg et al. 2010). Yet, despite the fact that language deficits have been thoroughly described, the neuropathophysiology behind language dysfunction is poorly understood. In this section, we turn to a discussion of how language processing systems also interact with the same cognitive control networks discussed above.

Semantic priming One way in which language comprehension has been studied from the word level to complicated discourse is through semantic priming. Semantic priming refers to the process by which a word is recognized faster if it is primed by a related word (Meyer and Schvaneveldt 1971). The effect has been interpreted as evidence of a semantic-feature network, where each word meaning is represented as a node within the network. During comprehension, individual nodes are activated for a short time and the activation spreads to related nodes, moving them toward their threshold for activation, and thereby reducing the reaction time for related word recognition (Kuperberg et al. 2010). This effect was initially measured using reaction-time tasks, and later by an event-related potential known as the N400, a negative-going waveform observed in response to unrelated word pairs (Chwilla and Kolk 2005). Studies measuring the N400 consistently showed increased or normal priming, with more prominent effects in thought disordered patients (Kuperberg et al. 2010; Pomarol-Clotet et al. 2008). This hyperpriming was interpreted as faster and farther activation within the semantic network, and was thought to explain the unusual associations observed in schizophrenia. This idea was further supported by studies that looked at indirectly associated words such as “chalk black” where the connection of the words requires an intermediate linking word (white). Indirect priming is observed in people with schizophrenia, but is present only at longer processing times in normal subjects (Kreher et al. 2008; Spitzer et al. 1993). Thus, people with schizophrenia appear to treat indirectly related words like related words, whereas normal subjects treat them as unrelated. Furthermore, the hyperpriming observed in schizophrenia disappeared if the complexity of the task increased. People with schizophrenia actually show reduced priming if they need to hold a word in memory, assign a relationship between words, or perform other types of controlled processing (Kreher et al. 2009; Minzenberg et al. 2002).

Context and organized speech The absence of priming under controlled conditions suggests that patients cannot use simple word associations to govern word processing. Priming at sentence and discourse levels suggest that language comprehension can be understood using the context model. Because people with schizophrenia may activate a larger network of primed words, they may not be able to

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develop and maintain sentence context to build meaning throughout a conversation. This may occur through poor working memory capacity, the overactivity of some semantic networks, and through the improper inhibition of irrelevant semantically related representations. Poor context maintenance could also lead to disorganized speech through the inability to maintain a speech goal (Kerns and Berenbaum 2003). Furthermore, complete loss of goal could lead to poverty of speech symptoms by preventing speech production (Barch and Berenbaum 1997). Sitnikova et al. (2002) tested the context model by using ambiguous words within a sentence, such as the word “bridge” that can refer either to the card game or to a structure. They found that, contrary to normal subjects, patients with schizophrenia did not show an increased N400 response when the first and second halves of a sentence referred to a different meaning of the ambiguous word. This finding suggests that patients do not integrate the initial context of the sentence with the second half. Another waveform frequently examined is the P600, which is a positive deflecting waveform thought to reflect conflict between the syntax-dictated sentence meaning and the meaning of the sentence governed by the individual words (Kuperberg et al. 2006; Sitnikova et al. 2010). Controls show a large amplitude response to unusual syntax-dictated sentence meanings, such as “the eggs ate breakfast” whereas patients show a smaller P600 response, indicating that they perceive the semantically related words “eggs”, “ate”, and “breakfast” without integrating them into the sentence context, and therefore do not perceive the verb–argument conflict. At the discourse level, context processing becomes even more important. The language content itself does not always contain all the information needed for full comprehension, and inferences based on previous associations are required. Cognitive control is needed to build a discourse representation integrating word and sentence meanings, interpreting inferences, suppressing irrelevant information, updating representations based on new information, and incorporating tone of voice, inflection, and facial expressions. There are many fewer studies looking at how subjects with schizophrenia build these representations over more than one sentence, but those that exist reveal context processing deficits (Kuperberg et al. 2010). One study used three sentence passages where the sentences were related, intermediately related, or unrelated. Controls showed a graded N400 response with the largest N400 for unrelated sentences. In contrast, the N400 did not vary across conditions for the patient group, suggesting they could not use information across sentence boundaries to construct a larger context representation. If the context was explicitly provided, however, patients were able to integrate sentence meaning (Ditman and Kuperberg 2007). Together, these findings show that patients can establish some context for simple sentence comprehension based on semantic priming of individual words and semantic memory of the relationship between these words.

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However, they become limited when integrative demands are higher and a strong context representation is required.

Language and working memory Working memory capacity has been shown to influence language comprehension and processing (Just and Carpenter 1992), and likely plays a role in storing verbal information online as discourse proceeds in order to integrate word and sentence meanings. Thus, working memory deficits may play a major role in formal thought disorder, disorganized speech, and poverty of speech (Melinder and Barch 2003). Event-related potential studies have shown that patients exhibit increased N400 amplitudes for all stimuli when words are presented at long time intervals, even if the words are semantically related (Salisbury 2008). This finding led Salisbury and colleagues to propose that, while words and associates may be properly activated, this information decays quickly due to poor working memory. They further assert that only the very strongest associations will be maintained in the working memory buffer owing to early decay of weakly associated concepts, creating a few overly strong associations that may bias interpretation even when not contextually appropriate. Another study found that patients with disorganized speech exhibit worse performance on the NBack test that requires subjects to remember N numbers back from a target (Kerns 2007). Thus, there may exist a threshold level of a combination of working memory capacity and context-processing ability that once crossed leads to the complete breakdown of goal directed language and thought.

Language and self-monitoring Poor self-monitoring of speech output may also contribute to disorganized speech in people with schizophrenia. This idea is consistent with the finding that patients are poor at evaluating their own cognitive performance (Medalia and Thysen 2008). Furthermore, decreases in ACC activation (Boksman et al. 2005), and dysfunctional fronto-cingulate connectivity (Spence et al. 2000) have been observed during verbal fluency tasks. Boksman et al. (2005) examined the BOLD response using a word-fluency task in medication-naïve patients, and found that patients generated fewer words per time period than healthy controls, and that this behavioral response was associated with significantly less brain activity in the ACC and right prefrontal cortex. These findings support the assertion that self-monitoring, governed by connections between the ACC and the DLPFC, is important for language processing. Results from priming studies may also be understood under poor conflict or error detection. Smaller amplitude N400s at the sentence and discourse level may indirectly reflect poor conflict detection between incongruous words or sentences. The inability to detect conflicting

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relationships within speech would theoretically disrupt the inhibition of irrelevant associations, and could therefore lead to more spreading activation through the semantic network, and a smaller response to incongruous higher-order language features. Reduced ACC activity, as seen in schizophrenia, would therefore lead to less activation of the already dysfunctional DLPFC, which would further hinder the development of context representation for language comprehension. The introduction of ambiguous word or sentence meanings that would normally engender conflict would fail to do so, thereby reducing the patients’ ability to process difficult speech and language. More research is needed into these aspects of the cognitive control of language in schizophrenia.

Cognitive control and language across tasks If cognitive control dysfunction is at the root of language impairments in schizophrenia, there must exist an association between difficulties on traditional cognitive tasks and language ability. A recent study by Becker et al. (2012) examined whether two language symptoms, paucity of speech and disorganized speech, were associated with specific cognitive control components, and found that poverty of speech was associated with both poor context maintenance and poor working memory, whereas disorganized speech was significantly associated only with context maintenance. These results provide evidence for the involvement of working memory and context maintenance in the production of organized speech. The full nature of this relationship has not yet been explored and further research is needed to assess performance on the cognitive tasks relative to specific language impairments.

Implications for treatment Understanding schizophrenia as a neurodevelopmental disorder characterized by disrupted prefrontal processing calls for the development of new treatment targets for patient care. Antipsychotics are effective in alleviating the positive symptoms of schizophrenia, such as hallucinations and delusions, but do little to improve cognitive functioning (Minzenberg and Carter 2012). Computer-based cognitive training has been shown to lead to improved verbal learning and memory and cognitive control that persists for months after training (Fisher et al. 2010). There has also been a recent focus in the development of drugs that target cognition. Dopamine receptors in the prefrontal cortex, glutamatergic excitatory synapses, serotonin receptors and the gamma-aminobutyric acid system were identified as potential molecular targets (Minzenberg and Carter 2012). Studies have also shown that repetitive transcranial magnetic stimulation applied over the prefrontal cortex can improve negative symptoms and cognitive deficits (Levkovitz et al. 2011; Moser et al. 2002), and direct current therapy may

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also be effective (Vercammen et al. 2011). Ideally, a combination of cognitive training, medication, and brain stimulation, could restore cognitive functioning to a level that would improve patients’ daily living. It remains to be seen if these new treatments improve language symptoms. If so, it would provide more definitive evidence for a unifying theory of cognitive dysfunction underlying both language and other cognitive tasks.

Conclusions Throughout this chapter, we have outlined the cognitive control deficits observed in schizophrenia and discussed how language abnormalities can be understood in relationship to these same mechanisms (Figure 10.1). We propose that schizophrenia is a neurodevelopmental disorder characterized by specific deficits in the function of prefrontal cortex. The context model of language dysfunction in schizophrenia asserts that context is important for organized language at all stages of processing. At the earliest stage, context is important for the activity pattern in semantic networks. In

Disorganized speech, behavior Paucity of speech, action

Self monitoring

WM

Language

Context

DLPFC Parietal cortex

ACC

Figure 10.1 Illustration of the context model whereby a dysfunctional dorsolateral prefrontal cortex (DLPFC) and poor connections with the parietal cortex and anterior cingulate cortex (ACC) lead to a faulty representation of context. This in turn leads to difficulties across many domains including self-monitoring, working memory (WM) and language. The symptoms of disorganization of both behavior and language directly follows with paucity of speech and action at the extreme

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schizophrenia, poor DLPFC and ACC function would lead to unusually large semantic maps that are not constrained by context, or normal-sized maps containing an unusual word association pattern. Disorganized mapping is compounded by the further need to build and maintain context as discourse moves beyond single words. Working memory plays an important role as discourse complexity proceeds. Furthermore, conflict monitoring is necessary to recruit additional control mechanisms when language selection demands are increased. These control processes might normally serve to enhance the representation of context to improve the probability of interpreting correct meaning and suppressing incorrect ones in ambiguous cases. A failure to self-monitor during language production also prevents patients from redirecting themselves back to a recognized goal. Finally, extralinguistic features such as tone of voice, inflection, or facial expressions are crucial to understanding normal discourse and require a strong representation of communicative goals. Further research is necessary to examine the precise relationship between cognitive control and language impairments in schizophrenia. It will be important to look at direct associations between impairment on tasks that engage distinct cognitive systems and language dysfunction. More work understanding language dysfunction at the discourse level will also provide useful insights into the everyday language processing deficits that impact communication in schizophrenia. Furthermore, the broad range of impairments that fall under language dysfunction has not been explored in relation to cognition. Finally, looking at the how treatments for cognitive defects across different modalities affect language would help validate the existence of a global context processing deficit. Definitive demonstration of the existence of a central context-processing deficit would improve our understanding of the disease and ultimately lead to better treatments and improved patient care.

References Barch, D. M. and Berenbaum, H. (1997) ‘Language generation in schizophrenia and mania: The relationships among verbosity, syntactic complexity, and pausing’, Journal of Psycholinguistic Research, 26: 401–12. Becker, T. M., Cicero, D. C., Cowan, N. and Kerns, J. G. (2012) ‘Cognitive control components and speech symptoms in people with schizophrenia’, Psychiatry Research, 196: 20–6. Bleuler, E. (1911) Dementia Praecox or the Group of Schizophrenias, New York: International Press. Boksman, K., Theberge, J., Williamson, P., Drost, D. J., Malla, A., Densmore, M., Takhar, J., Pavlosky, W., Menon, R. S. and Neufeld, R. W. (2005) ‘A 4.0-T fMRI study of brain connectivity during word fluency in first-episode schizophrenia’, Schizophrenia Research, 75: 247–63. Botvinick, M. M., Braver, T. S. Barch,, D. M., Carter, C. S. and Cohen, J. D. (2001) ‘Conflict monitoring and cognitive control’, Psychological Review, 108: 624–52.

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Kerns, J. G. (2006) ‘Anterior cingulate and prefrontal cortex activity in an fMRI study of trial-to-trial adjustments on the Simon task’, NeuroImage, 33: 399–405. Kerns, J. G. (2007) ‘Verbal communication impairments and cognitive control components in people with schizophrenia’, Journal of Abnormal Psychology, 116: 279–89. Kerns, J. G. and Berenbaum, H. (2003) ‘The relationship between formal thought disorder and executive functioning component processes’, Journal of Abnormal Psychology, 112: 39–52. Kerns, J. G., Cohen, J. D., MacDonald, A. W. 3rd, Cho, R. Y., Stenger, V. A. and Carter, C. S. (2004) ‘Anterior cingulate conflict monitoring and adjustments in control’, Science, 303: 1023–6. Kerns, J. G., Cohen, J. D., MacDonald, A. W. 3rd, Johnson, M. K., Stenger, V. A., Aizenstein, H. and Carter, C. S. (2005) ‘Decreased conflict- and error-related activity in the anterior cingulate cortex in subjects with schizophrenia’, American Journal of Psychiatry, 162: 1833–9. Kraepelin, E. (1919) Dementia Praecox and Paraphrenia, Robert E. Krieger, Huntington, NY: Publishing Co. Inc.. Kreher, D. A., Holcomb, P. J., Goff, D. and Kuperberg, G. R. (2008) ‘Neural evidence for faster and further automatic spreading activation in schizophrenic thought disorder’, Schizophrenia Bulletin, 34: 473–82. Kreher, D. A., Goff, D. and Kuperberg, G. R. (2009) ‘Why all the confusion? Experimental task explains discrepant semantic priming effects in schizophrenia under “automatic” conditions: Evidence from Event-Related Potentials’, Schizophrenia Research, 111: 174–81. Kuperberg, G. R. (2010) ‘Language in schizophrenia Part 1: An introduction’, Language and Linguistics Compass, 4: 576–89. Kuperberg, G. R., Sitnikova, T., Goff, D. and Holcomb, P. J. (2006) ‘Making sense of sentences in schizophrenia: Electrophysiological evidence for abnormal interactions between semantic and syntactic processing, Journal of Abnormal Psychology, 115: 251–65. Kuperberg, G. R., Kreher, D. A. and Ditman, T. (2010) ‘What can event-related potentials tell us about language, and perhaps even thought, in schizophrenia?’, International Journal of Psychophysiology, 75: 66–76. Lesh, T. A., Niendam, T. A., Minzenberg, M. J. and Carter, C. S. (2011) ‘Cognitive control deficits in schizophrenia: Mechanisms and meaning’, Neuropsychopharmacology, 36: 316–38. Levkovitz, Y., Rabany, L., Harel, E. V. and Zangen, A. (2011) ‘Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: A feasibility study’, International Journal of Neuropsychopharmacology, 14: 991–6. Liddle, P. F., Friston, K. J., Frith, C. D., Hirsch, S. R., Jones, T. and Frackowiak, R. S. (1992) ‘Patterns of cerebral blood flow in schizophrenia’, British Journal of Psychiatry, 160: 179–86. MacDonald, A. W. 3rd and Carter, C. S. (2003) ‘Event-related fMRI study of context processing in dorsolateral prefrontal cortex of patients with schizophrenia’, Journal of Abnormal Psychology, 112: 689–97. MacDonald, A. W. 3rd, Carter, C. S., Kerns, J. G., Ursu, S., Barch, D. M., Holmes, A. J., Stenger, V. A. and Cohen, J. D. (2005) ‘Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients

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11 Narrative language production in schizophrenia Andrea Marini and Cinzia Perlini

Language disturbances are among the main clinical features of schizophrenia (e.g. Andreasen and Grove 1986; Covington et al. 2005; Koeda et al. 2006). Consequently, clinicians often face the problem of how to assess and interpret these symptoms. This chapter focuses on the problem of language assessment in patients with schizophrenia and its interpretation. We begin by outlining the most accepted psycholinguistic models of language production. We then focus on the characteristics of language production in schizophrenia. In the review of the literature, we outline the potential contributions of techniques of narrative analysis to the already existing procedures of linguistic assessment. Finally, we draw some conclusions on the nature of the linguistic production deficits observed in patients with schizophrenia and their potential connections with other cognitive deficits, such as those affecting attention and executive functions.

An overview of the language production system Language is a complex cognitive function resting on the interaction between partially distinct processing levels organized along two dimensions (e.g. Glosser and Deser 1991; Marini et al. 2011; see also Chapter 12): a within-utterance or microlinguistic dimension, necessary for intrasentential functions; a between-utterance or macrolinguistic dimension, responsible for inter-sentential functions. The microlinguistic dimension is organized in a phonological level, crucial for the abstract categorization of speech sounds (i.e. phones) in language-specific phonemes, a word level, characterized by phases of lexical selection and access, and a grammatical level, where the morphosyntactic structures required by the words are generated, and words are grouped in syntagms that, in turn, form sentences. The microlinguistic dimension, then, organizes phonological or graphemical patterns into morphological strings and words (lexical processing) and determines the syntactic context each word requires for the generation of well-formed sentences (syntactic processing). The macrolinguistic dimension is organized in two main processing levels: a pragmatic level, where words or sentences are contextualized and

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inferences are drawn; and a text/discourse level, where those sentences that make up a written text or a spoken discourse are integrated in order to achieve its general meaning or gist. This is the static picture of the language system. We will now examine the dynamics of the process of language production. The currently accepted models hypothesize the existence of at least three stages (e.g. Levelt et al. 1999; Indefrey and Levelt 2004): a prelinguistic conceptual phase; a phase of linguistic formulation; and a phase of linguistic expression (e.g. articulation) where production actually takes place. In the prelinguistic conceptual phase, the speaker generates a mental model of the message he/she wants to produce. In doing this, he/she must retrieve the appropriate conceptual frame structure from long-term episodic memory (e.g. selecting the appropriate discourse genre). Then, this structure must be filled with the semantic information (e.g. participants, setting, etc.) that pertains to the intended message. The speaker needs to integrate what he/she wants to say with what has been previously said (linguistic context), together with the specific situation, place and time in which the communicative exchange takes place (extra-linguistic context, Levinson 1983; Johnson-Laird 1980). This allows the speaker to regulate the amount of information that he/she intends to communicate and its relevance with respect to what has been previously said (Grice 1975; Sperber and Wilson 1986). This conceptual information triggers the generation of appropriate propositions that must be organized at the macrolinguistic level by means of adequate cohesion and coherent links. In the phase of linguistic formulation, the preverbal message is converted into a speech plan. Here, lexical processing matches the intended meaning, formulated in the prelinguistic phase, with the corresponding lexical items stored in the mental lexicon. This operation is performed through a multi-stage process that entails a phase of lexical selection and one of lexical access. The process of lexical selection allows the speakers to select the lexical items that correspond to the intended meanings (Levelt et al. 1999). How this selection takes place is still not completely clear. Likely, it is achieved through an activation/inhibition mechanism. Each word has its own specific activation thresholds as a function of the frequency of its use and time elapsed since last activation: The lower the threshold level, the easier the access; the higher the threshold level, the more difficult the access. The activation of the target word is achieved through the co-occurring inhibition of semantically related competitors. This inhibition may be obtained by raising the competitors’ activation thresholds. If the speaker intends to say “apple”, the activated concept corresponding to the idea of APPLE enters the lexicon. Here, a selection mechanism is needed to properly select the target word (“apple”) among all other semantically related lexical items (“pear”, “orange”, “banana”, etc.). The activation threshold of the competitors is raised and the target word (“apple”) is selected. At the end of the lexical selection

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process, the target word has been activated. The formulator gains access to its morphosyntactic and morphological features (lemma level of word representation) and then to its syllabic and phonological form. In case of single-word production, the lexical information is then transmitted to the output system where articulatory configurations corresponding to the phonemes to be uttered are programmed and then implemented. In case of sentence production, such as in connected speech, the process of lexical selection and the access to a word’s lemma form the “functional level” of sentence processing. Here, the morphosyntactic information required by the selected word (i.e. its argumental structure) guides the process of sentence generation by means of thematic roles’ assignment and phrase generation. At the second level of sentence processing, the so-called “positional level”, the information contained in the lemmas of the selected words is used to generate the grammatical relations among the phrases and to build up well-formed syntactic representations (Garrett 1980; Chomsky 1995). It is now possible to access the syllabic and phonologic representation(s) of the selected word(s). This information is eventually sent to the output system where articulatory configurations corresponding to the phonemes to be uttered are programmed and then implemented (phase of linguistic expression).

Language production in schizophrenia Over the past few decades, a growing number of studies have focused on the description and interpretation of linguistic deficits in persons with schizophrenia. These efforts have allowed researchers in the field to characterize the linguistic abnormalities observed in these individuals in each level of linguistic processing. In what follows, we outline the major findings concerning both micro- and macrolinguistic skills. Microlinguis t ic abilit ies When engaged in narrative production tasks, persons with schizophrenia tend to produce speech samples of variable length (normal, such as in Marini et al. 2008; reduced, such as in Covington et al. 2005). This variability probably depends on the prevalence of the negative or positive symptomatology. Indeed, patients with negative symptoms are usually less productive than those in a positive phase. However, the verbal productivity of persons with schizophrenia can also be assessed by measuring their efficiency in producing words. One way to quantify such efficiency is undoubtedly linked to the analysis of their speech rate. This measure is usually calculated in terms of words uttered per minute. Studies performing this analysis showed that schizophrenia patients might produce speech samples with reduced speech rates even in narratives with normal length (e.g. Tavano et al. 2008; Perlini et al. 2012). As we will discuss later, this

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finding can hardly be interpreted as a pure consequence of difficulties in the process of lexical selection. Rather, it may be the epiphenomenon of a more general difficulty in macrolinguistic processing. A completely different way to estimate the efficiency of schizophrenic individuals engaged in narrative discourse production relates to the quality of their lexical production skills. From this point of view, difficulties have been widely reported in schizophrenia. These deficits have been interpreted as reflecting impairments on distinct aspects of lexical access and production. Although usually normal at the articulatory level (Chaika 1974; Marini et al. 2008), they may experience problems in the production of phonologically wellformed words (Andreasen 1979; McKenna 1994; Leeson et al. 2006; Vogel et al. 2009). These phonological problems may sometimes even lead to the production of neologisms (Covington et al. 2005). Furthermore, their speech can be characterized by flattened intonation (Cutting 1985), wordfinding difficulties (Andreasen 1979; McKenna 1994), and production of semantic substitutions for specific target words (i.e. semantic paraphasias; Bellani et al. 2009). At the level of grammatical processing, the language of persons with schizophrenia is usually characterized by reduced syntactic complexity (Morice and McNicol 1986; Fraser et al. 1986; Perlini et al. 2012). Further studies showed that the levels of syntactic complexity of their utterances: a) apparently deteriorate with the progression of the illness; b) are more severe in patients with prevalence of negative symptoms compared to those presenting a positive symptomatology (Thomas et al. 1987, 1990; King et al. 1990); and c) are associated with the early onset of the illness (Morice and Ingram 1982). It is worth noting that even when the levels of syntactic complexity are lower than normal, the correct use of syntactic rules seems to be usually preserved (e.g. DeLisi 2001; but see Walenski et al. 2010 for a description of grammatical impairments exhibited on a verb production task). Overall, the microlinguistic profile that we may derive from this brief outline is quite heterogeneous. The available data suggest preserved articulatory skills and morphological competence on the one hand, but defective semantic, phonological and partially even grammatical skills on the other. The reduced speech rate observed in some recent studies suggests that, with respect to unaffected individuals, those with schizophrenia are less efficient in the process of lexical selection. This interpretation seems to be only weakly supported by the occasional production of semantic paraphasias. For example, in the study by Marini et al. (2008), the linguistic abilities of a group of participants with schizophrenia were analyzed by administering a picture description task. The production of semantic errors by the schizophrenic individuals, significantly higher than in a control group of healthy participants, was limited to a mere 1% on a total production of approximately 86 words per story. Then, the reduced speech rate may be explained otherwise. Interestingly, in Marini et al. (2008), when the production of global coherence errors (which is a

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macrolinguistic measure) was included as covariate in the analysis, the production of semantic paraphasias was no longer significantly higher in the group of persons with schizophrenia. This suggests that the production of semantic substitutions (a sign of a problem of lexical selection) may not necessarily depend only on a problem in lexical selection. Rather, it may be an epiphenomenon of a disturbance in macrolinguistic processing. Illuminating data on this sense come from a study by Leeson et al. (2006), where the authors explicitly analyzed name retrieval as an indicator of the ability to access lexical-semantic knowledge in schizophrenia patients. Namely, the authors arrived to the same conclusion stating that “impaired lexical access was predicted by the symptoms of derailment, tangentiality and incoherence” (page 166) and concluding with the hypothesis that “semantic access difficulties in formal thought disorder occur due to disorganised activation within the semantic network” (page 167). Indeed, abnormalities in associative connections between words and concepts have long been considered a core feature of schizophrenia (e.g. Manschreck et al. 1988; Spitzer et al. 1994) and, in chronic schizophrenic patients, particularly those with positive thought disorder, they have been associated to anomalous increases in activity within inferior prefrontal and temporal cortices (Kuperberg et al. 2007). Importantly, this interpretation of the microlinguistic impairments observed in patients with schizophrenia may also extend to other domains as signaled by their verbosity, their abnormal speech rate, their inability to get to the point, and the frequent production of pronouns without antecedents, deictic terms with no clear referents, and verbs that make their discourse vague and ambiguous.

Macrolinguistic abilities Persons with schizophrenia have massive problems in the pragmatic use of language. Indeed, difficulties in dealing with non-literal expressions (e.g. sarcasms, proverbs, metaphors, irony, idioms, indirect requests) have been widely reported (e.g. Lee et al. 2004; Brune and Bodestein 2005; Penn et al. 2008; Mo et al. 2008; Mazza et al. 2008; Bora et al. 2008). These difficulties may be related to a general inability to make optimal use of contextual cues (Levy et al. 2010). In some cases, they have been related to a difficulty in generating a theory of mind (Sperber and Wilson 2002), i.e. in inferring the mental states of their interlocutors, their perspectives, and communicative intentions. For example, in a nice experiment by Brune and Bodenstein (2005), the performance of a group of persons with schizophrenia on a test assessing theory of mind predicted 39% of variance on a different test focusing on the comprehension of proverbs. Therefore, their pragmatic impairment may be related to a deficient ability to generate a theory of mind of their interlocutors that, in turn, may result from a more generalized cognitive impoverishment (Linscott 2005). Indeed, this interpretation of the data seems in agreement with their narrative profile. The speech of

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patients with schizophrenia is usually reported as disturbed, filled with irrelevant pieces of information and derailments (Andreasen 1979). Several studies confirmed the presence of problems dealing with both local and global coherence (e.g. Marini et al. 2008; Ditman and Kuperberg 2010; Kuperberg 2010; Perlini et al. 2012). Local coherence indicates the establishment of a conceptual connection among contiguous utterances, whereas global coherence refers to the conceptual connection among long-distant sentences. In Marini et al. (2008), for example, the group of schizophrenic participants produced samples of narrative language characterized by significantly more errors of both local and global coherence than those found in the language samples produced by the group of healthy participants. Indeed, their story-descriptions were barely informative and characterized by empty speech and the erratic insertion in the flow of speech of tangential utterances not directly linked to the main theme of the description. As previously noted, once measures of macrolinguistic discourse processing were included in the analysis as covariates, differences in the production of percentage of semantic paraphasias were no longer detectable. This indicates that the semantic errors produced by the participants with schizophrenia were an epiphenomenon of more general difficulties in the construction of a coherent, well-organized narrative. Furthermore, they were also significantly less informative than the group of healthy control individuals. A percentage of lexical informativeness was used to evaluate the informative levels of their narrative samples. This measure indicates the percentage of the uttered words that were not only phonologically well formed, but also appropriate from a grammatical and pragmatic point of view (e.g. Marini et al. 2011). It is likely that the abilities to produce coherent narratives and select contextually appropriate words rely on higher-order cognitive functions such as attention, executive functions and working memory, that make cognitive control possible (see also Chapter 10). Broadly speaking, the concept of cognitive control refers to the processes involved in carrying out goal-directed behaviors in the face of conflict (Rougier et al. 2005) and includes the ability to process the contextual information necessary to perform a given task (Becker et al. 2012). Interestingly, in Marini et al. (2008), the production of errors of global coherence correlated with scores obtained in tests assessing attention and working memory (e.g. trail making B; Reitan 1992), whereas the percentage of lexical informativeness correlated with the patients’ performance on the Raven’s progressive matrices (Raven et al. 2003), a test assessing non-verbal reasoning skills. Several studies confirmed in these patients the presence of problems with attention and other high-level cognitive abilities. For example, in a recent study attention, working memory and conceptual sequencing explained 29% of the variance in a measure of communication failure (Docherty 2012). Furthermore, when neurocognitive and social cognitive variables (i.e. emotion perception and theory of mind) were combined, they

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explained 51% of the variance in speech disorders in the group of patients (Docherty et al. 2013). Furthermore, there is also evidence in these patients of an association between altered linguistic production and problems with cognitive control (Harvey and Serper 1990; Docherty and Gordinier 1999; Kerns and Berenbaum 2002; Melinder and Barch 2003; Becker et al. 2012). For example, Becker et al. (2012) showed that, in these patients, poor skills of goal maintenance and verbal working memory storage might be related to alogia and the production of disorganized speech. In a similar way, converging evidence shows that these patients exhibit also difficulties with working memory. This is a complex cognitive function, which allows us to keep all necessary information online until a given task has been completed. According to an influential model, working memory is made up of four main components (e.g. Baddeley 2000): a visuo-spatial sketchpad; a phonological loop; a central executive; an episodic buffer. Persons with schizophrenia are particularly impaired in the central executive component that allows the manipulation of visual and verbal information allocated in the visuo-spatial and in the phonological subsystems (Barch 2005). As such, the central executive is likely involved in higher-order levels of linguistic processing (i.e. macrolinguistic). Overall, then, disturbances of working memory, along with additional deficits in the ability to pay attention to context may significantly contribute to generate difficulties in the phase of conceptual planning of the message and, at the lexical level, problems in the process of lexical selection. In the past 20 years, accumulating evidence from neuroimaging studies has further corroborated the hypothesis of a connection between problems in cognitive control, attention and working memory and the observed difficulties in the generation of coherent and informative narratives. Indeed, the deficits in context processing in patients with schizophrenia have been related to frontal cortical dysfunctions (Wood and Flowers 1990; Curtis et al. 1998; Barch et al. 2003; MacDonald et al. 2005). For example, MacDonald et al. (2005) showed that, when engaged in tasks requiring high context processing demands, healthy individuals and psychotic participants (but not persons with schizophrenia) experienced increased activity in the middle frontal gyrus, whereas patients with schizophrenia did not. Interestingly, also deficits in working memory in schizophrenia, and especially those involving the central executive component, have been specifically linked to bilateral functional alterations in the dorsolateral prefrontal cortex (Yoon et al. 2008), which is massively altered in persons with schizophrenia (e.g. Seidman et al. 1994; Zhou et al. 2007; Potkin et al. 2009; Volk and Lewis 2010). In a recent voxel-based morphometry study focusing on the same participants with schizophrenia enrolled in the Marini et al. (2008) study, Spalletta et al. (2010) explicitly showed that the altered production of global coherence errors and informative words were related to an altered brain network controlling linguistic behavior and including both subcortical and cortical frontal regions. More specifically,

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the deficit in lexical informativeness was linked to alterations of the left nucleus accumbens, together with volumetric alterations in a sub-region of the left dorsolateral prefrontal cortex that has recently been shown to play a pivotal role in the process of selection of contextually appropriate semantic representations among competing alternatives (Marini and Urgesi 2012; see Figure 11.1). Overall, these findings suggest that, in schizophrenia, the malfunction of a distributed cortico-subcortical network involving the left dorsolateral prefrontal cortex may lead to insufficient context processing and working memory disturbances and, ultimately, to altered high-level narrative abilities that trigger the production of errors of global coherence and reduce the amount of relevant information conveyed by the text/discourse.

Ll FG : X = -54, y = 18,

z = 20

Figure 11.1 Representation of the epicenter in the left inferior frontal gyrus (LIFG) found involved in the selection of informative words in individuals with schizophrenia (Spalletta et al. 2010) and healthy individuals (Marini and Urgesi 2012). The indicative outlines of BA 44 (in white) and BA 45 (in black) are delineated on the brain rendering to facilitate the localization (modified from Marini and Urgesi 2012)

Conclusions In this chapter we have discussed the available knowledge about language production in persons with schizophrenia. The picture emerging from this analysis of the literature confirms that linguistic deficits are highly pervasive in these patients. However, the discussion of the literature has also showed that the linguistic symptoms may often be an epiphenomenon of

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more general disturbances. This should restrain clinicians from overgeneralizing data obtained with traditional standardized tests for language assessment that focus on highly specific aspects of language production (i.e. semantic, morphological, and the like). Rather, they should include in their clinical practice procedures of narrative assessment in order to have the “big picture” of a patient’s real linguistic abilities. For example, even if several investigations have pointed to a potential “semantic deficit” in these participants, the application of a multilevel analysis of their discourse productions has clearly shown that the semantic disturbances can mask inner problems in the ability to generate a coherent situation model that may, in turn, be linked to more general difficulties in cognitive control. A final remark concerns the potential anatomo-functional correlates of the linguistic deficits described in this chapter. Indeed, the narrative difficulties observed in schizophrenia are apparently connected to structural and/or functional alterations in a widespread fronto-temporal and subcortical brain network, as suggested by both electrophysiological and neuroimaging studies (Marvel et al. 2004; Kircher et al. 2005; Kuperberg et al. 2007; Kuperberg 2008; Bellani et al. 2009). Together with subcortical regions (i.e. nucleus accumbens; Spalletta et al. 2010), this network includes frontal areas (i.e. left dorsolateral prefrontal cortex and premotor cortex) that are also crucial for other fundamental cognitive functions such as working memory, context processing and sequencing. Interestingly, the dorsolateral prefrontal cortex, together with a more diffuse white matter disruption in the above mentioned network, has been hypothesized to play an important role in the etiology and expression of schizophrenia-spectrum disorders (Bertolino et al. 2000; Woods et al. 2007; Zhou et al. 2007; Andreone et al. 2007; Potkin et al. 2009; Volk and Lewis 2010; Barch and Ceaser 2012; Castellani et al. 2012). Future studies should further analyze these important aspects of communication in schizophrenia.

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12 Social premorbid adjustment and linguistic abilities in first-episode schizophrenia Paula Suárez-Pinilla, Nicholas Chadi, Rosa Ayesa-Arriola and Benedicto Crespo-Facorro

Schizophrenia is a psychotic disorder usually characterized by withdrawal from reality, which involves alterations in cognition and emotions, language and thought, perceptions and affect. It is characterized by positive symptoms, such as delusions, hallucinations, disorganized thinking and disorganized behavior, and by negative symptoms, such as abolition, anhedonia, alogia and affective flattening (American Psychiatric Association 2000). Precisely identifying the onset of psychotic symptoms in an individual’s life course is a challenging task. In fact, psychotic disorders are highly dynamic in nature, and they present with great levels of inter-subject variability. Research has clearly shown that, in the early stages of psychosis, spontaneous mechanisms governing social interactions are altered (see also Chapter 8), bringing characteristic and recognizable changes in social capacities. Sentiments of strangeness or familiarity appear, sometimes in alternation, producing great instability. In these moments, individuals experience a state of “great worry”, a perception that implies an estrangement of the subject from the rest of his or her social group and which brings along uncertainty and distrust. As a result, social isolation is often seen in the prodromal phase of a first psychotic episode (Grivois and Grosso 1998). Importantly, the changes in language often seen in the early stages of psychosis contribute to the exacerbation of social isolation (Figure 12.1). Language, being the most valuable instrument of interpersonal communication, it is important to note that it is not limited to the simple expression of thoughts, but also includes mechanisms to allow thoughts and ideas to be understood by others (Frith 1992). Language disorders have long been considered a diagnostic indicator of schizophrenia. The main requirement to take into account is the knowledge, beliefs and attitudes of the interlocutor. This is often affected in the speech of patients; language is right in vocabulary and syntax, but there is a failure to structure the speech at higher levels (pragmatic use of discourse; Crow 1997, 1998; Frith 1992; see also Chapter 11). From an evolutionary perspective, authors such as T. J. Crow (1997, 1998), have proposed theories in relation to the central paradox that psychosis is associated with a substantial

Social premorbid adjustment and linguistic abilities

Premorbid adjustment

Language and social abilities First-episode psychosis

Changes in language

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Lack of hemisphere dominance for language

Premorbid personality Theory of mind

Figure 12.1 Interaction between social skill deficits and linguistic disabilities in psychosis

biological disadvantage, relating the genetics of cerebral lateralization to predisposition to psychosis (for a comprehensive discussion on this issue see also Chapter 4). The origins of the psychoses would relate particularly to cerebral asymmetry, associated with the specific human capacity for language (see also Chapter 6). Therefore, psychotic symptoms arise as confusions between thought and speech and through the abnormal attachment of meaning to perceived speech.

Premorbid personality It is often difficult to distinguish normality from the prodromal phase of a first psychotic episode. Yet, one might recognize a set of early symptoms that are strongly suggestive of a developing psychotic disorder. For instance, social isolation, sometimes seen with suspiciousness and magical thinking, dysthymic or anxious mood, a decrease in motivation and a decrease in the number of goal-directed behaviors might together result in a gradual decrease in the global level of functioning. These symptoms often precede the onset of active psychotic symptomatology and yield many similarities with other clinical entities, such as cluster A personality disorders. The significance of the specific prodromal elements mentioned above remains uncertain; could these represent etiological precursors of different types of psychotic disorders, or rather, could they influence and modulate the characteristics of the disorder without any causal significance? More research is needed to answer these questions (Schultze-Lutter et al. 2012; Yasuda et al. 2011).

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The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) suggests that cluster A personality disorders represent potential premorbid factors in the development of psychosis (American Psychiatric Association 2000). Individuals presenting with these disorders commonly struggle in their interpersonal relationships, owing to the extravagance of their behavior (often guided by their beliefs) and perform poorly in the theory of mind (one’s capacity to infer other peoples’ mental states). It is important to emphasize that those individuals with cluster A personality disorders can act in a very strange and unusual manner, but usually maintain contact with reality; they generally do not experience any perceptual alterations. In addition, it has been demonstrated that schizotypal personality disorders and schizophrenia are genetically related; some authors have even suggested that the first could be a phenotypically milder manifestation of the second (Ohi et al. 2012; Yasuda et al. 2011). It has been shown that, in individuals with a previous personality disorder, social roles change significantly after the conversion to schizophrenia. In a recent investigation by Schultze-Lutter et al. (2012), schizoid personality traits, (even more than schizotypal personality traits), were significant predictors of conversion to psychotic disorders. These traits were also related to more severe and persistent deficits in later converters. Prosody is the branch of linguistics that analyzes the concrete manifestations of words through their phonetic suprasegmental features. Individuals with schizotypal personality disorders frequently experience difficulties with the process of prosody. A deficit in prosody implies problems interpreting and organizing speech, decoding messages and meanings, as well as understanding emotional and social aspects of speech. This inevitably interferes with one’s ability to communicate and engage in appropriate social interactions (Cohen and Hong 2011). In 2010, an investigation conducted by Dickey et al. (2010) used functional magnetic resonance imaging (fMRI) to compare cerebral activity in healthy subjects and in subjects with a schizotypal personality disorder in tasks requiring the identification of prosody. Significant levels of electrical activity were seen in the superior temporal gyrus in both groups of subjects. Interestingly, a subsequent volumetric study showed a tendency towards smaller volumes in the left superior temporal sulcus (which partially superimposes with the superior temporal gyrus) in schizotypal patients. Thus, the well-documented alterations in executive functioning and phonological processing seen in subjects with a schizotypal personality disorder seem to contribute to the difficulties in the processing of prosody. This might correlate at least to a certain extent with the neuroanatomic variations observed in these patients (Dickey et al. 2010). The schizotypal personality trait of odd speech shares features with the disorganized speech seen in schizophrenia. Schizotypy is associated with differences in how meaningful stimuli activate related concepts in semantic

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memory. There are discordant results regarding semantic memory in schizotypy; an increased spread of activation to weakly related concepts at relatively short time intervals after a given meaningful stimulus, followed by decreased use of this context to activate related concepts at longer time intervals. In both, decreased left lateralization of language processing and prefrontal dysfunction are involved (Kiang 2010).

Premorbid adjustment in first episodes of psychosis Based on the concept defined by Strauss et al. (1977), premorbid adjustment refers to a person’s characteristics, with a special focus on interpersonal relations and occupational functioning, at any moment before the manifestations of florid schizophrenic symptoms. In other words, premorbid adjustment can be considered as a measure of the psychosocial “maturity level” reached by a subject before the beginning of schizophrenia. Premorbid adjustment must be understood as a biopsychosocial concept. It is predictive of the level of competence and psychosocial resources available to the individual at the onset of disease. Premorbid maladjustment is defined by the failure to reach one or more of these goals of maturation before the initiation of treatment (Strauss et al. 1977). Premorbid functioning is not a unitary construct and can be separated in at least two independent dimensions: social and academic (Greden 1991). Poor social premorbid adjustment is associated with negative symptoms. As such, poor premorbid social adjustment and significant social deterioration from childhood to adolescence may be hallmark features for people who will later on develop prominent negative symptoms. A poor premorbid social adjustment is also a unique marker for deficit subtype schizophrenia (Strauss et al. 2012). Poor previous adjustment, both social and academic, is associated with the severity of the general psychopathology (Monte et al. 2008); it also suggests neurodevelopmental anomalies before the onset of symptoms, which may serve as a unique premorbid marker for schizophrenia (Allen et al. 2005). Schizophrenic patients usually show similar degrees of social and academic deteriorations during childhood and early adolescence. However, there is a pronounced decline in the academic domain during late adolescence in first episodes of schizophrenia (Allen et al. 2005; Norman et al. 2005). A worse academic premorbid adjustment is common in first episodes of non-affective psychosis but not in affective psychosis. These results come from samples of patients in the early stages of nonaffective psychosis and contrast with previous studies of chronic patients, which suggested that social deterioration was greater than academic deterioration (Silverstein et al. 2002). Social and academic premorbid adjustments show different relations to gender and specific diagnoses in schizophrenia and related disorders. Females and those with a diagnosis of

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schizoaffective disorder were found to have better premorbid adjustment in the academic domain, but not in the social domain (Norman et al. 2005). A prospective data analysis about scholastic test results for subjects who later developed schizophrenia obtained a significant linear decrease in language scores over time; test scores dropped significantly between grades 8 and 11. This corresponds to ages 13–16 years, or the onset of puberty. Poor or declining scholastic performance may be a precursor to the cognitive impairment seen during the first episode of illness (Fuller et al. 2002). In evaluating a patient with a psychotic illness with such symptomatic variability as schizophrenia, it is thought that an evaluation process, which takes onset, course and outcomes into account, offers a comparative advantage in front of a one-time “snap-shot” type evaluation. Consequently, many investigations have used the level of premorbid functioning as an indicator for sub-classification of patients. This has led to the discovery of a significant relation between premorbid social functioning and long-term prognosis of schizophrenia. For a long time, it has been well known that patients who had undergone a first psychotic episode and who had a weaker premorbid social adjustment would show significantly higher relapse rates (Bodén et al. 2009; Rabiner et al. 1986). Interestingly, female patients usually tend to show higher levels of premorbid functioning. According to a range of measures, men have poorer premorbid adjustment and present with worse negative and less depressive symptoms than women, which may explain their worse medium term outcome. Findings of genderbased differences in brain morphology are inconsistent, but are present in areas that normally show sexual dimorphism, implying that the same factors are important drivers of sex differences in both normal neurodevelopmental processes and those associated with schizophrenia (Malla and Payne 2005). In addition, a significant correlation between poor premorbid social adjustment and the presence of premorbid personality changes seems to exist. This is especially the case in personality disorders that share common genetic characteristics with psychotic disorders, such as schizotypal and schizoid personality disorders (Silverstein et al. 2002). In first-episode psychosis, premorbid functioning is more important than other factors such as gender, duration of untreated psychosis, age of onset, or family burden in determining long-term outcomes and response to treatment. A study of 131 patients included in the Program of Assistance in the Initial Phases of Psychosis (PAFIP, Cantabria, Spain) describes the relations between clinical and functional variables before treatment and cognitive functioning after treatment (see Chapter 13 for a debate on cognitive remediation). The study concluded that a poorer premorbid social adjustment was associated with greater difficulties in executive functioning, motor dexterity and sustained attention (González-Blanch et al. 2007). The response to pharmaceutical treatment also appears to be an important element in the study of first psychotic episodes. One study that included

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172 patients who were part of the PAFIP program showed that patients with an earlier age of onset, a poorer premorbid adolescent functioning and milder psychopathology at the moment of onset were less likely to respond positively to pharmaceutical treatments. These findings place individuals presenting with a first psychotic episode and a weaker premorbid adjustment in their teenage years in a group of vulnerable individuals for which pharmaceutical treatments must be optimized (Crespo-Facorro et al. 2007). The increased incidence of psychosis in immigrants and other minority groups once again suggests that social factors play an important role in the etiology of psychosis (Schrier et al. 2001). In addition, Selten et al. (2010) have argued that states of social exclusion and social debacles are accompanied by levels of mesolimbic dopaminergic hyperactivity that are similar to those encountered in samples of untreated patients. This suggests that, in human beings, social exclusion can lead to increases in mesolimbic dopaminergic activity, thus increasing the risk of developing schizophrenia (Selten et al. 2010). The study and measure of premorbid adjustment has been attempted since the early 1950s. In this process, researchers have created different rating scales. A few of the most notable scales are: •

•

•

Philips Prognostic Rating Scale (1953): One of the first scales developed, includes three parts: premorbid history, possible precipitating factors and signs of psychotic illness. Investigators have used the first part of the scale (premorbid history) to divide patients into groups of strong and poor adjustment (Garfield and Sundland 1996). Zigler-Phillips Social Competency Scale (1960): A few years after the development of the Philips Prognostic Rating Scale, other scales that included methodological refinements were introduced. This allowed researchers to adapt to new concepts and facilitated administration. The theoretical concept behind the Zigler-Phillips Social Competency Scale is that an individual’s adaptive potential and psychological resistance in facing environmental stressors is a key element of his or her ability to recover from crisis situations. The Social Competency Scale was developed to measure premorbid functioning in the general population. After being used for such purposes, it proved useful in measuring premorbid functioning in schizophrenia patients as well (Westermeyer and Harrow 1986). Cannon-Spoor Premorbid Adjustment Scale (1982): Developed in an attempt to remediate to the difficulties encountered with previous scales. The main objectives were to create a scale that would prove useful for research purposes while accurately conceptualizing good premorbid adjustment (Brill et al. 2008).

The Premorbid Adjustment Scale was primarily engineered to measure the degree of success in reaching a certain maturity level at different phases of

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life. Social isolation was seen as one of the most obvious signs of poor premorbid adjustment, especially if present in late adolescence. The capacity to initiative sexual interactions with others, and the ability to function adequately outside the home (in college for example), were perceived as vital (Eggers and Bunk 2009). This scale was most widely used for the study of premorbid adjustment in schizophrenia. Its accuracy and predictive value for different aspects of the course of psychotic illnesses were confirmed in a broad number of studies (Brill et al. 2008). In summary, the alterations found in premorbid adjustment in patients with first psychotic episodes can relate to one of the following hypotheses: • • •

Alterations in premorbid adjustment could be a manifestation of a subject’s vulnerability to developing a psychotic illness. Alterations in premorbid adjustment could be a direct and early clinical manifestation or an early stage of psychosis. Alterations in premorbid adjustment could be a manifestation of other previous disorders that are related to or predictive of psychosis; for example, a personality disorder.

After the resolution of psychotic symptoms, a stable social life and a good level of social functioning have a significant influence on an individual’s long-term prognosis independently of negative symptomatology, which demonstrates the fundamental importance of early psychosocial interventions (Albert et al. 2011; Jeppesen et al. 2008). However, in the specific case of schizoaffective disorders, lower levels of negative symptoms might be a predictor of better outcomes and quality of life in the early stages of remission, when seen in conjunction with elevated, expansive, or irritable mood (Macmillan et al. 2007). It is important to consider the moment at which social adjustment is assessed. Recent studies have reported that social adjustment measured at the moment of admission in patients presenting with a first psychotic episode cannot be considered a valid prognostic marker for relapse (Jeppesen et al. 2008). Rather, in these patients, the most accurate indicator seems to be social adjustment after clinical stabilization (Velthorst et al. 2011). Finally, neuropsychological interventions in the early phases of psychosis seem to produce better results than later interventions. This suggests that there might be a parallel between schizophrenia and conditions that have an impact on neurodevelopment (Drury et al. 1998).

Theory of mind Before discussing language abilities of patients with schizophrenia, it is essential to say a few words about the theory of mind (ToM). This is defined as “the ability to infer, in oneself and in others, independent mental states

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such as desires, beliefs and emotions” (Frith 1992) . Other authors describe it as the skill to make inferences, interpretations and predict actions of oneself and others (Baron-Cohen et al. 2001; Guinea-Hidalgo et al. 2007). Theory of mind is one of the fundamental pillars of human social interactions. It comprises several cognitive levels, based on the reciprocal nature of social interaction, as observed in joint attention, the functional use of language, and the understanding of others’ emotions and actions. Some studies show significant differences in cognitive and emotional processing tests between patients with schizophrenia and healthy controls (Guinea-Hidalgo et al. 2007). In patients with schizophrenia, deficits in ToM are more specific indicators of the disorder than alterations in classic cognitive abilities such as attention, memory and language. There are small yet significant variations between different schizophrenic subtypes. For instance, in paranoid schizophrenia, especially if delusions are omnipresent, the alteration in ToM tends to be less intense and is thought to be mostly due to the inappropriate usage of contextual information. In disorganized schizophrenia, ToM and verbal intelligence are strongly correlated. In other subtypes of schizophrenia, the greater the importance of negative symptoms, the greater the deficits in ToM, especially if symptoms resemble those seen in autistic spectrum disorders. Many psychotic symptoms, for instance delusions of control and persecution, may best be understood in light of a disturbed capacity in patients to relate their own intentions to executing behavior and to monitor others’ intentions (Montag et al. 2011; Pickup and Frith 2011). Furthermore, some authors argue that the impairments in ToM could also be considered a consequence of other cognitive deficits (also encountered in schizophrenia) which precede and cause the disorder (Shamay-Tsoory et al. 2007). Anatomically, the areas that seem to have the greatest importance in determining abilities in ToM are the prefrontal cortex – especially the paracingulate cortex – the temporal cortex and the heteromodal cortical connections. The prefrontal cortex is the area that has allowed the development of human social intelligence. This is an area that shows consistent alterations in patients with schizophrenia (Selma-Sánchez 2008). Some authors have suggested that the mirror neuron system can contribute to the understanding of pathologies such as autism and schizophrenia, where it is related to the processing and meta-representation of movements, and especially, of “socially relevant actions” performed by other individuals. The importance of mirror neurons in ToM, essential in the acquisition of imitative functions, was confirmed in both humans and primates. In humans, these mirror neurons are neuroanatomically related to the premotor and inferior parietal cortices. Hence, a deficiency in the capacity to imitate others can lead to alterations in social roles and perceptions, which are often seen in individuals with psychotic disorders (Oberman et al. 2007).

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Deficits in ToM are strongly correlated with the use of irony, but not with the use of metaphors. In a study published in 2002, Langdon et al. claim that these two abilities each relate to separate cognitive processes. On the one hand, deficits in ToM and in the use of irony are related to important alterations in thought processes (leading to disorganization). On the other hand, deficits in the comprehension of metaphors are related to negative symptoms and executive functioning (Allen et al. 1993; Koelkebeck et al. 2008).

Changes in language in psychosis Language is produced via an interaction of a series of linguistic levels of representations interacting directly with one another (e.g. phonetic, phonological, prosodic, syntactic, lexical and semantic; for a detailed discussion on this issue, see also Chapter 11). Each component of the language-processing system interacts with and can be influenced by outside cognitive systems and processes, such as attention, working memory, executive functioning and non-linguistic semantic memory. Interestingly, patients seem to keep their lexical and semantic capacities relatively intact, with alterations in either or all of the four other linguistic representations (Allen et al. 1993; Andreasen 1979). When one examines coarse linguistic markers, people with schizophrenia use language relatively normally when compared with people with other neuropsychological conditions. For example, they do not have the halting unintelligible speech of Broca’s aphasia, nor do they produce the ‘‘word salad’’ classically attributed to Wernicke’s aphasia (although a minority of patients with severe formal thought disorder produce a ‘‘word salad’’ of their own). Thus, the impairments are both more subtle and intermittent than those observed in neurological disorders (Crow 1997; Frith 1992). As with other symptoms, language disorders can manifest in psychotic patients in a positive or negative form. For instance, slurring of speech and lack of speech content are examples of negative symptoms, while incoherence and speech derailment are examples of positive symptoms. Positive thought distortions are generally associated with acute schizophrenia and often improve with neuroleptic treatment. Of note, disorganized and unintelligible speech, other examples of positive linguistic symptoms, are a strong predictor of maladaptive social and vocational functioning (Kerns and Berenbaum 2002). There are at least two kinds of language impairments seen in psychotic patients: thought disturbances, or failure to maintain a coherent discourse plan, and schizophasia, which comprises various dysphasia-like impairments such as the use of neologisms and unintelligible utterances (Covington et al. 2005). Thought disorders and communication disturbances resulting in deviant verbalizations occur more frequently in first-degree relatives of patients than schizophrenia itself. This finding suggests that deviant

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verbalizations may represent a more penetrant familial expression of schizophrenia susceptibility genes than the illness in its full-blown form (MacDonald et al. 2009). Linguistic abilities are often affected in first psychotic episodes, further enhancing characteristic social deficits. Some of the most common alterations found in the language of patients presenting with a first psychotic episode are shown in Table 12.1. In a study of subjects who were in the early phases of psychosis, the complexity of discourse was low, even in the very initial stages of illness: their language was syntactically less complex than in control subjects. This difference persisted and was significant even after adjustment for social class, working memory, and attention (Thomas et al. 1996). It has been demonstrated through different psycholinguistic tests that subjects with schizophrenia show significant gaps in pragmatics, the component of language involving rules for effective and appropriate communication. This is also corroborated by the evidence that schizophrenia can cause specific structural alterations in language (textual and morphosyntactic; see Chapter 11). These difficulties in the capacity of structuring and ordering the different macrotextual constituents of speech are consistent with the hypothesis of a general cognitive deficit in subjects with schizophrenia (MacDonald et al. 2009).

Table 12.1 Some of the most common alterations found in the language of patients presenting with a first psychotic episode Language component

Alteration

Description

Non-verbal language

Facial expression

Lack of facial expression, lost gaze, inappropriate laughs

Physical contact

Inappropriate distancing or invasion of the interlocutors’ space

Volume of voice

Alterations

Tone of voice

Unexpressive or flat tone of voice (possibly disconnected from the message to be transmitted)

Speed of speech

Marked increase of speed or slurring of speech

Speech content

Monosyllabic responses often requiring multiple questions before desired answers can be obtained

Paralinguistic

Verbal

Answers to questions Monotonous content (often with no specific interest and frequently delirious), literal sentences (without metaphors)

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In one magnetoencephalographic (MEG) study of cross-modal semantic priming, the classic semantic priming effect, which is notoriously variable in behavioral studies of schizophrenia, was investigated. Intriguingly, the results show that whereas behavioral measures of priming (lexical decision responses) are relatively normal, the MEG response is not, suggesting that patients may recruit alternative neural circuits to maintain normal behavioral performance (Froud et al. 2010). Finally, a few other illnesses can mimic some or many of the language alterations seen in the early stages of psychosis. Three of the most relevant examples are: •

•

•

Mania: In manic individuals, positive language symptoms can be quite striking, but the thought process is less disorganized than in patients with schizophrenia. The use of neologisms is also much less important (Solovay et al. 1987). Wernicke’s aphasia: Patients with Wernicke’s aphasia show important deficits in the comprehension of speech, and produce speech samples that are partly or even completely devoid of meaning. Individuals with this type of aphasia may speak in long, meaningless sentences (logorrhea), add unnecessary words and neologisms when they speak, and erroneously exchange some words for others (semantic/verbal paraphasias). It seems that schizophrenic speech presents with more obvious bizarre themes, while aphasic individuals tend to show more paraphasic errors (Gerson et al. 1977). Autism spectrum disorders: Patients presenting with autism spectrum disorders have greater syntactic and pragmatic language symptoms, such as delayed echolalia, pedantic speech, and deficits in the appreciation of irony and sarcasm. Evidence shows that degrees of impaired social reciprocity are usually higher than in first episode of psychosis (Solomon et al. 2011).

Lack of hemispheric dominance for language The use of language plays many important roles in promoting social interactions, communication and cognitive functioning. It also allows for the attainment of high levels of cognitive and behavioral self-regulation. The use of language can be considered in two different ways. First, by the individual’s role in the communication process, as either a transmitter or receiver; and second, by considering which transmission channel is used, either oral or written. The production of languages relies on the dominance of its critical components in either one (or sometimes both) of the cerebral hemispheres. In the general population, over 90% of righthanded individuals show left-cerebral hemispheric dominance for language. The most pronounced of these asymmetries are present along the sylvian fissure in the superior temporal lobes in the area including

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Wernicke’s area (DeLisi et al. 1994). Thus, the human brain differs from that of all others mammals by having four quadrants of association cortex (left and right motor and left and right sensory), each with a distinct function. This communication complex is what enables human language abilities (Crow 1998). The normal, asymmetric brain is affected in schizophrenia. Language development, which requires hemispheric specialization, is altered, and results in incomplete lateralization, which affects inter-hemispheric communication and associated processes of language flexibility and ideational fluency. In men, greater asymmetry of the brain is correlated with a greater severity and earlier onset of schizophrenia (Crow 1997). Some elements of these theories have been recently criticized. One model proposes a single X-linked gene as being solely responsible for cerebral dominance, which might explain the anatomical and clinical differences between men and women with schizophrenia. This model contrasts with a second model, which suggests a polygenetic model for schizophrenia. There is also evidence that brain asymmetries are altered in patients with dyslexia and other developmental language problems, but this does not correlate with a higher incidence of schizophrenia (Angrilli et al. 2009; Sanjuán 1999). Recent neuroimaging studies have led to the illustration of these asymmetries. For instance, when compared with a group of healthy subjects, individuals with schizophrenia have a smaller Wernicke’s area in their dominant cerebral hemisphere. Furthermore, studies using diffusion tensor imaging to explore white matter organization show a fronto-temporal dysfunction as well as an inversion of the right–left lateralization in schizophrenic individuals. These anomalies cause a functional impairment predictive of damage in cognitive areas, which can lead to a better understanding of the changes underlying different psychotic symptoms. Hence, some of the characteristic symptoms of psychosis, such as difficulties in the interpretation and organization of speech, can be understood as alterations in normal brain asymmetries and cerebral hemispheric dominance (Sommer et al. 2001). In first psychotic episodes, the asymmetries in cortical structures at the level of the temporal and occipital lobes have a significant impact on cortical volumes. For instance, the increase in volume of cerebral ventricles and resulting decrease in cortical thickness-typical findings in the neuroimaging of schizophrenia – are thought to be a consequence of the overall decrease in volume of the left cerebral hemisphere and more specifically of the horizontal segment of the sylvian fissure (Honer et al. 1995).

Language and social abilities Spoken language is an excellent model of human behavior, important not only in playing a relational role between individuals, but also in fulfilling a

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communicative function. The cerebral structures that most closely relate to the cognitive decline, negative symptomatology and decreased premorbid adjustment seen in patients are the temporal lobe, the hippocampus, the caudate nucleus and the frontal lobe (Shamay-Tsoory et al. 2007). These structures also show the highest level of atrophy in these patients. In addition, subjects presenting with a first psychotic episode often have a deficit in the recognition of emotions (such as fear or sadness) through facial and phonetic modalities. This suggests a dysfunction at the level of the amygdala (Edwards et al. 2001). The main areas involved in social abilities (dorsolateral prefrontal cortex, Broca’s area, superior temporal cortex and inferior parietal cortex) are, for the most part, the last areas to reach complete development in children. These areas are also the sites of significant alterations in patients suffering from schizophrenia (Honer et al. 1995). At the neuroanatomic level, social abilities require complex interactions involving various cerebral structures working hand in hand: Verbal language areas in the left hemisphere, non verbal language areas in the right hemisphere, as well as frontal areas in charge of advanced cerebral functions such as abstract thinking and use of symbolism in language.

Conclusions The early phases of psychosis must be considered as a critical therapeutic period. In fact, a shorter duration of untreated psychosis is fundamental for the secondary prevention of potential long-term morbidity and incapacity. Premorbid social adjustment is of vital importance in predicting the prognosis of psychotic disorders. Moreover, it can provide guidance in setting therapeutic goals as well as in validating the efficiency of different treatments. The presence of an underlying personality disorder at the time of a first psychotic episode is correlated with inferior levels of premorbid adjustment. As it is the case with actions, patients with schizophrenia have difficulties generating spontaneous and coherent ideas while speaking. They often lack the ability to construct sentences in a way that is easily understood by others. This is very similar to what is seen in patients who have suffered frontal-lobe injuries, underlying the importance of frontal-lobe deficits in schizophrenia. Language impairments found in patients with schizophrenia can be divided in two categories: Problems with the thought and conceptualization of language, and problems with the production of language. When seen together, they most often lead to serious communication problems. The lack of normal asymmetry of brain lateralization compared with healthy subjects may explain, in part, language disturbances in first episode of psychosis. The abnormal hemispherical communication interrupts the normal flow of information processing. Other brain morphologic alterations could be significant reductions in

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cortical thickness and cortical gray matter volume. Among others, reading inability, problems in perception and in motor coordination may indicate a substantial risk to develop a mental disorder, such as schizophrenia. Considering the heterogeneity of symptoms and prognosis encountered in first psychotic episodes, it appears necessary to separate these episodes in different categories based on subtypes and phenotypes. Patients sharing similar courses of illness and characteristics at presentation – with special attention to alterations in language and social adjustment – should be considered, together in future studies addressing the diagnosis and treatment of schizophrenia.

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13 Symptoms, thought disorders and cognitive remediation treatment in schizophrenia Antonio Vita and Luca De Peri

The importance of cognitive impairment in people with schizophrenia has been established since Emil Kraepelin’s first description of the illness as dementia praecox (Kraepelin 1919). Nowadays, cognitive deficits are considered a core feature of schizophrenia, detectable at the onset of the illness (Gopal and Variend 2005), in neuroleptic-naïve patients (Saykin et al. 1994; Hill et al. 2004), and even in the prodromal phase of the disease (Simon et al. 2007; Fusar-Poli et al. 2012), and such impairment persists with the progression of the illness (Heaton et al. 2001; Morrison et al. 2006). Almost all patients demonstrate some decline in measures of neurocognitive functioning and the global cognitive deficit in schizophrenia averages between one and two standard deviations below the mean of healthy control subjects (Green et al. 2004), with prominent impairment in psychomotor speed, attention, verbal and working memory, and executive functions (Lee and Park 2005; Dickinson et al. 2007; Knowles et al. 2010). These deficits have been demonstrated to underlie part of the functional disability associated with the disorder (Jaeger et al. 2006; Niendam et al. 2006). Several studies have also shown that cognitive deficits are related to poorer outcome in different functional domains (Bowie et al. 2006, 2008), quality of life and psychosocial rehabilitation interventions (Evans et al. 2004; Green et al. 2004; Milev et al. 2005, Raffard et al. 2009). A consistent amount of research and clinical data suggest that the impact of pharmacological treatments on cognitive deficit of schizophrenia is at best modest. Conventional antipsychotics, which primarily block D2 dopamine receptors, may demonstrate no effect (Berman et al. 1986), or minimal beneficial effect on cognitive functioning (Serper and Harvey 1994), or can even further impair cognitive functioning (Sweeney et al. 1991). Also, traditional antipsychotics cause extrapyramidal symptoms, which significantly decrease speed of cognitive tasks involving motor output and readiness to respond. According to numerous studies (selectively reviewed, for instance, by Cassens et al. 1990 and Mortimer 1997), there is evidence that the effect of conventional antipsychotics on cognitive impairment of schizophrenia is small, with the exception of occasional improvement of attention (King 1990; Goldberg and Weinberger 1996).

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On the other hand, many other studies, reviewed for instance in the metaanalysis of Keefe et al. (1999) and Fakra et al. (2011), have suggested that treatment with second-generation antipsychotics may provide greater neurocognitive benefit to patients with schizophrenia than that with firstgeneration antipsychotics. Nonetheless, many of these studies had substantial limitations, such as the inclusion of samples of small size, the short duration of treatment, the absence of a comparator or the use as comparator of high doses of first-generation antipsychotics, and inattention to important clinical factors such as the relationship between cognitive and symptom change, anticholinergic treatment, and change in extrapyramidal symptoms (Fakra et al. 2011). Moreover, it is important to underline that also the impact of atypical antipsychotics on cognitive functions is rather limited, given the evidence of a differential effect of secondcompared with first-generation antipsychotics small to moderate (effect size [ES] range = 0.17 to 0.46 in the meta-analysis of Woodward et al. 2005). With this more detailed knowledge of the role and meaning of cognitive deficits in schizophrenia and the evidence of the limited efficacy of pharmacological interventions in mind, improvement in cognitive functions by means of non-pharmacological strategies, especially the so called “cognitive remediation” techniques, has become a relevant research issue and a significant target in the care of schizophrenia (Twamley et al. 2003; McGurk et al. 2007; Wykes et al. 2011). Cognitive remediation is a type of rehabilitation treatment offering exercises aimed at improving attention, memory, language, and/or executive functions, by means of different intervention modalities defined by their procedural characteristics and the method of training. The expected result is not only a positive effect on the targeted cognitive function, but also an indirect positive impact on functional deficits affecting everyday life. Recently, several cognitive remediation techniques, computerized and non-computerized, designed for individual or group settings, have been developed and adopted in the multimodal treatment approaches to the disorder, and studies analyzing their efficacy have recently been reviewed quantitatively (McGurk et al. 2007; Grynszpan et al., 2011; Wykes et al., 2011). On one hand, computer-assisted cognitive remediation (CACR) techniques, which enable selective treatment of different cognitive domains, have been shown to improve neurocognitive functions in schizophrenia in a wide range of cognitive domains (Grynszpan et al., 2011). Moreover, a number of studies have demonstrated that CACR may also affect symptoms and the psychosocial functioning of patients with schizophrenia (Bellucci et al. 2003; Wexler and Bell 2005). On the other hand, several studies examining non-computerized, individual- or group-based cognitive remediation found a significant improvement in cognitive performance associated with an improvement in psychosocial functioning of schizophrenia (for reviews see McGurk et al. 2007; Roder et al. 2011; Wykes et al. 2011). Among the group interventions, a large body of

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research suggests that integrated psychological therapy (IPT; Brenner et al. 1994) has positive effects on the outcome of schizophrenia. In a recent review of 36 studies performed by Roder et al. (2011), positive mean effect sizes favoring IPT over usual treatment (placebo-attention conditions and standard care) were found in the domains of symptoms, psychosocial functioning and neurocognition. Moreover, IPT-treated patients maintained their mean positive effects during an average follow-up period of 8.1 months. The more extensive meta-analysis conducted by Wykes et al. (2011) on 40 studies including 2,104 participants treated with different remediation approaches demonstrated that cognitive remediation affects positively global cognition (ES = 0.45), social cognition (ES = 0.45), but also psychosocial functioning (ES = 0.42), and, at a lesser degree, symptoms of schizophrenia (ES = 0.18). The effects seem at least in part independent from the specific approach applied, but seem more robust in clinically stabilized patients and when cognitive remediation is provided together with other psychiatric rehabilitation (Wykes et al. 2011). Nevertheless, several key issues on the efficacy and limits of cognitive remediation interventions in schizophrenia have not yet been investigated. In particular, despite convincing evidence of the efficacy of cognitive remediation on cognitive functions and functional outcome domains, there is still much debate in relation to the impact of cognitive remediation on psychopathology of schizophrenia. In particular, the effects of cognitive remediation on core symptoms of schizophrenia, especially those known to be related with specific cognitive abilities and/or investigated with neuropsychological tests, as thought and language disorder (RodriguezFerrera et al. 2001; Stirling et al. 2006; Kerns 2007; Kiefer et al. 2009), are not known. In this chapter, we discuss the literature data on the effectiveness of cognitive remediation on symptomatology of schizophrenia, and on the neuropsychological functions considered to be related to language and thought disorders, some of which are directly targeted or trained by cognitive remediation interventions. We present our own data relative to the application of different modalities of cognitive remediation in the “realworld” rehabilitative treatment of schizophrenia, with particular emphasis on their efficacy on thought disorders.

Effects of cognitive remediation interventions on negative symptoms in schizophrenia The efficacy of both computerized and non-computerized cognitive remediation interventions on negative symptoms in schizophrenia has been investigated by a number of studies. For instance, the controlled study performed by Bellucci et al. (2003) using a CACR method consisting of 16 computer training sessions administered weekly over an eight-week period

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evidenced an improvement of negative symptoms, assessed by means of the Scale for the Assessment of Negative Symptoms, in 34 outpatients with schizophrenia (P < 0.001). Further evidences of efficacy of rehabilitation of cognitive deficits by means of CACR methods derives from a controlled study by Bark et al. (2003), conducted with the neuropsychological educational approach to remediation (NEAR). In this study, the subjects’ scores on cognitive tests and Positive and Negative Syndrome Scale (PANSS) were measured at baseline, after ten sessions of CACR, and again four weeks after treatment. Only the remediation group showed significant and persistent improvement of negative PANSS subscale both at the end of the study (P = 0.02) and four weeks post-treatment (P < 0.05). As for noncomputerized interventions, a study performed by our group (Vita et al. 2011a) showed that the administration of the cognitive component of IPT (the first two subprograms i.e. cognitive differentiation and social perception = IPT-cog) for 24 weeks may be beneficial specifically for negative symptoms, and to a lesser extent, global symptom severity. In particular, this controlled study evidenced a significantly higher improvement of the negative subscale of the PANSS in patients after cognitive rehabilitation as compared with the treatment as usual (TAU) group (P = 0.001). We replicated this finding in a subsequent and larger study aiming to assess effectiveness of different modalities of cognitive remediation embedded within an integrated pharmacological and psychosocial treatment of schizophrenia (Vita et al. 2011b). In this study, both the IPT-cog (n = 26 patients) and CACR groups (n = 30 patients) improved more than the comparison TAU group (n = 28 patients) with respect to negative symptoms (P < 0.001). However, other literature reports a series of negative findings on the putative efficacy of cognitive remediation on negative symptoms. In the randomized controlled study by Lindenmayer et al. (2008), where the cognitive remediation program consisted of 24 hours of computerized practice over a 12-week period, no difference in negative symptoms severity in 85 schizophrenic inpatients was detected, either at the end of the rehabilitative intervention or during a 12-month follow-up period. Similarly, in the randomized controlled study by Hodge et al. (2010), who applied the NEAR intervention in 40 individuals with schizophrenia, no significant changes of the negative PANSS subscale scores over the 15 weeks period of treatment and the four months follow-up were reported. Surprisingly, there is preliminary evidence that remediation interventions may have even a partial detrimental effect on negative symptomatology, at least in special populations of schizophrenic patients. Klingberg et al. (2012) demonstrated that a number of patients under remediation worsened their negative symptoms over a 12-month follow-up. However, the rate was comparable with respect to other psychological interventions (cognitive behavioral therapy) and was relatively low, given the severity of the psychotic symptoms. On the basis of their results, these authors suggest that therapists who administer cognitive rehabilitative interventions should be

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aware of a subgroup of patients who may show symptom increases and who might require more intensive care. In conclusion, the available literature on the issue of cognitive remediation in schizophrenia, although not univocal, supports the notion of its efficacy on negative symptoms of the disease, as well as the need for an accurate clinical evaluation of patients potentially eligible for remediation interventions. There is evidence of the efficacy of both CACR and noncomputerized interventions on this symptom dimension of schizophrenia.

Effect of cognitive remediation interventions on positive symptoms in schizophrenia The possibility of a significant effect of cognitive rehabilitation on positive symptoms remains uncertain, even though some encouraging evidence obtained with the application of CACR and non-computerized modalities already exists. In particular, the application of CACR techniques has proven to significantly reduce the positive symptoms subscale of the PANSS (P = 0.03) after ten sessions of treatment and again for weeks posttreatment in the controlled study by Bark et al. (2003) performed in a sample of 54 inpatients. The efficacy on psychotic symptoms has also been shown by Lecardeur et al. (2009) in a controlled study where cognitive remediation therapy was administered to 16 patients suffering from schizophrenia. Their results demonstrate that cognitive remediation therapy can be useful in reducing clinical symptoms, since a decrease of positive symptoms after treatment was found only in the “active” but not in the control group (P = 0.009). Moreover, in our own experience (Vita et al. 2011b), we found that, after six months of treatment, patients undergoing cognitive remediation, both CACR and non-computerized interventions (IPT-cog), demonstrated significantly greater improvement in all psychopathologic measures as compared with patients following the usual setting of psychiatric and psychosocial care. Both the cognitive subprograms of IPT and the CACR interventions had a significantly larger effect on positive symptom severity as measured by the PANSS than usual treatment (P < 0.001). A possible explanation, although speculative, of the efficacy of cognitive remediation on positive symptoms of schizophrenia could be that improvement in cognitive functions may positively affect the patient’s insight into illness, which has been reported to correlate with the severity of positive symptoms (Buchy et al. 2009). On the other hand, improvement in cognitive flexibility has been suggested to reduce positive symptom severity (Lecardeur et al. 2009), in line with the hypothesis that dysfunction of lower-level functions could be implicated in the emergence of positive psychotic symptoms (Aleman et al. 2003). To conclude, the efficacy of cognitive rehabilitation interventions on positive symptoms of schizophrenia remains uncertain, as well as controversial are its speculative explanations. The relevant available literature

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consists of a small number of trials and further investigations are needed to get definitive conclusions on this issue.

Meta-analytic reviews of the efficacy of cognitive remediation interventions on negative and positive symptoms in schizophrenia The data on the efficacy of different cognitive remediation modalities on negative and positive symptoms of schizophrenia have been quantitatively reviewed in a handful of recent meta-analyses (McGurk et al. 2007; Wykes et al. 2011; Roder et al. 2011), which provided evidence of favorable effects. The meta-analysis performed by Roder et al. (2011) on the efficacy of IPT, conducted on 36 independent studies including 1,601 schizophrenic patients, showed that patients undergoing IPT showed greater improvement in several variables, including negative (ES = 0.42) and positive symptoms (ES = 0.45), than those undergoing a control treatment (placebo-attention condition or standard care), even though the difference of effect size between IPT and both control groups was not significant. Moreover, IPT-treated patients maintained their mean positive effects on symptoms during an average follow-up period of 8.1 months. The metaanalysis by McGurk et al. (2007), conducted on 26 randomized, controlled trials, including 1,151 patients, showed a small, but significant effect of both computerized and interpersonal rehabilitative interventions on symptoms of schizophrenia (ES = 0.28). In line with the latter finding, the subsequent quantitative review by Wykes et al. (2011) conducted on 2,104 participants with schizophrenia reported a small and transient effect on symptoms (ES = 0.17) that disappeared at follow-up assessment. Despite their methodological heterogeneity, findings from meta-analytic quantitative reviews consistently demonstrate the efficacy of remediation interventions on symptoms of schizophrenia, even if of small to moderate magnitude. Moreover, moderator analyses clearly indicate that cognitive remediation results of stronger effect sizes in studies that provide adjunctive psychiatric rehabilitation compared with those where no further rehabilitation interventions are provided. Nonetheless, the issue of long-term efficacy of cognitive rehabilitative interventions on negative and positive symptoms in schizophrenia is controversial and needs further investigations.

Effect of cognitive remediation interventions on psychopathological dimensions relates to language and formal thought disorders of schizophrenia To the best of our knowledge, none of the published papers aiming to assess the efficacy of cognitive remediation interventions have specifically investigated the effects of treatment on those psychopathological dimensions linked to language and formal thought disorders of schizophrenia. With the purpose of providing some preliminary information on this issue,

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we performed a further analysis of our own data on the effectiveness of different modalities of cognitive remediation in schizophrenia (Vita et al. 2011b), focusing only on these formal thought disorders or languagerelated psychopathological variables. The study sample consisted of 84 patients with DSM-IV-TR schizophrenia (mean age = 39 ± 9.9; n = 58 males) randomly assigned to two different cognitive rehabilitative interventions (IPT: n = 26; CACR: n = 30), or to usual rehabilitative interventions (n = 28), in a naturalistic setting of care. Clinical variables were assessed at baseline and after 24 weeks of treatment. In this post-hoc analysis, we first decided to select the PANSS items that could be related directly to thought and language disorders; i.e. the item “conceptual disorganization” from the positive PANSS subscale, and the item “lack of spontaneity and flow of conversation” from the negative PANSS subscale (Kay et al. 1987). We then compared the effects of remediation with treatment as usual on these outcome variables. Analysis of covariance of post-treatment values of these scale scores revealed significant differences between groups (conceptual disorganization F = 4.59; P = 0.035; and lack of spontaneity and flow of conversation F = 19.08; P < 0.001) with no significant difference between the two cognitive remediation modalities (P non-significant for both symptoms). Although these findings should be considered as preliminary and should be interpreted with caution, they may contribute to a better comprehension of the specific dimensions of schizophrenic psychopathology affected by cognitive remediation.

Effect of cognitive remediation on neuropsychological functions related to language and formal thought disorders in schizophrenia Despite a large body of studies that investigated the efficacy of remediation interventions on cognitive deficits in schizophrenia, none of them, to our knowledge, was designed to directly assess the impact of cognitive rehabilitation techniques on specific functional substrates or circuitry underlying language and formal thought disorders of schizophrenia. Thus, any inference on this issue can be derived only indirectly from the examination of studies targeting the cognitive dimensions which may have some relevance to language and formal thought disorders. With this purpose, we first performed a literature search aimed at identifying the cognitive domains linked to language and formal thought disorders of schizophrenia, as well as the neuropsychological tests useful to assess such neurocognitive functions. Second, a literature review was conducted on the issue of cognitive remediation in schizophrenia, to identify the papers that analyzed the efficacy of rehabilitative interventions on the so identified cognitive domains related to language and formal thought disorders. The scientific literature regarding the neuropsychological dimensions related to language and formal thought disorders of schizophrenia is not univocal. Nonetheless, it can be stated that there is a substantial consensus

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among studies on the prominent role played by executive dysfunctions and/or semantic system abnormalities, related to fronto-temporal neural networks, in the neuropsychological explanations of formal thought disorders (Goldberg et al. 1998; Shenton et al. 1992; Lui et al. 2009; Horn et al. 2010). As for disorders of language of schizophrenia – including speech comprehension, semantic or grammar consistency, verbal fluency, and sentence complexity – executive and/or (verbal) memory dysfunctions have been recognized as relevant neuropsychological substrates (DeLisi 2001). According to a well-established categorization (Nuechterlein et al. 2004), the following neuropsychological tests were identified to evaluate executive functions in schizophrenia: the Wisconsin Card Sorting Test (WCST), a test assessing reasoning and problem solving skills, the Wechsler Adult Intelligence Scale Block Design, and the Tower of London, whereas verbal fluency tasks were adopted as a measure of the semantic system domain. Verbal fluency tasks were also adopted for the investigation of language disorders in schizophrenia, as they assess both executive and semantic memory functions requiring language skills (DeLisi 2001) together with verbal memory tests (Nuechterlein et al. 2004). Thus, in order to examine the effect of cognitive remediation on language and thought disorder in schizophrenia (see also Chapters 5 and 6), the studies that utilized such neuropsychological tests or cognitive dimensions including such tests were considered for the present qualitative review. A group of studies investigated the efficacy of cognitive remediation on executive and semantic memory functions. The one performed by Sartory et al. (2005) was conducted with a controlled design on 42 patients with schizophrenia randomly assigned to a CACR intervention or to a standard TAU. The remediation group received 15 sessions of computerized cognitive training (Cogpack) over a three-week period. Neurocognitive functions were assessed at the beginning and end of this period. When compared with the control condition, remediation training resulted in improvements in verbal learning and executive function (verbal fluency) (P < 0.05). In the study by Ojeda et al. (2012), 90 patients with first-episode psychosis were randomly assigned to one of two groups: cognitive rehabilitation group (REHACOP) or occupational therapy. Patients in the REHACOP group received one-month structured group rehabilitation sessions (three per week) to improve fluency. Repeated assessments of semantic fluency and phonological fluency were conducted before and after treatment. Compared with occupational therapy, the experimental group produced significant additional improvements of verbal fluency score (P < 0.001). The improvement remained three months after the completion of treatment (Ojeda et al. 2012). More evidence comes from the study by Cavallaro et al. (2009), who assessed the effectiveness of intensive CACR added to a standard rehabilitation treatment in enhancing neuropsychological performance and daily functioning of patients with schizophrenia. This 12-week, randomized, controlled, single-blind trial was

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carried out on 86 patients with clinically stabilized DSM-IV schizophrenia. Patients were assessed on cognitive and daily functioning before and after either cognitive remediation or “placebo” training that had been added to their standard rehabilitation treatment. After three months, a significant improvement in executive functions was demonstrated in the active treatment group (P = 0.03). Evidence of a favorable effect of cognitive rehabilitation on verbal memory comes also from a multi-site community study that examined 40 individuals with schizophrenia who underwent cognitive remediation using the NEAR method (Hodge et al. 2010). Assessments, performed using the same neuropsychological battery and measures of psychosocial outcome among centers, were made at four time points: baseline, before the start of active intervention, at the end of active intervention and four months after the end of intervention. After participating in NEAR, patients showed significant improvements in verbal memory (P < 0.001). This effect persisted four months after the treatment ceased. The average effect size was mild to moderate. A comparison of the effects of an extended (12-month), standardized, CACR intervention with those of a computer-skills training control condition consisting of many of the elements of the experimental intervention – including hours spent on a computer, interaction with a clinician and non-specific cognitive stimulation – was performed by Kurtz et al. (2007). Forty-two patients with schizophrenia were randomly assigned to one of the two conditions and were assessed with a comprehensive neuropsychological test battery before and after treatment. Results revealed an overall improvement in both groups on measures of executive function and verbal memory (P < 0.001), but the cognitive remediation group showed a unique significant response of working memory as compared with the computer-treated subjects. d’Amato et al. (2011) investigated 77 patients with remitted schizophrenia, who were randomly assigned to fourteen two-hour individual sessions of CACR (n = 39) or to a control condition (n = 38). Remediation was performed using RehaCom software. Four procedures were chosen to train four cognitive functions involved in different stages of the information processing. Primary outcomes were remediation exercise metrics, neuropsychological composites (episodic memory, working memory, attention, executive functioning, and processing speed), clinical and community functioning measures. Cognitive performance concerning verbal working memory (P = 0.04) and verbal learning memory (P = 0.002) improved significantly in the remediation condition, while no significant change was reported in the control condition (d’Amato et al. 2011). An improvement in verbal learning function was also shown in the study of Lindenmayer et al. (2008). In this study, the cognitive remediation program consisted of 24 hours of computerized practice over a 12-week period and a weekly discussion group to facilitate transfer of cognitive skills to daily activities. A computer-control group received similar hours of staff and computer exposure without cognitive training exercises. Patients in the cognitive

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remediation group demonstrated significantly greater improvements after the three months of treatment than those in the control group in the composite measure of verbal learning (P = 0.04). Another demonstration of the efficacy of cognitive rehabilitation on verbal memory derives from a study conducted by our group, where 32 patients with schizophrenia were assigned to cognitive remediation (first two subprograms of IPT: IPT-cog) or usual rehabilitative interventions in a naturalistic setting of care. Clinical, neuropsychological and functional outcome variables were assessed at baseline and after 24 weeks of treatment. Only the IPT group improved significantly in the neuropsychological domain of verbal memory (P = 0.02), with specific significant correlations between neurocognitive performance and functional outcome changes (Vita et al. 2011a). Another consistent result derives from the controlled study conducted by Penadés et al. (2006), in which a total of 40 chronic patients with schizophrenia were randomly assigned for four months to one of two treatment groups – cognitive remediation (Frontal/Executive program) or cognitive behavioral therapy. Repeated assessments were conducted before and after treatments and at the end of a follow-up period of six months. Additionally, a method to establish reliable change was calculated from a separate sample of 20 patients with schizophrenia who were under standard medication without any kind of psychological treatment. Results showed that the cognitive remediation program administered to patients with a frequency of one-hour sessions two or three times a week over four months produced an overall cognitive improvement but especially in verbal memory (P = 0.001) and executive functions (P = 0.001). A number of studies have assessed the efficacy of remediation interventions in the early course of schizophrenia. Eack et al. (2009) investigated young patients with schizophrenia or schizoaffective disorder randomly assigned to cognitive enhancement therapy, a mixed model of computerized and interpersonal intervention (n = 31), or enriched supportive therapy (n = 27). Intent-to-treat analyses showed significant differential effects favoring cognitive enhancement therapy on verbal memory test during the first year of treatment (P = 0.008). After two years, moderate effects (ES = 0.46) were also observed for enhancing neurocognitive function. In a single-blind randomized controlled trial, Wykes et al. (2007) evaluated young patients with recent onset schizophrenia (average age of 18 years) and evidence of cognitive and social behavioral difficulties. The subjects were randomized in two groups, one receiving cognitive remediation therapy (n = 21), and the other standard care (n = 19) and assessed at baseline, after three months (post therapy), and at follow-up (three months post-therapy). The intervention was individual cognitive remediation therapy delivered with at least three sessions per week. The study evidenced significant post-treatment improvement of executive functions in the cognitive remediation therapy group but not in the usual treatment group (P = 0.04).

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Finally, also the extensive meta-analysis performed by Wykes et al. (2011), conducted on studies published until June 2009, confirmed the efficacy of cognitive remediation interventions in improving the cognitive dimensions and neuropsychological tests related to language and formal thought disorders of schizophrenia. In this review, significant effect size favoring cognitive remediation compared with control conditions were demonstrated for verbal working memory (ES = 0.34), verbal learning and memory (ES = 0.41), and reasoning/problem solving (ES = 0.57) cognitive domains. As stated at the beginning of this section, any inference about the efficacy of cognitive remediation on neuropsychological dimensions related to language disorders and formal thought disorders of schizophrenia remains indirect. Nonetheless, both computer-assisted, interpersonal and mixedmodel cognitive remediation interventions have shown to be effective in ameliorating neuropsychological functions linked to those symptomatological domains, with positive results both in the early phases of the disease and in chronic schizophrenia.

Conclusions There is now consensus on the efficacy of cognitive remediation in schizophrenia, with the strongest evidence regarding the improvement of patients’ negative symptoms and neuropsychological functioning. These findings have been replicated with different intervention modalities (CACR and/or interpersonal) in populations of both young, early, and chronic schizophrenia. Conversely, the efficacy of cognitive rehabilitation on positive symptoms, as well as its long-term effectiveness on schizophrenic psychopathology, remain questionable. There is also indirect, yet interesting, evidence, of a significant positive impact of cognitive remediation on the neuropsychological dimensions related to language and formal thought disorders of schizophrenia. Moreover, some evidence is available on the effectiveness and feasibility of some of the remediation approaches in the usual settings of care, with highest impact when embedded within a more comprehensive program of care including other rehabilitation interventions. Much less is known, however, on the specific dimensions of psycho- and neuropsychopathology more affected by cognitive remediation. In general, several issues remain open and need further study. The duration of the treatment effects is not known, and few and inconsistent findings are available on the possible moderators and mechanisms of treatment effects. More important to the present discussion, too preliminary and sparse findings are available on the effects of different modalities of remediation on specific clinical symptoms of schizophrenia and cognitive dimensions underlying such symptoms. The case of the differential effect of cognitive remediation on positive compared with negative symptoms of schizophrenia, or on such core symptoms as language and thought disorders, is emblematic of an area of great heuristic interest not adequately

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addressed by sufficiently focused research. Yet, shedding light on these effects could be of great help for both the clinician and the researcher. On the one hand, it could propose new strategies of augmentation of antipsychotic effectiveness, especially in those cases showing poor response or resistance to pharmacological treatment alone. A specific case of interest could be, for instance, that of the “deficit syndrome” of schizophrenia, or of stable and persistent negative symptoms insensitive to drug effects. On the other hand, it could open new windows and generate new hypotheses on the mechanisms of appearance of specific symptoms of schizophrenia, of disease chronicity and on strategies to counteract them. Another open issue in the research on the relationships between symptoms of disease and cognitive remediation effects is that of the clinical characteristics of individual patients predicting the efficacy of cognitive approaches. A better definition of the individual profile of “responders” or “non-responders” to different modalities of interventions would allow to take a further step towards a more personalized approach to treatment in schizophrenia, and could assist the clinician in often difficult cost-effectiveness decisions. This would usefully complement the already existing and growing literature and knowledge on the biological predictors of the effectiveness and tolerability of pharmacological treatment. Finally, in spite of its soundness as an obvious area of interest, very little is known of the interactions existing between cognitive remediation interventions and antipsychotic treatment in schizophrenia. All that is known on this issue derives almost exclusively from indirect observations or hypothetical, often speculative, “expert opinions”, but is not founded on sound and focused research. This research is, however, required if we want to shift from the traditional and conservative attitude of considering any approach other than pharmacological at best as an ancillary augmentation strategy of drug treatment in schizophrenia to a more mature integrative approach to treatment in which different evidence-based interventions may be considered relevant not only per se but also in their interaction to reach the highest possible outcomes of treatment in the individual patients. In this perspective, systematic studies on the relationship between pharmacological and cognitive remediation treatment effects, and on the possible pharmacological strategies to enhance the effectiveness of remediation interventions on different psychopathological dimensions of schizophrenia, are warranted.

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Part IV

Conclusion

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14 Concluding remarks Paolo Brambilla and Andrea Marini

In this book, we have debated the fascinating issue of the interconnections between language, psychopathology and schizophrenia in a clinical and evolutionary perspective. In the first section of the book, it has been pointed out that the neural bases of human language are circuits linking activity in different parts of the brain that are also implicated in learning and executing complex voluntary motor acts, including talking. Therefore, no structures of the human brain can be considered specific to language. Although human and non-human primate neural circuits and cortical structures appear to be similar, human genes that differ from those found in chimpanzees are good candidates for conferring the linguistic, cognitive, and motor capacities that distinguish humans from other living species. Also, it has been shown that the devices at the basis of the origin and the functioning of language are closely linked to the ability to navigate in space, based on the evidence of the narrative difficulties of individuals with deficits in spatial navigation. In particular, it has been highlighted that: (1) an essential feature of language is the ability to speak appropriately; (2) the ability to speak appropriately governs the production and comprehension of the flow of speech at the level of discourse; and (3) the same spatial processes implicated in discourse production–comprehension are involved in the origin of language. Finally, in the first part of the book, the problem of Self- and world-representation has been debated, showing that a minimal level of primary consciousness is present in all vertebrates, being sustained by the brainstem and hypothalamus. In contrast, narrative consciousness, which mainly correlates to episodic memory and language and is supported by medial and lateral cerebral structures, is uniquely present in the human species. The second section of the book focused on the brain abnormalities reported in schizophrenia. First, it has been outlined that, at a microscopic level, the human-specific asymmetries in minicolumnar spacing can explain the link between abnormalities of (left) cerebral dominance and language reported in patients with schizophrenia. At a system level, a neurodevelopmental dysmaturation of specific neural networks during adolescence might result in functional dysconnection in people at risk of

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the disease. In particular, reduced long-distance intercortical connections, but increased intra-regional connections have been reported in schizophrenia, ultimately leading to impairment of language, memory, and thought. Besides intra-hemispheric connectivity, altered inter-hemispheric communication mediated by the corpus callosum can also contribute to deficits of language in schizophrenia. More in general, thought disorder can be seen as an extreme version of language difficulties observed in schizophrenia, and has been found to be mainly supported by volumetric reductions of bilateral fusiform gyri, superior temporal gyri and dorsolateral prefrontal cortex. The third and last part of the book is dedicated to psychopathology. Initially, it has been noted that vulnerability to expressing altered language processing increases the probability of auditory hallucinations (i.e. hearing voices), which are a core symptom of schizophrenia consistently associated with abnormalities of left superior temporal gyrus. Furthermore, it has been shown that language symptoms of schizophrenia are strictly associated with faulty context processing. In particular, a disturbed control of higher-order cognitive functions, mainly sustained by the dorsolateral prefrontal cortex, appears to lead to macrolinguistic impairments in schizophrenia. However, it should be considered that, together with affected linguistic abilities, deficits of social and academic adjustments often precede the first episode of psychosis, and associate with the severity of the illness. Therefore, early cognitive remediation interventions can have significant positive impact on the neuropsychological dimensions related to language and formal thought disorders of schizophrenia. In conclusion, this book confirms that language disturbances are expressed even before the onset of schizophrenia in vulnerable subjects, resulting from intra- and inter-hemispheric functional dysconnectivity at both micro- and macro-structural levels. Furthermore, such language deficits in schizophrenia strictly correlate with executive function alterations, social adjustment and illness severity. Studies investigating the interplay between language, cognition and social function are therefore needed to further delineate shared and unique subserving neural networks, and to characterize specific subtypes of the disease. To do this, such studies should address the major methodological issues of the current imaging research in schizophrenia, thus recruiting large samples of highrisk and (unmedicated) first-episode patients in an epidemiological perspective, combined with genetic and epigenetic investigations. This will be crucial to overcome the validity of the illness as a unitary diagnostic construct, which remains questionable, owing to the heterogeneity within the diagnosis of schizophrenia and blurred boundaries with other psychiatric diagnoses. Finally, more research is expected to implement and validate innovative cognitive rehabilitation interventions on language dimensions in both early and chronic patients suffering from schizophrenia in order to improve their prognosis and quality of life.

Glossary and abbreviations

ACC Anterior cingulate cortex; it represents the frontal part of the cingulate cortex, surrounding the genu of the corpus callosum. It is involved in executive functions, emotional processing and salience and it has been suggested to be altered in schizophrenia. acromatopsia Disorder characterized by the loss of color perception due to bilateral damage to the extrastriate visual cortex and to the lingual and fusiform gyri. activation likelihoods Meta-analytical results from functional MRI studies, by which the collation of probabilities across studies yields voxel-wise activation likelihoods that indicate the level of convergence in location of activity across studies. AgCC Agenesis of the corpus callosum; a congenital disorder characterized by the complete or partial absence of the corpus callosum. akinetopsia Acquired pathological condition due to bilateral lesions to the middle temporal gyri, where patients lose their ability to recognize movement and to make predictions of the future position of objects. aphasia Acquired impairment in a person’s ability to use (i.e. to produce or understand) language. It is caused by injuries affecting brain regions involved in language processing. For most people, the epicenters of these neural networks are located within the left hemisphere. Modern scanning suggests that the classical view of language comprehension occurring in Wernicke’s area and production in Broca’s area is far too simplistic. apperceptive agnosia Clinical condition characterized by an inability to recognize forms and objects. It is usually linked to acquired diffuse lesions in ventrolateral brain regions. associative agnosia A neurological condition where patients are no longer able to recognize objects; even if they are able to recognize the single parts of an object, they do not succeed in integrating all the elements in a gestalt. It is usually linked to acquired lesions in the anterior-temporal lobe. autonoetic consciousness Corresponds to the humans’ ability to mentally represent and to become aware of their protracted existence across subjective time.

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Glossary and abbreviations

AX-CPT It is a version of the continuous performance task (see CPT) assessing working memory monitoring, response inhibition and consistency of the performance over time. basal block An anatomical component of the central nervous system, formed by the spinal cord, the brainstem, the cerebellum, the hypothalamus and the oldest portions of the telencephalon. basal ganglia Structures (i.e. putamen, caudate, globus pallidus) situated deep within the brain and forming part of neural circuits regulating motor control, cognition, attention and emotion. BOLD response (blood oxygen level-dependent); refers to the change in MRI signal as the amount of oxygen in the blood reduces to neural activity. It has specific characteristics that must be modeled in any analysis and are important in designing and interpreting fMRI studies. CACR computer-assisted cognitive remediation; a form of cognitive remediation which provides a standardized training with immediate feedback to the subject’s performance. CBT cognitive behavioral therapy. Psychotherapeutic approach aiming at the amelioration of dysfunctional emotions and of maladaptive cognitive processes and behaviors. CFLT Crossed finger localization test. It is used as a measure of the interhemispheric transfer of somatosensory information via the corpus callosum. Patients with partial or complete resection of the corpus callosum are impaired on this task. Cognitive enhancement therapy It is an integrated approach to cognitive remediation combining a computer-based cognitive training (specifically addressed to attention, memory and problem solving) and group-sessions of social cognition exercises. CPN callosal projection neurons. They are pyramidal neurons connecting left and right hemispheres and whose myelinated axons make up the corpus callosum. CPT Continuous performance task. It is a neuropsychological test commonly used to assess sustained attention performance over time. Charles Bonnet syndrome A clinical condition in which patients, generally elderly persons who go blind because of an eye disease, have complex visual hallucinations of which they are aware. chlorpromazine equivalents Different antipsychotics have varying potency and dose ranges. Chlorpromazine equivalents allow these different drugs to be combined into a single measure of drug dose by comparing them to a reference drug, chlorpromazine, and then summing the total dose for a specific individual. cognitive (“top-down”) control Defined as a set of higher-order functions that optimize and schedule lower-order functions. Typically, the source of the control is associated with activity in prefrontal cortex, whereas the target of the control is linked to activity in posterior cortical and subcortical regions. This term refers to the top-down modulation of

Glossary and abbreviations

235

cognitive processes based on higher-order representations such as goals or context. COMT catechol-o-methyl transferase. It is an enzyme that is particularly important for the metabolism of dopamine. Alteration of specific COMT polymorphisms (i.e. Val158Met) has been associated with some neuropsychological and brain structural alterations observed in schizophrenia. COS childhood-onset schizophrenia. It represents a rare and severe form of schizophrenia characterized by more marked neurodevelopmentalimpairments with respect to the adult disorder, but neurobiologically, diagnostically and physiologically continuous with it. core self A component of the mind of those living beings that are conscious of their world. It is connected to both semantic memory and affective processing. It is a form of consciousness of the Self and of the world that develops only at the present moment. corpus callosum The largest white matter bundle within the brain, composed of corticocortical projections connecting homologous regions of both cerebral hemispheres. cortex The outermost layer of the mammalian brain. CUD crossed–uncrossed difference. It is defined as the difference between the time necessary to transfer the information in crossed (stimulus presented in the opposite visual field, i.e. right visual fieldleft hand) and uncrossed (stimulus presented in the same visual field; i.e. right visual field-right hand) conditions. From CUD, it is possible to infer the inter-hemispheric transfer time (see IHTT). DCM dynamic causal modeling. A method developed by Dr Friston assessing the effective connectivity between brain regions, that is the influence that one neural system exerts on another. It relies on evaluating multiple neurobiological plausible competing network models. derailment In psychiatry, derailment refers to a thought disorder consisting in an unexpected change of direction in the train of thoughts in spontaneous speech and resulting in a sequence of unrelated ideas. Descartes’ problem The formulation used by Noam Chomsky in reference to the creative aspect of language use, that is to say to the ability to speak in a way that is coherent and consonant to the context. According to Chomsky, this is an unresolvable problem regarding the nature of language. diffusion tensor imaging (DTI) A type of MRI that images the structure and integrity of white matter (i.e. myelinated axons) in the brain. discourse (processing) High-level linguistic ability that allows individuals to connect written sentences or spoken utterances by means of cohesive and coherent ties, in order to formulate the main theme of a narrative discourse and integrate its linguistic and conceptual features in an integrated whole defined mental model. DLPFC dorsolateral prefrontal cortex. It is an area of the primate brain

236

Glossary and abbreviations

playing a key role in executive functions and suggested to be altered in schizophrenia. DSM Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association (www.psychiatry.org/practice/ dsm) dopamine A neurotransmitter of the family of the biogenic amines. It is produced within cells in the brainstem that project broadly to the striatum (see basal ganglia) and cortex (especially the frontal lobe). dorsal simultagnosia Acquired clinical condition linked to bilateral lesions to the occipito-temporal lobes. These patients lose cognition of the space surrounding them. ECT electroconvulsive therapy. Medical treatment consisting in the introduction of a controlled amount of electricity into the brain, producing a mild generalized convulsion. It is considered effective in the treatment of severe depression conditions, especially those resistant to pharmacological treatment. EEG electroencephalogram. The recording of brain’s electrical activity on the scalp. endophenotypes Any hereditary characteristic that is normally associated with a disease, but is not a direct symptom of that disease. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological. enhancement The increase in signal acquired by the MRI scanner by different tissues and oxygenation states (see BOLD response). ERP event-related potentials. It is an EEG-based technique which allows the registration of transient changes in the brain’s electrical activity in response to the presentation of a stimulus. ES effect size. In Statistics it represents the difference in the observed means divided by the pooled standard deviation of the samples. Effect size values are generally considered small if 0.2, medium if 0.5, and large if 0.8. EUFEST European First-Episode Schizophrenia Trial functional connectivity A group of approaches that aim to look at similarities in the pattern of BOLD enhancements or blood flow in different areas of the brain and infer from them that the areas are functionally linked when performing a task (including resting). functional MRI (fMRI) An extension of MRI that uses the BOLD response to infer neural activity while a specific activity (including resting) is performed in the scanner. GABA gamma-amino-butyric acid; one of the major inhibitory neurotransmitters in the brain. GAD glutamic acid decarboxylase. It is the enzyme responsible for the synthesis of the GABA. GAF Global Assessment of Functioning scale. It is a DSM-IV scale considering subject’s psychological, social, and occupational functioning on

Glossary and abbreviations

237

a hypothetical continuum of mental health-illness ranging from 0 (inadequate information) to 100 (no symptoms and superior functioning in a wide range of activities). genotype Genetic constitution of a cell or organism. genu The anterior part of the corpus callosum connecting the prefrontal and premotor parietal regions of the two hemispheres (see corpus callosum). global coherence The conceptual connectivity across distant sentences within a spoken discourse or written text. The production of tangential utterances is an example of error of global coherence. glutamate The most important excitatory neurotransmitter in the brain. GMV gray matter volume (see gray matter). gray matter A term referring to the parts of the brain and spinal cord with a high percentage of neurons (nerve cell bodies), in contrast to white matter, which is primarily composed of supportive tissue and connections between neurons (see White matter). gyrification The extent of folding of the cerebral cortex in mammals. hallucinations Sensory percept that occurs in absence of any external stimulation that is not under voluntary control by the person who experiences it. hemispatial neglect A condition in which the person is incapable of exploring the left hemispace. Generally, the person is not aware of this problem, and the deficit is present in both visual perception and visual imagery. This syndrome depends on a lesion in the infero-posterior parietal region of the right hemisphere. insight In general, in psychiatry, lack of insight is used to reflect poor awareness of illness. ICD International Classification of Diseases, published by the World Health Organization (www.who.int/classifications/icd/en). ICH Institute of Child Health, University College London IHTT inter-hemispheric transfer time. It represents a measure of the inter-hemispheric transmission time, possibly related to the structuralintegrity of the posterior corpus callosum. In healthy individuals the IHTT is of about 4 milliseconds but it is longer when the corpus callosum is sectioned or absent. interneurons A class of neurons that, in a majority of cases, connect nearby neurons within the gray matter. Interneurons are typically inhibitory and use the neurotransmitter GABA or glycine (see GABA). Interneurons thus differ from projection neurons whose axons travel through the white matter to reach more distant regions of the brain or spinal cord. IPT integrated psychological therapy. It is a group-based approach to cognitive remediation of patients with schizophrenia, which works on the improvement of both low and high order of cognitive functions in a first phase, and later on the development of social abilities.

238

Glossary and abbreviations

lexical informativeness A measure that allows to quantify the information content of the narrative sample produced by a patient. It refers to the production of appropriate lexical information units; i.e. those words that are not only phonologically well formed but also appropriate from a grammatical and pragmatic point of view. local coherence Reflects the extent to which each utterance of a narrative speech sample is conceptually related to the preceding one. loosening of associations see derailment macrolinguistic dimension One of the two dimensions of language analysis (see also microlinguistic dimension). It allows analysis of the way in which interlocutors derive the contextually appropriate meaning of a word or a sentence (pragmatic processing) and connect written sentences or spoken utterances by means of cohesive and coherent devices in order to formulate the mental model of a narrative discourse. magnetic resonance imaging (MRI) Manipulating a magnetic field within the scanner leads to different tissues within the body enhancing differently. This allows images to be acquired of these tissues. The images are acquired without any exposure to radiation. MEG magnetoencephalography. It is a non-invasive neurophysiological technique which records the magnetic fields generated by the neuronal activity naturally occurring in the brain. meta-analysis The statistical re-analysis of the results from several studies on a given argument. Meta-analysis allows to increase power and to provide higher-quality evidence for a specific association or intervention. microlinguistic dimension One of the two dimensions of language analysis (see also macrolinguistic dimension). It allows the analysis of the way in which interlocutors organize phonological or graphemical patterns into morphological strings and words (lexical processing) and generate the syntactic context each word requires for the production/ reconstruction of well-formed sentences (syntactic processing). minicolumn The smallest modular organization of the neocortex comprised of 80–120 neurons spanning layers II–VI in a vertical arrangement. The minicolumn can be compartmentalized into a core space having most cell bodies, apical dendrites and axonal projections, and a peripheral component having most of the inhibitory elements and synapses. MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. It is a neurotoxin involved in the pathophysiology of Parkinson's disease, which destroys the dopaminergic neurons in the substantia nigra. MRI see magnetic resonance imaging MTG middle temporal gyrus. It is a longitudinal gyrus running on the lateral surface of the temporal lobe, which has been suggested to be involved in different aspect of language processing. narrative self Consists of the ability to process declarative episodic memories that unify the Self into a single story.

Glossary and abbreviations

239

NEAR neuropsychological educational approach to remediation. It is an evidence-based approach to cognitive remediation combining neuropsychological and educational devices, specifically addressed to patients with schizophrenia. In this model, a set of carefully crafted instructional techniques is employed to provide highly individualized learning and to promote the improvement of daily cognitive functioning. negative symptoms Symptoms that describe the absence of normal functioning (e.g. flat affect, alogia, loss of motivation/interests, social withdrawal). neocortex see cortex neural circuits Link “local” activity, operations performed in specific structures of the brain, that together result in an observable action, thought process, or biological activity. neurite Any projection from the cell body of a neuron, whether it be an axon or a dendrite. neurochemistry The study of the composition, chemical structures, and chemical reactions of the nervous system or its components. neuroimaging Technologies that allow the analysis of the structures and/or functions of the brain. Neuroimaging procedures include MRI, coaxial tomographic scan, positron emission tomography, and functional MRI. neuropil (or neuropile) The background of the gray matter surrounding the cell bodies of neurons. It is composed primarily of unmyelinated axons and glia. neurotransmitters Chemicals released by presynaptic neurons that travel across the synaptic cleft to influence receptors on postsynaptic neurons. NMDA n-methyl-d-aspartate. It is a receptor of the glutamate neurotransmitter, playing a key role in synaptic plasticity and long-term memory. PAFIP Program of Assistance in the Initial Phases of Psychosis (Cantabria, Spain) PAG periacqueductal gray. It is a complex structure of the mesencephalonsurrounding the cerebral aqueduct, and connected to structures of both the basal and the superior block. The PAG is probably one of the most ancient structures devoted to the emotional-motor integration. PANSS Positive and Negative Syndrome Scale. It is 30-item and 7-point (1–7) rating scale specifically developed to measure the severity of symptoms in patients with schizophrenia. It consists of positive, negative and general psychopathology sub-scales. Parkinson’s disease A neurodegenerative disorder that primarily affects basal ganglia, disrupting neural circuits that regulate motor control, cognitive flexibility and other aspects of cognition, attention and behavior.

240

Glossary and abbreviations

petalia A type of cerebral asymmetry wherein one cerebral hemisphere projects beyond the outline of its opposite hemisphere. phenotype Manifest trait or characteristic of an organism. planum temporale A region of the brain that exhibits marked asymmetry across homologous aspects of both hemispheres. It is located within the sylvian fissure and is of functional importance to language. positive symptoms Phenomena experienced by patients that are generally absent in a healthy population (e.g. delusions, hallucinations, thought disorder, disorganized behavior). positron emission tomography (PET) An imaging technique where a radioactive substance is injected into the blood stream, allowing the blood flow around the brain to be measured. prediction error Humans learn that certain stimuli usually occur together. Psychological paradigms that test the process of learning these groupings, and then the violations of what has been learnt, have shown that specific neural networks are implied in the process of individuation of such violations. These areas are thought to reflect the prediction error accompanying the violations and show attenuated activations during these paradigms in schizophrenia and while intoxicated with ketamine. primary self Can be defined as the most ancient form of coherent Worldand Self-representation. It can be considered as an organizational unit coordinating the whole of sensations and of primordial emotions. proactive control A form of cognitive processing, where an established goal and context is used to bias behavior. reactive control A form of cognitive processing, where continual feedback from the environment is utilized to recruit additional control and adjust subsequent behavior. region of interest (ROI) A specified area of the brain where correlations between brain structure, function and other measures are made during the analysis. This approach increases statistical power as it reduces the number of correlations performed. relevance theory An inferential model of human communication proposed and developed by Dan Sperber and Deidre Wilson since 1986. According to relevance theory, any communicative process involves two different kinds of intentions: the informative intention, by which the speaker informs the listener of something; and the communicative intention, by which the speaker intends to inform the listener of his own communicative intention. When the recipient explicitly recognizes the communicative intention of the speaker, communication has a positive outcome. repetitive TMS (rTMS) The delivery of an extended series of closely spaced TMS stimulation pulses, in order to effect long-lasting changes in brain function. ROI analysis Evaluations of hypotheses about the functional properties

Glossary and abbreviations

241

of brain regions (i.e. aggregated over a pre-determined set of voxels), often chosen to reflect a priori anatomical distinctions within the brain. schizophrenia Psychotic disorder that may involve characteristic disturbances in thinking (delusions), perception (hallucinations), speech, emotions, and behaviours. selective sweep A process occurring whenever a genetic change confers an advantage to the individual in whom it occurs and rapidly spreads throughout the population. self-consciousness The ability to self-recognize. In developmental and comparative psychology, it is studied through mirror recognition tests. An organism is considered as Self-aware if it recognizes itself placed in front a mirror. self-monitoring deficits Impairment in monitoring one’s own intentions to perform a task, leading to its misattribution to an external source. semantic priming An effect whereby the activation of a given word facilitates the retrieval of semantically related words. This is reflected in reduced response times and lowered activation in specific brain areas in tasks of semantic categorization or naming. sensory gating The ability of the central nervous system to filter out redundant stimuli from all possible stimuli coming from the surrounding environment. serotonin A neurotransmitter that regulates many functions, including mood, appetite, and sensory perception. signal detection In psychology, signal detection theory is used to measure the way a perceptual/memory judgment is made under conditions of uncertainty. source-monitoring deficits Impairment in detecting the source of an event. According to the source-monitoring framework, errors are likely to occur when the characteristics of a percept/memory are dissimilar from what one would expect given the source. In schizophrenia, although auditory hallucinations are perceptually similar to real voices, they differ from real voices in their spatial, semantic and affective information. SPECT single-photon emission computed tomography splenium The posterior part of the corpus callosum connecting the parietal, temporal and occipital lobes of the two hemispheres (see corpus callosum). STG superior temporal gyrus. It is one of gyri of the temporal lobe, containing both the planum temporale and the Heschl’s gyrus, having a crucial role in auditory processing and human language. superior block Component of the central nervous system that is formed by the basal ganglia and the cerebral cortex, and subdivided in two components: medial and lateral, respectively (see also inferior block). sylvian fissure The lateral sulcus of the brain that divides the temporal lobe from both the frontal and parietal lobes.

242

Glossary and abbreviations

synaptic plasticity Refers to the malleability of the synapses that transmit information between neurons. It plays a key role in learning and rehabilitation. thought disorder A symptom of schizophrenia characterized by speech that is difficult to understand, owing to disrupted speech patterns. TAU treatment as usual. It is defined as the routine care as opposed to experimental treatments (pharmacological, psychotherapeutic, social) whose effectiveness has to be tested. TMS transcranial magnetic stimulation. It is a non-invasive method to cause depolarization or hyperpolarization in the neurons of the brain by means of a stimulating coil held close to the intended site of stimulation. ToM theory of mind. The ability to infer others’ mental states, perspectives and communicative intentions. tonotopic organization The spatial arrangement of different frequencies within anatomical structures of the auditory system (namely, primary auditory cortex and cochlea). topographical disorientation The inability to orient in the environment as a result of focal brain damage. It may result from the inability to make use of selective spatial information (e.g. environmental landmarks) or to orient by means of specific cognitive strategies, such as the ability to form a mental representation of the environment, also known as a cognitive map. transcriptional factor In the process of transcribing information coded in twin-stranded DNA to single-stranded RNA, these are potent factors in determining the expression of genes. They are “master-genes” that shape different bodies and brains in related species that share almost all of their other genes. universal grammar (UG) A linguistic theory developed by Noam Chomsky, according to which all human languages are constructed on the same, abstract template. V1 primary visual cortex. It is located in the occipital lobe and is responsible of the first stages of cortical processing of visual information. voxel-based morphometry (VBM) A whole-brain analysis approach of the structure of the brain. It segregates the brain tissue into gray matter and white matter and allows the analysis of these tissue classes separately. whole-brain analysis This approach looks at correlations between structure, function and other measures across the whole brain and usually uses an automated method. This allows all areas of the brain to be studied, but does reduce statistical power, owing to size of multiple comparison adjustments required. Wisconsin card sorting test (WCST) It is a neuropsychological task commonly used for the assessment of cognitive flexibility, abstract reasoning and problem solving skills.

Index

academic adjustment 232 acromatopsia 36, 233 akinetopsia 36, 233 amygdala 41, 82, 136, 139, 141, 143, 206 anencephaly 42 anterior cingulate cortex (ACC) 10, 12, 40, 81, 83, 137, 138, 140, 141, 143, 170, 233 antipsychotics 127, 174, 212, 213, 234 aphasia 53, 202, 204, 233 apperceptive agnosia 36, 233 associative agnosia 36, 233 associative learning 12, 13, 15, 83 astrocytes 62 asymmetry 1, 53–62, 102, 105, 106, 138, 195, 205, 206, 238 attention 11, 75, 82, 83, 99, 100, 140, 155, 168–70, 181, 186, 187, 198, 201–3, 213, 220, 234, 237 autonoetic consciousness 39, 42, 43, 233 Balint’s syndrome 36 basal block (of the central nervous system) 39, 40, 41, 234 basal ganglia 7–16, 39, 234, 236, 239, 241 brain imaging 2, 75, 118–20, 155, 164 Broca’s area 7–9, 14, 59, 60, 84, 106, 126, 137, 157, 206, 233 Broca-Wernicke theory 7, 9 Cajal-Retzius cells 62 Calbindin 61, 62 Calretinin 61 Charles Bonnet syndrome 37, 234 Chimpanzees 7, 12, 13, 16, 39, 59, 60, 64, 231

Chomsky, Noam 12, 22, 23, 30, 183, 234, 240 Cingulate 10–12, 14, 29, 40, 41, 79–81, 83, 123, 125, 127, 129, 136 - 138, 140–4, 157, 170, 173, 201, 233 code model 23, 24, 30 cognition 7, 15, 16, 26, 36, 54, 57, 74, 75, 82, 97, 99, 107, 137, 141, 142–4, 153, 168, 174, 176, 194, 214, 232, 234, 235, 237 cognitive control 2, 79, 83, 128, 155, 168–72, 174, 175, 186, 187, 189 cognitive enhancement therapy 221, 234 cognitive remediation therapy 216, 221 cognitive science 22, 163 coherence 22–4, 27–30, 100, 184, 186–8, 235, 236 computer assisted cognitive remediation (CACR) 213, 234 connectivity 2, 54, 57, 59, 60, 62, 63, 73, 74, 76, 79, 81, 82–5, 97, 99, 100, 102–7, 125, 127, 128, 139, 159, 161, 163, 169, 173, 232, 235 consciousness 33–5, 37, 39–43, 124, 231, 233, 234, 239 context 2, 22, 26, 55, 75, 124, 127, 168–76, 181, 182, 185–9, 197, 201, 232, 234, 236–8 core self 38, 235 corpus callosum 2, 58, 59, 62, 63, 79, 96–107, 232, 233, 234, 235, 237, 241; body 58, 96, 97, 102; genu 40, 96, 104, 106, 107; isthmus 58, 96, 102; rostrum 96, 104; splenium 96, 97, 103, 104, 107 crossed–uncrossed difference 98, 235 delusions 38, 61, 120, 135, 136, 139, 154, 164, 174, 194, 201, 238, 239

244

Index

Descartes’ problem 22, 235 diffusion tensor imaging (DTI) 10, 98, 122, 159, 205, 235 discourse 1, 22, 24, 25, 27–9, 100, 169, 171–3, 176, 182, 184, 185, 186, 188, 189, 194, 202, 203, 231, 235, 237, 238 disorganization 118–20, 126–8, 137, 138, 168, 169, 175, 202, 218 domain specificity 23 dorsolateral prefrontal cortex (DLPFC) 10–12, 127, 140–2, 169, 175, 187–9, 206, 232, 235 dreaming 33, 34 electroconvulsive therapy (ECT) 161, 236 emotion 11, 12, 35, 38, 40–2, 80, 82, 100, 136, 137, 141–3, 154, 155, 157, 160, 162, 163, 168, 186, 194, 196, 201, 206, 234, 238, 239 evoked related potential (ERP) 57, 61 evolution 1, 7, 15, 22, 23, 30, 42, 43, 54, 56, 58–60, 105, 194, 231 executive functions 3, 28, 81, 137, 140, 181, 186, 196, 198, 202, 212, 213, 219–21, 232 first-episode psychosis 161, 195, 198, 219 FOXP2 gene 1, 7, 14–16 functional magnetic resonance imaging (fMRI) 11, 75–7, 79, 80–2, 84, 99, 101–3, 106, 123, 124, 126, 127, 170, 196, 234, 236 functional outcome 141, 168, 214, 221 genes 1, 7, 13–16, 64, 73, 84, 144, 159, 160, 203, 231, 240 gliosis 62 glutamic acid decarboxylase (GAD) 61, 236 gray matter 1, 40, 53, 58, 63, 78, 121, 122, 125, 127, 135, 143, 157, 159, 161, 163, 207, 237, 239, 242 hallucinations 2, 37, 38, 53, 60–2, 83, 84, 120, 135–40, 144, 153–64, 174, 194, 232, 234, 237, 240, 241 Heschl’s gyrus 53, 55, 56, 58, 60–3, 100, 106, 136, 138, 142, 157 Hippocampus 12, 26, 81, 127, 136, 138–40, 157–9, 206 imaging see brain imaging

inferior frontal gyrus (IFG)à 8, 79, 81, 84, 100, 106, 126, 129, 137–41, 155, 157, 188 insula 41, 123, 124, 126, 136–44, 155, 157, 158 integrated psychological therapy (IPT) 214, 237 inter-hemispheric communication 2, 96, 98, 100, 103, 105–7, 232 inter-hemispheric transfer time (IHTT) 98, 106, 237 language comprehension 9, 12, 23, 25, 27, 54, 55, 59, 100, 121, 157, 169, 171–4, 185, 202, 204, 219, 231, 233 language production 2, 7, 24, 25, 27, 29, 99, 100, 102, 118, 119, 123, 157, 169, 170, 172, 174, 176, 181–9, 204, 206, 231, 233, 235–7 laterality 54, 102, 106 left hemisphere 53–5, 57–9, 61, 62, 99, 105, 106, 156, 206, 233 lexicon 182 longitudinal studies 142, 143 macrolinguistic 2, 25, 181–7, 232, 238 mental mind travel 1, 28, 39, 43 microlinguistic 181, 184, 185, 237 middle temporal gyrus 55, 100, 122, 124, 156, 238 minicolumn 2, 56–60, 62–4, 231, 238 mirror Self-recognition 39, 43 narrative analysis 2, 181 narrative Self 1, 38, 39, 42, 43, 238 natural selection 22 Neanderthal 16 negative symptoms 105, 135, 140, 141, 144, 162, 164, 168, 174, 183, 184, 194, 197, 200–2, 206, 214–16, 222, 223, 239 neglect 37, 236 neural networks 1, 7–10, 12, 14, 15, 39, 105, 107, 119, 204, 219, 231–3, 237, 238 neurobiology 39, 104, 135, 155 neuroimaging 11–13, 39, 43, 54, 64, 75, 77, 97, 99, 104, 105, 107, 120, 122, 128, 136, 155, 159, 169, 187, 189, 205, 239 neurons 12–15, 37, 57, 59, 61–4, 99, 104, 201, 234–7, 240 neurophysiological level 34

Index neuropil 57, 59, 60, 63, 239 neuroplasticity 55, 63, 64 neuroscience 33, 35, 38, 74, 75, 160 oligodendrocytes 62 optic tectum 40 orbitofrontal cortex 121, 137, 138, 140–2 out-of-body experience 34, 37 Parkinson’s disease (PD) 9, 10, 14, 239 Parvalbumin 61, 62 periacqueductal gray (PAG) 40, 41, 239 petalia 54, 59, 240 phrenology 8, 9, 75 phonology 25, 53, 61, 79, 100, 125, 157, 158, 181, 183, 184, 186, 187, 196, 202, 219, 236, 237 planum temporale 53–63, 100, 105, 120, 121, 136, 138, 139, 240 Poffenberger paradigm 98 positive symptoms 61, 105, 121, 128, 136, 137, 140, 141, 144, 162, 164, 174, 183, 184, 194, 202, 216, 217, 222, 240 Positive and Negative Syndrome Scale (PANSS) 126, 128, 136, 138, 215, 216, 218, 239 positron emission tomography (PET) 76, 119, 169, 239, 240 pragmatics 22, 23, 30, 203 prediction error 130, 240 prefrontal cortex 10–13, 40, 62, 63, 74, 79, 83, 106, 121, 126, 127, 139–44, 169, 173–5, 187–9, 201, 206, 232, 134, 235 premorbid adjustment 3, 195, 197–200, 206 primary auditory cortex 1, 53, 57, 60, 136, 157, 240 primary self 38, 240 psychopathology 1, 2, 82, 135–7, 143, 144, 155, 197, 199, 214, 281, 222, 231, 232 psychosis 3, 53, 61, 80, 82, 105, 122, 126–8, 130, 139, 142, 144, 159, 161–4, 169, 194–200, 202–6, 219, 232, 238 pyramidal neurons 57, 59, 62, 63, 99 relevance theory 24, 240 representation 1, 25–8, 33–40, 41, 43, 102, 103, 107, 121, 130, 172–6, 183,

245

188, 201, 202, 231, 234 right hemisphere 37, 54, 55, 57, 58, 61, 96, 100, 101, 106, 122, 206, 236 rubber hand illusion 34 schizoid personality 196, 198 schizophasia 202 schizophrenia 1–3, 16, 24, 29, 38, 53, 60–4, 73–85, 96, 98, 103–7, 118–31, 135–7, 139–44, 153, 155–64, 168–76, 181, 183–9, 194, 196–207, 212–23, 231, 232, 233, 235–7, 239–42 self-consciousness 38, 241 sequencing 10 selective sweep 16, 241 semantic priming 126, 171, 172, 204, 241 social adjustment 3, 142, 160, 197, 198, 200, 206, 207, 232 social function 2, 80, 103, 135, 141, 143, 198, 200, 232 spatial navigation 1, 23, 25, 28–30, 231 speech 2, 7, 9, 12, 15, 16, 24, 25, 55, 84, 100–2, 118–22, 125, 130, 140, 155, 157, 170–5, 181–7, 194–6, 202–5, 219, 234, 238–40 structural magnetic resonance imaging 135 superior block (central nervous system) 39–41, 241 superior colliculus 36, 37, 40, 41 superior temporal gyrus (STG) 60–2, 83, 99, 100, 105, 120, 127, 136, 156, 196, 232, 241 Sylvian fissure 53, 59, 204, 205, 241 synaptic plasticity 15, 83, 242 syntax 10, 12–15, 23, 30, 172, 194 theory of mind (ToM) 42, 80, 141, 143, 185, 186, 195, 196, 200, 201, 242 third-person perspective 33, 34 thought disorder 2, 3, 60, 61, 118–26, 128–31, 135–40, 168, 171, 173, 185, 202, 214, 217–19, 222, 232, 235, 240, 242 topological map 57 transcranial magnetic stimulation (TMS) 161, 162, 164, 174, 240, 242 transcriptional factor 7, 14, 16, 242 universal grammar (UG) 22–4, 30, 242 virtual reality 33

246

Index

visual illusion 34 visual information 35, 36 visual system 35, 36 voices 155, 160, 163, 232, 241 Wernicke’s area 7, 9, 53, 55, 59, 84, 120, 205, 233 white matter 58, 62, 64, 78, 79, 96–8, 100, 102, 104, 107, 122, 159, 163, 189, 205, 235, 236, 242 Wisconsin card sorting test (WCST) 11, 219, 242 working memory 3, 12, 73, 74, 81–3, 123, 128, 168–70, 173–6, 186–9, 202, 203, 212, 220, 222