Implanted Minds: The Neuroethics of Intracerebral Stem Cell Transplantation and Deep Brain Stimulation [1. Aufl.] 9783839414330

Table of contents :
CONTENTS
Introduction
INTRACEREBRAL STEM CELL TRANSPLANTATION
Brain, Mind and Regenerative Medicine: Ethical Uncertainties and the Paradox of their Technical Fix
Can Intracerebral Interventions Change our Self? – Neuroethical Implications of Ontological Assumptions
Parfit’s Concept of Personal Identity and its Implications for Intercerebral Stem Cell Transplants
Changes in Personality: Possible Hazards Arising from Stem Cell Grafts – An Ethical and Philosophical Approach
Establishing Regenerative Medicine for the Human Brain: Ethical Aspects of Intracerebral Stem Cell Transplantation
Experimenting Innovative Cell Therapies for Parkinson’s Disease: A View from Ethics
Coping and Expectations of Patients with Amyotrophic Lateral Sclerosis
DEEP BRAIN STIMULATION
Deep Brain Stimulation in Psychiatric Disorders
The Essential Tension: On Ethical and Historical Conundrums in the Trajectories of Deep Brain Stimulation
Changes in Personality: Possible Hazards Arising from Chronic Implantation of Electrostimulation Devices such as Deep Brain Stimulation Systems (DBS) or Advanced Electronic Neuroprostheses
Personality Changes through Deep Brain Stimulation of the Subthalamic Nucleus in Parkinsonian Patients – An Ethical Discussion
Manipulating the Brain – An Ethical Challenge? Lessons from Deep Brain Stimulation in Movement Disorders
Questions on Deep Brain Stimulation on Children and Juveniles with Neuropsychiatric Disorders with Extremely Adverse Course
Traditional vs. Modern Neuroenhancement: Notes from a Medico-ethical and Societal Perspective
Contributors

Citation preview

Heiner Fangerau, Jörg M. Fegert, Thorsten Trapp (eds.) Implanted Minds

Heiner Fangerau, Jörg M. Fegert, Thorsten Trapp (eds.)

Implanted Minds The Neuroethics of Intracerebral Stem Cell Transplantation and Deep Brain Stimulation

Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.d-nb.de

© 2011 transcript Verlag, Bielefeld All rights reserved. No part of this book may be reprinted or reproduced or utilized 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 publisher. Cover layout: Kordula Röckenhaus, Bielefeld Proofread by Heiner Fangerau, Jörg M. Fegert, Thorsten Trapp Typeset by Laura Schütte Printed by Majuskel Medienproduktion GmbH, Wetzlar ISBN 978-3-8376-1433-6

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CONTENTS

Introduction

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HEINER FANGERAU & THORSTEN TRAPP

INTRACEREBRAL STEM CELL TRANSPLANTATION Brain, Mind and Regenerative Medicine: Ethical Uncertainties and the Paradox of their Technical Fix

15

HEINER FANGERAU

Can Intracerebral Interventions Change our Self? – Neuroethical Implications of Ontological Assumptions

31

JOSEF QUITTERER

Parfit’s Concept of Personal Identity and its Implications for Intercerebral Stem Cell Transplants

45

JAN GOLDSTEIN

Changes in Personality: Possible Hazards Arising from Stem Cell Grafts – An Ethical and Philosophical Approach

57

CHRISTIAN P. BÜHRLE

Establishing Regenerative Medicine for the Human Brain: Ethical Aspects of Intracerebral Stem Cell Transplantation

91

JENS CLAUSEN

Experimenting Innovative Cell Therapies for Parkinson’s Disease: A View from Ethics ALEX MAURON & SAMIA HURST

107

Coping and Expectations of Patients with Amyotrophic Lateral Sclerosis

123

MIRJAM RUPP, PAULA BUDDE, HEINER FANGERAU, MARTIN TEGENTHOFF & TORSTEN GREHL

DEEP BRAIN STIMULATION Deep Brain Stimulation in Psychiatric Disorders

137

MAREKE ARENDS & HEINER FANGERAU

The Essential Tension: On Ethical and Historical Conundrums in the Trajectories of Deep Brain Stimulation

151

FRANK W. STAHNISCH

Changes in Personality: Possible Hazards Arising from Chronic Implantation of Electrostimulation Devices such as Deep Brain Stimulation Systems (DBS) or Advanced Electronic Neuroprostheses

183

CHRISTIAN P. BÜHRLE

Personality Changes through Deep Brain Stimulation of the Subthalamic Nucleus in Parkinsonian Patients – An Ethical Discussion

223

SABINE MÜLLER

Manipulating the Brain – An Ethical Challenge? Lessons from Deep Brain Stimulation in Movement Disorders

251

THOMAS D. HÄLBIG

Questions on Deep Brain Stimulation on Children and Juveniles with Neuropsychiatric Disorders with Extremely Adverse Course

281

JÖRG M. FEGERT

Traditional vs. Modern Neuroenhancement: Notes from a Medico-ethical and Societal Perspective

291

DOMINIK GROSS

Contributors

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Introduction HEINER FANGERAU & THORSTEN TRAPP

Regenerative Medicine, Deep Brain Stimulation (DBS) and Neuroethics are three expanding areas of study. Regenerative Medicine and DBS are novel biomedical technologies with therapeutic potential, while Neuroethics is a collective term used to describe the social and philosophical implications of manipulating the brain and mind. These three topics are closely inter-connected. For example, Regenerative Medicine or DBS can be applied to the Central Nervous System (CNS) to control or treat abnormal brain function or a distressed mind. This situation raises special ethical issues concerning the possible influence of electrodes that act upon neural networks or stem cells that become integrated into these networks and their possible influence on the patient’s personality. For example, does the integration of stem cells or electrodes into the brain change the concept of a neural system? Does a neural system containing foreign cells or electronic devices differ from one that does not contain them? These are the questions the book addresses from a practical, theoretical and ethical viewpoint. Furthermore, a historical perspective of the social accountability and hopes and fears inspired by these technologies will also be provided. Neuroethics was only recently established as a sub-discipline of bioethics. Since 2005, the topic has assumed increasingly more space in bioethical and clinical journals. The American Journal of Bioethics (AJoB), for example, has launched a quarterly supplement called JoBNeuroethics, and the Journal of Cognitive Neurosciences announced and

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published a series of essays on neuroethics.1 Broadly conceived, Neuroethics seeks to examine the philosophical, social and legal implications of new developments in the neurosciences. Whereas some of the topics addressed by Neuroethics may be similar to classical bioethical issues (e.g., informed consent, protection of probands during research, etc.), others lie exclusively within the realm of Neuroethics, most likely because of the special role of the brain in the self-image of man. Arguments in favour of a neuro-exceptionalism closely resemble the discussions surrounding genetic exceptionalism.2 Both practical and metaphysical problems arising from the neurosciences are discussed well beyond the classic body-mind problem. Examples include legal regulation of psychostimulants, the relationship between the “self” and the brain, free will and the complex connections between behaviour and the CNS. Nevertheless, the need for an autonomous discipline of neuroethics is dubious because the questions it confronts can be answered using classical ethics and the established principles of medical ethics.3 Neuroethical topics might be roughly divided into the realms of the social, the political and the “individual self”, which encompass clinical practice as well as theoretical issues. On the social and political levels, current neuroscientific research evokes three main topics of discussion noted by the public: 1) functional digital imaging, such as that used in lie detectors or detection of emotions, 2) cognitive performance enhancement, and 3) direct marketing of psychostimulants, which may verge on consumer manipulation. On the level of the “individual self”, classic questions concerning free will or responsibility for one’s own actions are combined with a resurgence of the debate of the biological basis of these intangible phenomena. Particular points of discussion include the brain’s status as the organ of self-representation and its significance for an individual’s personality. This special status is challenged by many of the clinical-practical and ethical implications of neuroscientific research and therapy, including predictive testing, which specifically deals with incidental findings or therapeutic measures that influence the self and personality.4 1

2 3 4

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C.f. Farah, M. (2007) “Social, Legal, and Ethical Implications of Cognitive Neuroscience: ‘Neuroethics’ for Short”, in: Journal of Cognitive Neuroscience 19: 363-364. Farah, M.: Neuroethics (2004) “A Guide for the Perplexed”, in: Cerebrum 6: 29-38. Birnbacher, D. (2009) “Neuroethics and Stem Cell Transplantation”, in: Medicine Studies 1 (1): 67-76. Illes, J., S. Bird (2006) “Neuroethics: a modern context for ethics in neuroscience”, in: Trends in Neuroscience 29: 511-517. For an overview

INTRODUCTION

In the near future, Regenerative Medicine therapies will surely come to the fore. In both Neurology and Psychiatry, Regenerative Medicine aims to replace lost or dysfunctional brain cells with transplantation of brain tissue, specifically stem cells, which raises philosophical questions. If the brain is conceived as a component of or as the carrier of an individual’s personality or self, then operations on the brain can be seen as intrusions upon one’s character. The danger of possible character changes after brain surgery was incorporated as a central theme of neuroethics several years ago.5 However, the emergence of Regenerative Medicine and stem cell transplantation should revitalize this topic. A loss of neural cells and/or their normal function underlies many neurological diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease and stroke. However, there is great variability across diseases in the cause and nature of cell loss. Parkinson’s disease entails a loss of dopamine-producing neurons in the striatum by neurodegeneration, whereas cerebral ischemia involves the loss of complete brain areas caused by interruption of their oxygen and nutrient supply. Encouraged by the first clinical successes of Regenerative Medicine, researchers are now seeking to use this technology to target diseases currently lacking adequate treatments, specifically by using naïve or neutrally-differentiated stem cells to replace the lost or damaged cells. Numerous studies have shown that intracerebral transplantation of naïve or neuronally-differentiated adult or embryonic stem cells leads to recovery of function in animal models of Parkinson’s disease and stroke. However, the mechanisms that effect functional improvements have not yet been clarified. Intracerebrally-implanted stem cells may take over functions lost due to disease, perhaps by integrating into existing neural networks. Moreover, transplantation most likely enhances endogenous regeneration by activation of growth factors. Patients suffering from Parkinson’s disease or stroke already receive cell transplantation therapy in clinical studies, though how these treatments mediate improvement still remains to be fully established. In addition, these therapies evoke many ethical questions. If foreign neurons, which possess their own genetic programming, are integrated into neural networks that constitute intrinsic factors of a person’s character, and this intervention changes neural circuit function, does this

5

of different issues and a comprehensive bibliography see for example Saskia K. Nagel (2010) “Ethics and the neurosciences. Ethical and social consequences of neuroscientific progress” (Paderborn: Mentis). Northoff, G. (1996): “Do brain tissue transplants alter personal identity? Inadequacies of some ‘standard’ arguments”, in: Journal of Medical Ethics 22: 174-180.

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entail alteration of the self? Is there a difference between the replacement of degenerated neurons with non-integrating cells that solely secrete neurotrophic factors as a sort of mini-pump and stem cells that integrate into and re-establish or reorganise neuronal networks? In this context, special attention must be devoted to stem cell-derived neurons that have neuroendocrine function, since relatively few neuroendocrine cells can impact signalling of a magnitude of neurons via secretion of neuroactive hormones. Finally, for more than 60 years, neuroscientists have attempted to control human behaviour, motor and sensory functions using DBS. These attempts have raised public concern in the past, including Robert Heath’s early studies, in which electronic brain stimulation was used to cure schizophrenic patients or septal stimulation was reported to induce heterosexual behaviour in a homosexual man.6 In addition to raising questions of autonomy, informed consent and human dignity, the public has been concerned about controlling the mind by electronic stimulation devices. Jose Delgado went so far as to deduce from his own and other studies on electronic brain stimulation that it might be an ethical imperative to control the mind with the help of DBS in order to create a “psycho-civilized society”.7 However, Delgado himself acknowledges that “the phrase ‘control of human behaviour’ is emotionally loaded” (p. 247). Even today, the idea of controlling the mind or changing personality underlies many of the fears and ethical issues associated with DBS. As with intracerebral stem cell transplantation, the view of the self and the possibility that brain stimulation may change the self frames the theoretical and ethical discussion in clinical practice. To conclude, the “implantation of minds” involves control of the brain and mind. Whereas the implantation of stem cells seeks to control loss, degeneration and regeneration of cells, DBS aims to control movements, thoughts, emotions and behaviour. The ethical implications of both approaches to induce technology on the brain and mind are discussed from different perspectives in this book. The first section is mainly dedicated to the implications of intracerebral stem cell trans-

6

7

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Heath, R.G. & H.C. Becker (1954) “Studies in schizophrenia: a multidisciplinary approach to mind-brain relationships” Cambridge, MA: Harvard University Press. Moan, C.E. & R.G. Heath (1972) “Septal stimulation for the initiation of heterosexual activity in a homosexual male”, in: Journal of Behavior Therapy and Experimental Psychiatry 3: 23-30. Delgado, José Manuel Rodríguez (1971) “Physical control of the mind: toward a psychocivilized society” New York et al.: Harper & Row (First Edition 1969).

INTRODUCTION

plantation, while the second section discusses DBS. Nevertheless, the two sections are inter-related. The book begins with an overview by Heiner Fangerau of the beginnings of Regenerative Medicine and the paradox of a technical fix for ethical dilemmata caused by applying Regenerative Medicine to the brain. Next, Josef Quitterer discusses whether intracerebral interventions can change the self. This reasoning is continued by Jan Goldstein in his analysis of Parfit’s concept of personal identity and its implications for stem cell transplants. Possible changes in personality are also the topic of Christian Bührle’s deliberations about the potential negative impact of stem cell grafts on plasticity. This issue is further discussed by Jens Clausen from a medical-ethical perspective. With his reasoning about creating “part-human beings”, he introduces the ideas of speciesism and first-in-human trials, which are discussed in detail by Alexandre Mauron and Samia Hurst in their ethical analysis of innovative cell therapies for Parkinson’s disease. Finally, Mirjam Rupp and colleagues ask opinions and expectations of novel therapies of patients suffering from amyotrophic lateral sclerosis, a possible target for Regenerative Medicine. Mareke Arends and Heiner Fangerau introduce the section concerning DBS with synchronous and diachronous perspectives on the use and ethics of this technology in psychiatry. Next, Frank Stahnisch discusses the ethical and epistemological issues of DBS from a historical perspective. Christian Bührle then raises the question of the possible danger for personality inherent in the application of DBS. This topic is expanded by Sabine Müller in an essay on the effects of DBS on personality and their evaluation according to the principles of biomedical ethics. Thomas Hälbig discusses ethical lessons from DBS in movement disorders, and Jörg Fegert adds an additional clinical viewpoint by examining the use of this technology in children and juveniles suffering from neuropsychiatric disorders with extremely adverse courses. Finally, looking ahead, Dominic Groß calls for the development of parameters that might underlie the social acceptance of neuroenhancement, a possible future application of DBS. The book is the result of an interdisciplinary workshop on “implanted minds” held at the end of 2008. The overall intention of the publication this book is to give an interdisciplinary overview of the problem of implanted minds from different perspectives, and we hope that these essays will foster further research and discussion on this subject, as intracerebral transplantation of stem cells and DBS will certainly continue into the future.

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We owe our gratitude to all the contributors and to Laura Schütte for helping to realize this publication. For the editors Heiner Fangerau and Thorsten Trapp

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I NTR ACEREBR AL S TEM C ELL T RANSPL AN T ATION

Bra in, Mind and Re ge nerative Me dic ine : Ethical Uncertainties and the Paradox of their Technical Fix HEINER FANGERAU

Introduction: The Paradox of a Technical Fix for Some Bioethical Dilemmas “Regenerative Medicine” is a new branch of medicine that reflects a rekindled interest in healing or replacing lost, pathologically altered or degenerated tissue or organs: their restitutio at integrum. Although regeneration and medicine are closely related, they have rarely been directly associated with each other. The relatively new term “Regenerative Medicine” was probably coined by Leland Kaiser around 1992 and was popularised by the American researcher William A. Haseltine in 1998 (Lysaght and Crager 2009). One of the few early books that directly addressed the central role of “Regeneration and Transplantation in Medicine”, was published in 1910 by Dietrich Barfurth. This book summarised the main features of research and practice in Regenerative Medicine, as they had been established at the end of the 19th century and as they are still valid today. Barfurth stated that transplantation always requires surgery and that regeneration usually does, and while especially the joint procedure of the implantation of embryonic tissue is effective, both regeneration and the transplantation of embryonic tissue are closely related to metaplasia and tumorigenesis. Barfurth also raised the ethical issue of researchers conducting regeneration and transplantation experiments. For his per15

HEINER FANGERAU

spective research in that area to gain knowledge was solely possible on plants. According to his views research in animals and humans would morally require the higher aim of healing. Not the gain of knowledge but healing as “the intrinsic object of medicine”, and benefit for the human being should be the ideal behind the application of such techniques (Barfurth 1910: 5f.). The modern term “Regenerative Medicine” embodies this meansend-orientation by combining the positive connotations of biological regeneration research (youth, health, restitution) with the medical goals of healing. Haseltine’s popularisation of the term occurred in the same year (1998) in which human embryonic stem cell cultures were first established by James A. Thomson (Thomson et al. 1998). This constituted a breakthrough opportunity for the medical use of regeneration research, but at the same time an ethical challenge concerning the use of human embryos for research purposes. The moral uncertainty related to these approaches does not question the goal of regenerative therapy, but rather pertains to the approaches being used to reach this goal. Principally, these concerns can be traced back to two different problems: 1. Beings are created which do not normally exist in nature, namely clones; and 2. the exploitation and disposal of potential human life – that is the embryos that are generated by therapeutical cloning or by stem cells, theoretically could become human beings, if implanted into an uterus (Edwards 2004; Gilbert 2004). Beyond these moral uncertainties, there are also technical uncertainties. For example, stem cells implanted in rat brains can be tumourigenic, an objectionable and unintended effect (Shih et al. 2007). Thus, the question is not just “is biomedicine allowed to do what it can,” but also “can biomedicine do what it portends to do?”. As a consequence, Barfurth’s older dilemma of experimentation with living species versus the aim of healing resurrected directly linked to Regenerative Medicine. Many subsequent statements by scientists and politicians have defended the necessity of regeneration research for the development of cures for e.g. Morbus Parkinson, Alzheimer’s disease, stroke etc. (see for example Andres et al. 2008). Innovations such as the use of adult stem cells, artificial parthenogenesis, and the reprogramming of adult cells have sought to circumvent the ethically critical use of human embryos. These alternatives have been embraced by political figures and the public as welcome solutions to their ethical concerns (Fangerau 2005). Headlines such as “Testicle stem cells avoid ‘ethical problem’” (Washington Times, October 9, 2008) appeared in many newspapers. However, all of these solutions obscure the issue that regeneration’s

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objectives may lead to the development of germ cells and embryos raised from reprogrammed body cells. A “means-end-orientation” underlies the two main justification strategies surrounding this issue, which are strikingly similar to those Barfurth used one hundred years ago: the first strategy recalls the goal of all research (which is knowledge in general and healing in medicine specifically), and the second promotes acceptance of biotechnical solutions for bioethical questions. The identification of continuities and discontinuities in the acceptance of these strategies is crucial for a detailed understanding of current ethical challenges like the implementation of stem cell surgery in the brain or deep brain stimulation. It may also provide insight into the development of medicine by examining the simultaneous rationality and paradox that: a) the goal of developing cures can supersede ethical concerns about research, and b) biotechnical solutions for biotechnically induced ethical problems are accepted without scrutiny of the underlying problematic bioethical beliefs. This article analyses the historical contingency of the acceptability of the “means-end-orientation” in medicine, focusing on synchronic and diachronic shifts in action perspectives to explain the rational appearance of a moral paradox. It aims at explaining why technologies like Regenerative Medicine or deep brain stimulation meet public fears although their intention is delivering cures. After a brief overview of the history of regeneration research and its connection to brain physiology around 1900, two contradicting views of nature will be analysed in order to contribute to current debates about Deep Brain Stimulation and Regenerative Medicine in connection with brain tissue. Prevalent around 1900, these views of the brain and mind adopted differing perspectives on appropriate medical approaches to diseases of the brain and the circumstances under which research for the sake of medicine is acceptable. These views are used as a foundation to explore the underlying reasons for: a) shifts in the acceptance of electrical stimulation, regeneration research and neural tissue engineering over time; and b) the insufficiency of technical solutions and means-end-orientated justifications in overcoming moral uncertainties about regeneration research and the mind.

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R e g e n e r a t i o n a n d W o r l d V i ew s The history of Regenerative Medicine is marked by four trends which needed to come together to give birth to this new branch of medicine: understanding physiological regeneration in living beings, transplantation techniques, cell culture techniques, and fertilisation research. Each of these has received enthusiastic responses and faced ethical scepticism. Several systematic and comprehensive attempts to characterise regeneration were made in the 18th century. The public responded vividly to the research of Abraham Trembley, René Ferchault de Réaumur, Lazzaro Spallanzani, and Charles Bonnet, viewing their results as miraculous and/or frightening (Dinsmore 1991; Buscaglia and Duboule 2002; Moeschlin-Krieg 1953). The experiments of Trembley and Spallanzani shattered widely held beliefs about the character of living matter and changed some fundamental theories regarding the phenomenon of regeneration. Trembley established the link between regeneration and reproduction, which constitutes regeneration research until today, by artificially producing several new mature individuals by surgically dividing a polyp. On the basis of this link, Spallanzani fostered an epigenetic understanding of development that contradicted prevalent preformistic and predeterministic beliefs about the organisation of life on earth.1 His discovery that urodeles could regenerate complex forms, such as limbs, contradicted the predominant view that the structures of higher living beings had been preformed in the egg. The doctrine of preformation itself justified the beliefs in predestination, and in the security of animals’ positions in natural hierarchies and humans’ positions in social hierarchies (“scala naturae”, Dinsmore 1996). Regeneration research coalesced with the evolutionary ideas of the 19th century, and the observation of cell differentiation and proliferation, to question the static world view that had dominated until the end of the 19th century. This caused scientific insecurities and moral uncertainties that repeatedly arose, for example, when Gustav Born reported the creation of chimeras by transplantation of embryonic tissue from one amphibian to another in 1897, when the physiologist Jacques Loeb reported successful artificial parthenogenesis in 1899, when Ross Harrison in 1907 and Alexis Carrel (with Montrose Burrows) in 1911 reported the creation of immortal cell cultures (Das 1990; Fangerau 2005; Freed 2000: 34-36; Landecker 2007; Maienschein 1983; Witkowski 1979, 1983), or when W. Gilman Thomson announced “successful brain 1

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For details see Van Speybroeck et al. (2002)

BRAIN, MIND AND REGENERATIVE MEDICINE

grafting” in dogs and cats in 1890 (Anonymous 1890). The discourse surrounding these scientific events ranged from enthusiasm to scepticism, and the implications for biology and medicine were carefully considered and discussed. While the scientific value of the regeneration experiments was praised, their practical value was doubted even in journals like Science (Anonymous 1890). In particular, their ontological implications were widely discussed. The findings of Jacques Loeb are used here as an example. Around 1900 Loeb announced successful artificial parthenogenesis in sea urchins, and the hybridisation of sea urchin eggs with sea stars. He was also the first scientist to induce embryological development in sea urchins without sperm cells by changing the electrolyte solution surrounding them. He thereby became a celebrated scientist and public figure, appearing on the cover of Harper’s Weekly. Salacious jokes referred to his work with parthenogenesis because it evoked the idea of Loeb having proved the scientific possibility of immaculate conception. His research on fertilisation and regeneration was compared to the creation of life. The Boston Herald published the headline, “Creation of Life. Startling Discovery of Prof. Loeb. Lower Animals Produced by Chemical Means. Process May Apply to Human Species. Immaculate Conception Explained.”2 Similar to modern scientific discoveries but far more vehemently Loeb’s research was popularised not only as a step forward towards medical cures, but also as fundamentally dangerous. The research of other regeneration, transplantation and cell-culture researchers was similarly marked as potentially injurious to human self-image. Soon it was linked to brain physiology and psychology. For example, H. G. Wells’ novel Dr. Moreau and press reports written about the discoveries of scientists such as Born appealed to basic fears regarding biomedical research. The Bangor Whig and Courier, a newspaper serving the predominantly rural population of Maine, linked regeneration research to psychological control over living beings in an article titled, “Monsters to Order. Ingenious Scientists Put Their Wits to Work” (Bangor Daily Whig and Courier, Friday, March 4, 1898: 4). Caricatures depicted scientists’ attempts to control regeneration and reproduction, and emphasised their alleged lust for breaking taboos. One satirist sketched Loeb with a cage full of chimeras (“Dr. Loeb exhibits a few of his new creations...”), in which Loeb appears pleased that the chimeras address him as “papa” (Pauly 1987, Fig.11). 2

For a survey, see Pauly (1987); Harper’s Weekly (13. Dezember 1902: 1936); Boltzmann (1905); The Boston Herald (Nov 26, 1899: 17).

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Among other journals, the family news magazine The Cosmopolitan published by W. R. Hearst in 1912 more clearly expressed the dangers of regeneration research. This journal argued that such research attempted to explain life phenomena with chemistry and physics: “[…] If you and I are merely physico-chemical compounds, slightly more complex than a potato…what is the basis of our moral code? If man can lump together sand and salt and by pouring water on them create life, what becomes 3 of the soul?”

Such statements reflect the challenges to the contemporary understanding of nature posed by regeneration scientists employing experimental methodologies, such as Born, Carrel, and Loeb. Commentators worried that the new powers of biological research might engender new moral problems, and feared that the new biology would undermine traditional moral values. Especially Loeb fired these anxieties with both his experiments and the promotion of his idea to free the brain from its notion as an ethically exceptional organ differing from other body parts. He argued: “The analysis of instincts from a purely physiological point of view will ultimately furnish the data for a scientific ethics.” (Loeb 1900: 197) The prevalent contemporary “organological world view” did not accommodate these scholars’ research questions or their scientific methods of answering them. Briefly, organological world views are characterised by the belief that a vital force binds the individual parts of an organism, and that these individual parts are inextricably intertwined and interconnected. This perspective allows emergent phenomena, ruled by the vital force to join a whole that is more than the sum of its parts. The core disciplines of this world view are theology and philosophy. Its epistemology is marked by holistic tendencies that see correspondences between macro- and microcosm. These create a cyclical relationship between the researcher and the object of research, such that everything in the object is repeated in or has an effect on the researcher. The researcher consequently acts solely as an observer who reports on behaviours in and characteristics of nature. The bioethical action perspective that is descendent from this world view promotes the respectful preservation of the natural status quo. From this perspective, experimental manipulations and attempts to control nature distort the natural world and irresponsibly disarrange its

3

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Quoted from Turney (1995). Here, further similar reactions can be found.

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wholeness. Goethe articulated this belief in the aphorism, “Nature will reveal nothing under torture; its frank answer to an honest question is ‘Yes! Yes! – No! No!’ More than this comes of evil.” (Miller 1995: 307)4 This view was often paired with religious orientations that attributed nature’s expediency and perfectness to a divine influence.5 This pervasive perspective views regeneration research, transplantation, artificial reproduction, and cell culturing not as expressions of creation, but as the destruction of nature and the existing moral order. A means-end-orientation cannot excuse regeneration research within this conceptual framework, even if it offers cures. Technical solutions for ethical concerns are similarly unacceptable. Some researchers were accordingly scared by their own hubris; for example, Wilhelm Roux, the founder of developmental mechanics, wrote the following about his 1888 embryological experiments: “[…] I plunged a sharp needle in the frog’s egg, not without feeling an inner horror that I dared to interfere in such a way with the mysterious complex of the developmental processes of a living creature.” (Roux 1905: 47)

Others debated the organological world view, provoking an ontological clash. Loeb programmatically introduced readers to his early experimentation with organ regeneration in marine animals with the words, “I have undertaken the task of finding out whether and by what means it is possible in animals to produce at will in the place of a lost organ a typically different one – different not only in form, but also in function.” (Loeb 1891: 1)

For him the aim of his research was not analytical, he had “another and higher aim, which is synthetical or constructive, that is, to form new combinations from the elements of living nature, just as the physicist and chemist form new combinations from the elements of non-living nature.” (Loeb 1893)

4

5

For a short analysis of Goethe and his view on nature and “delicate empiricism” as a scientific method see among others the interesting approach by Bywater (2005). A comparison of organological and mechanistic world views and their counterparts has been given by Köchy (1997). A short and precise overview was published by Allen (2005); Müller (2008). The bioethics of organological and mechanistic world views were discussed by Köchy (1998).

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Life phenomena were for Loeb physicochemical processes, and he sought to understand their underlying mechanisms by gaining technical control over living organisms. He summarised these ideas in a letter to his mentor, physicist Ernst Mach: “The idea I have in mind is that man himself can interfere with animated nature as a creator to possibly form it according to his will. This way at least a technology of living things could be obtained. Biologists call it a creation of monstrosities; railways and telegraphs and all the other achievements of the technology of inanimate matter are consequently monstrosities as well, at least they were not created by nature, man did not discover them.” (Loeb to Mach, November 11, 1894, DMM, translation by the author)

Loeb further stated that biology would only become a science when abiogenesis was made possible by technical means, and that he wished to apply biotechnology to mental, social, and ethical questions. He argued that human ethics must be the result of chemical processes in the brain, just as human existence was based on physicochemical mechanisms. He believed that humans ate, drank, acted, and reproduced because they were compelled like machines to do so, not for metaphysical reasons (as Loeb named any reason outside of physic-chemical explanations). The same compulsion applied to workmanship, maternal love, a sense of community, and the struggle for justice. Deviations were caused by economic or social conditions, or by genetic mutations (Loeb 1912). The core disciplines of such a mechanistic world view were mathematics, physics, and chemistry. Its epistemology can be characterised by positivism, materialism, and mechanism, which resulted in a predominantly experimental methodology. The corresponding action perspective used technology to address ethical concerns. Comparison of the organological and mechanistic understandings of nature reveals a fundamental methodological and moral shift. On an ethical level, the mechanistic world view embraced a technical control and authority that had been unacceptable from the organological viewpoint (Table 1).

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Table 1: The investigation of nature from a mechanistic and an organological perspective and the following action perspectives Level of Concern Reference disciplines Epistemology

Research method Action Perspectives

Organological Perspective Theology Philosophy Holism Macrocosm / Microcosm Observation and description Respect and keep the status quo

Mechanistic Perspective Mathematics Physics, Chemistry Positivism Mechanism, Materialism Experiment und control (Bio-)Technology, bioengineering

I n t e r ve n i n g i n t h e B r a i n a n d M i n d Current developments in stem cell research and related regenerative and therapeutic exploration are predominantly governed by the mechanistic approach. This world view has become the standard and style-forming pattern underlying biomedicine. It has determined the current medical understanding of the brain and has allowed medical interventions such as the implantation of stem cells or electrodes. The means-end orientation is to some extent a legitimate justification for biomedical research, and allows technical solutions to be offered for ethical dilemmas of biotechnological origin without reflecting on technology itself. If technical control can be employed to solve a problem within a given world view, this principle must also apply (however circular) to technically produced ethical problems. Such principles apply to the exploration of the brain and mind. Loeb argued around 1900 that mind as a function of the brain including memory, psychology, instincts, and behaviour could be explained in purely physicochemical terms. He stated that, “the physiology of the brain has been rendered unnecessarily difficult through the fact that metaphysicians have at all times concerned themselves with the interpretation of brain functions and have introduced such metaphysical conceptions as soul, consciousness, will, etc. One part of the work of the physiologist must consist in the substitution of real physiological processes for these inadequate conceptions.” (Loeb 1900: V)

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He thus believed that mind as a brain function is a physical and chemical physiological process, and considered it to be susceptible to the (chemical) instillation of ideas (Loeb 1912: 62), education (Pavlovian conditioning), and electrical or chemical stimuli. For example, Loeb considered the penal code a means to “strengthen the inhibitory associations of weaker members of society” (Loeb 1900: 234; also in more detail Loeb 1899). Almost 70 years later, Jose Delgado proposed that electrical brain stimulation could be used to civilise the human psyche. Adopting a perspective similar to Loeb’s, he argued that mind control through the application of electrodes would continue the evolutionary process through mental liberation and self-domination. Such liberation of the brain from biological constraints or innate biological influences could improve society by controlling, for example, aggressive behaviour (Delgado 1969; Horgan 2005). This perspective brings to mind Loeb’s statement that, “[…] in the end, science will carry out such a revolution in ethics as it has done in our material life before” (Loeb 1904-1905: 784). Delgado’s beliefs were not always taken seriously (e.g. Rothenberg 1970), and the modern understanding of the brain has revealed that it is far too complex to be easily “psychocivilized”, as Delgado suggested, nevertheless currently active neuroscientists make statements such as the following, in accordance with Loeb: “If we make statements on freedom of will we apply the conceptual tools from our laboratory to formerly philosophical questions – and for the first time we end up with scientifically based answers.”6

Conclusion Many models have been produced to explain the prevalence of materialistic and mechanistic views such as the biomedical research paradigm in Western societies including both aspects the history of ideas and the social history of science.7 These models agree that developments within the medical sciences cannot be interpreted in isolation, but only within social and historical contexts.8 Biomedical explanations thus seem to 6

7 8

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Wolf Singer in an interview, in: Die Zeit, 14.07.2005 (Nr. 29) “Wenn wir Aussagen zur Willensfreiheit machen, wenden wir das konzeptuelle Werkzeug aus unseren Labors auf ursprünglich philosophische Fragestellungen an – und kommen dabei erstmals zu naturwissenschaftlich untermauerten Antworten”. Translation by the author. For overviews see among others Dijksterhuis (2002); Rothschuh (1978); Wittkau-Horgby (1998). Ludwik Fleck has hinted at this connection very precisely some time before Thomas Kuhn and others (Fleck 1980).

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provide an acceptable “rationalization”, in Max Weber’s sense, as the primum movens of Western societies. A rationalising perspective approaches social actions and interactions through calculation (e.g. of efficiency); in this way, it intrinsically contradicts motivations or speculations derived from mysticism, religion, custom, emotion or tradition. Such considerations of efficiency and predictability are central to the modern biomedical approach.9 Although the goal of Regenerative Medicine or Deep Brain Stimulation for medical purposes is not questioned, ethical uncertainties about endeavours such as stem cell research or abusing Deep Brain Stimulation for intentionally altering a person’s mind persist. Neither the goal of finding cures nor the development of techniques that avoid the use of embryos have overcome basic concerns about the status of nature and human attempts to control nature or human mind. These unresolved issues may indicate the incomplete dominance of the mechanistic model in societal beliefs. The organological, materialistic and mechanistic viewpoints presented here are extreme positions that are often softened or compromised in the reality of the laboratory. For example, Barfurth and Roux articulated such justifications and discomfort when presenting their research. Similarly, current researchers metaphorically invoke the magic of Mother Nature10 when they have difficulty providing full explanations for the complex processes of life. Although the mechanistic paradigm dominates the technological sector of biomedicine, its dominance vanishes when medicine is considered in a social context. Critique of the mechanistic model is still a component of normative discussions regarding bioengineering or technical fixes for the human brain. The inherent insecurity in biomedical means – the uncertainty of results of biomedical healing attempts – has also contributed to disenchantment with a purely mechanistic approach. At the beginning of the 21st century, the mechanistic model has lost some of its appeal. The increasingly perceived complexity of life processes, such as regeneration, has impeded simplistic explanations based on causal-analytic calculation. Despite conceptual acceptance of the basic tenets of mechanistic biomedicine, some patients nevertheless feel uncomfortable with an impersonal or analytical treatment option when they are ill. Physicians who have been educated under the bio9

For this and the following questions compare the excellent surveys of Hewa (Hewa 1994; Hewa and Hetherington 1995). 10 E.g. “It is certain that many different strategies will be attempted before we can recapitulate even a small fraction of the success and efficiency that has resulted from hundreds of millions of years of research and development by Mother Nature” (Badylak 2005: 36).

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medical mechanistic paradigm see the “art of medicine”, which is nurtured by organological tenets, endangered by a mechanistically constituted action perspective.11 The mechanistic viewpoint thus enjoys broad intellectual and rational acceptance in society, but also contradicts the moral intuition and empirical experience of many people. This disparity is caused by the different speeds at which rationalising processes proceed in biomedicaltechnical and sociocultural contexts. Following Weber, Jürgen Habermas defined the process of rationalisation as the gradual extension of purposive-rational action into nearly all spheres of social life, even though such action may directly contradict traditional moral values and ethics (Habermas 1969; 1968). Such asynchrony results in areas of conflict. The growth of this area over time due to different speeds of rationalisation processes in the sphere of values and purposive-rational action helps to explain temporal shifts in acceptance of regeneration research and other mechanistic approaches in medicine, as well as the failure of technical solutions and means-end orientated justifications to eliminate moral uncertainties about such research. Recognition of non-parallel development in the rationality of purposes and values highlights the sociocultural contribution to the growing perception of the limits of the mechanistic approach and the critique of its research goals, such as therapeutic cloning or the fear of mind control due to deep brain stimulation. This process accompanies scientific, biotechnological progress. Uncertainty about the mechanistic world view is growing as its limits become better understood; these limits, in turn, must be considered in relation to the organological perspective. This arena of contradiction may be historically and philosophically examined. Regenerative Medicine and for example deep brain stimulation for psychiatric disorders (which might be understood as mind control) may not continue as a publicly funded field of research unless both purposive-rational actions and traditional concerns can be addressed. The dichotomy between mechanistic and organological world views may thus still need to be challenged, with the goal of their integration. Knowledge of Regenerative Medicine’s history and of mechanistic and organological views of the brain and mind may facilitate the future establishment of “implanted minds” as an interdisciplinary field of research that includes neuroscientists, philosophers, and historians of science.

11 See for example the plea for the integration of holistic concepts and evidence based medicine and the quoted literature in the Journal of Evaluation in Clinical Practice (Miles 2009a, 2009b).

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References Allen, Garland E. (2005) “Mechanism, vitalism and organicism in late nineteenth and twentieth-century biology: the importance of historical context”, in: Studies in History and Philosophy of Biological and Biomedical Sciences 36: 261-283. Andres, Robert H., Raymond Choi, Gary K. Steinberg & Raphael Guzman (2008) “Potential of adult neural stem cells in stroke therapy”, in: Regenerative Medicine 3/6 (Nov): 893-905. Anonymous (1890) “Successful brain grafting”, in: Science 16/392: 7879. Badylak, Stephen F. (2005) “Regenerative medicine and developmental biology: the role of the extracellular matrix”, in: Anatomical Record. Part B. The New Anatomist 287/1 (Nov): 36-41. Bangor Daily Whig and Courier, Friday, March 4, 1898 Barfurth, Dietrich (1910) Regeneration und Transplantation in der Medizin (Jena: Gustav Fischer). Boltzmann, Ludwig (1905) Reise eines deutschen Professors ins Eldorado (Leipzig: Barth). Buscaglia, Marino & Denis Duboule (2002) “Developmental biology in Geneva: a three century-long tradition”, in: International Journal of Developmental Biology 46/1 (Jan): 5-13. Bywater, Bill (2005) “Goethe: a science which does not eat the other”, in: Janus Head. Journal of Interdisciplinary Studies in Literature, Continental Philosophy, Phenomenological Psychology, and the Arts 8/1: 291-310. Das, Gopal D. (1990) “Neural transplantation: an historical perspective”, in: Neuroscience and Biobehavioral Review 14/4 (Winter): 389-401. Delgado, José Manuel Rodriguez (1969) Physical control of the mind: toward a psychocivilized society (New York: Harper and Row). Die Zeit, 14.07.2005 (Nr. 29), Interview with Wolf Singer. Dijksterhuis, Eduard Jan (2002) Die Mechanisierung des Weltbildes. 2. Nachdruck der Ausgabe 1956 (Berlin/Heidelberg/New York: Springer). Dinsmore, Charles E. (ed.) (1991) A history of regeneration research – milestones in the evolution of a science (Cambridge: Cambridge University Press). Dinsmore, Charles E. (1996) “Urodele limb and tail regeneration in early biological thought: an essay on scientific controversy and social change”, in: International Journal of Developmental Biology 40/4 (Aug): 621-627.

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Edwards, Robert G. (2004) “Stem cells today: A. Origin and potential of embryo stem cells”, in: Reproductive Biomedicine Online 8(3): 275306. Fangerau, Heiner (2005) “Can artificial parthenogenesis sidestep ethical pitfalls in human therapeutic cloning? An historical perspective”, in: Journal of Medical Ethics 31/12 (Dec): 733-735. Fleck, Ludwik (1980) Entstehung und Entwicklung einer wissenschaftlichen Tatsache: Einführung in die Lehre vom Denkstil und Denkkollektiv (Frankfurt: Suhrkamp Verlag). Freed, William J. (2000) Neural transplantation: an introduction (Cambridge, MA: MIT Press). Gilbert, David M. (2004) “The future of human embryonic stem cell research: addressing ethical conflict with responsible scientific research”, in: Medical Science Monitor 10(5): RA99-103. Habermas, Jürgen (1968) Technik und Wissenschaft als „Ideologie“. (Frankfurt: Suhrkamp). Habermas, Jürgen (1969) Protestbewegung und Hochschulreform. (Frankfurt: Suhrkamp). Harper’s Weekly, December 13, 1902. Hewa, Sowa (1994) “Medical technology: a Pandora’s Box?” in: The Journal of Medical Humanities 15/3: 171-181. Hewa, Sowa & Robert W. Hetherington (1995) “Specialists without spirit: limitations of the mechanistic biomedical model”, in: Theoretical Medicine 16: 129-139. Horgan, John (2005) “The forgotten era of brain chips”, in: Scientific American 293/4: 66-73. Köchy, Kristian (1997) Ganzheit und Wissenschaft. Das historische Fallbeispiel der romantischen Wissenschaft (Würzburg: Königshausen & Neumann). Köchy, Kristian (1998) „Organologische versus mechanistische Bioethik. Über spezifische ethische Programme bei verschiedenen Lebenstheorien“, in Eve-Marie Engels (ed.), Ethik der Biowissenschaften. Geschichte und Theorie. Beiträge zur 6. Jahrestagung der DGGTB in Tübingen 1997 (Berlin: Verlag für Wiss. und Bildung). Landecker, Hannah (2007) Culturing life: how cells became technologies (Cambridge, MA: Harvard University Press). Loeb, Jacques (1891) Untersuchungen zur physiologischen Morphologie der Tiere. I. Über Heteromorphose (Würzburg: Georg Hertz). Loeb, Jacques (1893) “On some facts and principles of physiological morphology”, in: Biological Lectures delivered at Woods Holl (Boston: Gin and Co.): 37-61.

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Loeb, Jacques (1899) Einleitung in die vergleichende Gehirnphysiologie und vergleichende Psychologie, mit besonderer Berücksichtigung der wirbellosen Tiere (Leipzig: Johann Ambrosius Barth). Loeb, Jacques (1900) Comparative physiology of the brain and comparative psychology (New York: Putnam). Loeb, Jacques (1904-1905) „Zur neueren Entwicklung der Biologie“, in: Annalen der Naturphilosophie 4: 188-203. Loeb, Jacques (1912) “The mechanistic conception of life”, in: Popular Science Monthly 80: 5-21. Loeb, Jacques (1912) The mechanistic conception of life (Chicago: University of Chicago Press). Lysaght, Michael J. & Janet Crager (2009) “Origins”, in: Tissue Engineering Part A., Jul;15(7): 1449-1450. Maienschein, Jane (1983) “Experimental biology in transition: Harrison’s embryology, 1895-1910”, in: Studies in History of Biology 6: 107-127. Miles, Andrew (2009a) “On a medicine of the whole person: away from scientistic reductionism and towards the embrace of the complex in clinical practice”, in: Journal of Evaluation in Clinical Practice 15/6 (Dec): 941-949. Miles, Andrew (2009b) “Towards a medicine of the whole person – knowledge, practice and holism in the care of the sick”, in: Journal of Evaluation in Clinical Practice 15/6 (Dec): 887-890. Miller, Douglas (ed.) (1995) Goethe, Johann Wolfgang von: Scientific studies (Princeton, NJ: Princeton University Press). Moeschlin-Krieg, Beate (1953) Zur Geschichte der Regenerationsforschung im 18. Jahrhundert (Basel: Benno Schwabe). Müller, Sabine (2008) „Paradigma Organismus versus Paradigma Mechanismus – zwei wissenschaftstheoretische Leitbilder“, in Dominik Groß, Gertrude Cepl-Kaufmann & Gereon Schäfer (eds.), Konstruktion von Wissenschaft (Kassel: Kassel University Press): 13-28. Pauly, Philip J. (1987) Controlling Life: Jacques Loeb and the engineering ideal in biology (New York: Oxford University Press). Rothenberg, Albert (1970) “Physical control of the mind: toward a psychocivilized society”, in: Yale Journal of Biology and Medicine 43/1: 55-58. Rothschuh, Karl E. (1978) Konzepte der Medizin in Vergangenheit und Gegenwart (Stuttgart: Hippokrates-Verlag). Roux, Wilhelm (1905) Die Entwickelungsmechanik: ein neuer Zweig der biologischen Wissenschaft; eine Ergänzung zu den Lehrbüchern der Entwickelungsgeschichte und Physiologie der Tiere; nach einem 29

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Vortrag gehalten in der ersten allgemeinen Sitzung der Versammlung Deutscher Naturforscher und Ärzte zu Breslau am 19. September 1904 (Leipzig: Engelmann). Shih, C.C., S.J. Foreman, P. Chu, M. Slovak (2007) “Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice”, in: Stem Cells and Development 16(6): 893-902. The Boston Herald, November 26, 1899. Thomson, James A., J. Itskovitz-Eldor, S.S. Shapiro, M.A. Waknitz, J.J. Swiergiel, V.S. Marshall & J.M. Jones (1998) “Embryonic stem cell lines derived from human blastocysts”, in: Science 282: 1145-1147. Turney, Jon (1995) “Life in the laboratory: public responses to experimental biology”, in: Public Understanding of Science 4/2 (Apr): 153-176. Van Speybroeck, Linda, Dani De Waele & Gertrudis Van de Vijver (2002) “Theories in early embryology: close connections between epigenesis, preformationism, and self-organization”, in: Annals of the New York Academy of Sciences 981 (Dec): 7-49. Witkowski, Jan A. (1979) “Alexis Carrel and the mysticism of tissue culture”, in: Medical History 23: 279-296. Witkowski, Jan A. (1983) “Experimental pathology and the origins of tissue culture: Leo Loeb’s contribution”, in: Medical History 27: 269-288. Wittkau-Horgby, Annette (1998) Materialismus: Entstehung und Wirkung in den Wissenschaften des 19. Jahrhunderts (Göttingen: Vandenhoeck & Ruprecht).

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Ca n Intracerebral Inte rve ntions Cha nge our Se lf? – Ne uroethica l Implications of Ontologica l Ass umptions JOSEF QUITTERER

Introduction A satisfying answer to the notorious neuroethical question ‘how do intracerebral interventions influence personal identity?’ does not depend only on clinical details of brain surgery; it depends also on the meaning which is given to the concepts of ‘personal identity’ and ‘self’. In my paper I analyze how different concepts of the self frame the answers to neuroethical questions concerning personal identity. In my analysis I compare a narrative (ontologically weaker) understanding of the self as it is presupposed by Daniel Dennett, Owen Flanagan and Gerhard Roth with a biological (ontologically stronger) concept of the self as it can be found in the works of Antonio Damasio, George Butterworth and others. It can be shown that the narrative concept of the self leads to an overestimation of the influence of intracerebral interventions on personal identity.

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I n t r a c e r e b r a l I n t e r ve n t i o n s a n d Personal Identity The brain as the correlate of our entire mental life is generally conceived as the substratum of our personality – of our self. We can assume that the introduction of foreign material into the brain affects our personality or even personal identity in a similar way as it is affected by brain damages or other severe changes in the neural system. Dieter Birnbacher distinguishes clearly between the change of personality and the change of personal identity – the first being an alteration of our psychological identity, the second being an alteration of the numerical identity of a person (Birnbacher 2006: 274).1 It is obvious that the change of personal identity has different ethical implications than the change of personality: After a change of personal identity the human being is not the same person any more as she was before the intracerebral intervention; a change of our personality, though, could – under certain circumstances – be morally justified. It is something which might happen to us also in everyday life. The qualitative difference in the ethical appraisal of the alterations of personhood, in connection with the new technical possibilities of intracerebral interventions, requires a reconsideration of “the criteria for personal identity and personality changes” (Hansson 2005: 523). For an adequate evaluation of the ethical implications of intracerebral interventions we need not only a detailed analysis of the neurophysiological, brain-functional and cognitive effects of the respective interventions but also a clarification of the criteria and conditions of personal identity: What must be the case that a person after an intracerebral intervention is the same person as he or she was before the intervention? In the following analysis I present two different conceptions of personal identity and their neuroethical implications. The first conception of personal identity is ontologically weak, that means it does not presuppose a robust notion of the self; the second presupposes an ontologically stronger concept of personal identity by assuming that the self is grounded in the biological reality of the human organism.

1

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Birnbacher also mentions that a severe alteration of our psychological identity might lead to a disruption of the numerical identity of a person. (Birnbacher 2006: 276)

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A ‘Weak’ Concept of Personal Identity and the Self – John Locke and Contemporary Neurophilosophy In contemporary philosophy of mind the criteria and conditions of personal identity are generally subsumed under the concept ‘self’. The self is generally seen as a theoretical entity which accounts for the (diachronic) identity of a person. Without doubt it was John Locke who made the notion of ‘self’ a prominent term in modern philosophy. Rejecting the elder notion of ‘soul’ as unclear and inaccessible to human experience he deemed the concept of self to be sufficient for guaranteeing personal identity throughout life. The introduction of the term ‘self’ by John Locke is connected with a clear distinction between the identity conditions of organisms and the identity of persons. The identity of organisms (humans, animals, plants) is determined by “the self-organizing biological event that maintains the organism’s complex internal structure” which we call life (Olson 2007: 28).2 Human beings have the persistence-conditions of organisms; therefore the diachronic identity of human beings depends on the selforganizing biological event which constitutes the life of the human being. Human beings as organisms persist only if their life persists (Olson 2007: 29). Human persons, though, have different persistence- or identity-conditions. The diachronic identity of persons – according to Locke – is not constituted by the same life but by the same self. The self binds together the different mental episodes which belong to one person. As the unifying principle of our mental life the self guarantees the diachronic identity of human persons: “For since consciousness always accompanies thinking, and it is that which makes every one to be what he calls self, and thereby distinguishes himself from all other thinking things, in this alone consists personal identity, i.e. the sameness of a rational being: and as far as this consciousness can be extended backwards to any past action or thought, so far reaches the identity of that person; it is the same self now it was then; and it is by the same self with this present one that now reflects on it, that that action was done.” (Locke 1694: Ch. 27, § 9)

2

“An animal is a living organized body; and consequently the same animal […] is the same continued life communicated to different particles of matters, as they happen successively to be united to that organized living body.” (Locke 1694: Ch. 7, § 8)

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Based upon this definition, the diachronic identity of persons is constituted exclusively by the cognitive capacity of self-reflection or self-consciousness: x is the same person as y iff [if and only if] x possesses the same consciousness as y. This implies that autobiographical memory plays an essential role in the constitution of diachronic personal identity: x is the same person as y iff x has the same consciousness as y, and x has the same consciousness as y iff x has the ability to remember previous conscious states of y as her (x’s) conscious states. The capacity to remember and the ability to ascribe to oneself previous experiences is the prerequisite for establishing personal identity trough time. Only in this case a subject can understand itself as being the same over longer periods of time and develop a personal self. For Locke self and personal identity are obviously the results of self-representing cognitive activities. The thing we call a ‘self’ is based on consecutive acts of consciousness bound together by our ability to remember. Human persons are, thus, constituted solely by their ability to recall into consciousness what they attribute to themselves because of having experienced it personally. The decisive point in Locke’s theory of personal identity which is relevant for our topic is the divergence of the identity-conditions of human organisms and of human persons: Human organisms start to exist with the beginning of their life; human persons begin to exist not before the human organism has developed the capacity of self-representation or self-reflection. The identity-conditions of persons are conceived as relations between different mental states. As far as we can remember, as far relations between mental states can be established by the subject so far the identity of a person can be extended. We count to our self only these mental states that are connected to our consciousness. The human organism is of no further importance for Locke’s conditions of personal identity. Consciousness alone suffices. The conclusions following from this account are shown in Locke’s famous example of the body switch between the prince and the cobbler: One body can realize more than one person and one person can be realized in more than one body (Locke 1694: Ch. 27, § 15). In contemporary philosophy of mind and cognitive science, Locke’s notion of the self is predominant. The self is seen as the result of the capacity of self-representation. This capacity does not presuppose a robust notion of the self; according to this view, the self is a useful fiction of the self-representing organism. As such, it is largely independent from the underlying organism. This independence of the personal self from the organism is emphasized, for example, by the philosopher Daniel Dennett. In his popular book Consciousness Explained 34

CAN INTRACEREBRAL INTERVENTIONS CHANGE OUR SELF?

Dennett distinguishes between the ‘biological self’ and the personal (autobiographical) self (Dennett 1991). The biological self is given to all organisms which are able to distinguish (implicitly) between themselves and their environment – a capacity which Dennett ascribes also to protozoa (Dennett 1991: 414). The biological self is anchored in the biological structure of organisms. Its limits coincide with the limits of the body of the organism. The crucial point is that according to Dennett the personal self of adult human beings diverges from the biological self. Whilst the biological self is a physical reality, the personal or autobiographical self of adult human beings is only a conceptual construct based upon the cognitive capacities of self-representation. The limits of the personal self are not confined through the biological structure of the human organism. The biological self of protozoa, for instance, is defined through the membrane of the cell. The personal self can be extended far beyond the limits of the organism – to personal belongings, social relations etc. Moreover, the biological and the personal self have different physical correlates: The biological self is based upon the homeostatic processes of the organism. The physical correlate of the personal self, on the other hand, is not the working organism within the limits of its body but the parallel distributed neurological processes in a highly plastic brain (Dennett 1991: 187). The plasticity of the brain is the physical prerequisite for the possibility that the personal self can detach itself from the biological self. In the brain there is nothing corresponding to the unity and centeredness of the personal self as it is experienced in everyday life, there is no ‘proper physical correlate’ for the self (Dennett would call it ‘proper self’). ‘Proper physical correlate’ can be defined as a physical entity whose causal role corresponds to the causal role of the mental entity. That means that there is a physical correlate for the personal self in a similar way as there is one for illusions or false beliefs: Something must be going on in a person’s brain when she is convinced that she is Napoleon when in fact she is not; in this sense, the belief “I am Napoleon” has a physical correlate. But there is no proper physical correlate for this illusion – there is no state of affairs in the physical world which corresponds to the propositional content of the belief that she is Napoleon. A similar opinion is shared by many philosophers and cognitive scientists when it comes to the assumption of the self: There is nothing in the physical world – that means in the brain – which corresponds in the proper sense to what we have in mind when we refer to ourselves. For Thomas Metzinger the personal self is the product of the ‘self-misunderstanding’ of a system which self-represents itself (Metzinger 1993: 157), for Dennett the self is an explanatory fiction 35

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(Dennett 1991: Ch. 13). In a similar vein as Dennett and Metzinger argues the neurobiologist Gerhard Roth who considers the self as an illusion. Similar to Dennett, Roth refers to decentralized working processes of the human brain in order to support his illusion-thesis of the human self (Roth 2003: 394f.). In the brain there is nothing which corresponds – as a proper neural correlate – to the unity and centeredness of the psychological self as it is experienced in everyday life. For Dennett and Roth the assumption of personal identity (a robust concept of the self) has to be rejected because it leads to dualism which is not reconcilable with a scientific outlook of the world.3 If the self is a fiction and our intuition of personal identity is an illusion, the question arises why the evolution produced such a bizarre phenomenon. For this reason, Dennett and others stress the evolutionary advantage of such false assumptions concerning the self and diachronic personal identity. They tend to explain the self or related folk psychological assumptions as some sort of ‘useful fiction’ (Dennett 1991; Flanagan 1992; Metzinger 1993; Roth 2003). For Dennett, generating a self serves to improve the chance of survival of cognitive systems. The capacity of self-representation in this sense is a complex tool for guaranteeing the survival of the individual. Forms of self-representation do not have to be referred to a biological self but through selfrepresentation a self is constituted in the first place. Our selfrepresentations are structured in such a manner that a self can be ascribed to them only retrospectively. For this reason Dennett calls the self a ‘centre of narrative gravity’. The self is no real entity but an explanatory fiction or a useful theoretical construct – it is ontologically weak.

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For Dennett there are only two possibilities to deal with the phenomenon of the human self: Either someone becomes a dualist and interprets the self as the manifestation of a spiritual, non-physical reality or someone is willing to pay the price for a less obscure and more scientific view of the matter and unmasks the self as fiction. Only if someone is willing to accept the self as a fiction of self-representing biological systems then the non-scientific assumption of a soul or “soul-pearls” (as Dennett puts it) becomes superfluous (Dennett 1991: 423).

CAN INTRACEREBRAL INTERVENTIONS CHANGE OUR SELF?

Neuroethical Implications of the Weak Concept of the Self and Personal Identity Departing from this ontologically weak concept of the self, the probability that intracerebral interventions affect personal identity is very high. Self and personal identity are obviously based upon specific brain processes. In particular, the neocortical areas where the higher cognitive functions – like memory, self-understanding etc. – are located, are extremely relevant for this concept of identity. When the cortical regions of the brain which are responsible for the cognitive functions of self-representation, memory and moral evaluation, are constitutive for the personal self, any intervention in these areas can change our self and as such our personal identity. Let us assume, for the sake of the argument, that intracerebral interventions can be used in future for restoring the conscious access to disconnected mental contents. Such disconnections can appear in different forms of amnesia, in which patients are unable to recover their own memories. The intracerebral intervention could probably be used to integrate lost memories again into the autobiographical self of the person. Since the ontological status of the self is very weak – it is only a useful fiction – there can be only pragmatic criteria for the medical indication of such an intervention. According to this view, regaining access towards past experiences is not reasonable, if it would be a disadvantage for the cognitive system. This point can be made more explicit in cases of the so called ‘dissociative identity disorder’ (DID). In these cases of memory dissociation different memories are ‘owned by different selves’. DSMIV-TR lists the following criteria for diagnosing DID: The presence of two or more distinct identities or personality states (each with its own relatively enduring pattern of perceiving, relating to, and thinking about the environment and self); at least two of these identities or personality states recurrently take control of the person’s behaviour; inability to recall important personal information that is too extensive to be explained by ordinary forgetfulness (American Psychiatric Association 1994).4 For Dennett, cases of DID are a clear sign that the idea of a personal self is just fictional. According to his interpretation it is sometimes 4

It must be noted that criteria and classification of DID are still under debate. Cases of DID are reported in Everest (1999), Beer et al. (1994), Okugawa et al. (2005). Most physicians agree with the theory that childhood psychological traumata, especially sexual abuses, are associated with the phenomenon of DID.

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rather disadvantageous for a cognitive system to attribute all experiences to one self alone. For the ‘psychological survival’ of some persons the production of other selves might provide an advantage. The ontological status of these additional selves is the same as the one of the ‘original self’ – a helpful fiction for the system to fulfil specific tasks of selfrepresentation. In this case, an intracerberal intervention which leads to an overall integration of the dissociated selves might be counterproductive. To sum up: If intracerebral intervention should be used in the future for a therapy of our self-representational capacities, the following ethical constraints are implied by an ontologically weak self: • The goal of the intracerebral therapy is not per se the overall integration of all mental contents into one self. Unity in itself is not a criterion for a successful therapy. As we have seen above, the self is seen as a fiction generated by the organism for purposes of survival. Under normal circumstances the slogan ‘one self per body’ is correct, but in contrast to the biological self a clear correlation between personal self and body is not possible. Normally, a human being has just one self where current and past experiences of the organism are integrated into a coherent whole. There are, though, cases where a non-ambiguous correlation between biological and psychological self is not desirable. • The ontologically weak self of Locke, Dennett and others is dependent on the cognitive functions of self-representation, autobiographical memory, conceptual memory etc. Self and personal identity is generated by these cognitive functions. Therefore, any intervention which affects brain areas with neural correlates of these higher order mental capacities will directly affect personal identity as well. These neuroethical implications can be derived from a weak concept of self and personal identity. In this view there is a clear distinction between the identity conditions of organisms and persons or – to put it in the words of Daniel Dennett – between the biological and the narrative (personal) self. Now I would like to turn to a different view on personal identity in which the identity conditions of human organisms and persons are coextensive.

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An O n t o l o g i c a l l y S t r o n g e r C o n c e p t o f P e r s o n a l Identity – the Self as a Biological Reality An Argument from Developmental Psychology Dennett’s proposal to consider the biological and the personal self as inhomogeneous does not seem to be backed up by results from developmental psychology. George Butterworth explored extensively the origins of self-perception in infancy (Butterworth 1992). In agreement with Dennett, Butterworth shows that a biological self – an implicit knowledge about the limits and functions of one’s own body – can already be verified in unborn foetuses. Butterworth emphasizes, however, that there are no reasons for distinguishing sharply between the biological self as the basis of all proprioceptions and goal oriented behaviour on the one hand and higher forms of self-conception on the other hand. These different kinds of selves are not incompatible with each other. The higher forms of self-conception presuppose the more basic ones. There is a continuum beginning with primitive ways of bodily self-perception and terminating with a mature concept of an autobiographical self in adult human beings: “The point is that movement synergies reveal properties of the material self as an organized totality; species typical developmental processes will determine the extent to which such aspects of the categorical self become elaborated within higher order cognitive processes.” (Butterworth 1992: 108)

According to this view, the biological self of a human being is the biological foundation of the personal or conceptual self.

Damasio: Neurological Mappings of Bodily Functions Further evidence for the thesis that there is a continuum between the biological and the personal self, is provided by the neurobiologist Antonio R. Damasio. Damasio and other experts in neurobiology maintain that an adequate understanding of the mental is possible only in conjunction with the representation of bodily processes. Moreover, the traditional mind-body problem is not reducible to a mind-brain problem, as many philosophers of mind suggested in the last decades. New approaches in cognitive science and philosophy of mind tend to soften the strict dichotomy between the realm of the mental and the realm of the physical. The realm of the mental is broadened toward states that embrace bodily aspects as well. For instance, recent contributions treat 39

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the role that emotions play within cognitive and rational processes. These accounts come along with a more fully developed conception of the physical: The work of Damasio and other experts in the field of cognitive science indicates that the physical correlates of states of consciousness are not assumed to be single neural events or activity patterns. Increasingly scientists become aware of the relevance of basic functional principles of the living organism and their multilevel neurobiological mappings for the generation of consciousness.5 Damasio argues against the thesis that physical correlates of higher forms of (self-) consciousness are to be found exclusively in the cerebral cortex. He shows that (self-) consciousness also depends on structures that belong to older phylogenic areas of the brain which are closely interconnected with biological functions (Damasio 1999). Damage of parts of the diencephalon, of the brainstem or the upper part of the formatio reticularis leads to various forms of consciousness-loss. These structures are responsible for the regulation of basic living functions of the organism – the so-called ‘inner milieu’. The stripline between the parts of the formatio reticularis whose damage leads to a change or loss of consciousness and those parts whose damage does not entail such consequences is quite clear. From the fact that these brain areas are essentially involved in the control and representation of bodily processes, Damasio draws the conclusion that there is a direct connection between subjective experience, neuronal representation and the control of bodily processes (Damasio 1999: 236). Core-consciousness is immediately connected with permanent representations of fundamental organic functions. It is the so-called ‘proto-self’ that makes this constant representation possible. Bodily processes are grounded in a unifying biological principle, which persists soundly from the beginning to the end of our life: “The reason why representations of the body are well suited to signify stability comes from the remarkable invariance of the structures and operations of the body. Throughout development, adulthood, and even senescence, the design of the body remains largely unchanged. To be sure, bodies grow in size during development, but the fundamental systems and organs are the same throughout the life span and the operations that most components perform change little or not at all.” (Damasio 1999: 141)

5

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See e.g. the interdisciplinary anthology by De Preester and Knockaert (2005).

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Since these basic regulatory mechanisms are relatively stable, they provide the best candidate for referring to an identical subject, as it is presupposed in self-consciousness. A central condition for the development of human subjectivity and self-consciousness is thus the representation of a dynamic equilibrium (homeostasis) of the various organic states through the proto-self. Selfconsciousness arises, if an object, the organism, and the relation among the two are represented. The neurobiological basis of this proto-self is the representation of the causal relation between (interior and exterior) objects and the organism. Emotions play a central role in the transmission of these processes by mental pictures. Emotions accompany bodily changes and the reactions that are elicited by outer or inner objects. Emotions serve as markers that make these interplays of bodily reactions, objects and self accessible for an extended consciousness (memory) at a later point in time (Damasio 1994). The organisational principle which controls fundamental bodily functions is the biological basis of the proto-self. Without this principle, neither consciousness nor self-consciousness could arise.6 The organisational principle that represents the constitution plan for our bodily structure constitutes on a fundamental level, what we call personal identity. There is a biological basis on which our capacity to refer to ourselves can be grounded. The intuition that we remain the same during time is not a fiction but refers to a biological reality – the organisational principle of our bodily functions which remains essentially the same during time.

Neuroethical Implications of the Stronger Concept of the Self ‘Stability’ of the Self The first neuroethical implication of this ontologically stronger concept of the self is a lower probability that intracerebral interventions affect personal identity. The reason for this is that – unlike the weak self – the reality underlying the strong self is not limited to specific cortical processes. Fundamental bodily functions together with their multilevel mapping in the brain are good candidates for being proper correlates of mental phenomena like self-consciousness, subjectivity and our intuition 6

“Moment by moment, the brain has available a dynamic representation of an entity with a limited range of possible states – the body.” (Damasio 1999: 142)

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of personal identity. Bodily functions remain the same even when they are not actualized. They are dispositional in character and thus, not adequately understandable within a framework of mere event-ontology. This does not mean that event-like brain processes do not play a decisive role in the constitution of consciousness. They are crucial for the representation and cognitive processing of those fundamental bodily functions which keep an organism alive. But if they are affected in brain interventions, it does not necessarily affect our personal identity, because our identity is not exclusively dependent on these neural correlates of higher order self-representational capacities. It is the organizational and functional structure of the human organism and its multilevel mapping in the brain that are fundamental for the formation of a self. “No component remains the same for very long, and most of the cells and tissues that constitute our bodies today are not the same we owned when we entered college. What remains the same, in good parts, is the constitution plan for our organism structure and the set points for the operation of its parts. Call it the spirit of the form and the spirit of the function.” (Damasio 1999: 144)

If the permanent representation of basic regulatory mechanisms in the so called proto-self is the fundament of the identity of a conscious subject, intracerebral interventions have a lower probability to affect personal identity. When intracerebral interventions affect the neural correlates of memory, self-representation, the structure and functional principle of our organism remain largely unchanged. Self-representation can generate the impression of identity and unchangeability of a stable self as long as this invariant organisational principle of our organism is constantly represented as well.

Therapeutic Objectives of Intracerebral Interventions If intracerebral intervention should be used in the future for a therapy of our self-representational capacities, the following ethical constraints are implied by an ontologically strong self: The personal self is based upon an underlying biological self; therefore, the goal of an intracerebral therapy is the restoration of the unity between the organic (bodily) self and the autobiographical personal self. Recalling the discussion of DID in the first section, the stronger concept of the self presupposes that physicians and psychiatrists do consider DID-patients still as the same persons. They would agree with Dennett, that developing subpersonalities might be a strategy to cope with traumatic experiences, but

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contrary to Dennett they would not deduce from this clinical diagnosis that the concept of a self or of personal identity as such is fictional. The point of departure of an intracerebral therapy would be one person who suffers under the dissociation of specific mental contents and personality traits. If intracerebral intervention should provide a tool for the reintegration of these dissociated mental contents or even dissociated ‘selves’, it should be used for the purpose of reintegration. Physicians and psychiatrists should try to reintegrate the various developed sub-personalities into one self again – as they in fact try to do with non-invasive methods in standard therapies of DID. Few kinds of this disease have proved to be advantageous for the patients. Most of them, however, present great psychological strain for the patients. The reason for this suffering is – according to the strong self-view – the dissociation of specific self-representational activities from the ‘original self’ which is grounded in the biological self. To reassume: Departing from an ontologically stronger concept of the self, intracerebral intervention is not qualitatively different from other (non-invasive) therapies of cognitive dysfunctions. There is no reason to overestimate the influence of intracerebral interventions on personal identity. The probability that personal identity is affected by brain interventions is lower than under the assumption of a weak self. For this reason there is no need to develop a special neuroethics for intracerebral interventions. Standard bioethics (ethical constraints for therapies, autonomy of the patient etc.) suffices, though it should be adapted for the techniques of brain intervention.

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References American Psychiatric Association (ed.) (1994) Diagnostic and statistical manual of mental disorders (DSM IV-TR), Fourth Edition (Washington). Beer, Denise, John Beer & Joe Beer (1994) “Multiple personality: selfrape”, in: Psychological Reports 75: 1263-1267. Birnbacher, Dieter (2006) Bioethik zwischen Natur und Interesse (Frankfurt a. M.: Suhrkamp). Butterworth, George (1992) “Origins of self-perception in infancy”, in: Psychological Inquiry 3: 103-111. Damasio, Antonio R. (1994) Descartes’ error. Emotion, reason, and the human brain (New York: Putnam). Damasio, Antonio R. (1999) The feeling of what happens. Body and emotions in the making of consciousness (New York: Harcourt Brace). Dennett, Daniel C. (1991) Consciousness explained (Boston: Little, Brown). De Preester, Helena & Veroniek Knockaert (eds.) (2005) Body image and body schema. Interdisciplinary perspectives on the body (Amsterdam: John Benjamins Publishing Company). Everest, Pauline (1999) “The multiple self: working with dissociation and trauma”, in: Journal of Analytical Psychology 44: 443-463. Flanagan, Owen (1992) Consciousness reconsidered (Cambridge, MA: MIT Press). Hansson, Sven Ove (2005) “Implant ethics”, in: Journal of Medical Ethics 31: 519-25. Locke, John (1694) An essay concerning human understanding, Second Edition, 1694. Metzinger, Thomas (1993) Subjekt und Selbstmodell. Die Perspektivität phänomenalen Bewusstseins vor dem Hintergrund einer naturalistischen Theorie mentaler Repräsentation (Paderborn: Schöningh). Okugawa, Gaku, Kenji Nobuhara, Mami Kitashiro & Toshihiko Kinoshita (2005) “Perospirone for treatment of dissociative identity disorder”, in: Psychiatry and Clinical Neurosciences 59: 624. Olson, Eric T. (2007) What are we? A study in personal ontology (Oxford: Oxford University Press). Roth, Gerhard (2003) Fühlen, Denken, Handeln. Wie das Gehirn unser Verhalten steuert (Frankfurt a. M.: Suhrkamp).

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Parfit’s Concept of Personal Identit y and its Implications for Intercerebral Stem Cell Transplants JAN GOLDSTEIN

Introduction From the capacity to consent to the relationship between physical and mental phenomena, many at first glance rather different considerations are related to the subject of neuroethics. Despite this diversity, they share a common trait in that they deal – directly or indirectly – with our belief that the brain possesses certain special properties (Northoff et al. 2006). From a philosophical point-of-view, the brain is unique because we often assume it is the seat of personality (Birnbacher 1995). We know that changes of the brain, both structural and physiological, lead to changes of personality and thus, potentially, to changes of personal identity (Northoff 2001; Birnbacher 1995). Furthermore, with the recent advances in the neurosciences, new therapeutical approaches have emerged that attempt to utilize such changes of the brain for the treatment of patients (Lindvall et al. 2004; Lindvall and Kokaia 2006). One particular example of this is the treatment of chronic neurological diseases by transplanting tissue or cells directly into the brain in order to restore the anatomic structure or to counteract pathophysiological changes. While these are undoubtedly exciting prospects with regard to the potential benefits, they also pose important questions that need to be answered if we are to decide whether or not we ought to use these 45

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treatments. Some of them might be put this way: if the brain is indeed the seat of personality, what are the consequences of changing its structure? Can we modify the brain without necessarily modifying the underlying person? Will the patient after the treatment be the same person as before the treatment? These are the questions that I’d like to comment on in this essay. First of all, I will briefly explain why I believe the question of personal identity to be crucial in the assessment of intracerebral stem cell transplants. I will then present, in necessary detail, a concept of personal identity suggested by Derek Parfit which, as I believe, corresponds particularly well to the gradual structural changes brought about by stem cell transplantation (see Parfit 1992, 1971). Finally, I will take a look at the transplantation of stem cells from the point-of-view of Parfit’s concept and propose some possible consequences for our evaluation of this form of treatment.

Parfit’s Concept of Identity For doctors and researchers alike, the first obligation should be to their patients. If it is true that the first principle of medicine ought to be do no harm, and if it is true that a particular treatment changes the identity of the patient, then that treatment should be abandoned. For if the patient after the treatment is a different person than the patient before the treatment, then we should conclude that the original person has been harmed to death; for, surely, the survival of a person requires the persistence of his identity. But are these deceptively simple considerations really true? While we do, in actual life, assume that the survival of a person requires the persistence of his identity, it may be argued that this is not, in fact, a necessary condition of survival. One of the philosophers who are most 1 commonly associated with this claim is Derek Parfit. In the following I will give a brief introduction to his view of identity. I will then discuss a particularly important thought experiment known as the ‘fission case’, which tries to show that identity is not what matters in survival. Parfit’s concept of personal identity is often illustrated with the example of a Star Trek device called the ‘transporter’, which is used to transport objects by destroying them at the original place and creating an 2 exact copy at the destination. In addition to transporting objects in this

1 2

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According to Noonan (2003). For a more detailed example of this approach, see Noonan (2003).

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way, however, in the series it is also frequently used to transport people. At first glance, though, this might seem absurd; after all, it is clear that I will be killed when I step on the platform. The fact that an exact replica of mine is being created in a different place would seem to be of rather little consolation. According to Parfit, however, this is all that ought to matter to me. In his view, we do not as such have any particular reason to be concerned with our personal identity or even our own survival in the future. Instead, what matters is (or ought to be) whether there exist in the future people to whom we are – at least to some degree – bound by the relations of psychological continuity and psychological connectedness. This claim needs further elaboration. Parfit argues that many of our problems concerning personal identity stem from two believes that we usually, but perhaps wrongly have about the identity of persons: first, that the question about identity – such as “will there be someone identical with me in 10 years?” – always has an answer, and second, that there are important judgments that we can only make if we know the answer to this question. One such judgment would be the answer to the question “will I be alive tomorrow?”. Parfit suggests that this is a belief in what he calls the ‘special nature’ of personal identity: it is always determinate, even though we do not believe this to be the case with the identity of other things. One common example of this is the identity of nations. We do not, for instance, believe that there is a clear answer to the question “was England the same nation after 1066?”. Thus, Parfit’s strategy in implementing his own concept of personal identity involves two steps. First, he tries to show that both the belief that personal identity is always determinate and the belief that important judgments rely on it are implausible. He then proposes a way of making these judgments without presupposing personal identity. In order to show the implausibility of the two beliefs, Parfit makes use of several imaginary cases. These cases, though for the most part being technically impossible as of yet, still manage to shed some light on our beliefs regarding personal identity. One particularly important case is known as the ‘fission case’, which Parfit believes to show that personal identity is not what actually matters to us: imagine that a person – Mr. Brown – is fatally injured and his brain is divided into two exactly similar parts, each of which is then transplanted into the body of one of his two brothers. Each of the resulting people would have the memories and the character of Mr. Brown, and each would believe to be Mr. Brown. We would then have to decide whether Brown did not survive; did survive as one of the two 47

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people; or did survive as both of them. Or, put differently, we would have to decide whether Mr. Brown will be one, either or neither of these people. Note, first, that this imaginary case makes certain empirically doubtful assumptions, mainly that a) the brain can be equally split in two without losing its functions, and b) that the two halves of the brain are exactly alike. But note also that despite these assumptions, the case still appears to be conceivable enough to tell us something about our beliefs in personal identity. We therefore ought to consider the possible answers to the question whether Brown would survive or not. The first possibility is that Brown did not survive. Parfit claims that this is implausible, given the facts that a) people have in fact survived even when one hemisphere was destroyed, for example due to a stroke, and b) that the transplantation of a complete brain is often described as an extreme case of transplantation where a complete body is being transplanted onto the patient’s brain. If these facts are true, then it should also be true that Mr. Brown would survive even if only one half of his brain was transplanted into a new body. But if so, how could two successes mean a failure? The second possibility that Mr. Brown survives as one of the two people would seem equally implausible. For if both of the halves were exactly similar, then so would be both of the resulting people. How could Brown be one of them rather than the other? This leaves the third claim that Brown would survive as both people. The problem with this description is the following: after the surgery, both of the resulting people will be able to live their lives separately from each other, they will have different experiences and will most likely develop differently. After a while they might be so different that they would appear to be different people. However, we would still have to regard each of them as identical to Mr. Brown. This seems absurd. Mr. Brown cannot be two different people. According to Parfit, in this imaginary case, all of the three possibilities seem implausible. Given our common belief that the question of personal identity always has an answer, this certainly poses a problem. But he suggests that this need not be the case. He proposes that whether Brown survives as one, either or neither of the people is not a question of different possibilities for which we need to identify the correct one, but that these are merely different descriptions of a single outcome. He believes that we already know everything there is to know about the case even though we do not have an answer to the question of personal identity.

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If this is true, then it would seem that we do not need a judgment of personal identity to answer other important questions, for such a judgment would not provide any additional basis for decisions. Personal identity would not really matter to us. What we should ask instead is “how should Brown regard the prospect of the division?”. Or, in more general terms: “what matters to us in survival?”. 3 Parfit’s view is a so-called reductionist view. According to him, reductionists belief that the fact of a person’s identity over time just consists in the holding of certain more particular facts, such as, for example, the physically continuous existence of a brain, or the holding of various kinds of psychological continuity. In contrast, nonreductionists belief that we are separately existing entities, distinct from brain, body and experiences. One of the best-known examples of such a view is the Cartesian Pure Ego, a substance distinct from the physical. According to this view, whether or not two individuals are the same person can be answered by asking whether they share the same Cartesian Ego. However, an alternative form of non-reductionism involves the claim that, while we aren’t separately existing entities distinct from our brain or body, personal identity is a so-called ‘further fact’ which doesn’t just consist in physical and / or psychological continuity. This is what Parfit calls the Further Fact View. Essentially, Parfit claims that the question of personal identity can be answered by only referring to the psychological properties of a person and that these properties are what really matters in survival. To do so, he distinguishes two general relations: psychological connectedness and psychological continuity. Psychological connectedness is the holding of what he calls “particular direct psychological connections”, such as memories, beliefs or intentions, between two individuals. There are, for instance, direct memory connections between two people X now and Y 10 years ago if X can remember some of Y’s experiences. In this sense, two people are psychologically connected if any number of particular direct psychological connections hold between, which means that this relation could hold to any degree, lesser or higher. However, for X and Y to be the same person, they would need to be connected enough, which Parfit suggests to be the case if they are connected by at least half of all the connections that hold over every day in the lives of nearly every actual person. He calls this strong connectedness. This would mean that, for X now to be the same person as Y 10 years ago, X would need to have to have at least half the number of memories, beliefs, intentions and so on, combined that Y possess. 3

Here I closely follow Parfit’s argumentation from Parfit (1992): 210ff.

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The second general relation that Parfit distinguishes is psychological continuity, which he defines as “the holding of overlapping chains of strong connectedness”. In this sense, I am psychologically continuous with another person if I am connected to that person – directly or indirectly – by a chain of strong connectedness, so that every individual along the chain is strongly connected to the person preceding him. Thus, I can truthfully claim that I am psychologically continuous with myself 10 years ago because I am strongly connected to myself yesterday, when I was strongly connected to myself two days ago – and so on – without any break in the chain. In contrast, I cannot so easily claim that I am also psychologically connected to myself 10 years ago, because in all that time I have gained new psychological connections and lost others. For once, I hardly remember what school was like 10 years ago, but in exchange I remember perfectly well what it was like to write this essay. Therefore, psychological continuity can be considered to be a transitive relation; psychological connectedness, however, cannot. Because identity is a transitive relation, any criterion for personal identity must also be transitive, which is why Parfit suggests that psychological continuity can be used as that criterion. He proposes that X today is one and the same person as Y at some past time if and only if 1) X is psychologically continuous with Y, 2) this continuity has the right kind of cause, and 3) it has not taken a ‘branching’ form in which the continuity holds for more than one person, as in the fission case. However, as I have argued, personal identity may not be what really matters to us. But if so, what does matter? According to Parfit, it is what he calls Relation R: psychological connectedness and/or psychological continuity, with the right kind of cause. What we should consider to be the right kind of cause is still open for debate; Parfit himself favors a wide version of this claim in which any reliable cause would be sufficient. Others may support the narrow version where only the normal cause – the brain – is the right kind of cause. In any case, because both psychological connectedness and psychological continuity are matters of degrees, so, too, is Relation R. This is the reason that Parfit claims that the survival of a person is a matter of degree. In this sense, how much of me survives in the future depends on how many psychological connections hold between me and my future self, e.g. after brain transplantation. When we now think back to the fission case, how should we feel about Mr. Brown’s brain being transplanted in two different bodies? Parfit believes that the best description would be to say that Mr. Brown is neither of the resulting people. However, he would add that Mr. Brown survives as both of them nonetheless. Brown and each of the 50

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resulting people are psychologically connected, because, as we supposed, each hemisphere contains all the memories and other psychological connections of Brown before the surgery. Since the resulting people are also bound to him by chains of strong connectedness, they are psychologically continuous with Brown, as well. If these two relations are what matters in survival, then we have to conclude that Brown survives as both of them. But this doesn’t necessarily mean that Brown is identical with any of them, because Parfit’s criterion for personal identity applies only to cases where psychological continuity takes a non-branching form. In every other case, he considers the question of personal identity to be an empty question. Therefore, according to his view, we should say that Brown survives as both of the people, without necessarily being identical with any of them.

Implications for Intracerebral Stem Cell Transplantations I would now like to propose some implications of Parfit’s argument for the stem cell-treatment of chronic neurological diseases. First, I will make some general remarks about neurological diseases from Parfit’s point-of-view. I will then address the issue of stem cell transplantation. Most of the potential targets of stem cell therapy are generally 4 associated with certain changes in personality. Examples include dementia and depression associated with Parkinson’s disease as well as the potentially extensive changes following a stroke involving the forebrain. From the point-of-view of Parfit’s concept, these changes are likely to lead to changes of psychological connectedness. Dementia, for instance, can interfere with the ability to remember experiences, and memory is a vital relation for psychological connectedness. Depression, as another example, may change a person’s intentions up to the point of replacing them with apathy. It seems likely that this loss of connections can lead to a reduced psychological connectedness between the past self and the present self of the patient. This is not surprising given the fact that we are frequently aware of changes in a patient’s personality. However, even though we are aware of changes in personality, we generally do not assume that there is also a change in personal identity. Rather, in most of the cases we would intuitively believe that the person suffering from

4

See Lindvall et al. (2004), Lindvall and Kokaia (2006) for a selection of candidate diseases and Northoff (2001) as well as Ropper et al. (2005) for details on their association with personality changes.

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Parkinson’s is the same person as before he had the disease, even though he may have had a change of character. In Parfit’s view, our ground for believing in the survival of a person involves two different criteria: first, presence or absence of psychological connectedness, and second, presence or absence of psychological continuity. We have further concluded that neurological diseases may lead to changes in psychological connectedness. However, because survival as well as psychological connectedness is a matter of degree, only a substantial change – meaning the loss of strong connectedness – could cause the patient after he acquired the disease to be a different person than before. As we do not possess a technology that allows us to fully quantify the connections that a person possesses, this is difficult, if not impossible to prove empirically. However, Parfit argues that the appropriate way of using this relation is that each speaker has to decide for himself whether he sees sufficient evidence to defend the claim that there is enough connectedness. This is equivalent to our intuitive way of saying that a person has changed in some respect even though we still believe he is essentially the same person. It is likely that in most cases the change of a patient’s personality is simply not enough to convince us of a change of identity. However, there may be cases where this is not so. A severe case of stroke involving large parts of the brain, including the forebrain, may be one example. The second criterion for the survival of a person is the presence of absence of psychological continuity, which was defined as overlapping chains of strong connectedness. This relation is likely to hold for most of the chronic neurological diseases targeted by stem cell-programs because many of them are characterized by a gradual progression of the underlying pathophysiological processes, thereby usually leading to gradual rather than abrupt changes in personality (Ropper et al. 2005; Northoff 2001). In terms of psychological connections, a patient in the late stages of Parkinson’s or Multiple Sclerosis may be significantly less psychologically connected to his former self; however, given the usually gradual progression of the disease, it may still very well be true that the patient is strongly connected to himself from day to day even though he is, all in all, loosing psychological connections. The only case where psychological continuity will not hold is if the chain of strong connectedness is broken at some point, meaning that the patient will be connected to his former self by less than half his connections. It is likely that primarily abrupt pathophysiological changes in the brain, e.g. cases of stroke, can bring this about in a medical context. Given these considerations regarding the diseases, what possible grounds could be forwarded by critics for denying survival after intra52

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cerebral stem cell transplants? If we accept Parfit’s concept, we could make the following argument: up until now it seems that we cannot reasonably expect to create a complete replication of the patient’s former brain structure (see, for instance, Lindvall and Bjorklund 2000 or Lindvall et al. 2004). We also know that the brain is extensively interconnected, which suggests that even precise transplantations in a clearly defined area can lead, directly or indirectly, to physiological changes in other neural networks. If these facts are true, then it would seem that changes in the personality of a patient after transplantation cannot simply be described as regaining lost functions or relations. Rather, we have to assume that some relations will remain lost and that the patient will possess some new character traits, brought about by the somewhat changed structure of the brain. These, in turn, can affect previously held psychological connections. This possibility might increase if areas in the brain are affected that are crucial to personality. Therefore, put in Parfit’s terms, intracerebral stem cell transplants can very well lead to significant changes of psychological connectedness, depending on the areas involved and the functional outcome of the transplantation. This would provide a basis for the claim that the patient would not survive the treatment. It may not be a sufficient basis, however, because for us to accept that the patient would not survive, the loss of connections between the former and the later person has to be extensive enough – meaning the loss of strong connectedness. If so, it seems the changes brought about by stem cell transplants would need to be much more extensive than we would reasonably expect from slight differences in structure alone. It would particularly seem unlikely that localized changes of a limited amount of cells, e.g. in the treatment of Parkinson’s disease, could lead to such extensive changes in connectedness. But even in severe cases of stroke, for instance, in which large parts of a hemisphere are damaged and need to be replaced, this condition would not be easily met, for there would still be a mostly unaffected second hemisphere and some remaining healthy parts of the damaged hemisphere. We cannot, of course, simply conclude from this that more than half of all the relations would still be present, given the facts that first, the two hemispheres are extensively interconnected and cooperate to perform intellectual functions which are possibly necessary for relations of interest for personal identity, and, second, that the psychological relations aren’t necessarily equally shared among the two. But it would mean that even this scenario, in which large parts of a hemisphere need to be replaced by stem cell-therapy, wouldn’t necessarily break psychological connectedness. Given the lack of a device that would allow us to quantify all the relations, we would have to resort to Parfit’s suggestion 53

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and decide for ourselves whether we would see enough connections or not. After all, the patient after the treatment would still possess many of the psychological connections that he had before the surgery. In this sense, we could at the very least claim that the former person has survived to some degree and partly continues to live on after the surgery. Parfit would possibly consider this case to be a borderline case of survival which is neither clearly a case of survival nor of death. A similar argument could be made for psychological continuity: we have already seen that except for extreme cases, stem cell transplants are unlikely to break the strong connectedness of a patient. Furthermore, so far there seems to be no reason to expect that stem cell transplants would lead to temporary fluctuations of psychological connectedness, such as extensive temporary losses of memories, intentions, opinions and so forth, which might be able to break psychological continuity. Given our still limited knowledge regarding the details of stem cell transplantations, such strong fluctuations remain a conceivable possibility. But even if they do occur, we could in most cases still appeal to the relation of psychological connectedness to support the claim that the patient survives the treatment. In the beginning, I suggested that if we found that the patient does not survive the intracerebral transplantation, we ought to abandon that treatment according to the principle not to harm. But as I have argued, even the more extreme cases shouldn’t be seen as equivalent to death. The choice whether to accept the transplantation or not is not a choice between survival and death, but rather between two different outcomes of which neither can be considered death. Despite the ambiguity in the extreme cases, accepting the treatment would still be a viable option for the patient. If this is true, then it seems that we would have to consider intracerebral stem cell transplants to be an ethically adequate tool for the treatment of patients.

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Summary In summary, I have argued that the question of personal identity has important implications for our assessment of intracerebral stem cell transplants. I have presented Derek Parfit’s concept of personal identity, which revolves around the claim that identity is not what matters in survival. Instead, I have explained his proposal that what matters is Relation R: psychological continuity and/or psychological connectedness, with the right kind of cause; and that Relation R holds to degrees. I have defined psychological connectedness as the holding of particular direct psychological connections such as remembering or intending and psychological continuity as the holding of overlapping chains of strong connectedness. I then applied Parfit’s concept to intracerebral stem cell transplants by first claiming that many chronic neurological diseases are in fact associated with changes of the two relations, even though these changes are usually not enough to justify denying survival. I also argued that even borderline cases, in which stem cell transplants may potentially lead to extensive character changes, should not be seen as equivalent to death but rather as survival in degrees. Finally, I have concluded that based on Parfit’s concept, intracerebral stem cell transplants are an ethically adequate tool for the treatment of patients.

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References Birnbacher, D. (1995) „Identität der Persönlichkeit und Identität der Person: Philosophische Fragen im Zusammenhang mit der Transplantation von Hirngewebe“, in: Zentralblatt für Neurochirurgie, 56: 180-185. Lindvall, O., & A. Bjorklund (2000) “Cell replacement therapies for central nervous system disorders”, in: Nature Neuroscience, 3(6): 537-544. Lindvall, O., Z. Kokaia & A. Martinez-Serrano (2004) “Stem cell therapy for human neurodegenerative disorders – how to make it work”, in: Nature Medicine, 10 (suppl.): 42-50. Lindvall, O. & Z. Kokaia (2006) “Stem cells for the treatment of neurological disorders”, in: Nature, 441: 1094-1096. Noonan, H. W. (2003) Personal identity, Second Edition (London: Routledge). Northoff, G. (2001) Personale Identität und operative Eingriffe in das Gehirn: Neurophilosophische, empirische und ethische Untersuchungen (Paderborn: Mentis). Northoff, G., J. Witzel & B. Bogerts (2006) „Was ist „Neuroethik“ – eine Disziplin der Zukunft?“, in: Nervenarzt, 77: 5-11. Parfit, D. (1971) “Personal identity”, in: Philosophical Review, 80: 3-27. Parfit, D. (1992) Reasons and persons (Repr.) (Oxford: Clarendon Press). Ropper, A.H., R.H. Brown, R.D. Adams & M. Victor (2005) Adams and Victor’s principles of Neurology, Eighth Edition (New York: McGraw-Hill).

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Cha nge s in Pers onalit y: Pos s ible Hazards Ar is ing from Stem Cell Grafts – An Ethica l a nd Philos ophical Approac h ∗ CHRISTIAN P. BÜHRLE

Ab s t r a c t Several scenarios are conceived where stem cell (SC) implantation may cause ethical issues concerning the respective ontological conditions of the host brain, the implant itself, and the resulting chimera. Here, depending on the philosophical point of view of the researcher, the mindbody problem merits special attention, since the brain is widely believed to be the material base of mind, personality, and self, perception of the self or self-reflexion (e.g. the reductionist physicalism position). On the basis of various constellations and thought experiments we are going to ask the question, how and when SC-grafts that interact with a compromised brain might evoke practical ethical problems. Primarily, we will discuss the probabilities of behavioural or personality changes induced by SC-grafts. Scope and impact of the ethical consequences of using SCs – immaterial of their source and developmental potential – in brain regenerative medicine are not nearly as well recognized by workers in this or related disciplines as they merit to be. SCs are not the simple, adjustable building blocks for replacing destroyed brain structures as they are widely believed to be. They are highly dynamic ∗

The author is most grateful to Dr. Utako B. Barnikol for stimulating and in-depth discussions. Without the secretarial and research help of Ms. Jessica Steinert this essay would not have been possible.

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entities in need to be closely controlled and require precise information about how to develop into appropriate; i.e. therapeutically useful phenotypes without interfering with the surviving material substrate of mind. The result of an ill-conceived SC implantation may turn out to be quite undesirable. If SCs were to be used in the human CNS, efficient security measures, such as molecular switches operable from outside the brain – should be DNA-encoded for deactivating these cells as soon as any complications are detected. Additionally to biological reconstruction, we will review relative merits and shortcomings of electronic neuroprostheses as totally controllable, deterministic instruments for emulating lost brain structures as well as of deep brain stimulation techniques for correcting dysfunctions responsible for movement disorders.

Introduction The ethical problems we attempt to address here may roughly be broken down into three categories: Conventional hazards to the recipient, i.e. the patient, resulting from possible damage to his or her health, nondirected malfunctions of the brain and intentional, directed influences on it, i.e. mind control (Bear et al. 1995; Place 1956; Searle 1980, 2005; Graham-Rowe 2003). Moderate to serious ethical problems arise, when a stem cell (SC) graft either incorrectly conducts, falsely processes or alters the information (Becker 2005) that previously, i.e. before neurotrauma or stroke, had been properly handled by the original circuit (Castrén 2005; Rolls and Treves 1998). These malfunctions also include information generated by the SCs themselves, such as random noise or oscillations. It would certainly be too far-fetched to insinuate that an SC graft is able ‘to have a life of its own’ or to have something remotely resembling ‘objectives’ or a ‘will of its own’ (Rolls and Treves 1998). For this, the graft’s degree of complexity, its number of neurons, and - in terms of systems theory – its correlation dimension is too low (Mekler 2008; Hegger et al. 1999; Turing 1950). Thus, the scenario that the graft, by itself, somehow actively takes control of the host brain is certainly more fiction than science. Nevertheless, the presence or absence of a SC graft strictly speaking always influences ‘mind’ or ‘personality’, since the system state of the brain will change after creating a chimera consisting of host and graft cells, since the material base is altered due to SCgrafting as compared to the pre-lesional conditions.

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Here, we would like to point out that the philosophical aspects of our discussion – in particular those pertaining to the mind-body problem (Kim 1995; McGinn 1989; Churchland 1986; Le Doux 2002; McClamrock 1995; Pinel 1997; Pinker 1997; Popper and Eccles 2002; Smart 1956; Hacker 2003; Mach 1886; Searle 1980, 2005) – will rest on a widely acknowledged and accepted special form of monism (Spinoza 1670; Wittgenstein 1954). This subpart of monism is called physical reductionism (Jonas 1966) and has a strong following among natural scientists and, especially, neuroscientists. Briefly, physical reductionism means that the brain is the material substrate for, e.g. thought, cognition, the self and the reflection thereof (Dreyfus, H. 1979; Dreyfus, S. 1986). Further, physical reductionism postulates that there is no spiritual dimension to brain function and to the latter’s interaction with the outside world (but Churchland 1981). Looking at the problem from a different angle: If the total system ‘brain’ is, to a certain extent – either mild or quite severe – compromised by traumata, diseases or degenerative (Hou and Hong 2008) disorders, single or multiple structural/functional subsystems are destroyed or damaged (Hoehn et al. 2002). Hence, the previously homeostatic dynamics are disturbed and the material damage is reflected in symptoms that may be visible to the physician, acting as a conscientious observer from the outside, such as motor disturbances, cognitive deficits, dysfunctions with learning and memory, or changes in individual personality traits. These indicators of material damage may stay below the ‘detection limit’ of the observer and of the level of diagnostic tools applied, and therefore go unnoticed, or they may manifest themselves in severe clinical symptoms or syndromes. The term ‘brain plasticity’ has been coined to describe a phenomenon that is only barely – if at all – understood (Bach-y-Rita 2005; Wieloch and Nikolich 2006; Ross and Verfaillie 2008). Even without intervention, said brain plasticity will, in many cases, cause a spontaneous amelioration when functions the material substrate of which is postlesionally or degeneratively damaged or defunct, will be shifted to other brain areas or volume elements (Wieloch and Nikolich 2006). Sometimes, this spontaneous beneficial action may lead to apparently complete clinical remissions, although from the viewpoint of systems theory and systems dynamics the state of the brain has been and still is severely altered as a result of the initial damage. Here, we must already ask the question, whether the post-lesional ‘damaged’ brain is – from an ontological point of view – still the same as the pre-lesional ‘intact’ brain. The answer to this question will be the pivot around which the subsequent discussion will revolve. If one 59

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strictly adhered to monism in the form of physical reductionism, the answer would be ‘no’, because the material substrate from which the mind emanates has been altered. Consequently, the mind has been altered too. If ‘brain plasticity’ works successfully (Ross and Verfaillie 2008), the observables, i.e. the clinical symptoms become ameliorated, or even disappear. Thus, they will fall below the ‘detection limit’ of normal diagnostic measures and only specialized tests (such as in cognition or motor scores etc.) will be able to pin down functional deviations from the respective age-corresponding values in healthy subjects. However, any changes in thought, the more subtle emotions, reasoning, briefly, anything that happens with the brain, should – supposing the brain being the material basis of ‘mind’, ‘self’ and ‘personality’ – be likewise disturbed, i.e. the intrinsic, higher brain functions that are not observable from the outside (Lakoff and Nuñez 2000) would not be spared from the initial disturbance and the subsequent – if any – attempts of ‘brain plasticity’ (Colotla and Bach-y-Rita 2002) at restituting the previous state should also influence these functions. Quite naturally, such changes in the ‘interior workings of the mind’ must remain elusive for an outside observer.

Brain Plasticity Nevertheless, brain plasticity or – in a broader sense – the reaction of the brain following injury or disease is a natural phenomenon in vertebrates It is mostly a result of the mind/soul problem that this becomes relevant here, meaning that we must not uncritically project findings obtained in phylogenetically lower species that generally lack higher brain functions, such as rodents, onto man (Kim 1995; McGinn 1989). Owing to the pluri- or even totipotency of SC or progenitor cells it is unpredictable what they will do once they have been grafted (Ross and Verfaillie 2008; Kempermann et al. 2004). Here, it is important to realize that the moment of implantation or engraftment constitutes ‘the point of no return’: Once implanted, it is impossible for the researcher or the physician performing stem cell therapy to control the SC any longer. Ontologically, they are an entity of their own and, most importantly, they are additionally autonomous and sometimes extremely dynamic in their proliferation. This dynamical behaviour is also reflected in the SCs’ attempt to differentiate into phenotypes that are ontogenetically more advanced, i.e. more complex, than they are themselves.

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Anyhow, differentiation from a simple SC into a more elaborate phenotype requires information, i.e. negentropy. It is a matter of controversy, whether this information is imprinted in their genome, or obtained from the microenvironment of the host tissue or results from contribution of both.

Al t r u i s m , I n f l u e n c e o f D e ve l o p m e n t a l S i g n a l s a n d C u e s o r S t o c h a s t i c B e h a vi o u r In spite of ‘altruistically’ coming to the assistance of the damaged brain, as has been implicitly assumed in most early studies concerning their therapeutical utilization (Zhang et al. 2008), their primary ‘objective’ is survival. The SC may develop into neoplasms by dedifferentiation or into a cell phenotype otherwise benign with functions that are detrimental to the entire system if these cells are at the wrong place (Erdö et al. 2003; Dirks 2008). For instance, this occurs in the simple case that they secrete substances, or neurotrophic factors, which are inappropriate and have untoward effects upon the entire system. Even if taken from the same species, their DNA is different from that of the host brain. In addition, to the best of our knowledge, such SCs are naïve, never having been exposed to something different than to their culture medium and Petri dish. To dwell on this topic: Ontologically, they have nothing to do with the host tissue they are implanted into, that is, a mismatch appears to be pre-programmed. Assumed that at least part of them survive the grafting procedure, we are confronted with the question: “what or who are they?”. A normal telogenically differentiated neuron is, on its own, only an operating part in a series of systems of increasing complexity. It is, though, an extremely intricate building block or – more abstractly – an active, nonlinear and temporospatially instationary and therefore quite variable and adaptable circuit component (Mendell and Henneman 1971; Miller et al. 1985; Lloyd 1943, 1945) that has ontogenetically differentiated in a way permitting it to perform one or a certain manifold of tasks within the framework of a given system – both morphologically and functionally. To this end, it has undergone all stages of development (Shankle et al. 1999) which only can take place when all ‘cues’ and ‘key stimuli’ are timed perfectly. We have to emphasize in this context that this schedule must be followed precisely to prevent developmental errors (Rakić 2002a, 2002b; Bystron 2008; Shankle et al. 1999).

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B e h a v i o u r o f N o n - t e l o g e n i c a l l y D e ve l o p e d S C s By contrast to a telogenically differentiated neuron or glia cell, the direction the development a transplanted SC will take is unknown at implantation time. There is good evidence that implanted SC may contact the surviving host neurons by forming chemical synaptic contacts as shown immunohistochemically by the demonstration of synaptophysin at the terminations of the processes being mutually extended by neuralized SCs and survivors in the host brain to the dendritic tree or the soma of the other cell. Thus, morphologically, bidirectional connections terminating in structures closely resembling synaptic boutons do exist between SCs and host neurons. The presence of synaptophysin does not imply, however, that these contacts are operational and indeed act as synapses conveying information from one cell to the other. There is hard evidence that cultured SCs form connections among each other that terminate in and behave like neurotransmitter-based chemical synaptic contacts (Auerbach 2000). In other words, a worst-case scenario must assume that SC do not only introduce a different DNA into the system, but – what may consequentially be even more serious – generate or distort information delivered to them by the surviving sub-systems in a manner that important brain functions, either simple or higher ones, e.g. such being involved in cognition or self-cognition, are disturbed in a manner or to an extent that the resulting outcome is no longer clinical subliminal, but manifests itself in behavioural peculiarities, or even in psychiatrically productive symptoms such as delusions, or symptoms of paranoia (Mamelak 1998; Freed 2002; Freed et al. 2003; Freed et al. 1990). Such risks can never be excluded completely, because neither the functions of the graft nor those of the brain are fully understood. For the case of malfunctions no contingency plans can be set up, describing counter-measures to be taken in order to avoid emerging functions that are undesirable and to confine possible detrimental consequences for the system as a whole. We have to realize that the conceivable number of such mismatches or maladaptations, like the release or wrong neurotransmitters, or an incorrect positioning of the synapses on the target cell’s postsynaptic membrane is virtually infinitesimal. The clinical outcome in each individual case will differ in an unpredictable manner, being dependent on • size and location of the graft, • its distance to microanatomic structures that facilitate SC migration, such as white matter,

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• • •

the mutual strength and operational state of synaptic contacts between graft and host tissue, the composition of the neurohumoral microenvironment the graft is embedded in, as well as the topographical distance to host structures that are material sources of higher brain functions and many other factors that may be extremely important, but have not even been identified.

Hazards of Grafting Cells into a Compromized Brain The question, whether the result of grafting stem cells into an ailing brain, with the SCs building a circuit that sufficiently closely emulates a defunct structural function unit so that this ‘replacement function’ does not significantly differ from that of the said brain before injury, may still be denominated a brain in the classical sense is not relevant here. The outcome is a combination of the original organ with a simulation circuit built by using components taken from a different organism. Does this ontological difference have any practical meaning? Such as: • Ontologically, the original, now defective organism is only partially identical with the intact original one. • The simulation circuitry is an entity ontologically different from the recipient brain. As a result of the excessive connectivity of the brain, the SC circuit poses a possible threat to the ‘personality’ of the owner of the host brain. The SC graft is an entity with an origin different from that of the host brain. The development of the brain in humans may be assumed to have been completed by the age of 14 to 17 years (Shankle et al. 1999). By contrast to this, the SC graft still has a large dynamic potential since the SCs are developmentally very young, unlike normal neurons that are already 14 to 17 years old. Therefore it would be naïve to assume that they are differentiated telogenically, i.e. that they are at a stage, where they only can undergo limited changes of connectivity, such as ‘normal’ synapse formation or altering the strength of different synaptic pathways. It may – as indicated above – well be doubted, whether the electrochemical synapses are functional at all, and – if so – whether their information transmitting parameters and properties correspond to those of ‘ordinary’ synapses between cells that have gone through the regular ontogenetic developmental sequence (Shankle et al. 1999).

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Their prospective potency of the SCs or even precursor cells is anything but exhausted. Thus, they may develop into entities quite different from what is expected by the researcher or clinician. Recent animal experiments have shown that the host brain may lose control over the differentiation of SC under unfavourable conditions which results in a malignant transformation of the SC and in the death of the host following brain tumor (Erdö et al. 2003). Likewise, the SC may differentiate into a circuit with functions that widely differ from those of the defunct structure, the replacement of which had been the objective proper of SC grafting. These newly developed functions may turn out to be detrimental or even disastrous to the host system. We have already mentioned this and just want to reiterate to strengthen this pivotal point: The SC graft is well able to build up a ‘connectivity’ of sense by itself, i.e. connections and even synapseforming of SC grafts has been well documented (Auerbach 2000). Likewise, the graft may become functionally integrated into the circuitry of the compromised brain, meaning that both ontologically different entities (graft / host) may exchange information. Now, the question which is fundamental to our reflections, arises in a twofold manner: Does the connectivity developing within the graft make sense from a functional point of view, meaning: Is the graft capable of processing information like the bioelectric signals characterizing chemical synaptic transmission? If yes, we have to more closely examine the function of the SC graft: Is there a tendency to functionally replace or restitute the pre-existing and now defunct original host brain structure or volume? We have already studied that and consider it hardly possible, since the graft has no a priori knowledge of the structure to be replaced. Local cytoarchitecture and extracellular scaffolding are mostly also destroyed, the neighbouring neurons may belong to systems that have nothing in common with the defunct one, and even if there are survivors from the damaged original structure, they have neither a priori nor a posterioriknowledge about the developmental sequence of events, its timing, the factors and ‘cues’ necessary to rebuild the eradicated structure from scratch in a way that is – teleologically speaking – useful for the damaged or degenerating host brain (Newman and Bakaray 2008; Hou and Hong 2008; Li et al. 2008). Even if all this knowledge would be at hand, the boundary conditions set by the host, like proper afferent signals that influence connectivity, synaptic strength and processing capability of the SC-based replacement structures were still lacking. Here, it is certainly a complicating factor that this bioelectrical information flux is spatiotemporally non-stationary and nonlinear (Mendell and 64

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Henneman 1971; Miller et al. 1985). Just to accentuate an individual aspect of this: In the ontogenetic youth of the host brain, when all subsystems are still developing in interaction with others, this ‘information pattern’ may be assumed to be quite different from that prevailing after ontogenetic maturation of the brain. In our model experiment, we simply do not know with what kind of information and at what bandwidth (decreased, increased, or unchanged) the graft would be supplied by the host. This is not only true for acute neurotrauma or stroke, but also for degenerative diseases such as M. Parkinson or Alzheimer’s disease (Allen 2008; Adeli et al. 2008; Hou and Hong 2008). For information processing, even in a simple network created in the laboratory, connection number, individual position and general pattern, neurotransmitter released, dendritic arborization and synaptic strength of each individual input to the simple ‘petri-dish’ network are extremely critical (Hodkin and Katz 1949; Hodgkin and Huxley 1952; Fatt and Katz 1951, 1953; Coombs et al. 1955; Rall 1990, 1962, 1964, 1967, 1977; Rall and Segev 1987; Rall et al. 1992; Segev and Rall 1988; Segev et al. 1995; Shepherd et al. 1985; Goldstein and Rall 1974; Holmes and Rall 1992). Therefore, it is even more unlikely than the restitution of lost functions that had been ‘emanations’ of the neural structures damaged or eliminated, to create or synthesize – on the basis of an SC graft – an entity that is able to perform a function of its own. Practically speaking, in a further thought experiment we might assume that, in place of the original one, there might have developed a structure that can read and decode bioelectrical information supplied by the host brain, however, the circuitry would not correspond to or simulate that of the defunct structure, but, nevertheless also process information and format it in a way that the host brain likewise could read and interpret this processing result. As a consequence of the different circuitries of the original structure and that of the SC-graft, the processing result would differ from that before the disastrous event or the onset of disease or from that obtained under the same conditions from another person’s intact brain. To give this thought experiment more impact, one may postulate, that this information is not useful for the host brain, but either neutral (irrelevant) or detrimental (in its most simple form, an autonomous generator, i.e. an epileptic focus). For clarification, the topics ‘true’ or ‘false’ are irrelevant here, since the differing results arise from a difference in signal processing of the input signals with the nature of both signal transfer functions again being ‘emanations’ of the underlying neural wiring, implementing amplification, preference of

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certain intrinsic signal pathways over others, filtering, simple logical decisions and, finally, re-encoding. We believe that this scenario is the one intuitively most feared, because it implicates that the graft, by supplying the brain with information different from that prevailing in the brain before the lesion, or, in a normal, intact brain, eventually may lead to deleterious results. To put all this into perspective, it is absolutely necessary to consider the probability of such a development occurring. As already discussed, neural information processing, or even de- and encoding of information requires a highly organized physical basis, meaning a complex, purposeoriented neural network. If already the replication of a destroyed structural/functional entity by a SC graft that would be positioned in place of the original structure, hoping that the graft receives some developmentally relevant information from the surroundings, appears to be quite unlikely for the lack of a priori knowledge and the absence of blueprints of the appropriate circuit that may even be encoded in the DNA of each cell but impossible to retrieve from this library, because the ‘cues’ provided by the surrounds do not suffice to communicate to the cells which of the multiplicity of the circuits encoded in their genome would be the most appropriate one to select and to execute, the probability that an ‘alternative’ circuit, being able to communicate with the host brain would arise from an SC implant is small but not negligible. Interference with brain function on a medium to high level by an SC-implant, with the SC-implant ‘taking over’ important aspects of the mind such as personality changes, or alteration of an individual’s cognitive abilities is therefore a conceivable and real danger, whereas influencing the mind as a whole unspecifically is even more probable but less problematic. It appears that guided, intentional mind control – unless some means would be devised by which to communicate with the SC from an extracranial position – remains rather improbable for the near and intermediate future (cf. Kim 1995; McGinn 1989). However, in the absence of defined developmental guidelines as discussed above, growth and development of a SC-graft may default to the most simple scenario: Random growth, random development and consequently, random circuits. Without external stimuli and without self-organizing properties which have not been reported for stem cells, it is most likely that a random (‘nonsense’) circuit will develop. Whether such a circuit is detrimental to or dangerous for the brain depends to a high degree on the position of the graft and to the strength of the communication links with the host brain. 66

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D i f f e r e n t C o n c e i va b l e F a i l u r e M o d e s of the Graft a) Communication: The SC grafts differentiate – under the influence of factors and ‘cues’ provided by their environment-into neuron-like, astrocyte-like and oligodendrocyte-like cells (Goldman and Nottebohm 1983). Since the developmental time lines are not synchronized in either case (Shankle et al. 1999), a large amount of information that is presumably present and pertinent to development meant to be transmitted to them from their microenvironment is lost, because they are unable to interpret the respective signals or cues at their still immature developmental stage. There may also, for instance, be a transmitter mismatch between the graft and the host cells, or such fundamental differences in the data formats as to make them unreadable and undecipherable for the SC or the surviving neurons, respectively. It is highly probable that the SC-derived cell lines are, at implantation time, equipped only with a minimum of features (Hoehn et al. 2002). These would suffice just to later identify them by their immunophenotype as neurons (NeuN), astrocytes (GFAP) and oligodendrocytes (GalC) and to prompt the cells to make some attempts at differentiation which, however, for the reasons outlined above, have to remain abortive. As laser confocal microscopic studies have shown, there would, for instance, no elaborate dendritic trees be formed but only a few rudimentary main dendrites in neuralized SC. Functionally, however, they are naïve, dumb cells that have an information deficit of months to years, i.e. the host cells are already telogenically transformed. The SC graft has, however, the prospective ability that the individual cells it consists of not only connect among each other, but also to cells of the host having survived the incident. Since the SC-graft has no a priori knowledge of the structural and functional unit it is meant to develop into, and there is only very limited information conveyed to them by neurohumoral signals or by chemical synaptic transmission, they are virtually clueless. Thus, when setting up connectivity, the result will be a state requiring minimum energy (2nd law of thermodynamics), meaning that the resulting circuit is a functionally random, i.e. a nonsense circuit. Every ‘learning step’, that is every step towards advanced development and therefore, augmented functions, would require a reduction in entropy, i.e. a gain in information, and thus consume energy (Gould et al. 1999; Laubach et al. 2000; Tan and Bullock 2008). 67

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b) Learning: Hence, what morphologically may look promising under the fluorescence microscope or the laser confocal scanner, is most probably without much practical value for restituting a disabled structure/function. However, one must not dismiss the possibility that information from host cells connected to graft neurons learning by repeated occurrence etc., change the connectivity of the graft in a way that resembles or implies learning (Tan and Bullock 2008; Fingelkurts An.A. and Fingelkurts Al.A. 2004; Fingelkurts An.A. et al. 2005; Gould 1999). Consequently, connections only rarely used would be weakened even further, while connections with a high information flow would be strengthened, their synaptic contacts stabilized and the synaptic weights increased (Wieloch and Nikolich 2006; Wessberg et al. 2000). The SC graft would therefore contribute to information conduction and processing, being interposed between two surviving structures that, before this, had no means of exchanging information at all. Of course, this scenario works only, when the SC are still able to learn by re-wiring their mutual connections. Essentially, this would mean that a random neuronal circuit is transformed into a functionally beneficiary one, where this transformation is mediated by surviving brain structures (functional specialization of a general non-functional random circuit capable of learning by supplying it with meaningful information; [Tan and Bullock 2008]). c) Most probable case: The SC graft sets up a multitude of connections among its elements and, to a lesser extent, to surviving cells of the host brain. Hence, there are only sparse and questionably operational synaptic connections to ‘survivor’ neurons adjacent to the graft. Consequently, the SC graft would not regularly cooperate with the host neurons and remain a ‘dummy’ circuit, because it would also be unable to receive, decipher or transmit meaningful information that might advance its transformation from a functionally meaningless circuit to a specialized one. Nevertheless, it is absolutely possible that this graft develops random, disordered or oscillatory signals of its own, i.e. a kind of very primitive neuronal activity. In favourable cases, this activity would just be ignored by synaptically connected circuitry close by and pose no other problem than producing additional noise. If, on the other hand, this malfunctioning graft would produce a bioelectrical signal that could be read and decrypted by virtue of its 68

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simplicity, by a neighbouring host brain unit that might even be on a hierarchically higher level, then the situation would become totally unpredictable. Depending on the ‘spurious signal’, the sensitivity of the host circuit, the latter’s transfer function and on its projections, the system in which it is integrated, would all contribute to determining the reaction to the SC-generated output. Here, it is absolutely possible that the introduction of a stimulus deviating from the normal spatiotemporal discharge pattern may severely upset higher brain functions, thus altering the mind or certain aspects of it (Lakoff and Nuñez 2000). We believe that an unsuitable stimulus may – at least theoretically – mimic many clinical entities in psychiatry. If one adopts a holistic view, according to which different brain functions are more or less equally distributed among the neural tissue, as opposed to earlier concepts such as ‘localization theory’, one must assume that a single input – provided it is above the noise level, influences the entire brain, to a greater or lesser extent, since the latter’s constituents are all connected with each other either by simple monosynaptic or quite involved polysynaptic pathways (Fingelkurts An.A. and Fingelkurts Al.A. 2004; Fingelkurts An.A. et al. 2005; Wessberg et al. 2000). With this holographic concept of brain function, many aspects of brain plasticity may be explained (Allen 2008; Ross and Verfaillie 2008). Likewise, this concept demonstrates that the functional activity of an SC-graft cannot be assessed isolated from the host brain, but – on the contrary – must be judged under real-world conditions, i.e. the graft has to be observed while being embedded in and interacting with the host. d) No function: The SC graft manages to survive in the host neuropil, but is unable to exchange any information with it. Thus it cannot feed ‘beneficial’ or ‘detrimental’ information to the system.

The Ontological Status of Stem Cell Grafts If we replaced each dysfunctional or defunct cell with a stem cell that has exactly the same properties the damaged cell had when it was still fully operational, we would wind up with a brain simulation based on stem cells. Ontologically, the original brain and the simulations are entirely different things, although they have the same properties and cannot be distinguished from each other by an outside observer. 69

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If we restricted ourselves to only replace damaged cells by their functionally equal surrogates, we would have the original brain, containing a stem cell-based simulation of the defective function or structure. As follows from the prerequisites of this thought experiment, the emulated structure / function would interact with the original and the ‘repaired’ brain containing this emulated sub-system, being – ontologically – also different from the original one. Again, they would be indistinguishable from the outside. If the simulation of the entire brain or of the damaged structure/function were less than perfect, for instance, because the dendritic tree of some neurons in the stem cell-based simulation would be slightly different geometrically or neurochemically, then also both systems would be, in addition to be ontologically different, no more functionally homologous. In another thought experiment we would precede as follows. We would initially engineer the SC to be transplanted with DNA sequences coding for hyper- or depolarizing ionic transmembrane channels that may be gated at will from outside the brain. On hyperpolarization, for instance, there would be no activity of these cells, not even impulse propagation, since the threshold for firing a spike would be too high. On slight pre-depolarization one would increase impulse conduction or generation and so, rather unspecifically, de- or increase the percentage of total information flux within the structures made up of stem cells, provided, a solution had been chosen that replaced a defunct one by a copy thereof. Thus – at a first approximation – stem cell-contributed information generation, propagation and processing could be switched off by setting all SC to the ‘high’ state, i.e. by hyperpolarizing them maximally. The ‘survivors’ without the controllable channels in their membrane would of course remain unaffected. During each switching action, both, system state as well as dynamics of the brain, or – more exactly spoken – of the brain and its partial simulation would be severely altered. Exactly the same is true for this construct’s ontological situation which would change from ‘supported by SC’ to ‘unsupported by SC’ and back. Note that this is only possible by alternatingly putting the SCbased simulation circuitry into the functional states of ‘not existent’ and ‘disabled’ or ‘existent’ and ‘enabled’. Such an experiment, if indeed performed, could provide important clues relating to the ontological state expressed by a functional substitute. However, the subtle differences thus occurring could easily be masked by purely functional changes that would occur, when a previously enabled structure is disabled or vice versa – not unlike switching artefacts in an electronic 70

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circuit. Eliminating these obfuscating influences is again only possible in thought experiments. Suppose two brains: one modelled around an important structure, such as the brainstem, midbrain, diencephalon but lacking the isocortex, consequently a stem cell-based isocortex modulated by original cells in the sense mentioned above (absolute fidelity), and the other, a brain, the isocortex of which is original and the phylogenetically older structures are stem cell emulations. By switching back and forth, i.e. by comparing the emanations of both brain models, it should again be possible – if absolute fidelity of the simulation were guaranteed, to discern, whether ontological differences are reflected in functional deviations. According to present knowledge, it appears more than doubtful, that it will be possible at all to create a working brain in its entirety even from totipotent stem cells, because there is probably only one singular set of boundary conditions under which this is possible. It is unrealistic to attempt creating these conditions, under which development of stem cells into a complex structure such as the brain may take place, because they, as well as their sequence, are unknown. The strongest argument against SC rebuilding a lost structure with sufficient fidelity is the fact that the grafted SCs would develop on a timeline completely different from that of the surviving brain cells. SC would be grafted into a system already having matured and experienced a multitude of developmental ‘cues’ and being exposed to all factors necessary to trigger, at the respectively correct times, the expression of certain genes, leading to the structural and functional end point, i.e. a nerve cell that is capable of more than expressing the most general behaviour of neurons, e.g. regenerative discharges upon depolarisation, activation of dendritic and somatic de- and/or hyperpolarizing currents that are either voltage-specific or depend on the binding of locotypical ligands like neurotransmitters or neuromodulators. The conundrum is: Are these cells able to build circuits that conduct or even process information in a way sufficiently similar to that of the now defunct original circuitry? This would be one way to replace the lost brain structure, meaning that the nervous tissue is replaced by a 1:1 SC copy. The evidence indicates that this is wishful thinking rather than a sensible assessment of the situation. Intuitively, the alternative, more promising, way would call for restructuring the surviving ‘hardware’ to re-direct information, circumventing the lesion and conveying this information to still operational brain structures that may able to properly decode, reduce, process and route the information, so that the content may be interpreted by the 71

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surviving part of the brain and translated into e.g. sensory cognition (visual or acoustic input), activation or deactivation of peripheral effectors (speech, motion), or – most important in this context – into the spatially and temporally non-stationary and non-linear discharge patterns that are believed to underlie basic as well as higher brain functions. Both scenarios are highly idealized since the first one would call for a template or blueprint according to which the SC would be used as structural and functional building blocks for remodeling the compromised or damaged structure viz. function (Wiskott et al. 2006; Arrias-Carrión et al. 2009; Fallon et al. 2000). From a quite basic view, reconstruction lacking such a blueprint, i.e. being in need of information how to rebuild, is in conflict with the 2nd law of thermodynamics. This remains true, even if the system does not strictly fulfill the thermodynamically defined criteria for which this law holds, e.g. the system being absolutely confined. Proliferative SC activity that would result in something different from and more complex than just a structure or an agglomeration of cells that are randomly interconnected with perhaps non-operational synaptic contacts and, e.g. a meaningless transfer function or output signals that cannot be deciphered (e.g. noise), is impossible, because that would mean that the system’s entropy was spontaneously reduced, i.e. information generated. The developmental steps required during ontogenesis to produce even a comparatively simple and phylogenetically conservative structure such as the hippocampus, or any straightforward motor nucleus is only understood rather incompletely (Eriksson et al. 1998; Aimone et al. 2006; Aimone et al. 2007). The more so is a complex multiloop disorder like Parkinson’s disease. Thus, the therapeutic results of transplantation therapy are still inconclusive (Arias-Carrión et al. 2006, 2007; Check 2003; Freed et al. 1990, 2002; Hall 2008; Höglinger et al. 2004; Mamelak 2008; Newman and Bakay 2008; Suchowersky 2008). Here the most fundamental criticism of regenerative medicine in the CNS sets in. Whereas in a macroscopical graft like a parenchymatous organ (heart, kidney, liver etc.) the difficulties today are more of a technical than of an ethical nature, concerning, for instance, graft malfunction or immunologically mediated graft rejection, in the CNS there are not only formidable technical and conceptual obstacles, but there is always the conviction from a materialist-positivist angle that the brain indeed harbours the mind or the self, and that each brain is absolutely unique (Kim 1995; McGinn 1989) among all others. Ethical problems with therapies influencing the brain, be it by SC grafting, by surgical lesional intervention or by electrical stimulation 72

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techniques, so that they cause one of its individual and unique personal properties to be changed as a consequence of therapy have been in existence since neurosurgery was added to the methodological arsenal of medicine. The same is true for psychotropic, i.e. mind-altering pharmacological substances. For the field of neurosurgery, we may only mention prefrontal lobotomy (leucotomy) in its original form (Moniz 1937; Jansson 1998) and its variants, such as ‘undercutting’ (Scoville 1951), a very crude intervention according to today’s standards, where the bi-directional thalamofrontal and frontothalamic fibre tracts connecting the frontal lobe to the rest of the brain by way of the thalamus have been severed (Moniz 1937; Heller et al. 2008; Scoville 1949, 1951, 1953; Braslow 1997; El-Hai 2007; Hoffman 1949; Kalinowsky and Scarff 1948; Swayze 1995; Tooth and Newton 1991; Tranøy et al. 2005). This technique was, for instance, used to treat patients who were habitually aggressive and sociopathic. Prerequisite of this major therapeutic invasion always resulting in gross white matter damage of the brain was, however, the refractoriness of symptoms to other therapeutic modes then available. Quite from the beginning of using this method, it became clear that prefrontal lobotomy had the most severe effects on personality, cognition, and perception of the self, just to name a few (Jansson 1998; Menninger 1948; Comité Consultatif National d’Ethique 2002). Although aggression was indeed brought under control, the price to be paid for this was high indeed, since virtually all traces of individualism were erased, affective behaviour was wiped out and personality was destroyed nearly completely. Although this method had been hailed for over one decade, it was swiftly abandoned, when the first neuroleptics were introduced into psychiatric therapy (Delay and Deniker 1957).

O n t o l o g i c a l I s s u e s w i t h R e g e n e r a t i ve M e d i c i n e Even if the attempts of the emerging field ‘regenerative medicine’ at reconstructing defunct parts of the brain were successful, we would immediately be confronted with the question concerning the ontological meaning of this stem cell graft. Would its possible capability to communicate with the remaining system transform the graft into a part of the brain, despite the information content fixed in the genome (Dawkins 1976; LeDoux 2002) or other intracellular storage media differing between graft and host cells as well as would the time-scale of ontogenesis? Would the grafted SC ontologically be reduced to 73

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replaceable building blocks or spare parts, or would we be compelled to see them as autonomous entities which may be • parasitic • symbiotic, or • autonomous? What would be the objective and subjective consequences of this for the individual, whose brain had been manipulated? One could reduce the question to a purely utilitarian one, with the details depending on the functions first lost and subsequently regained by SC grafting, for instance: if the clinical outcome with respect to the remission of the symptoms caused by brain damage would be ‘better’ with grafting than without, the procedure would have been a success. However, even for simple motor disturbances the set of criteria for assessing the clinical outcome are purely phenomenological, and are not strictly quantifiable. In addition, reducing the question like this would make it meaningless, because only one of the various aspects of dysfunction would be studied and – perhaps – elucidated. Anyway, would the chimeric nature of a brain thus ‘cured’ have any ethical consequences worth discussing, or, put differently, what influence would a piece of non-self introduced into the material correlate of the self have on the latter? Would the argument hold that it was mostly the host brain that modelled, or even determined, the previously quasi-amorphous and functionally clueless SC into useful parts of circuitry, or would the notion prevail that the SC were still surviving parts of a foreign individual which were pressed into duty in a different and individual organism? What the question boils down to is, would the process of assimilation also make the SC part of one integrated self, would the SC remain only the meaningless functional entities they had been before, or would we – ontologically – have to deal with a mind, part of which is foreign, or put more directly, with an iatrogenic personality. Practically, the answer would be rather simple: If the patient underwent no significant personality changes then one might assume that assimilation prevails to an extent making the question meaningless. However, if personality changes, differences in cognition, reasoning etc. or, in the most extreme case, alterations in self-perception and/or in the perception of others having known the patient before the incident occurred, they might be attributed to defects resulting from trauma or disease in the first place. If, however, the changes in the higher brain functions mentioned above (being only an arbitrary selection from a great many functions) became quite atypical or bizarre when put into 74

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relation with the initial mode of partial brain failure, one may indeed be inclined to suspect an influence of the SC graft upon the self beyond the damages the material surrogate of this ‘self’ has sustained previously. From an extreme point of view, each neural element of the brain is connected more or less directly to all other nerve cells (Fingelkurts An.A. and Fingelkurts Al.A. 2004; Fingelkurts An.A. et al. 2005). Following this holographic view, the brain functions – with some exceptions – are not localized to specific areas but distributed among the entire, hypercomplex system. This is especially true for the higher, i.e. the more abstract, brain functions. Thus, in principle, the SC graft, even if small, would – according to that line of thought – in principle influence each host neurone, thus making an imprint, if ever so weak, on the entire system. Hence, any graft, dependent on volume and position in the brain, would in principle have the capacity to change mind and self. As this is an experiment of thought, in practice, influences exerted by small grafts would vanish in biological or thermic noise, and only large grafts would actually be able to change the way a person thinks. Would this be tolerable? To clarify this, we must study, whether this influence is unspecific or specific, meaning whether all functions (conduction and processing of information) are generally depressed, attenuating intracerebral communication, if we assume that the SC circuitry is composed of predominantly inhibitory neurons thus attenuating any information flow routed through the respective area, or enhancing information flow, if the neurons were excitatory. The other conceivable possibility would be an intentional attempt controlled from the outside at gaining direct access to the brain circuitry via stem cells. Quite naturally, this is only a very crude construct which would most certainly not be manifested in a pure form under real world conditions. We believe to have now lined out that stem cell grafting has indeed the capacity to change a person’s mind and self, if we make the following assumptions: • The brain indeed harbours the human mind, intellect, specific and singular personal traits that are emotional or intellectual in nature, or, in a wider sense, his/her ‘personality’. • These attributes of the respective individual are not strictly localized within the brain, i.e. linked to certain anatomical substrates as was believed for a long time – so to speak as a continuation from phrenology to neurophysiology – but they are spatiotemporally distributed, non-linear and non-stationary functions, • to extend this assumption even more, we might add that – with respect to localization – there appears to be a certain hierarchy: Simpler, e.g. motor-functions are indeed confined to certain brain 75

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• •

volumes (pre- and postcentral cortex), whereas more intricate ‘hardwired problem solvers’ that probably require a larger and also variable number of neurons to operate correctly by time-dependent recruitment, appear to become increasingly distributed, or spread throughout the parenchyma, the ‘higher’, more complex and abstract they are. Taken together, the simpler functions or tasks may be easier to localize, while the higher ones appear to be of a more ‘holographic’ nature. However, this must be considered just a rather general trend. Without stretching our imagination too far, we may well assume that each nerve cell is connected to all others by additional modalities. This comprises simple, monosynaptic contacts or polysynaptic connections over many stations acting as relays. Likewise, less conventional modalities may be links formed by electrical synapses or, more unspecifically and slower working influences exerted by one cell upon others by way of changing the composition of the extracellular fluid, e.g. by altering the concentration of neuromodulating substances such as the endorphins, the enkephalines, the prostaglandins or a huge variety of other substances known to influence the pre- and postsynaptic neuronal membrane.

Let us do a further thought experiment: We suppose that there is an exact SC-derived copy of each individual neuron, glia- or other cell of a living brain. Ontologically, it is clear, that the original neuron and its SC-derived counterpart are completely diverse. Let us further assume that we were able, using very advanced techniques, to replace each individual neuron by its SC copy. After having begun with the replacement process, we would rather quickly have created a chimera of original and SC-derived neurons and glia cells. Ontologically, the state of the remaining original cells has not changed, but what has happened to the SC-copies? As per function, these copies are perfect substitutes of the removed original cells. If the mind rested on the intact function of the brain which implicitly depended on its structural integrity, it is obvious that they would not have changed functionally. The ‘owner’ of the brain will behave, act and perform as he would have done if the original cells had not been replaced by the SC-derived replicas. However, is the mind, ontologically the same as it had been before, or is it only partly identical with the original? If the latter was true, what about the state the replicas are in? Are they just operational, but ontological different parts of the chimera? Have they been integrated by the brain as elements of its own, and are therefore legitimate members of one brain

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and one mind by virtue of the original host cells having imprinted their ontological status upon the SC-derived exact copies? If we extend this experiment further and replace all original cells by their SC-copies, one might assume that the mind, due to the functional identity, remained the same to a conscientious observer. Thus, the mind would have been transferred from the original brain to a different substrate. Several questions arise: is the mind still the same as it had been before? Is it a perfect replica of the original mind, since it emanates now from a substance ontologically different from the original brain, or is the mind still ontologically the same, since it had been the emanation of the ‘original’ brain which it continues to be, because the substrate is an exact copy of the original brain? Is the owner of the now SC-based brain still him-/or herself? The same issues arise, if the new substrate was a ‘fictitional’, immensely complex electronic circuit that perfectly emulated neuronal and glial interplay as well as information handling. Research into so called ‘hard artificial intelligence (AI)’ is concerned with these problems (Newell and Simon 1963; Hawkins and Blakeslee 2004; Howe 1994; McCarthy et al. 1955; McCarthy and Hayes 1969; McClamrock 1995; Russel and Norvig 1995; Moravec 1976; Turing 1950; Bennet 1998; Briscoe and Novitch 2008; Buchanan 2005; Minsky 1967, 2006; Johnston 2008; Weizenbaum 1976; Zhang 2008; Zhdanov 1988). As we identified a variety of negligible to severe ethical issues in the context of stem cell grafting, warranting attention as obstacles for their use in human beings, we should discuss them and assess, whether it may be morally justifiable to graft stem cells, in order to eventually attain the objective of regenerative medicine in the brain; i.e. restitution ad integritatem. Let us assume that these ‘technicalities’, like the prevention, for instance, of malignant dedifferentiation, or the SC targeting problem have been solved, and that there are toti- or pluripotent cell lines that can be grafted safely into the central nervous system. The main practical issue – from our point of view – is now the fact that immediately after grafting we lose control over the graft, its inherent dynamics, and about its interaction with the recipient’s tissue. Since our knowledge about stem cells, in particular when interacting with the CNS, is so limited we believe that attempts at therapeutically using them in human beings are, at the least, very premature at the present time, since we cannot even roughly assess the consequences of a medical intervention that probably completely overturns the systems dynamics and the general characteristics of the original brain. We must not forget that this substrate is in fact the singular and unique brain of a 77

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human being which – from the reductional physicalism point of view – emanates mind and personality of one likewise unique individual. The following discussion will unfold – in the context of the mindbody question in philosophy – on the basis of said physical reductionism which – in the neurosciences – is arguably a well accepted position. We have now established a tentative position concerning SCgrafting; the latter is – at the moment of this writing – already technically feasible but unpredictable both concerning its biological and philosophical consequences for the host. We have also determined that there are many technical obstacles to be overcome to replace a damaged part of the brain with a simulation thereof based on SCs. If scrutinized closely, each of these obstacles appears insurmountable in the near (decades) or more remote (centuries) future. If it is our concern to protect the brain from iatrogenic, yet uncontrollable influences, or even from wilful, intentional attempts at mind and personality control to evil ends, we might – at least for the moment – relax and rely on the brain’s immense complexity as its best self-defence mechanism. This, however, is only a technical limit, and it would not be for the first time that some revolutionary scientific ‘Erkenntnisgewinn’ annihilates this last stance of protection. Thus, I believe that intentionally performing stem cell work in humans that would have mind-, self- and thought-altering capacities or consequences should be considered a criminal offence and codified as such on a national as well as on an international level being penalized accordingly. With an analogous problem which may be considered a precedent and is discussed elsewhere, prefrontal lobotomy was already forbidden under the law of Russia, formerly the Soviet Union, as early as 1950, while no such measures were taken in the Western countries (Приказ МЗ СССР 1003 (9 дек. 1950); Order of the Supreme Soviet of the USSR No. 1003 issued on December 9th, 1950). For the first time in human history, we are now, technologically, in a position to ‘get into other people’s heads’. Thus far, the sheer complexity of the human brain which is, from our limited point of view, considered by many laymen, scholars and neuroscientists alike, the most intricate piece of matter in the universe, has ultimately reduced any attacks directed against the self to nil. These attempts are equivalent to forcefully intrude into the most valuable asset of a person, i.e. the inner sphere of privacy and the free will (Price 2005), meaning the freedom of choice. All known brainwashing techniques, instrumentalizing psychological tools such as Pavlovian, non-Pavlovian and operant conditioning, pharmacological intervention, extreme fear and stress etc. have so far 78

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failed to tear down that last barrier which defends the individualist inner workings of the brain. In comparison to gaining a direct access to this core substrate from which the individualist and unique mind of each human being emanates, all conventional brainwashing procedures, which, by themselves are already quite efficient, must appear to be child’s toys. This may be a most radical position, but the author is firmly convinced that this barrier should be upheld at all cost, in order to protect the very core of humanity. In his own conviction he would be better off dead as a result of his refusal to undergo a therapy that is capable to undermine his notions, thoughts and beliefs, to erode or abolish his self and his perception thereof and to change or eradicate his unique personal traits, than to purely survive and live a life that is not his own, but only an unintentional or intentional construct resulting from circumstances, other persons’ malevolent actions or a combination of both. It is his personality that discerns him from other human beings who are likewise unique and should also be protected from procedures that, among many other issues, may interfere with or abolish their freedom of choice. An intentional and wilful intrusion into this domain may carry the danger that, under the pretext of medical aid, each and every individual may live in danger to be converted from an individual subject into a controllable object – a mere puppet on a string and a perfect ‘Manchurian Candidate’.

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Fallon, J., S. Reid, R. Kinyamu et al. (2000) “In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain”, in: Proc Natl Acad Sci USA. 97 (26): 14686-14691. Fatt, P. & B. Katz (1951) “An analysis of the end-plate potential recorded with an intracellular electrode”, in: J Physiol. 115: 320370. Fatt, P. & B. Katz (1953) “The effect of inhibitory nerve impulses on a crustacean muscle fibre”, in: J Physiol. 121: 374-389. Fingelkurts, An.A. & Al.A. Fingelkurts (2004) “Making complexity simpler: multivariability and metastability in the brain”, in: International Journal of Neuroscience. 114(7): 843-862. Fingelkurts An.A., Al.A. Fingelkurts & S.A. Kähkönen (2005) “Functional connectivity in the brain – is it an elusive concept?”, in: Neuroscience & Biobehavioral Reviews. 28(8): 827-836. Freed, C.R., R.E. Breeze, N.L. Rosenberg, S.A. Schneck, T.H. Wells, J.N. Barrett, S.T. Grafton, J.C. Mazziotta, D. Eidelberg & D.A. Rottenberg (1990) “Therapeutic effects of human fetal dopamine cells transplanted in a patient with Parkinson’s disease”, in: Prog Brain Res. 82: 715-721. Freed, C.R. (2002) “Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson’s disease?”, in: Proc Natl Acad Sci USA. 19; 99(4): 1755-1757. Comment on: Proc Natl Acad Sci USA.19; 99(4): 2344-2349. Freed, C.R., M.A. Leehey, M. Zapata, K. Busted, L. Thompson & R.E. Breeze (2003) “Do patients with Parkinson’s disease benefit from embryonic dopamine cell transplantation?”, in: J Neurol.; 250 Suppl 3: III44-46. Goldstein, S.S. & W. Rall (1974) “Changes of action potential shape and velocity for changing core conductor geometry”, in: Biophys J. 14: 731-757. Goldman, S.A. & F. Nottebohm (1983). “Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain”, in: Proc Natl Acad Sci USA. 80 (8): 23902394. Gould, E., A. Beylin, P. Tanapat, A. Reeves & T.J. Shors (1999) “Learning enhances adult neurogenesis in the hippocampal formation”, in: Nat Neurosci. 2 (3): 260-265. Graham-Rowe, D. (2003) “World’s first brain prosthesis revealed”, in: New Scientist, Mar 12, 2003. Hacker, P. (2003) “Philosophical foundations of neuroscience”, Blackwell Pub. 82

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Hall, V.J. (2008) “Embryonic stem cells and Parkinson’s disease: cell transplantation to cell therapy”, in: Ann Acad Med Singapore. 37(3): 163-2. Hawkins, J. & S. Blakeslee (2004) On intelligence (New York, NY: Owl Books). Hegger, R., H. Kantz & T. Schreiber (1999) “Practical implementation of nonlinear time series methods”, in: The TISEAN package CHAOS 9: 413. Heller, A.C., A.P. Amar, C.Y. Liu & M.L. Apuzzo (2008) “Surgery of the mind and mood: a mosaic of issues in time and evolution”, in: Neurosurgery. 2008 Jun; 62(6 Suppl 3): 921-940. Republished from: Neurosurgery. 2006 Oct; 59(4): 720-733; discussion 733-739. Höglinger, G.U., P. Rizk, M.P. Muriel et al. (2004) “Dopamine depletion impairs precursor cell proliferation in Parkinson disease”, in: Nat Neurosci. 7 (7): 726-735. Hoehn, M., E. Küstermann, J. Blunk, D. Wiedermann, T. Trapp, S. Wecker, M. Föcking, H. Arnold, J. Hescheler, B.K. Fleischmann, W. Schwindt & C. Bührle (2002) “Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat.”, in: Proc Natl Acad Sci USA.10; 99(25): 16267-16272. Hodgkin, A.L. & B. Katz (1949) “The effect of sodium ions on the electrical activity of a crustacean nerve fibre”, in: J Physiol. 108: 3777. Hodgkin, A.L. & A.F. Huxley (1952) “A quantitative description of membrane current and its application to conduction and excitation in nerve”, in: J Physiol. 117: 500-544. Hoffman, J.L. (1949) “Clinical observations concerning schizophrenic patients treated by prefrontal leukotomy”, in: N Engl J Med. 241: 233-236. Holmes, W.R. & W. Rall (1992) “Electrotonic length estimates in neurons with dendritic tapering or somatic shunt”, in: J Neurophysiol. 68: 1421-37. Hou, L. & T. Hong (2008). “Stem cells and neurodegenerative diseases”, in: Sci China C Life Sci. 51(4): 287-294. Epub March 27, 2008. Review. Howe, J. (1994). Artificial Intelligence at Edinburgh University: a perspective (November 1994). Jansson, B, (1998). Controversial Psychosurgery Resulted in a Nobel Prize. http://nobelprize.org/nobel_prizes/medicine/articles/moniz/ Johnston, J. (2008) The allure of machinic life: cybernetics, artificial life, and the new AI. (Cambridge, MA.: MIT Press). 83

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Es ta blis hing Re ge nerative Me dicine for the Human Brain: Ethical Aspects of Intrac erebral Stem Cell Transpla ntation JENS CLAUSEN Considerable progress has been made the last few years in our understanding of stem cell biology and devising sources of cells for transplantation. New methods are also being developed for cell delivery and targeting to affected areas of the body. These advances have fueled optimism that new treatments will come for millions of persons who suffer from neurological disorders. But it is the current task of scientists to bring these methods from the laboratory bench to the clinic in a scientifically sound and ethically acceptable fashion (Panchision 2006).

Introduction Intracerebral cell transplantation is a field of basic and clinical research directed towards developing therapies – or at best even cures – for severe diseases affecting the human brain such as neurodegenerative disorders including Parkinson’s disease and Huntington’s disease. Cells are transplanted into the brain of patients to replace lost or dysfunctional cells. By functionally and accurately integrating into the host’s brain circuits transplanted cells should take over the functions of the diseased 91

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ones. Thereby symptoms should be alleviated and eventually, the disease may even be cured. In animal models and even in some patients there is evidence for behavioural improvements after cell transplantations (Bjorklund et al. 2003). However, results have been variable so far. In addition to these direct cell-therapeutic attempts, recently, neural stem cells have been seeded on a probe to improve integration of an implantable electrode into the surrounding brain tissue (Purcell et al. 2009). Brain implantable devices are in clinical application as deep brain stimulators for treating end stage Parkinson’s patients (Deuschl et al. 2006; Weaver et al. 2009). In human trials, electrodes for recording brain signals have been implanted to direct prosthetic devices with these signals (Hochberg et al. 2006). For all of these brain technological approaches long-term biocompatibility and survivability are essential in order to achieve reliable signal transduction. These devices raise ethical questions on their own (Clausen 2008; 2009). When stem cell seeded electrodes are used additionally ethical aspects of intracerebral cell transplantation have to be considered. The objective of this essay is to examine ethical issues related to intracerebral cell transplantation with respect to the more direct cell therapeutic approach. Since it is not yet clear which cell type may prove most suited for therapeutic purposes, initially different cell types and their ethical implications are examined. This is followed by a section on the ethical aspects concerning the transplantation of cells – regardless of which cells are used. Against the backdrop of these more general sections, finally, ethical questions related to clinical research purposes are discussed.

Which Cells for Intracerebral Transplantation? Medical Obstacles There is a variety of different sources for cells for regenerative medicine. So far, most evidence is available on cells stemming from aborted fetuses. They have yielded very diverse but partly very encouraging results for cell-based therapies for Parkinson’s diseases. Empirical evidence stemming from experimental transplantations to human brains shows rather variable outcomes of the trials. On the one hand, these results indicate that cell transplantation may be in principle a therapeutic option for neurologic and neurodegenerative diseases. On the other hand, two prospective double blind studies from NIH provided a major 92

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backlash to the field of transplantation of fetal cells for curing neurodegenerative disorders. These prospective double-blind, placebocontrolled trials tested intracerebral cell transplantation for Parkinson’s disease against sham surgery.1 The results of these studies have been quite of disillusioning: One study concluded that “fetal nigral transplantation currently cannot be recommended as a therapy for PD” (Olanow et al. 2003). In the second study older patients did not benefit from cell transplantation whereas younger patients (under age 60), each compared to the sham surgery control group did (Freed et al. 2001). Due to the limited therapeutic benefit of fetal cell transplantation and the availability of other cell sources like stem cells it is not yet clear, which cells may be best suited for intracerebral transplantation. Of course, this is a scientific and medical question, but not exclusively. Since there is a long lasting and ongoing debate about the moral status of unborn developmental stages of humans, the question about the best cells has also an ethical dimension. With respect to fetal cell transplantation ethical guidelines used to mainly focus on the relationship between abortion and cell transplantation. The Network of European CNS Transplantation and Restoration developed recommendations on how to harvest fetal cells in an ethical justifiable way (Boer 1994).

Ethical Quandaries Moral status expresses whether and how something or someone has in itself moral value and must be taken into account in ethically relevant decisions. Born human beings are commonly seen to have the highest moral status, namely full moral status. With regard to the human embryo or fetus moral status indicates, on effect, the extent of life protection he or she deserves. There is controversy among scientists, ethicists, general public and within these groups at what point in time the developing human organism acquires full moral status. Setting aside the controversy on the exact developmental stage crucial for full moral status, there is widespread agreement amongst all these groups that even before this state is reached the human embryo deserves special respect. This respect gradually increases with development. Since ‘respect’ is too vague a criterion to base ethical decisions on it, what respect for embryos means typically is expressed by three principles: the principles of pro-

1

The control group underwent a sham surgery where holes were drilled into the scull, but no cells were transplanted.

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portionality, probability and subsidiarity (see De Wert 2004; Clausen 2010). Principle of proportionality: It is widely accepted that embryos may only be used in high-ranking research settings. Clinical relevance, for instance, can be an important enough goal to justify embryo research. Since it will not suffice to pursue an important goal the Principle of probability formulates the second requirement. Even for high-ranking research, a human embryo may only be taken even for high-ranked research when there is already a proof of principle for the important goal e.g. shown in animal research. With respect to the Principle of subsidiarity human embryo research can only be justified when there is no available alternative to attain the important goal. Each of these three principles is by itself necessary and altogether they are sufficient to express respect for the human embryo. In this way the principles of proportionality, probability and subsidiarity formulate necessary requirements for the ethical justification of human embryo research.

Cell Ranking The gradualist position stating that the early human embryo deserves respect has three implications: Ethically justified research should not use human embryos, if possible. If necessary, however, as few embryos as possible should be destroyed. And these embryos should be as early in their development as possible. This leads to a ranking of different cell sources with gradually increasing ethical quandary (Table 1). With regard to the briefly sketched position on what kind of respect a human embryo deserves, it comes as no surprise that the cells for which no embryo destruction is necessary are in general preferable to all other cells which necessitate on a destruction of an embryo. Within the latter group ES-Cells created from embryos primarily generated but no longer needed for IVF-treatment are preferable because generating these cells and doing research on them will not destroy an embryo on top of the ones which nevertheless would die.2

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This does, however, not mean that changing the intention from procreation to research alters the moral status of the embryo. The status remains the same. But in addition to the moral status embryo research is ethically only justifiable when the ‘parents’ informed and freely donate the no longer needed embryos for research. Without parents’ consent research is not justified not because of a different moral status of the embryo but because of the missing donation.

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Table 1: Cell Ranking Different cell sources for intracerebral transplantation with ethical challenges increasing from top to bottom. Embryo Destruction Necessary?

No

Yes

Cell Type Somatic cells Adult stem cells Cord blood stem cells IPS cells ES-Cells from surplus Embryos (ES-)Cells from aborted fetuses ES-Cells from Embryos created for research NT-ES-Cells

Stage of Embryonic Development

How many Embryos?

ø

None

5 day blastocyst

A few thousand

12-16 week fetus

A few per treatment

5 day blastocyst

A few thousand

A few 5 day blastocyst hundred per treatment

In order to prevent the habitual creation of more embryos than needed for IVF solely for the purpose of satisfying research needs Germany strictly regulates IVF-practice through the embryo-protection law (Embryonenschutzgesetz). Respect for embryos is accounted for by allowing only to create as many embryos as needed for IVF. This could secure that as few as possible embryos in surplus are created through procedures of assisted reproduction. Since ES-cell lines are held to be immortal, theoretically one single embryo could be enough to meet all ES-cell needs. In practice, however, thousands of embryos are needed to finally establish the ES-cell line(s) which may one day be used for clinical applications like intracerebral cell transplantation. This is due to inefficient harvesting-procedures and because it is still not clear, which standards the cells should meet to be suitable for clinical application.

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The same is true for cells stemming from embryos solely created for research purposes. Nevertheless, these cells are ranked ethically more problematic than cells from surplus embryos and even the cells from aborted fetuses, because the latter two use developmental stages which would die anyway. Creating patient-specific cells through nuclear transfer (NT) – the procedure used to clone Dolly the sheep – in animal experiments remains an extremely inefficient procedure which has not been proven to work in humans. To make this procedure work will – if at all successful – depend on creating and destroying thousands of human embryos.3. In addition to the research needed each treatment will probably necessitate the creation of a few hundred embryos per patient.4 In Table 1 the ethical ranking of the cells is based solely on the criterion of moral status. Implicitly this presupposes that everything else is the same, especially the therapeutic benefit of all the different types of cells. As noted above, from a technical perspective it is still not clear which cell type may be the best suited for transplantation. The varying results with fetal cells encourage the search for alternatives. But what if ES-cells would yield a better therapeutic effect than all cells for which no embryo has to be destroyed and the latter may nevertheless have some therapeutic effect? Which cell type would then be preferable? With respect to alternative cell sources, their therapeutic potency, technical complexity of generating them, and moral status Heidi Mertes, Guido Pennings and André Van Steirteghem stress that “the presentation of embryonic stem cell research as unethical and of embryo-free stem cell research as ethical is therefore too simplistic” (Mertes et al. 2006: 2754). However, it is still an unsolved question how to compare and rank the different cell types when weighing a potential therapeutic effect against the respect for the embryo. Concerning both it is not just a yes or no decision but a question of degree.

3

4

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Some claimed classical nuclear transfer and an altered variation of this procedure do not produce an embryo, and therefore harvesting ES-cells from these entities is ethically sound. Elsewhere I have shown why both is not convincing (Clausen 2010). This cell-ranking is based, however, on the assumption that all these cells are equally useful for therapeutic purposes. The picture becomes even more complex when different cell types vary in the degree of their therapeutic usefulness. Since it is still unclear which cell type may be clinically useful for what kind of treatment this dimension of the ranking is left unconsidered here.

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Transplanting Cells Inducing Brain Tumour Formation through Cell Transplantation From animal experiments it is well known that transplanting ES cells frequently induces formation of brain tumours (Freed 2002). This is one of the most important obstacles in developing save therapies from human pluripotent stem cells (Carpenter et al. 2009). However, not only undifferentiated cells, but even ES cells already differentiated into neuronal phenotypes before transplantation induce tumours (Merkel et al. 2007: 105f.). Although dopamine neurons derived from fetal midbrain can survive 14 years without pathology (Mendez et al. 2008), a recently published case report from Israel demonstrates that even transplanting fetal neural stem cells into the brain of a human subject can result in tumourigenesis (Amariglio et al. 2009). If it is not possible to reduce or avoid transplantation-induced tumour formation the possibility of curing through intracerebral cell transplantation will be heavily restricted. Due to risk-benefit analyses this possible therapeutic option would be limited to patients in whom every other therapy or not-treating at all induces even greater risks. For Parkinson’s disease for which powerful drugs (e.g. Levodopa) and in a later stage a neuro-technological approach (deep brain stimulation) are clinically established this cases will probably be extremely rare, although the already existing therapies are not free from – sometimes severe – side-effects.

Transplanting Psychological or Personality Characteristics In addition to the general concern of altering personality or personal identity through brain interventions,5 cell transplantations into the human brain are suspicious of transplanting psychological or personality characteristics of the donor to the patient (Walters 1988). However, personality and personal identity are not defined by brain functions 5

Of course, treating a patient suffering from severe neurodegenerative disorder like Parkinson’s disease will have an impact on the personality and personal identity of this patient even if the intervention has no sideeffects. Therefore, an ethical analysis has to distinguish between wanted alterations and unwanted – ethical objectionable changes in personality traits. For discussion of changing personality and/or personal identity through brain interventions see (Northoff 1996; Merkel et al. 2007: 189ff.; Northoff and Heinzel 2007) and contributions of Josef Quitterer and Jan Goldstein in this volume.

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alone, but are a complex interplay of brain, body and environment. The human mind is not solely a function of the human brain, but an embodied and embedded phenomenon (Glannon 2009). Even with regard to the brain-related part of personality Merkel and colleagues hold that “transfer of personality from (minced or suspended) fetal donor tissue to the host brain is erroneously put forward as a possible drawback of neurotransplantation.” (Merkel et al. 2007: 104). The reason for this is that even the neural aspect of personality is not located in a specific well-defined brain area or encoded by special neurons, but based on the activity of different partly interacting neural networks with various inputs and outputs from and to other parts of the brain and the body. The conditions of the host brain at the site of implantation direct maturing and functional integration of the implanted cells. Since conditions in the adult brain are completely different from the ones in fetal neural networks and because of cell separations there is no need to fear that the personality or a part of it can be transferred from one organism to another through intracerebral cell transplantation. In order to ensure transfer of personality or other human characteristics will under no circumstances occur in cross-species transplantation Phillip Karpowicz and colleagues recommend to separate cells before transplantation (Karpowicz et al. 2005).

Creating Part-human Beings Transplanting human cells into animals is necessary in order to test the potential for differentiation into the desired cell type, principle functioning and possible side-effects of potential new cell sources like hES cells or their derivatives. Such preclinical testing is regarded “analogous to the standard testing of drugs, transplants, and medical devices in animals before human clinical trials” (Commitee on Guidelines for Human Embryonic Stem Cell Research 2005: 39). From this perspective it seems to be ethically required to create part-human beings before commencing clinical trails in order to minimize risks for human research subjects. For instance, in an animal model – 6-hydroxydopamine-lesioned parkinsonian rats – human ES cell-derived dopamine neurons on the one hand demonstrated substantial functional recovery. On the other hand, these cells were subject to phenotypic instability and undifferentiated expansion, both of which recommends utmost caution with clinical application of these cells (Roy et al. 2006). Against earlier hopes, hES cells and their derivatives do not evade immune rejection. Results of xenografting human cells into mice (Swijnenburg et al. 2008b) as well 98

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as allogenic transplantation of murine ES cells (Swijnenburg et al. 2008a) suggest that these cells are immunogenic and need immunesuppressive therapy for long-term survival in cell therapy. Somatic cell nuclear transfer (SCNT) – the procedure used to create Dolly the cloned sheep – was suggested to avoid immune rejection of transplanted cells. This procedure, however, would be in need for a huge amount of mature human oocytes. Since this cell source is in very short supply and harvesting the oocytes is ethically suspected to be an exploitation of women in need the use of animal oocytes for SCNT seem to present a possible alternative for circumventing immune response. Mixing animal oocytes with human cells by SCNT will result in embryos consisting of an animal cytoplasm containing animal cell organelles and a human nuclear genome. There is little evidence that even classic SCNT may be able to overcome immune rejection of transplanted cells (Tabar et al. 2008); for the use of animal oocytes in SCNT it is yet uncertain whether this procedure can be a way of circumventing immune response in the host tissue. Since the need for immunosuppression will be influenced by the site of implantation and the central nervous system is held to be an ‘immuneprivileged’ site, intracerebral cell transplantation may require only transient immunosuppression (Carpenter et al. 2009). Ethical discussion on creating part animal part human beings adduces some principle objections based on species integrity, moral taboo or human dignity (Karpowicz et al. 2005). All of these arguments, however, are subject to fundamental criticism and seem not convincing in their approach to fundamentally reject the creation of part human part animal being (Baylis and Fenton 2007). There is a weaker argument that in creating part human part animal beings we would face moral confusion, since we do not know anymore how to value these creatures. Are they with respect to their moral status more like animals or more like humans or even none of both? Because we do not have answers to these questions some argue we should not create part-human part-animal beings. Another recommendation addressing this moral confusion could be to define the moral status of these novel part-human chimeras through discussion. This would create a moral basis for arguing for or against whether, when and which chimera research may be ethically justified.

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Clinical Research When is intracerebral cell transplantation an appropriate alternative, for which physicians should offer their patients to participate in research trials? Of course there is not the one and only answer to this question, since situations vary in many aspects for different diseases. Therefore ethical aspects of clinical research should be separately discussed for Huntington’s disease and Parkinson’s disease – two of the main targets for intracerebral cell transplantation. Huntington’s disease is a heritable, progressive and untreatable neurodegenerative disorder in which the patients develop severe movement and cognitive incapabilities. This fatal disease is caused by mutations (increased CAG repeats) in the huntingtin gene. Intracerebral cell transplantation was initiated as an attempt to replace lost neurons, thereby decrease patient’s movement and cognitive symptoms and at best cure the entire disease. A recent study presented discouraging results for this attempt – at least with respect to the current methods (Cicchetti et al. 2009). A decade after transplantation a patient’s autopsy presented an explanation why the initial therapeutic effects were but mild and transient. The transplanted cells – although without huntingtin mutation – were strikingly more affected by degenerative changes than the host striatum. The observed pathological processes are incompatible with clinical benefit. Cicchetti and colleagues explain these sobering results with excitotoxicity and inflammatory mechanisms playing a significant role in transplant degeneration. If these results were reproduced in other patients already transplanted this would present a major setback for the initial hypothesis that transplanting cells without huntingtin mutation into the striatum could cure Huntington’s disease. Consequently, new strategies have to be developed and tested in animal models before Huntington patients get the next intracerebral cell transplantation. In Parkinson’s disease – in contrast to Huntington’s disease – there are alternative therapeutic approaches for treatment. Outcome in motor symptom control often can be increased trough medication like levodopa. This is the standard approach in idiopathic Parkinson’s although side-effects are sometimes severe. Even when medication is not an option for treatment anymore there exists a technical intervention for treating motor symptoms of end-stage Parkinson’s patients. Stimulating basal ganglia of these patients through deep brain stimulation is a symptomatic therapy which can significantly improve the severe motor impairments.

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This special situation for Parkinson’s has to be taken into account when it comes to an ethical evaluation. Whether and when are research trials on intracerebral cell transplantation ethically justifiable? With respect to the fact that there are already established therapies, and cell transplantation may – if ever – only in a distant future provide a therapy the answer will not be trivial. To give the answer is especially challenging before the backdrop of the potential benefit of intracerebral cell transplantation. If the cell therapeutic approach works it may offer a real cure for neurodegenerative disorders like Parkinson’s, not just a treatment of symptoms as DBS and medication. PD is caused by substantial neuro-degeneration in the substantia nigra. Thus transplanting healthy cells may provide a therapy for this severe disease by restoring graft-cells to substitute neural function. The hope is that the approach of intracerebral cell transplantation may not just alleviate symptoms but provide a real cure for the neurodegenerative basis of the disease. This would be a great advantage compared to DBS and current medications which are just symptomatic approaches. But whether curing through cell transplantation is feasible still remains unclear. This uncertainty is, however, one of the major reasons why research is necessary. A central question for clinical research therefore remains: which patients should be included in the necessary trials? The ethical judgment on fair patient selection depends on different criteria. Ezekiel Emanuel and colleagues hold that research should be carried out with the most suitable individuals. Patient selection should be primarily based on the scientific aim of the research trial. Those who may generate the most valid results are preferred. Additionally, a fair distribution of risks and benefits is required. Research should be done on subjects who – as an individual or as part of a group – could profit from possible future benefits of the research results. Professional and institutional policies and practices governing this research are greatly needed (Mathews et al. 2010).

Conclusion Intracerebral cell transplantation suggests huge promises for therapies or even cures of currently sometimes barely treatable neurodegenerative diseases. In order to make possible that such therapies may become reality there is still a lot of research do be done. Overcoming the technical and medical obstacles should be embedded in analysing the related ethical issues. These include an adequate cell ranking based on 101

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ethical and medical criteria, examining and addressing general safety issues including the tumour induction and fair patient selection for clinical trials.

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Deuschl, G., C. Schade-Brittinger, P. Krack, J. Volkmann, H. Schafer, K. Botzel, C. Daniels, A. Deutschlander, U. Dillmann, W. Eisner, D. Gruber, W. Hamel, J. Herzog, R. Hilker, S. Klebe, M. Kloss, J. Koy, M. Krause, A. Kupsch, D. Lorenz, S. Lorenzl, H.M. Mehdorn, J.R. Moringlane, W. Oertel, M.O. Pinsker, H. Reichmann, A. Reuss, G.H. Schneider, A. Schnitzler, U. Steude, V. Sturm, L. Timmermann, V. Tronnier, T. Trottenberg, L. Wojtecki, E. Wolf, W. Poewe & J. Voges (2006) “A randomized trial of deep-brain stimulation for Parkinson’s disease”, in: New England Journal of Medicine 355(9): 896-908. Freed, C.R. (2002) “Will embryonic stem cells be a useful source of dopamine neurons for transplant into patients with Parkinson’s disease?”, in: Proceedings of the National Academy of Sciences of the United States of America 99(4): 1755-1757. Freed, C.R., P.E. Greene, R.E. Breeze, W.-Y. Tsai, W. Dumouchel, R. Kao, S. Dillon, H. Winfield, S. Culver, J.Q. Trojanowski, D. Eidelberg & S. Fahn (2001) “Transplantation of embryonic dopamine neurons for severe Parkinson’s disease”, in: New England Journal of Medicine 344(10): 710-719. Glannon, W. (2009) “Our brains are not us”, in: Bioethics 23(6): 321329. Hochberg, L.R., M.D. Serruya, G.M. Friehs, J.A. Mukand, M. Saleh, A.H. Caplan, A. Branner, D. Chen, R.D. Penn & J.P. Donoghue (2006) “Neuronal ensemble control of prosthetic devices by a human with tetraplegia”, in: Nature 442(7099): 164-171. Karpowicz, P., C.B. Cohen & D. Van Der Kooy (2005) “Developing human-nonhuman chimeras in human stem cell research: ethical issues and boundaries”, in: Kennedy Institute of Ethics Journal 15(2): 107-134. Mathews, D.J., J. Sugarman, H. Bok, D.M. Blass, J.T. Coyle, P. Duggan, J. Finkel, H.T. Greely, A. Hillis, A. Hoke, R. Johnson, M. Johnston, J. Kahn, D. Kerr, J. Kurtzberg, S.M. Liao, J.W. Mcdonald, G. Mckhann, K.B. Nelson, M. Rao, A. Regenberg, A.W. Siegel, K. Smith, D. Solter, H. Song, A. Vescovi, W. Young, J.D. Gearhart & R. Faden (2008) “Cell-based interventions for neurologic conditions: ethical challenges for early human trials”, in: Neurology 71(4): 288293. Mendez, I., A. Vinuela, A. Astradsson, K. Mukhida, P. Hallett, H. Robertson, T. Tierney, R. Holness, A. Dagher, J.Q. Trojanowski & O. Isacson (2008) “Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years”, in: Nature Medicine 14(5): 507-509. 104

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Merkel, R., G. Boer, J.M. Fegert, T. Galert, D. Hartmann, B. Nuttin & S.K. Rosahl (2007) Intervening in the brain: changing psyche and society (Berlin: Springer). Mertes, H., G. Pennings & A. Van Steirteghem (2006) “An ethical analysis of alternative methods to obtain pluripotent stem cells without destroying embryos”, in: Human Reproduction 21(11): 27492755. Northoff, G. (1996) “Do brain tissue transplants alter personal identity? Inadequacies of some “standard” arguments”, in: Journal of Medical Ethics 22(3): 174-180. Northoff, G. & A. Heinzel (2007) “The self in philosophy, neuroscience and psychiatry: an epistemic approach”, in T. Kircher & A. David (eds.), The Self in Neuroscience and Psychiatry (New York: Cambridge University Press) Olanow, C.W., C.G. Goetz, J.H. Kordower, A.J. Stoessl, V. Sossi, M.F. Brin, K.M. Shannon, G.M. Nauert, D.P. Perl, J. Godbold & T.B. Freeman (2003) “A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease”, in: Annals of Neurology 54(3): 403-414. Panchision, D. (2006) “Repairing the nervous system with stem cells”, in: Department of Health and Human Services USA & National Institutes of Health (eds.), Regenerative medicine 2006 (Terese Winslow): 35-43. Purcell, E.K., J.P. Seymour, S. Yandamuri & D.R. Kipke (2009) “In vivo evaluation of a neural stem cell-seeded prosthesis”, in: J Neural Eng 6(2): 026005. Roy, N.S., C. Cleren, S.K. Singh, L. Yang, M.F. Beal & S.A. Goldman (2006) “Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomeraseimmortalized midbrain astrocytes”, in: Nature Medicine 12(11): 1259-1268. Swijnenburg, R.J., S. Schrepfer, F. Cao, J.I. Pearl, X. Xie, A.J. Connolly, R.C. Robbins & J.C. Wu (2008a) “In vivo imaging of embryonic stem cells reveals patterns of survival and immune rejection following transplantation”, in: Stem Cells Dev 17(6): 10231029. Swijnenburg, R.J., S. Schrepfer, J.A. Govaert, F. Cao, K. Ransohoff, A.Y. Sheikh, M. Haddad, A.J. Connolly, M.M. Davis, R.C. Robbins & J.C. Wu (2008b) “Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts”, in: Proceedings of the National Academy of Sciences of the United States of America 105(35): 12991-12996. 105

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Tabar, V., M. Tomishima, G. Panagiotakos, S. Wakayama, J. Menon, B. Chan, E. Mizutani, G. Al-Shamy, H. Ohta, T. Wakayama & L. Studer (2008) “Therapeutic cloning in individual parkinsonian mice”, in: Nature Medicine 14(4): 379-381. Walters, L. (1988) “Ethical issues in fetal research: a look back and a look forward”, in: Clinical Research 36(3): 209-214. Weaver, F.M., K. Follett, M. Stern, K. Hur, C. Harris, W.J. Marks Jr., J. Rothlind, O. Sagher, D. Reda, C.S. Moy, R. Pahwa, K. Burchiel, P. Hogarth, E.C. Lai, J.E. Duda, K. Holloway, A. Samii, S. Horn, J. Bronstein, G. Stoner, J. Heemskerk & G.D. Huang (2009) “Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial”, in: Journal of the American Medical Association 301(1): 63-73.

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Experimenting Innovative Cell Therapies for Parkinson’s Disease: A View from Ethics ALEXANDRE MAURON & SAMIA HURST

Introduction: Mapping the Ethical Issues Parkinson’s disease (PD) is one of the commonest neurodegenerative diseases, causing enormous human suffering as well as an increasingly heavy burden for health care systems and social support networks. Given the worldwide increase in life expectancy, its prevalence is expected to rise sharply in the near future (Dorsey et al. 2007). Since established pharmacological treatments have major limitations as regards long-term use, intense efforts are underway to find innovative therapies for PD. Among these, cell therapy raises particular interest. While earlier work had explored the transplantation of foetal mesencephalic tissue with relatively promising, but controversial results (Schwarz et al. 2006), today’s research aims mainly at deriving dopaminergic neuronal progenitor cells from human embryonic stem cells (hESC), with a view to transplanting these neurons into the patient’s brain and hopefully restore nigrostriatal function on a long-term basis (Li et al. 2008). A research consortium has recently been established at the University of Geneva Medical School to link up seven research groups 1 active in basic and applied research regarding cell therapy for PD. One of the goals of this consortium is to establish a close and permanent interdisciplinary collaboration between all relevant subprojects, which 1

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include an ethics subproject managed by the present authors. For ethicists, this provides a rather unique opportunity for a direct and continuous engagement with concrete research efforts, as well as a permanent dialogue with biomedical researchers with different fields of expertise working towards a common goal. This brings a specific intellectual challenge, namely to categorize bioethical issues in terms of their direct relevance to an ongoing research endeavour, as opposed to pursuing such topics in a more academic style, i.e. following the lead of purely conceptual and systematic interests. We identified three topics that will certainly need focused attention, plus a fourth one for which we are less sure whether and how it may be pursued. These topics include ethical questions related to (1) the derivation of hESC from human early embryos, (2) neurobiological experimentation on animals, with special emphasis on research involving non-human primates, and (3) exploring the ethical prerequisites to initiating clinical studies in human subjects. The fourth topic is the purported link between neurological grafting and personality change, an issue that has been the focus of much philosophical reflection and speculation. In the following, we will not attempt a broad overview of these topics. Rather – and given that our work within the Geneva Parkinson Project is still at an early stage – we wish to identify and briefly discuss those subtopics which we believe demand more concrete attention.

T h e H u m a n E m b r yo a n d Al l T h a t Invasive experimentation on early human embryos has long energised unending controversies about the moral standing of prenatal human life. Yet these debates took a new turn during the last decade with the discovery that human embryonic stem cells could be derived from very early embryos resulting from in-vitro fertilization. The much more recent discovery of induced pluripotent stem cells (iPS), entailing as it does a realisation that pluripotentiality is not irretrievably lost during cell differentiation, has given a new lease on life to these somewhat hackneyed debates. Although we did participate in these (Mauron and Baertschi 2004; Baertschi and Mauron 2009), our objective in this project is much more practical. In Europe, philosophical discussions, religions convictions, political controversy, and compromise-building efforts as regards human embryo research interacted in a highly nationspecific manner (Mauron and Jaconi 2007). The resulting legislation and regulatory climate is fragmented accordingly and beset with problems and confusions that differ from country to country. Our aim is therefore 108

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to work out the practical consequences of the ethical and political debates in Switzerland, including the rather contradictory Swiss legislation, as they impinge on the Geneva Parkinson Project. Swiss legislation on in-vitro fertilization still reflects the mood that prevailed during the nineties, which was rather conservative and sceptical towards reproductive technology. As a result, both the Federal Constitution and the Reproductive Medicine Act of 1998 erected major barriers for human embryo research. Article 119 of the Constitution specifies that “No more human ova may be developed into embryos outside a woman’s body than are capable of being immediately implanted into her”. This not only prevents freezing of embryos for a subsequent treatment cycle but seemed at the time to legislate spare embryos out of existence. Nevertheless, it soon became clear, even to non-specialists, that spare embryos were an inescapable reality unless one outlawed invitro fertilization altogether (which was indeed favoured by some politicians). By the early years of this century, a shift of public opinion towards a more liberal stance on several bioethical issues had become 2 apparent from several nationwide votes. By 2004, the Swiss people had voted in favour of the Stem Cell Research Act, which made it legal to derive embryonic stem cells from spare embryos and to do research on them. However, earlier legislation that the new law would seem to contradict was neither abrogated nor amended. Since then, stem cell researchers and government offices struggle to cope with this perplexing situation, which is not just a legal technicality but also raises some important ethical questions. Couples are now permitted to donate embryos to research once these have become spare, i.e. are no longer needed for infertility treatment. But since cryopreservation of embryos is still illegal, this means that the decision to donate has to be made under time pressure, which may compromise the informed consent process. In fact, in the international literature, donating ‘fresh’ embryos is considered particularly troubling ethically (McLeod and Baylis 2007). However this is presently the only access to human embryos for research in Switzerland, except for the vintage frozen embryos left over from the time before the Reproductive Medicine Act was enforced. Such down-to-earth issues may be far removed from philosophically ‘interesting’ problems about the human embryo but we believe they are just as much in need of competent ethical analysis.

2

1998, rejection of a very prohibitionist regulation of genetic engineering; 2000, rejection of a bill proposing to outlaw in-vitro fertilisation and donor insemination; 2002, adoption of a more liberal abortion law.

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Non-human Primates as Experimental Models: Speciesism with a Good Conscience Animal experimentation in general has long been a focus of ethical controversy, militant struggles and political confrontation. Issues more directly relevant for the Geneva Parkinson Project are raised by the specific need for experiments on non-human primates. Although aspects of the pathophysiology of PD can be studied in rats and mice, experimentation on monkeys (usually macaques) is recognised to be an indispensable stepping stone on the road towards novel therapies for PD and other degenerative diseases of the central nervous system (European Commission 2002). Invasive experimentation on hominid apes such as chimpanzees goes against an emerging ethical consensus in Europe and a corresponding ban would probably not affect biomedical research significantly (Knight 2008). However, an extension of this ban to primates in general, including species such as macaques and marmosets, would be considerably more threatening to many aspects of biomedical research. Currently, such a prohibition is not a utopian prospect since there are targeted political efforts to move the European Union towards a phasing-out of non-human primate research leading up to a total ban. Lobbying by ‘antivivisectionists’ resulted in Written Declarations by 393 members of the European Parliament demanding an end to nonhuman primate research, with the European Commission replying in 2008 that complete replacement by alternative methods is not presently possible (RDS: Understanding Animal Research in Medicine 2008). What often makes these debates frustrating is that the scientific community and opponents of animal research (including academic ethicists arguing for the ‘anti-speciesist’ position) largely talk past each other. On the one hand, scientists argue from the practical need for primate research to advance biomedical research and meet the rightful demand of patients and future patients for therapeutic progress. On the other hand, academics and activists opposed to primate experimentation advance utilitarian arguments mandating equal consideration of interests of all sentient beings, especially as to the avoidance of suffering (Singer 2002), or in the more radical cases invoke a concept of animal rights (Regan 2004), to oppose such research. So it would seem that practical considerations are pitted against ethical principles, and that the ethical high ground is left by scientists to their opponents. This impression is strengthened by the powerful rhetoric of ‘speciesism’, i.e. the purportedly unjustified elevated status given to Homo sapiens over other sentient species in animal experimentation, farming, and other uses of animal life for human purposes. This puts the scientific community on the de110

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fensive, since it would seem to place the ‘anti-speciesist’ fight against discrimination of non-human sentient animals on the same moral footing as unanimously approved struggles against racism and sexism, and seems to make the former as morally imperative as the latter (Ryder 1989). We believe that the biomedical science community should not be content to explain the need for primate research, but should confront the ethical issues head-on. This means that the arguments of anti-speciesists should be analysed thoroughly and answered convincingly. In a nutshell, the basic ethical issue is this: biomedical research avails itself of the resemblance between human biology and that of experimental animals. For any given biological question, a short ‘translational distance’ between animal and human is what makes an animal model valuable. Yet the closer a given animal model is to human functioning as regards susceptibility to pain and cognitive abilities, the more troubling the ethical question of animal use becomes. As regards higher brain function, a short translational distance – such as makes primate research valuable in the first place – becomes a close normative proximity and thus it exacerbates the basic ethical paradox of animal experimentation. One might retort that proximity becomes identity in human subjects research, but with humans the crucial difference is that informed consent is possible. A human can give or refuse consent, so that were all other things truly equal, one ought to experiment less on animals than on humans! And then, as Regan pointed out, why should animals sympathize with the cause of human medicine and be pressed into the service of human needs? These are important arguments but they are not without flaws, which will be discussed briefly here. The anti-speciesist stance posits equality between humans and animals, modulated by the strength of specific interests. But from Bentham to Singer, anti-speciesists have been highly selective in choosing features for which a comparison between humans and animals actually makes sense. If one takes the benthamite tack and emphasises sentience and the capacity to suffer, defenders of animal experimentation may then point to the many human interests that are promoted by animal experimentation and have no animal equivalent, such as forestalling death, planning ahead for a life in good health, providing equitable access to the means to a high quality of life, etc. Moreover, if informed consent is a rightmaking feature of human experimentation, it is so because humans have an interest in having their autonomy rights respected, an interest animals cannot have since they have no such rights. Taking these specifically human interests seriously reintroduces a hierarchy that puts human above non-human animals. The more ambitious strategy of the ‘animal 111

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rights’ approach would seem more promising in sustaining a strict egalitarian stance between humans and non-humans. One could ground animal rights in their inherent worth (or ‘dignity’, to use the language of the Swiss Animal Protection Act of 2005). The problem here is that ascription of inherent worth is heavy with metaphysical presuppositions, at least if it is supposed to do for animals what human dignity does to basic human rights. What does the work here is a matter of belief in the quasi religious meaning of the word, rather than a conclusion that would pass muster in a liberal democracy. Finally there is the question of why animals should sympathize with sick humans. Indeed, but why should humans sympathize with sick animals? Or healthy ones, for that matter? Speciesism can be critiqued as a form of moral solipsism, as in Singer’s vision of the ‘expanding circle’, but that does not amount to a refutation. After all, humans do make efforts to be moral, animals usually do not. Human feel guilty for actions for which non-human carnivores go scotfree. To put it provocatively, trying to be moral is a curse that befalls humans exclusively. Is that fair? At the end of the day, strict equality founders on the realization that being a moral agent, and not a mere moral object, has to count. We have presented elsewhere a concept of a ‘higher’ moral status that might be shared by humans and some other animals on the basis of inter-species altruism (Hurst and Mauron 2009). This results in a defensible conception of a two-tiered animal ethic. The first tier is based on sentience and aims at preventing animal suffering and promoting animal welfare in a way that is compatible with extensive animal research. The second, ‘higher’ tier, focuses on the proto-moral abilities of some animals increasingly evidenced by primatologists (De Waal 1997). It points to a (necessarily partial) symmetry between active and passive moral subjects and would presumably justify much stricter restrictions on invasive experimentation on some primates, or in some cases a downright ban. This ethical framework makes no claim to be non-speciesist however, nor do we feel that it has to.

F i r s t - i n - h u m a n T r i a l s : w h e n a n d h ow As regards both topics presented so far, our aim is to move from an extensively researched general theme to specific ethical guidance relevant to a particular biomedical research project. The question of translating pre-clinical research to the clinical setting is rather different and will necessitate more ‘basic’ bioethical analysis. Obviously, there is a vast bioethical literature and a detailed regulatory environment for human subject research generally. However, this framework is largely 112

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geared towards testing new molecules in the context of drug development. It does not readily fit other scenarios of first-in-human experiments for device implantation or cellular therapeutics, such as those involving the transplantation of stem cell-derived dopaminergic progenitors into the human brain. In the case of early phases of this research involving transplantation of foetal tissue, specific points such as the link between foetal tissue transplantation and abortion did generate some ethical commentary and guidelines at the time (Boer 1994; Bopp and Burtchaell 1988). There was, however, no systematic development of a comprehensive ethical framework on either the prerequisites or the form of first-in-human studies. The central issues in first-in-human studies of cell therapy for PD will thus have to be identified, both as regards pre-clinical requirements authorizing the passage to human trials, and the design of these human trials themselves. Ethical issues related to the decision to start enrolling human subjects include (1) minimizing risks, which implies first reaching sufficient control and knowledge of the risks to human subjects through the preclinical phases of testing, and (2) assessing the social value of the planned research with human subjects. Criteria to identify the stage at which inclusion of human subjects can begin have been well defined in drug testing, and described in documents defining Good Laboratory Practice (GLP) required for example to apply for a New Drug Application with the US FDA (FDA 1998). These criteria include the results of both in-vitro and in-vivo tests, with the purpose of assessing an experimental drug’s effect on target organs, pharmacokinetics and – dynamics, toxicity including any term carcinogenicity or teratogenicity, and the identification of the No Observable Effect Level (NOEL) that will serve as a basis for calculation of the first doses administered to humans. Pre-clinical tests include animal studies, which are typically required to include at least two species, the choice of which is based on obtaining the best possible correlation to human trials. Translational distance – the degree of interspecies differences in key absorption, metabolic, or target systems and organs with humans – is a crucial element here. Although these criteria are well established, they presume the paradigm of drug development and are only partially applicable to cell therapy. Defining when risks are sufficiently understood and controllable will require the development of new benchmarks in close collaboration with both pre-clinical and clinical researchers. Assessment of the social value of first-in-human testing also raises distinct difficulties in tests other than drug studies, such as the 113

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transplantation of a specific cell type. The usual framework to assess social value presumes broad applicability of the tested therapy through industrial production of the study drug. First-in-human studies of dopaminergic progenitor cell transplantation would be different in at least two ways. Firstly, they would constitute a form of transplantation; a technique which can be learned and taught, and therefore broadly used once established, but which shares at least as much with the surgical as with the medical therapy paradigm (this distinguishes cell therapy not only from drug-based therapy but also from treatment with biologics that rely on biotechnology for their production). Discrepancies between surgical research and the more usual paradigm of drug development have been pointed out in surgery already, and these distinctions may be relevant here also (Biffl et al. 2008; Reitsma and Moreno 2003). Secondly, the degree to which results may be generalized across stem cell lines is still an open question. It is possible that part of the process of bringing an experimental therapy to human studies may have to be renewed for each different line. Whether this must be the case is, however, an empirical question at least partly amenable to experimentation prior to the first human study. Addressing the social value of firstin-human transplantation of dopaminergic progenitor cells will thus also require close collaboration between laboratory scientists and ethicists, as well as the inclusion of clinical researchers in the design of pre-clinical experiments. Regarding ethical issues in study design, considerable attention has focused on the ethics of phase I (Agrawal and Emanuel 2003) and more recently phase 0, (Abdoler et al. 2008; Kimmelman 2007) clinical studies, but this too has followed the drug development paradigm. Therefore, we will have to rethink these issues as applied to cellular transplantation, with reference to the general framework for the protection of human subjects of research. A synthesis of requirements for ethically justifiable research found in existing codes and regulations describes seven principles universally applicable to ethical clinical research. These principles include social value, scientific validity, fair subject selection, favourable risk/benefit ratio, independent review, informed consent and respect for enrolled participants (Emanuel et al. 2000). Applying these principles to first-in-human studies of dopaminergic progenitor cells developed within this project allows the identification of some of the specific challenges posed in testing this therapeutic approach. These will include: • Risk minimization for human subjects (Grady 2004; Shamoo and Resnik 2006), in relation with the biological properties of the cells, of the site of transplantation, and of the surgery as such. 114

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• •

•

Subject selection and the protection of vulnerable persons in the context of a disease which can alter cognition (Warner and Nomani 2008). Obtaining sufficiently informed consent for a complex procedure, (Cox et al. 2006) as well as understanding that the aim of the study is to gain knowledge (Wendler and Grady 2008). The therapeutic misconception, or the mistaken expectation that the primary aim of research is the personal interest of the individual subject (Henderson et al. 2007), can be expected to be especially strong with an intervention which would simultaneously be invasive, technologically very innovative, and possibly a last chance for patients for whom previous therapy has failed. Complex issues related to the possible need of a sham surgery placebo control (Horng and Miller 2003).

While each of these aspects has received some attention, most have not been specifically developed to the point of applicability to CNS stem cell-derived cellular transplantation.

Ontological Quandaries: Do They Matter? Does intracerebral cell transplantation of live cells, as contemplated in this as well as in many other cell therapy approaches of neurological diseases, alter personal identity? If it does, is that a bad thing? This is the question that is closest to the general theme of this book. In keeping with our practice-oriented outlook, we will not attempt a systematic treatment of this fascinating philosophical problem, and other contributors examine it in much more detail. Rather, we will ask a much more limited question. Suppose one can realistically anticipate something like deep ontological effects on the recipient of intracerebral cell transplants: do these effects raise an ethical issue that is conceptually distinct from the more ordinary ethical considerations of benefits and harms in humans subjects research? Although the debate harks back to several strands of reflection within the philosophy of mind, as well as to Parfit’s influential philosophical dissection of personal identity, as a public controversy in central European countries, it seems to have started in the early nineties in connection with the ‘Decade of the Brain’. A German neurologist, D.B. Linke, wrote a popular book opposing neural cell grafting, arguing forcefully that any introduction of foreign cells into the human brain amounts to a change in personal identity and is ethically suspect on that 115

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account (Linke 1993). Further examination of underlying premises in this debate soon showed that proponents and opponents of intracerebral transplants sometimes share, and sometimes differ, in their underlying ontological assumptions (Northoff 1996). Generally speaking, there seem to be divergent presuppositions at two levels: • What is the appropriate definition of personal identity? • How does intracerebral transplantation impinge on personal identity, however defined? Personal identity is traditionally conceived as the numerical identity of persons (Audi 1999). This is an all-or-none property, either it is changed by some intervention or it is not. Either the person on the receiving end of an intervention remains the same person or she becomes someone else. Alternatively, personal identity can be defined in terms of a bundle of stable qualities that a given person possesses. This brings us close to the psychological notion of personality, which comprises different dimensions, all of which can be assessed as more or less central or peripheral to what a particular person is ‘really’ like and which admit of change by degrees. One should also note that neither numerical identity nor personality correspond to qualitative identity, which is the relational property of exact similarity and which is not relevant in the present context (Ferret 1998). Equipped with these notions, we can now ask what the notion of change amounts to as regards personal identity. We have seen that numerical identity refers to ‘sameness’ in the strongest possible sense. Therefore, ‘changing numerical identity’ would mean that someone ceases to exist, someone else is brought into existence, and there is some sort of connection between the two events. On the other hand, for it to be at all useful, the concept of numerical identity has to be quite tolerant to ‘non-essential’ change, such as happens in the course of someone’s life. We would want to say, reasonably enough, that the 14th Dalaï Lama Tenzin Gyatso alive today is the same person, i.e. has the same numerical identity, as one Lhamo Dhondrub who was born in 1935 in north-eastern Tibet and was officially declared to be the new Dalaï Lama in 1940. Perhaps a change in numerical identity occurred when the 13th Dalaï Lama died and was reincarnated in the present Dalaï Lama. Or perhaps not (the analysis of Buddhist theology in terms of elementary concepts of Western metaphysics is a regrettably underresearched subject). If we now go back to the question whether cell transplantation in the brain changes personality while keeping our focus on numerical identity, the question becomes the following: is 116

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intracerebral transplantation the sort of intervention of which numerical identity is tolerant? There may well be disagreements on this, on account of conceptual disagreements about numerical identity and divergent assumptions related to the philosophy of mind. For instance, for an identity theorist as regards the mind-brain problem, the consequences of neural grafting are quite possibly compatible with the preservation of numerical identity. If “I am my brain” (as Thomas Nagel famously said), then the numerical identity of persons is the numerical identity of brains. As long as a particular brain can be said to be the same brain through time, no change in numerical identity has occurred, even with massive interventions. But then, the identity theorist could just as well claim that even a minimal transplant makes the recipient’s brain “no longer the same brain”. This conundrum hinges upon what quality or quantity of change counts as ‘real change’ for numerical identity, no matter whether it is change in the identity of persons or of brains; quite possibly, we are actually less sure of what constitutes ‘essential’ change in a brain than in a person. Perhaps interpreting the question of change in terms of personality instead of numerical identity is more promising. As explained earlier, personal identity understood as personality refers to a bundle of relatively stable characteristics of a person. ‘Changing personality’ means that the selfsame person persists in existence but has undergone some significant change in important aspects of character, habitual behaviour, and the like. Consider the classical neuroscience icon Phineas Gage. A foreman on a railroad construction site in Vermont in 1848, Gage had a tamping iron blown through his head while preparing a charge of black powder that exploded prematurely. Although this is controversial to this day, Gage probably suffered extensive damage involving the left frontal lobe. He recovered without noticeable neurological symptoms but displayed extensive changes in character. Formerly described as an intelligent, even-headed and shrewd businessman, he became “fitful, irreverent, and grossly profane, showing little deference for his fellows. […]. His friends said he was ‘No longer Gage’” (Macmillan 2006). Obviously, he was still Gage numerically speaking, but his personality had undergone massive changes for the worse. In the case of Phineas Gage, then, we have a clear example where change in the structure of the brain did indeed result in what we might call a ‘real change’. But was this change fundamentally different from other sorts of harms? The question can now be formulated thus: Was Gage harmed by the change qua change, or by the fact that this change left him diminished in his social competence and his ability to make 117

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evaluative judgments? Let us imagine some fanciful brain transplant that would have restored a functional frontal cortex to Phineas Gage, such that he would have been restored back to his old self. Would Gage have suffered an additional harm because he underwent a second change, or would we not rather say that the initial harm was corrected by the transplant? It seems fairly obvious that the second change induced by the futuristic treatment must be seen as a benefit. Changes to the brain can be bad, such as those who affected Gage on account of his accident; they can be good, as is presumably the case for successful neurological or psychiatric treatment. We are back to square one, i.e. to the ordinary ethical valuation of benefits and harms caused by innovative treatment. There is no point in setting the brain radically apart from other organs, when it comes to assessing the ethics of therapeutic interventions. To sum up, in the context of intracerebral grafting, the concept of numerical identity has some limited utility, in the sense of showing that change is possible. Yet while interpreting personal identity as numerical identity of persons is theoretically correct, it turns out to be unhelpful since it would seem to drown us into a morass of unclear distinctions between ‘essential’ and ‘accidental’ properties of persons and/or brains. Therefore, it is probably more to the point to ask whether intracerebral transplantation alters personality in the psychological sense. Cell therapy for PD could well change the patient’s personality, especially considering the undesirable psychological alterations that are often associated with advanced PD itself. This aspect of cell therapy could even be a good thing, if the alterations caused by PD could be attenuated or reversed. Changing personality as the side effect or even the main purpose of brain interventions is not bad a priori. Therefore, the ethical question is not whether this treatment changes personal identity (however defined) but whether it does more good than harm. In other words, there is no separate ‘identity based’ ethical argument, distinct from the ordinary ‘health-and-well-being based’ ethical argument.

Final Note Our aim in this paper was to provide an overview of ethical issues that are of direct relevance to Geneva Parkinson Project researchers working on the development of a future stem cell based treatment of PD. We also believe that many of these considerations are more generally relevant to biomedical research on degenerative diseases of the central nervous system. In addition, we exemplify a way of working on bioethical issues 118

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that differs from their more traditional academic treatment. Each of the four topics we have touched upon here are classically considered separate subjects of bioethical analysis and debate, with a specific literature and a tradition of research that is mostly driven by intrinsic philosophical interest. In comparison, our treatment of these problems is unavoidably sketchy, but the need for direct relevance to a particular research project enables greater integration across these questions. There is still a long way to go in order to make bioethics a truly applied discipline, and we hope our work can be a contribution to that goal.

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References Abdoler, E., H. Taylor & D. Wendler (2008) “The ethics of phase 0 oncology trials”, in: Clin Cancer Res 14/12 (Jun 15): 3692-3697. Agrawal, M. & E.J. Emanuel (2003) “Ethics of phase 1 oncology studies: reexamining the arguments and data”, in: JAMA 290/8 (Aug 27): 1075-1082. Audi, R. (ed.) (1999) The Cambridge Dictionary of Philosophy (Cambridge: Cambridge University Press) s.v. ‘Personal identity’. Baertschi, B. & A. Mauron (2010) “Moral status revisited. The challenge of reversed potency”, in: Bioethics, Feb; 24(2): 96-103. Epub Dec 5, 2009. Biffl, W.L., D.A. Spain, A.M. Reitsma, R.M. Minter, J. Upperman, M. Wilson, R. Adams, E.B. Goldman, P. Angelos, T. Krummel & L.J. Greenfield (2008) “Responsible development and application of surgical innovations: a position statement of the Society of University Surgeons”, in: J Am Coll Surg 206/3 (Jun): 1204-9. Boer, G.J. (1994) “Ethical guidelines for the use of human embryonic or fetal tissue for experimental and clinical neurotransplantation and research. Network of European CNS Transplantation and Restoration (NECTAR)”, in: J. Neurol. 242/1 (Dec): 1-13. Bopp, J. & J.T. Burtchaell (1988) “Human fetal tissue transplantation panel: statement of dissent”, in “Report of the human fetal tissue transplantation panel”, I: 45-71. Cox, A.C., L.J. Fallowfield & V.A. Jenkins (2006) “Communication and informed consent in phase 1 Trials: a review of the literature”, in: Support Care Cancer 14/4 (Jan 28): 303-309. De Waal, F. (1997) Good natured: the origins of right and wrong in humans and other animals (Boston: Harvard University Press). Dorsey, E.R., R. Constantinescu, J.P. Thompson, K.M. Biglan, R.G. Holloway, K. Kieburtz, F.J. Marshall, B.M. Ravina, G. Schifitto, A. Siderowf & C.M. Tanner (2007) “Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030”, in: Neurology 68/5 (Jan 30): 384-386. Emanuel, E.J., D. Wendler & C. Grady (2000) “What makes clinical research ethical?”, in: JAMA 283/20 (May 24-31): 2701-2711. European Commission Scientific Steering Committee (2002) “The need for non-human primates in biomedical research”. http://ec.europa.eu/food/fs/sc/ssc/out253_en.pdf/. Accessed Feb 12, 2009. FDA (1998) CDER Handbook. Requirements: pre-clinical research. Ferret, S. (1998) L’identité (Paris: Flammarion). 120

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Grady, C. (2004) “Ethics of vaccine research”, in: Nat Immunol 5/5 (May): 465-468. Henderson, G.E., L.R. Churchill, A.M. Davis, M.M. Easter, C. Grady, S. Joffe, N. Kass, N.M. King, C.W. Lidz, F.G. Miller, D.K. Nelson, J. Peppercorn, B.B. Rothschild, P. Sankar, B.S. Wilfond & C.R. Zimmer (2007) “Clinical trials and medical care: defining the therapeutic misconception”, in: PLoS Med 4/11 (Nov 27): e324. Horng, S. & F.G. Miller (2003) “Ethical framework for the use of sham procedures in clinical trials”, in: Crit Care Med 31/3 Suppl (Mar): S126-130. Hurst, S.A. & A. Mauron (2009) “Articulating the balance of interests between humans and other animals”, in: American Journal of Bioethics 9/5: 17-19. Kimmelman, J. (2007) “Ethics at phase 0: clarifying the issues”, in: J Law Med Ethics 35/4 (Winter): 727-733, 514. Knight, A.D. (2008) “The beginning of the end for chimpanzee experiments?”, in: Philos Ethics Humanit Med 3/1 (Jun 2): 16. Li, J.Y., N.S. Christophersen, V. Hall, D. Soulet & P. Brundin (2008) “Critical issues of clinical human embryonic stem cell therapy for brain repair”, in: Trends Neurosci 31/3 (Mar): 146-153. Linke, D.B. (1993) Hirnverpflanzung. Die neue Unsterblichkeit auf Erden (Hamburg: Rowohlt). Macmillan, M (2006) “The Phineas Gage Information Page” (Victoria, Australia: Deakin University) http://www.deakin.edu.au/hmnbs/psychology/gagepage/. Accessed Feb 10, 2009. Mauron, A. & B. Baertschi (2004) “The European embryonic stemcell debate and the difficulties of embryological Kantianism”, in: J Med Philos 29/5 (Oct): 563-581. Mauron, A. & M.E. Jaconi (2007) “Stem cell science: current ethical and policy issues”, in: Clin Pharmacol Ther 82/3 (Sep): 330-333. McLeod, C. & F. Baylis (2007) “Donating fresh versus frozen embryos to stem cell research: in whose interests?”, in: Bioethics 21/9 (Nov): 465-477. Northoff, G. (1996) “Do brain tissue transplants alter personal identity? Inadequacies of some ‘standard’ arguments”, in: J. Med. Ethics 22/3: 174-180.

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RDS: Understanding animal research in medicine (2008) “The importance of non-human primate research in the EU”. http://www.rds-online.org.uk/pages/page.asp?iToolbarID=5&i_ PageID=2712. Accessed Feb 10, 2009. Regan, T. (2004) The case for animal rights (Berkeley: University of California press). Reitsma, A.M. & J.D. Moreno (2003) “Surgical research, an elusive entity”, in: Am J Bioeth 3/4 (Autumn): 49-50. Ryder, R.D. (1989) Animal revolution: changing attitudes towards speciesism (Oxford, UK; Cambridge, MA, USA: B. Blackwell). Schwarz, J., S.C. Schwarz & A. Storch (2006) “Developmental perspectives on human midbrain-derived neural stem cells”, in: Neurodegener Dis 3/1-2: 45-49. Shamoo, A.E. & D.B. Resnik (2006) “Strategies to minimize risks and exploitation in phase one trials on healthy subjects”, in: Am J Bioeth 6/3 (May-Jun): W1-13. Singer, Peter (2002) Animal liberation (New York: Ecco). Warner, J. & E. Nomani (2008) “Giving consent in dementia research”, in: Lancet 372/9634 (Jul 19): 183-185. Wendler, D. & C. Grady (2008) “What should research participants understand to understand they are participants in research?”, in: Bioethics 22/4 (May): 203-208.

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Coping a nd Ex pe ctations of Patie nts w ith Am yotrophic La tera l Sc leros is MIRJAM RUPP, PAULA BUDDE, HEINER FANGERAU, MARTIN TEGENTHOFF & TORSTEN GREHL

Ab s t r a c t A cooperative research project between the University of Düsseldorf and the Neurology Clinic at the University Clinic Bergmannsheil Bochum, investigated the question of how patients and their relatives cope with an incurable and progressively advancing illness, using Amyotrophic Lateral Sclerosis (ALS) as an illustrative example. ALS is an age-related neurodegenerative disease marked by damage to specific cells of the central nervous system, namely motor neurons. At present the illness is fatal, as there is no causal therapy available; only symptomatic characteristics can be treated. Since this disorder is virtually untreatable, the question of what hopes and expectations are held by patients and their relatives is of interest to clinicians. Here we present the psychological constitution, the quality of life, the way in which the disease is handled and the attitude toward alternative therapeutic interventions of people affected with ALS. We hope to shed some light on the question whether patients perceive especially intra-cerebral interventions as an option for future cure or whether they put their hopes in similar futuristic, sciencefictional therapies. Preliminary results suggest that investigatory interventions are not at the forefront of a patient’s consciousness.

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Introduction Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder of unclear etiology. The pathogenesis of the disease is also not yet entirely understood. Neurodegeneration in ALS patients occurs virtually exclusively in the motor neurons of the motor cortex and brain stem as well as in the anterior horns of the spinal column. The disorder generally progresses quickly with fatality after an average of three years post diagnosis. Typical symptoms include motor deficits with atrophic paresis and increased muscle reflexes or spasticity. However, the development and clinical manifestation of the disease varies greatly between individuals. Atrophic paresis of one extremity is an initial clinical manifestation of approximately 80% of patients with ALS. Approximately 20% of patients primarily describe a bulbar symptomatology characterized by speech and swallowing disorders. Accompanying symptoms may include pathological laughing and crying, psychological disorders and cognitive deficits. The global prevalence of ALS is about 3-8 cases per 100,000, while the incidence of the disease is about 1-4 cases per 100,000. The disease most commonly affects people in the sixth to eighth decade of life. The sporadic form of ALS (SALS) accounts for the majority of cases while the familial form (FALS) accounts for about 10% of cases. SALS and FALS cannot be clinically differentiated. There is no causal therapy in the treatment of ALS. The goal of current therapies focuses on the quality and prolongment of life. An increasing insufficiency of the pulmonary muscles is most often the ultimate cause of death. While ALS patients maintain hope of a therapy that will cure or at least stop the progression of the disease, physicians must explain the limitations of modern treatment being offered. Because there is a disparity between patient expectations and therapeutic reality the question of how patients cope with their diagnosis and prognosis is of interest. In addition, patient knowledge of, or interest in investigational intervention possibilities such as stem cell therapy or Deep Brain Stimulation (DBS) is of consequence. One goal of the current research therefore, is to clarify the type of information that may be useful to ALS patients upon diagnosis. With the clarification of this issue, we hope to contribute to the improvement of clinical advice given to patients with ALS and also to provide general encouragement in the implementation of new (investigational) and promising forms of therapy. Lastly, the question of the extent to which hope in new therapies can positively influence the life quality of patients suffering from fatal illnesses is of relevance. 124

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B r i e f O ve r v i ew o f t h e C u r r e n t S t a t e o f R e s e a r c h There has been much investigation concerning the affective condition of ALS patients. However, the results of these studies are conflicting. For example, some studies have shown an increase in depressive symptomatology among ALS patients (Kuebler et al. 2005), while others have shown only minimal or no depressive symptoms present in patients suffering from ALS (Rabkin et al. 2005). Most studies agree, however, that quality of life among ALS victims is not necessarily correlated with the extent of physical limitations (Goldstein et al. 2002; Robbins et al. 2001). In addition, Lule et al. (2008) concluded that the quality of life of ALS patients does not significantly vary from that of healthy control subjects. While most prior studies have focused on the areas of depression and quality of life in ALS patients, few inquiries have been made about the way in which patients and their families cope with the illness. The researchers who have addressed the issue of coping have used openended questionnaires. For example, in response to the question of who or what can ease the burden caused by ALS, patients stated that family and non-specific mechanisms such as positive thinking, along with various technical aids are useful (Hecht et al. 2002). In another study using open-ended questions (Young and McNicoll 1998), patients stated that cognitive and intellectual stimulation were instrumental in coping with the illness. To date, only one study has investigated the role of alternative therapy as a coping mechanism (Wasner et al. 2001). This report found that out of a group of 171 patients with ALS, 92 patients reported the regular use of complementary or alternative medicine (CAM). The most common therapies reported were acupuncture (47%) and homeopathy (40%), followed by naturopathy (24%) and esoteric treatment (20%).

O b j e c t i ve Based on the results of the study by Wasner et al. (2001), we investigated the coping mechanisms used by patients with ALS. In particular, we were interested in what forms of coping are used and how patients evaluate quality of life if depression is present. In addition, how knowledge of new or alternative therapies affects the ALS patient and his/her family was considered.

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Methods The ALS depression inventory (ADI-12) (Kuebler et al. 2005) was used to measure depressive symptoms. This 12-item instrument provides a one dimensional construct (“mood, anhedonia, energy”) that assesses the presence or absence of depressive symptoms. Scores can range between 12 (no sign of depressive symptoms) and 48 (highest level of depression). The FKV-15 (Hardt et al. 2003), a shortened version of the Freiburg questionnaire (FKV) (Muthny 1986) was used to assess coping skills. The FKV-15 consists of 15 items, categorized into five scales: active handling, depressive handling, distraction, minimization and compliance. Quality of life was assessed with the Munich List of Quality-of-Life Dimensions (MLDL) (Von Steinbüchel et al. 1999). The MLDL measures satisfaction with the quality of life in psychic, physical, social and behavioral areas. The 19 item instrument is divided into four subscales (psyche, body, everyday life and social life), and includes an overlying assessment of “life in general”. Patient hope was assessed with questions on the expected probability that a cure for ALS will be developed and the expectation that the patient would benefit from such a therapy. (Hammelstein and Roth 2002). Therefore, hope was measured as a condition or as an emotion of positive expectations. In addition to the implementation of the 3 instruments described above (ADI-12, FKV-15, MLDL) and the assessment of hope, data on which therapeutic methods of treatment the patients were currently using or had used in the past and what they expected from the use of the treatment was also collected.

Results Participants A total of 47 patients (27 males, 20 females) and 40 family members answered the questionnaires between March, 2008 and January, 2009. The patients were between 28 and 78 years of age (mean = 58.57; SD = 12.02). The majority of the patients were married or in a relationship (n = 38; 80.9%). The majority of patients (n = 39; 84.4%) came to the study with a companion (32 attended with a partner or spouse, and seven came with a son or daughter). At the time of questioning, 37 (80.4%) of 126

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the patients were taking the glutamate blocker, Rilutec. The score of the ALS-FRS (functional rating scale) for participants was between 13 and 45 (mean = 36.74; SD = 8.06).

Quantitative Results1 Depressive symptomatology was assessed through the ADI-12. The participants (n = 45) scored a mean value of 23.42 (SD = 5.96; range = 13 to 34) with 11 (24.4%) patients scoring above 28, a score indicating a clinically relevant depression (Kuebler et al. 2005). Coping with ALS was evaluated by the FKV-15. Our results indicate that active coping, distraction and compliance were the coping mechanisms most often used (Figure 1).

Average Value

Figure 1: Coping as measured by the FKV-15 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0

3,51 2,36

Active coping (SD=.79; n=47)

1

3,97

3,67

2,47

Depressive Distraction Minimization Compliance coping (SD=.86; (SD=.89; (SD=.85; (SD=.65; n=45) n=47) n=47) n=45)

Not all patients were able to fill out all questionnaires and some participants did not answer individual items on a questionnaire. The number of responses for each questionnaire therefore varies.

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Life quality was assessed by the MLDL (Figure 2). The patients were most satisfied with their social life, followed by everyday life. The mean response to the question of life satisfaction (0 = very unsatisfied to 10 = very satisfied), was 7.21 (SD = 2.60, n = 43). Figure 2: Quality of life as measured with the MLDL 9 7,87

8

Average Value

7

6,51

6,81 6,19

6 5 4 3 2 1 0 Psyche (SD 2.45; n=42)

Body (SD=1.92; Every day life Social life n=42) (SD=2.31; n=40) (SD=2.2, n=42)

The estimated probability of an effective therapy as well as the expectation of personal use of this therapy was measured in 13 patients with a visual analog scale. The following questions were rated on a scale from 1 to 10 (1 = very unlikely, 10 = very likely): “I think that it is (probability) that there will be an effective therapy against currently untreatable and progressive neurological disorders within the next five years” and “I think that it is (probability of affiliation) that I will be one of the people that can profit from such a therapy”. The mean value obtained from the question concerning effective therapy was 6.48 (SD = 3.74) and the mean value obtained concerning affiliation was 6.69 (SD = 2.83). A paired t-test for between the two variables was not significant.

Qualitative Results During a consultation with a psychologist, patients (n = 41) were posed various open-ended questions. Two questions concerned therapeutic methods (“What do you personally use?”) and the expected result (“What result do you expect?”). At the time of questioning, 11 patients 128

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(26.8%) were in ergo-therapeutic treatment, 16 patients (39%) were involved in logopedic treatment and 28 patients (68.3%) used physiotherapy or pursued various sports activities (e.g. cycling, multiple answers possible). The patients also listed treatment by a traditional healer, the use of homeopathy, stochastic resonance therapy, traditional Chinese medicine and acupuncture or the use of horvi enzyme crolatus (snake venom), various tea mixtures and the alteration of nutritional habits to an alkaline diet. In response to expected results (multiple answers possible), 22 patients hoped to prolong life, and 6 hoped to slow the progression of symptoms. One patient answered: “I would be happy if it could be stopped, but it continues to progress”, one patient hoped for healing, maintenance of current abilities and life quality or an improvement in eating or speaking, while 2 patients did not hope for any results. None of the questioned participants asked about or commented on current stem cell therapy or deep brain stimulation.

Discussion According to the results of the ADI-12, nearly 25% of the patients had a clinically relevant depression. This result is in agreement with other studies, such as Lule et al. (2008) finding that the minority of ALS patients are affected by depression. However, other studies (e.g. Kübler et al. 2005) found a higher rate of depression among ALS patients. The cause for the different results in various research groups may be attributed to the measuring instruments used. In the paper from Kübler et al is a direct comparison between ADI and BDI, and with the BDI they found higher rates of depression. The BDI for instance, may be influenced by the physical symptoms of ALS. For example, item D of the BDI which asks the patient to rate the statement, “I can enjoy things as I did in the past” may be negatively answered by ALS patients, since they are physically impaired in the performance of previously enjoyable activities, which could be incorrectly understood as an indication of depression. Physical limitations therefore, can be a confounding variable and misconstrued as depression in ALS patients. Active coping, distraction and compliance were used more often than other coping methods. A high score on the active coping scale indicates a problem based strategy characterized by the search for information and personal actions. The distraction and compliance scales

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consist of just two items each, which allows limited room for interpretation.2 It is difficult to compare the quality of life of ALS patients in our study with the quality of life of other populations since we did not test healthy controls. However, a comparison between the MLDL results of the ALS patients in the current study with quality of life scales used in other studies, suggest that ALS patients consider their life quality worse than healthy controls but better than patients with a brain tumor (Von Steinbüchel et al. 1999). The assumption that the perceived life quality is low with such a serious illness as ALS cannot be confirmed with our results. There was no significant difference between the perceived probability that a curable therapy will be developed and the perceived probability of affiliation with a group that would benefit from such treatment. However, the expected probability of benefiting from treatment was higher than the perceived probability of such treatment being developed. According to Hammelstein and Roth (2002), these results indicate a great amount of hope. While our results did not provide significance, this issue should be further studied. Interviews with a psychologist indicated that patients use alternative (e.g. traditional healer) as well as complementary (e.g. ergotherapy, logotherapy) therapies. The psychological interview indicated that some patients were interested in new, investigational methods of treatment such as lithium. Prior studies have investigated the correlation between the effects of treatment and expectations of ALS- patients (Wasner et al. 2001). The results indicated that the less the patient expected, the greater the results and the higher the subjective benefit. Therefore it is reasonable to suggest that patients realize an enhancement in wellness regardless of objective improvement of symptoms and attribute this enhancement to the treatment. While it is a challenge to provide hope to patients suffering from ALS, it is necessary to speak openly about treatment options. Questions concerning therapeutic possibilities should be answered honestly so that the patient does not develop expectations that cannot be realized. It is also important to identify the financial burden which can occur from the use of untested or insufficiently tested methods of treatment. Attention should also be taken to realize that hope can have an important impact on the quality of life for ALS patients and thus clinicians should 2

Nevertheless, there are only few alternative scales. In a further study to be published we used the FKV.

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emphasize treatment of the accompanying symptoms of the disorder (e.g. salivation and pathologic laughing or crying) which can be reduced. There are many areas of research in the treatment of ALS still open to investigation. The patients participating in this study were able to visit the consultation and thus, were generally not in the last stages of the illness. For this reason, a generalization of the results to all stages of ALS is not possible. Future studies should focus different stages of ALS and put an emphasis on the topic of hope. Ways in which the ALS patient can remain hopeful despite their diagnosis and prognosis should be addressed. In addition, future research should investigate the effects alternative or complementary treatment methods can have on ALS patients, not only on physical symptoms but also in psycho-social areas (e.g. life quality).

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References Goldstein, L.H., L. Atkins & P.N. Leigh (2002) “Correlates of quality of life in people with motor neuron disease (MND)”, in: Amyotroph Lateral Scler Other Motor Neuron Disord 3(3): 123-129. Hammelstein, P. & M. Roth (2002) „Hoffnung – Grundzüge und Perspektiven eines vernachlässigten Konzeptes“, in: Zeitschrift für Differentielle und Diagnostische Psychologie 23 (2): 191-203. Hardt, J. et al. (2003) „Was misst der FKV? Eine Überprüfung des Freiburger Fragebogens zur Krankheitsverarbeitung bei Patienten mit unterschiedlichen Erkrankungen“, in: Zeitschrift für Klinische Psychologie und Psychotherapie 32 (1): 41-50. Hecht, M. et al. (2002) “Subjective experience and coping in ALS”, in: Amyotroph Lateral Scler Other Motor Neuron Disord 3(4): 225-232. Kuebler, A. et al. (2005) „Das ALS-Depressionsinventar (ADI): Ein Fragebogen zur Messung von Depression bei degenerativen neurologischen Erkrankungen (Amyotrophe Lateralsklerose)“, in: Zeitschrift für Klinische Psychologie und Psychotherapie 34(1): 1926. Kuebler, A., S. Winter, A.C. Ludolph, M. Hautzinger & N. Bierbaumer (2005) “Severity of depressive symptoms and quality of life in patients with amyotrophic lateral sclerosis”, in: Neurorehabil Neural Repair, 19: 182-193. Lule, D. et al. (2008) „Depression und Lebensqualität bei Patienten mit amyotropher Lateralsklerose“, in: Deutsches Ärzteblatt, 105(23): 397-403. Muthny, F.A. (1986) Freiburger Fragebogen zur Krankheitsverarbeitung (Weinheim: Beltz). Rabkin, J.G. et al. (2005) “Prevalence of depressive disorders and change over time in late-stage ALS”, in: Neurology 65(1): 62-67. Robbins, R.A. et al. (2001) “Quality of life in ALS is maintained as physical function decline”, in: Neurology 56: 442-444. Von Steinbüchel, N., M. Bullinger & I. Kirchberger (1999) „Die Münchner Lebensqualitäts-Dimensionen Liste (MLDL): Entwicklung und Prüfung eines Verfahrens zur krankheitsübergreifenden Erfassung von Lebensqualität“, in: Zeitschrift für medizinische Psychologie 3: 99-112. Wasner, M., H. Klier & G.D. Borasio (2001) “The use of alternative medicine by patients with amyotrophic lateral sclerosis”, in: J Neurol Sci 191(1-2): 151-154.

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Young, J.M. & P. McNicoll (1998) “Against all odds: positive life experiences of people with advanced amyotrophic lateral sclerosis”, in: Health and social work 23: 35-43.

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Deep Brain Stimulation in Ps yc hia tric Dis or ders MAREKE ARENDS & HEINER FANGERAU

Introduction Deep Brain Stimulation (DBS) is a novel, reversible surgical intervention for the treatment of psychiatric disorders. Recent studies comprising small samples of patients with obsessive-compulsive disorder and depression have generated promising results. However, neurosurgical interventions in psychiatric patients raise ethical concerns based on the historical context of traditional, irreversible psychosurgical procedures, such as lobotomy. Therefore, this essay reviews the history of traditional psychosurgical procedures and reviews the experimental use of DBS in different psychiatric indications. Finally, DBS will be compared to earlier psychosurgical methods, and ethical concerns about DBS will be considered based on the bioethical principles reconstructed by Beauchamp and Childress. The main conclusions of this summary are that ethical concerns about DBS may arise due to confusion of DBS with historical psychosurgical procedures, and DBS differs from psychosurgery in some important aspects that should mitigate such ethical concerns.

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P s yc h o s u r g e r y: A H i s t o r i c a l O u t l i n e One of the first hints at the role of the frontal cortex in human behaviour was provided in 1848 by the case study of Phineas Gage. Gage was a railroad construction supervisor who survived an accident in which an iron pole impaled his head, entering through his left cheek, destroying his left eye and frontal cortex, and finally penetrating the back of his right skull. He survived this accident without any relevant somatic complications. After several months, however, changes in his personality occurred: he transformed from a friendly, even-tempered individual to an aggressive, volatile man, causing him to lose both his job and his friends (“Gage was no longer Gage”, Macmillan 1986). Gage died in 1860 after a series of epileptic seizures. Over a century later, Hanna and Antonio Damasio (1994) recovered Gage’s skull and used computer imaging techniques to show that the iron rod damaged most of the ventromedial region in the frontal lobes bilaterally. Based on other cases of ventromedial frontal lobe lesions and similar observations of subsequent behavioural changes that affected social function, the Damasios concluded that this part of the brain is responsible for social behaviours. The term ‘psychosurgery’ refers to surgical interventions targeting the brain to treat mental disorders. One point which is often overlooked in the history of psychosurgery is that Gottlieb Burckhardt (1836-1907) performed the first psychosurgical procedures as early as 1888, several decades before the work of the more prominent Egas Moniz (18741955). Assuming that excessive, pathological sensory impulses impact the frontal cortex to cause socially deviant behaviour, Burckhardt intended to suppress this behaviour by interrupting the connections between the sensory and motor cortex in the temporal lobe. He published his methods in the Allgemeine Zeitschrift für Psychiatrie (“General Journal of Psychiatry”) in 1891. Burckhardt’s experiments comprised psychosurgical treatment of six patients: four were diagnosed with ‘original paranoia’, one with dementia and one with mania. All of these disorders shared symptoms of aggressive or violent behaviour. After treatment, one patient died within 5 days, two patients showed no change, two patients were described as ‘more quiet’ and one patient showed a clear improvement. Burckhardt presented his results at the Berlin Medical Congress in 1889. However, neither his method nor his results were respected by his colleagues. Having experienced this rejection, Burckhardt uttered: “Doctors are different by nature. One kind adheres to the old principle: first, do no harm (primum non nocere); the other one says: it is better to do something than do nothing (melius

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anceps remedium quam nullum). I certainly belong to the second category” (Burckhardt 1891; Joanette et al. 1993; Manjilia et al. 2008). Some fifty years later, in 1936, the term ‘lobotomy’, also known as 1 ‘leucotomy’ or ‘prefrontal leucotomy’ was introduced. It was primarily coined by Egas Moniz from Lisbon, who was honoured for his scientific achievements in this area when he was invited to receive the Nobel Prize in 1949 “for his discovery of the therapeutic value of leucotomy in certain psychoses”. Moniz was inspired at the 1935 Neurology Conference in London by a discussion about treating the function of the frontal and temporal cortices. The discussion was stimulated by the experiments of Fulton and Jacobson, (Jacobson 1935) who performed cortical mapping in non-human primates. Since the procedures of the respected and well-known Moniz presented good outcomes without serious side-effects or deaths, lobotomy was perceived to be an effective and benign treatment. Egas Moniz and his colleague Almeida Lima performed the procedure in 20 individuals, reporting seven recoveries, seven improvements and six unchanged patients (Moniz 1936, 1994; Wind and Anderson 2008). Interestingly, Moniz became an invalid and retired in the year 1945 after he was injured by a gunshot to his spine by one of his patients he lobotomized before. In the years following Moniz’ first reports, the neurologist Walter Freeman and the neurosurgeon James Watts modified this method to develop the ‘transorbital leucotomy’ in 1936. This procedure was performed with an instrument that resembled an ice-pick and was therefore often called the ‘ice-pick method’. It could be performed by one person and was inexpensive and relatively quick, lasting about one hour; anaesthesia was induced via electric shocks. This brought about some dangers and ethical concerns: in some cases, the transorbital leucotomy was performed under suspect circumstances and by unqualified individuals. It is estimated that in the USA alone, more than 18.000 lobotomies were performed in 1951 (Swayze 1995). A comparable number of operations is estimated to have occurred in England, as psychosurgery was a standard practice of the medical culture until the development of psychotropic drugs. In Germany leucotomy also became part of popular culture. In the movie ‘Oberarzt Dr. Solm’ from 1954, for example, the practice was popularized as a controversial but useful healing practice. 1

These terms are often used synonymously and describe the same procedure; lobotomy contains the Greek term “lobos” which usually refers to the frontal lobe, while leucotomy means the white matter of the brain, described by the Greek term “leukos”. Both terms describe the same procedure: surgical or chemical cutting of nerve fibers in the prefrontal cortex.

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The question arises as to how this procedure had such widespread acceptance despite its often harmful outcomes. Potential explanations include the overcrowding and expense of psychiatric hospitals and the paucity of effective therapeutic options for psychiatric disorders (Mashour et al. 2005). Subsequently, lobotomy was a welcome opportunity to relieve the strain of these disorders.

Deep Brain Stimulation (DBS) DBS is a neurosurgical method, which presupposes the cooperation of individuals from several disciplines (e.g., neurosurgeon, physicist, radiologist and clinician, such as a neurologist or psychiatrist). The procedure consists of two parts: implantation of electrodes followed by implantation a generator. First, electrodes are implanted in a defined intracerebral target using stereotaxic techniques. This procedure can be performed while the patient remains conscious under local anaesthesia, which has the advantage of allowing side-effects and sometimes intended effects to be identified via testing performed during the procedure. Next, a generator is placed underneath the chest muscle. This is a common procedure, similar to implanting generators for cardiac pacemakers. The most serious risk of the surgical procedure is intracranial bleeding, which occurs in approximately one percent of the cases and can cause irreversible complications or death. Other potential risks may be procedure-related, such as wound infection and general complications, or hardware-related, such as the dislocation of electrodes (insufficient fixation or tension of the extension cable, migration of the generator or breakage of electrodes, which requires replacement). Furthermore, treatment-related complications caused by the stimulation may include neurological, psychiatric and cognitive changes, or other symptoms like weight gain. In a five-year follow-up of 49 patients with bilateral stimulation of the subthalamic nucleus (STN) for Parkinson’s disease, the most frequent transient side-effects were wound-healing problems, general health complications, delirium (related to the surgical procedure) and hypomania (related to the stimulation). Permanent procedure-related side-effects in these 49 patients included intracerebral haemorrhage and dementia (2 patients each), while permanent treatment-related side-effects included weight gain (41 patients), eyelidopening apraxia (15 patients) disabling dyskinesia (4 patients) and apathy and hypomania (1 patient each; Krack et al. 2003). The underlying mechanisms by which DBS affects the brain are not well understood. Traditionally, stimulation of a particular brain area was 140

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thought to over-activate this area until it shut down, creating a similar behavioral effect as a neurosurgical lesion. Other hypotheses for how DBS works include synaptic depression, inhibition and ‘jamming’, in which DBS may reduce pathological firing patterns and thereby normalize oscillatory activity (Fukuda et al. 2007; McIntyre et al. 2004). The hypothesis that DBS modulates pathological network activity seems to be the most well-accepted explanation at present.

A Short History of DBS and its P s yc h i a t r i c I n d i c a t i o n s Since Alim-Louis Benabid (1987) first introduced DBS for tremor in the 1980’s, more than 10.000 interventions have been performed for various neurological disorders. The development of DBS emerged from a period of detailed research on the physiology of the brain using electrical stimulation, beginning with experiments on dogs conducted by Eduard Hitzig and Gustav Fritsch as early as the 1870’s. They found that electrical stimulation of the anterior lobe provoked motor reaction of the contralateral side. In 1874, Robert Bartholow stimulated the cortex of a mentally deficient female patient suffering from a basal cell carcinoma, which had eroded her skull, to provoke epileptic seizures. The woman died shortly after the stimulation, which caused fierce criticism of brain stimulation and of invasive brain interventions in non-competent patients (Morgan 1982). In the following years, the development of DBS made considerable progress, especially after introduction of the stereotactic method by Spiegel and Wycis in 1947 and after the treatment of epileptic patients with electrical stimulation by the Canadian neurosurgeon Wilder Penfield in the years 1928 - 1960. In the 1950’s, the first attempts to treat psychiatric disorders with electrical stimulation occurred, mostly in the USA for example by José Delgado and Robert Heath (Delgado et al. 1952; Heath et al. 1954), unfortunately under conditions that are ethically questionable by current standards (Baumeister 2000). To date, only a few experiments have used DBS treatment in psychiatric disorders, reporting potential benefits in obsessive compulsive disorder, depression and addiction, as summarized below. Interestingly enough only very few studies take into account the disputes about the questionable theoretical foundations of DBS in psychiatric disorders and the ethical concerns regarding the application of DBS in psychiatric patients that followed the publication of Robert Heath’s DBS-study “Studies in Schizophrenia” (Heath et al. 1954).

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DBS in Obsessive Compulsive Disorder DBS has been used for obsessive compulsive disorder that is treatmentresistant, defined as non-responsive to psychotherapy or drug treatment. Variable stimulation parameters and targets complicate a clear evaluation of the success of DBS in this disorder (Lipsman et al. 2007). However, one recent study concluded that half of the patients showed a positive response (measured by the Yale-Brown-Obsessive-Compulsive Scale) after three years of stimulation of the anterior part of the internal capsule (Greenberg et al. 2006). Another target is for example the nucleus accumbens, which comprises part of the reward system of the brain (Sturm et al. 2003; Nuttin et al. 2003; Abelson et al. 2005; Gabriels et al. 2003).

DBS in Depression Three research groups have published results from DBS applied to depressed patients, and each stimulated a different brain area. Helen Mayberg conducted the largest study, comprising 20 patients who were treatment-resistant, defined as non-responsive to four different antidepressant therapies, including electroconvulsive treatment (ECT), cognitive behavioural psychotherapy (CBT) and various drug treatments. Subjects all had a diagnosis of major depression, which persisted longer than one year, and a sum score in the Hamilton Depression Rating Scale (HRDS) of more than 20. Exclusion criteria were suicidal behaviour and psychiatric or somatic comorbidities. For the first six months of the study, patients received high frequency bilateral DBS of subgenual cingulate white matter. This region was chosen based on the hypothesis of a disturbed connectivity between cortical, limbic and subcortical areas in depression, which is supported by observations of reduced activity in the cingulate cortex when depression improves (Ressler and Mayberg 2007). At the six month follow-up, four of the patients showed an improvement, defined as a decrease of more than 50 percent in the HRDS sum score. Of these four cases, three were considered to be in remission, defined as a decrease in the HRDS to less than 8 points. As a control condition, at the six-month time point, stimulation was changed to the OFF-mode for four weeks in half of the patients in a double-blinded design; after these four weeks, stimulation was changed back to the ON-mode for the remainder of the study. During the OFF-mode, the patient’s mood remained stable, but energy, initiative, concentration and activity decreased. After 12 months, 142

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positron emission tomography (PET) of intracerebral regional blood flow demonstrated a change of metabolic activity at the stimulation target and throughout the previously identified depression network, providing evidence that modulating the circuit causes antidepressant effects. At this 12-month time point, 12 of the 20 patients showed an improvement (more than 50 percent decrease in HDRS), and 7 of these 12 patients were in remission (HDRS score less than 8). No long-term side-effects were reported. In the second trial, a group led by Donald Malone, director of the Cleveland Clinic’s Psychiatric Neuromodulation Center, treated 15 patients with refractory depression with bilateral stimulation of ventral capsule/striatum. The response rate was 40 percent at the first follow-up at six months and increased to 53.3 percent at the last follow-up (Malone et al. 2008). The third trial, performed in Germany by Schlaepfer et al. (2008), included three patients on stable medication over a period of six weeks who had “very treatment-refractory major depression”, defined as failure to respond to psychotropic drugs, CBT and ECT. The authors reported that stimulation of the nucleus accumbens improved mood in all three patients with no severe side-effects.

D B S i n Ad d i c t i o n Kuhn et al. (2007) published a case study of a 54-year-old patient suffering from severe agoraphobia with panic attacks, secondary depressive disorder, and alcohol addiction. He was treated with bilateral DBS of the nucleus accumbens, which was associated with a slight reduction of anxiety and depression, as well as a remarkable decrease in substance abuse: one year after surgery, the patient consumed alcohol only occasionally. Other studies are in progress.

Ethical Considerations Some DBS trials show promising results for neurological disorders and other severe mental diseases. At first glance, DBS seems to be well tolerated by patients. However, patients’ acceptance of DBS has not yet been systematically explored. Furthermore, despite good outcomes, studies sometimes show unexpected results. For example, a survey by Schüpbach et al. (2006) with the questioning subtitle “Neurosurgery in Parkinson. A distressed mind in a repaired body?” showed that in most 143

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of 29 patients who received DBS for Parkinson’s disease, social capacities were impaired after surgery except in the categories of ‘partnership’ and ‘work’. These results were unexpected because one could suppose, that increase of motor symptoms would be followed by a simultaneous impairment in partnership and work. The authors suggested that a potential reason for this impairment could be the difficulty experienced by both patients and their relatives in adapting to the patients’ improved physical health. Manipulation of the brain by DBS may be stigmatized due to negative association with questionable historic brain manipulation techniques (i.e., lobotomy and involuntary ECT). In addition, a person’s identity and personality are often assumed to be localized to the brain, and the public may resist biotechnical treatment options that affect these attributes. Accordingly, studies show good acceptance of psychotherapy but greater moral concern about biological treatment options like ECT or psychotropic drugs (Angermeyer et al. 1993; 2004). In fact, DBS and classical psychosurgery share some similarities, as both methods are invasive surgical procedures affecting the brain and have certain risks like intracranial bleeding. Nevertheless, there are also some crucial differences between these procedures, most notably that DBS is reversible, can be adjusted (i.e., by changing stimulus parameters) and creates a minimal lesion, while ablative neurosurgical procedures are ireversible and create a much larger lesion.

T h e P r i n c i p l e - b a s e d Ap p r o a c h o f Beauchamp and Childress Beauchamp and Childress (1979) described four principles that help to identify potential ethical issues in the field of medical intervention. These principles are considered to be socially-accepted values and act as a moral base for medical procedures and decision-making processes. The principle of respect for autonomy concerns the decision-making capacity of autonomous persons, which enables them to make informed choices about treatment based on information about the procedure and alternatives, prognoses, etc. The principle of beneficence takes into account the weighing of the benefits of treatment against its risks and costs, demanding that the healthcare professional acts in a way to profit the patient. The principle of nonmaleficence requires that no harm be done to the patient. Certainly, all treatment may involve some harm, but the harm should not be disproportionate compared to the benefits of

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treatment. Finally, the principle of justice encompasses a fair distribution of benefits, risks and costs and similar treatment options for all patients. When dealing with patients suffering from mental disorders, these principles may be challenged. One crucial point is that reduced capacity of consent occurs frequently in patients with schizophrenia or dementia. Here, the principle of autonomy could be affected. The solution to this problem often involves implementation of a legal guardian who is empowered to make decisions and/or to give advice to the patient. Usually, the need for the capacity to consent and the ability to handle complex information grows with the risks of the planned procedure. DBS is an invasive method that can lead to death, rendering indispensable the capacity to make sensible decisions (Helmchen et al. 1989). Of course, the same abilities are necessary for some drug treatments with dangerous or irreversible side-effects (e.g., clozapine carries the risk of potential life-threatening agranulocytosis, and first-generation antipsychotics can cause tardive dyskinesia). Deciding not to undergo treatment may disturb quality of life and/or shorten life expectancy. Therefore, following the principle of beneficence, the clinician should advise undergoing a medical treatment if not having treatment would be disadvantageous. If there is evidence that DBS is a sufficient and efficacious treatment, the principle of beneficence might even demand its use. However, following the principle of nonmaleficence, it is necessary to balance the risk of the intended treatment with the burden of the untreated illness. The principle of beneficence considers the well-being of the patient. This paradigm could conflict with the autonomy of the patient, for example when the patient does not accept the illness and therefore has no psychological strain to produce the motivation to seek therapy. Several studies show that psychological strain and insight are associated with a reduced quality of life and probably with the urge to seek treatment (Stengler-Wenzke et al. 2006). Following this observation, it is assumed that patients with illness-insight and psychological strain could be more motivated to receive DBS treatment than patients without. It seems plausible that if an individual does not feel ill, he or she will not see the need for treatment. Finally, the problem arises as to whether every patient with a severe mental disease could benefit from DBS. Because it is not yet an established treatment, DBS is performed only in small groups of patients in experimental settings. At present, it is only possible to receive DBS under conditions in which other treatments have failed, typically as a participant in a research study. Hence, very few patients meet the inclusion criteria of a clinical trial. Patients with a reduced capacity of 145

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consent or with a legal guardian are often excluded from clinical trials. Here, a conflict with the principle of justice might occur, since this group has a clear disadvantage. In summary, DBS seems to be a well-accepted option in treatmentresistant neurological diseases and some mental disorders. When performed by an experienced, multidisciplinary team, historical concerns associated with early psychosurgery are minimized. Ethical conflicts may occur in patients with neurological conditions, and these merit careful consideration.

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References Abelson, J.L., G.C. Curtis, O. Sagher, R.C. Albucher, M. Harrigan, S.F. Taylor, B. Martis & B. Giordani (2005) “Deep brain stimulation for refractory obsessive-compulsive disorder”, in: Biol Psychiatry 1;57(5): 510-516 Angermeyer, M.C., T. Held & D. Görtler (1993) „Pro und Contra: Psychotherapie und Psychopharmakotherapie im Urteil der Bevölkerung“, in: Psychother Psychosom med Psychol 43: 286-292. Angermeyer C. & H. Matschinger (2004) “Public attitudes towards psychotropic drugs: have there been any changes in recent years?”, in: Pharmacopsychiatry 37: 152-156. Baumeister, A.A. (2000) “The Tulane Electrical Brain Stimulation Program a historical case study in medical ethics”, in: J Hist Neurosci 9(3): 262-278 Beauchamp, T.L. & J.F. Childress (2001) Principles of biomedical ethics, Fifth Edition (New York: Oxford University Press), (First Edition 1979). Benabid, A.L., P. Pollak, A. Louveau, S. Henry & J. de Rougemont (1987) “Combined thalamotomy and stimulation stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease”, in: Appl Neurophysiol. 50(1-6): 344-346 Berrios, G.E. (1997) “The origins of psychosurgery: Shaw, Burckhardt and Moniz”, in: Hist Psychiatry 8: 61-81 Burckhardt, G. (1891) „Über Rindenexzisionen als Beitrag zur operativen Chirurgie der Psychosen“, in: Allg. Zeitschrift für Psychiatrie 47: 463-548 Damasio, H., T. Grabowski, R. Frank, A.M. Galaburda & A.R. Damasio (1994) “The return of Phineas Gage: clues about the brain from the skull of a famous patient”, in: Science 264(5162): 1102-1105 Delgado, J.M., H. Hamlin & W.P. Chapman (1952) “Technique of intracranial electrode implacement for recording and stimulation and its possible therapeutic value in psychotic patients”, in: Confin Neurol. 12(5-6): 315-319 Fukuda, K., T. Wakuda, M. Kageyama, K. Kitamura, M. Tanaka, Y. Tawata, T. Miyauchi & S. Ishida (2007) “Psychotic symptoms, epilepsy, mental retardation, and brain malformation in a patient with 45,XO/46,XX mosaicism: detection of mutation of ARX molecule”, in: Psychiatry Clin Neurosci. Feb; 61(1): 134. Gabriels, L., P. Cosyns, B. Nuttin, H. Demeulemeester & J. Gybels (2003) “Deep brain stimulation for treatment-refractory obsessive147

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compulsive disorder: psychopathological and neuropsychological outcome in three cases”, in: Acta Psychiatr Scand. 107(4): 275282. Greenberg, B.D., D.A. Malone, G.M. Friehs, A.R. Rezai, C.S. Kubu, P.F. Malloy, S.P. Salloway, M.S. Okun, W.K. Goodman & S.A. Rasmussen (2006) “Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder”, in: Neuropsychopharmacology 31(11): 2384-2393 Heath, R.G., H.C. Becker (1954) Studies in schizophrenia: a multidisciplinary approach to mind-brain relationships. (Cambridge, MA: Harvard University Press). Helmchen, H., S. Kanowski & H.G. Koch (1989) „Forschung mit dementen Kranken: Forschungsbedarf und Einwilligungsproblematik“, in: Ethik Med 1: 83-98. Krack, P., A. Batir, N. Van Blercom, S. Chabardes, V. Fraix, C. Ardouin, A. Koudsie, P.D. Limousin, A. Benazzouz, J.F. LeBas, A.L. Benabid & P. Pollak (2003). “Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease”, in: N Engl J Med 13;349(20): 1925-1934. Kuhn, J., D. Lenartz, W. Huff, S. Lee, A. Koulousakis, J. Klosterkoetter & V. Sturm (2007) “Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?”, in: J Neurol Neurosurg Psychiatry 78(10): 1152-1153. Jacobsen, C.F. (1935) “Function of frontal assoziation areas in primates”, in: Arch Neurol and Psychiat 33: 558. Joanette, Y., B. Stemmer, G. Assal & H. Whitaker (1993) “From theory to practice: the unconventional contribution of Gottlieb Burckhardt to psychosurgery”, in: Brain Lang. 45(4): 572-587. Lipsman, N., J.S. Neimat & A.M. Lozano (2007) “Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: the search for a valid target”, in: Neurosurgery 61(1): 1-11. Lozano, A.M., H.S. Mayberg, P. Giacobbe, C. Hamani, R.C. Craddock & S.H. Kennedy (2008) “Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression”, in: Biol Psychiatry. 15; 64(6): 461-467. Epub Jul 18, 2008. Macmillan, M.B. (1986) “A wonderful journey through skull and brains: the travels of Mr. Gage’s tamping iron”, in: Brain Cogn. 5(1): 67-107. Malone, D.A. Jr., D.D. Dougherty, A.R. Rezai, L.L. Carpenter, G.M. Friehs, E.N. Eskandar, S.L. Rauch, S.A. Rasmussen, A.G. Machado, C.S. Kubu, A.R. Tyrka, L.H. Price, P.H. Stypulkowski, 148

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J.E. Giftakis, M.T. Rise, P.F. Malloy, S.P. Salloway & B.D. Greenberg (2008) “Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression”, in: Biol Psychiatry. (Oct 6). Manjilia, S., S. Rengachary, A. Xavier, B. Parker, M. Guthikonda & (2008) “Modern psychosurgery before Egas Moniz: a tribute to Gottlieb Burckhardt”, in: Neurosurg Focus 25 (1): E9. Mashour, G.A., E.E. Walker & R.L. Martuza (2005) “Psychosurgery: past, present, and future”, in: Brain Res Rev.;48(3): 409-419. Mayberg, H.S., A.M. Lozano & V. Voon (2005) “Deep brain stimulation for treatment resistant depression”, in: Neuron 45: 651-660. McIntyre, C.C., M. Savasta, B.L. Walter & J.L. Vitek (2004) “How does deep brain stimulation work? Present understanding and future questions”, in: J Clin Neurophysiol 21: 40-50. Moniz, E. (1936) Tentatives opératoires dans le traitement de certaines (Paris: Masson). Moniz, E. (1994) “Prefrontal leucotomy in the treatment of mental disorders”, in: Am J Psychiatry 151: 236-239. Morgan, J.P. (1982) “The first reported case of electrical stimulation of the human brain”, in: J Hist Med Allied Sci 37: 51-64. Nuttin, B.J., L.A. Gabriels, P.R. Cosyns, B.A. Meyerson, S. Andreewitch, S.G. Sunaert, A.F. Maes, P.J. Dupont, J.M. Gybels, F. Gielen & H.G. Demeulemeester (2003) “Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder”, in: Neurosurgery 52 (6): 1263-1272. Ressler, K.J. & H.S. Mayberg (2007) “Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic”, in: Nat Neurosci. 10(9): 1116-1124. Schlaepfer. T.E., M.X. Cohen, C. Frick, M. Kosel, D. Brodesser, N. Axmacher, A.Y. Joe, M. Kreft, D. Lenartz & V. Sturm (2008) “Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression”, in: Neuropsychopharmacology 33(2): 368-377. Schüpbach, M., M. Gargiolo, M.L. Welter, L. Mallet, C. Béhar, J.L. Houeto, D. Maltete, V. Mesnage & Y. Agid (2006) “Neurosurgery in Parkinson disease: a distressed mind in a repaired body?”, in: Neurology 66: 1811-1816. Spiegel, E.A., H.T. Wycis, M. Marks & A.J. Lee (1947) “Stereotaxic apparatus for operations on the human brain”, in: Science 10 106 (2754): 349-350.

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Stengler-Wenzke, K., M. Kroll, H. Matschinger & M.C. Angermeyer (2006) “Subjective quality of life of patients with obsessivecompulsive disorder”, in: Soc Psychiatry Psychiatr Epidemiol 41(8): 662-668. Sturm, V., D. Lenartz, A. Koulousakis, H. Treuer, K. Herholz, J.C. Klein & J. Klosterkötter (2003) “The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxietydisorders”, in: J Chem Neuroanat 26(4): 293-299. Swayze, V.W. (1995) “Frontal leukotomy and related psychosurgical procedures in the era before antipsychotics (1935-1954): a historical overview”, in: Am. J. Psychiatry, 152 (4): 505-515. Wind, J.W. & D.E. Anderson (2008) “From prefrontal leukotomy to deep brain stimulation: the historical transformation of psychosurgery and the emergence of neuroethics”, in: Neurosurg Focus 25 (1): E10

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The Esse ntia l Te ns ion: On Ethica l a nd Historical Conundrums in the Tra jectories of Deep Brain Stimulation

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Introduction The thought-provoking concept of ‘Implanted Minds’ can be addressed from quite different interdisciplinary perspectives, such as from the clinical and basic scientific fields, from biomedical ethics and the 1 philosophy of mind and brain science. In focusing here on some of the ∗

1

This article is a substantially revised and augmented version of a paper, which the author gave at the workshop “Implanted Mind? The Neuroethics of Intracerebral Stem Cell Transplantation and Deep Brain Stimulation” at the University of Duesseldorf (Castle Mickeln) on November 7th, 2008. I wish to thank the Alexander von Humboldt Foundation and the Montreal Neurological Institute for their financial support during the research phase of this project. Dr. Thomas Haelbig (Paris) gave important scientific input regarding the modern neurostimulatory methods; the librarians and archivists of the Osler Library of the History of Medicine of McGill University (Montreal) helped to find crucial archival material and historic images and, last but not least, the discussion with the participants of the workshop in Duesseldorf helped significantly to expand further on the historiographical argument within the ethical contexts. Furthermore, the author wishes to thank Ms. Donna Hill and Mrs. Beth Cusitar for their assistance with the editing of the English language of this chapter. A number of authors have already addressed this problem. Their writings might be consulted for introductory purposes to the ethical problem

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early research trajectories of Deep Brain Stimulation (DBS) since the 1930s, the current chapter adds another view to the discussion and puts forward a history of medicine and neuroscience perspective regarding the ethical problems involved. It thus develops further in a recent exploratory paper by the author, which appeared in the journal Wuerzburger medizinhistorische Mitteilungen and which focuses on the issue of medical manipulation during the technological development of 2 modern neurostimulatory approaches (Stahnisch 2008). It will be argued here that some of the ethical considerations – that can be historically identified and contextualised throughout their contemporary trajectories –took their origin from primarily collaborative programs. A critical assessment must therefore follow them back into the respective subdisciplines in creating a fuller understanding of the particular ethical 3 problems and limitations at hand. It is the aim of this chapter to trace some of the modern neuromanipulative approaches from deep brain stimulation further back to 4 their historical development, while comparing some modern DBS

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(Metzinger 1996; Birnbacher 1996; Galert 2005; Schoene-Seifert et al. 2009). In this earlier article, an in-depth comparison between recent neuromanipulative DBS approaches and historical methods has been provided. It has thereby shown that electrophysiological stimulation approaches were developed – following the Second World War – and began to crucially change the functional capacity of the human brain. Many contemporary debates regarding neuroethical applications therefore appear problematic in significant respects: Of major concern, for example, is the increasingly blurred conceptual boundary furnished by the complex relations between clinical research, therapeutic intention and physiological restitution. This problematic relationship has been studied by a number of other scholars (Vollmann 2000; Bockenheimer-Lucius and Kettner 2005) and will serve as a central vantage point for the current article as well. With regard to the manifold ethical considerations involved, readers are deferred to a recent study of the author, co-written with members of a pilot group, including Jonathan Kimmelman, Andrew Fenton, Alan Fine, Eric Racine, Lynette Reid, Mary Sunderland, Walter Glennon, and Ian Mitchell, supported by the Canadian Institutes of Health Research (CIHR). It addresses “States of Mind: Emerging Issues in Neuroethics” and focuses especially on ethical considerations in the invasive treatment options in Parkinson’s Disease (PD). A number of problematic relationships from that ethical field also impinge on discussions of deep brain stimulation (see Kimmelman et al. 2009). Introductory historical accounts written by neurologists or neurosurgeons, often portray this development in a simplistic form as a mere success story for neurological patients, without paying attention to the serious ethical

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programs with those ‘outmoded’ methods for electrophysiological 5 alteration of the human cortex and deep brain structures. In the first part, an overview on current-day deep brain stimulation methods and some of the ethical problem fields shall be given. In the second and more extensive part, central trajectories of neurostimulation research since the 1930s will be described and put into context. Shortly before and right after the Second World War, deep brain stimulation approaches were developed by neurologists and psychiatrists such as Otfried Foerster (1873-1941) at the University of Breslau (Germany), Wilder Penfield (1891-1976) at McGill University in Montreal (Canada), and Robert Galbraith Heath (1915-1999) at the Tulane School of Medicine in New Orleans (United States of America). These individual approaches eventually converged in the resulting methods of deep brain stimulation as they are practiced today. From placing the diverse DBS developments in a comparative perspective with the often differing stances on patients’ consent (Roelcke 2004), their relation to public media perception (Diefenbach et al. 1999), or the preparation of research funding requests to government agencies are analyzed within respect to the ethical framework in which these programmes historically progressed (Dees 2004). In so doing, the historical exposé will also include methods and approaches, which the recent discussion might not 6 recognise as ‘deep brain stimulation’ in the accepted sense of the term. By mapping out the foundational biomedical and technological advances some significant connections, important co-developments and continuing ethical problem fields will become evident. For particular structural reasons, this divergent set of approaches marks one theoretical tradition in the neurosciences that comprised of similar practices and technologies being later transferred into a number of contributing 7 working groups. Finally, in the last part of this chapter, the respective neurostimulation approaches shall be discussed with a view to their impact on patients’ integrity, autonomy and the precarious doctor-

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conundrums that henceforth pertain to the health care system (Krauss and Volkmann 2004.) Scholars like Alan Baumeister have pointed to the seemingly different ethical situation of the early neurostimulatory approaches developed in university hospital settings between the 1930s and 1960s (Baumeister 2000). The preferred target areas in recent deep brain stimulation programmes are, for example, the Thalamus system and the Globus pallidum region (Agid 1999; Kupsch et. al. 2003). Although quite different interdisciplinary perspectives were involved in the historical field of neurostimulation, they nevertheless included similar structurally ethical conundrums (see Fins 2004).

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patient relationship. While viewing neuroscientific trajectories from a seemingly synoptic perspective, the ecologies of moral decision-making on the part of some prominent historical protagonists, such as Wilder Penfield or Robert G. Heath are explored and thoroughly compared to present-day neuroscientific and ethical perspectives. Moreover, those types of ethical problems which relate to the altered historical relationship between doctor and patient indeed raise key questions about the ethical status of ‘informed consent’, by pointing to the worrisome and meandering course that has shaped the boundaries between neuroscientific research interests, clinical applications and therapeutic strategies.

M o d e r n N e u r o s t i m u l a t o r y Ap p r o a c h e s i n t h e DBS Context In this section, a brief overview on the neurostimulatory approaches of the last twenty years is provided, where disciplinary history editorials, neurological concept papers, or summarised introductions by neurologists (such as Krauss and Volkmann 2004) to be the paradigm historical narrative of their field. Similar views figure extensively in précis chapters and textbooks on deep brain stimulation and display no substantial difference between the comprehensive accounts in the German and English-speaking literature (Demeter 2007; Rzesnitzek 2008; Tarsey 2008; Talan 2009). Sporadically, these authors connect some of the recent developments back to earlier neurophysiological work, such as the laboratory-based stimulation approaches in the animal experiments of Gustav Theodor Fritsch (1837-1927) and Eduard Hitzig (1838-1907) (Fritsch and Hitzig 1870), precursors of the gate control theory (Schiller 1990), or the somewhat accidental clinical discovery of the thalamus stimulation in pain treatment (Tasker 2001). But, these accounts mostly neglect important forerunners and predevelopments which belong to the epistemological big picture of Deep Brain Stimulation8 as well as the ethical concerns of the therapeutic approaches in specific clinical contexts.9

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Such epistemological concerns include, for example, an insufficient knowledge of many deeper brain functions, the complex physiological network properties, or the inadequate understanding of accompanying emotional states in the respective patients (Farah 2005). The clinical context has been reflected most often in psychiatric literature with regard to the ethical conundrums of ‘informed consent’ for mentally ill and paediatric patients including the experimental nature of the method

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Figure 1: Depiction of the motor centres of the cortex of a dog as published by Fritsch and Hitzig (1870)

Source: Fritsch, Gustav & Eduard Hitzig (1870) „Ueber die elektrische Erregbarkeit des Grosshirns“, in: Archiv fuer Anatomie, Physiologie und wissenschaftliche Medicin 50(1): n.pag. (Osler Library of the History of Medicine, McGill University, Montreal)

These contexts are often not mentioned or, if they are, remain insufficiently addressed as will be pointed out in the second part of this chapter. For the sake of argument, it may suffice here to mention the broader historical background, while in the meantime describing some fundamental developments in the short time period that modern neuroscientists take as their ultimate ‘history’. Of course, these developments cannot be regarded in complete isolation from the general stunning progress of the neurosciences in the past decades, to which many protagonists of this interdisciplinary field have rightly pointed to (e.g. Rose 2005; Nutt et. al. 2006). Since the American Decade of the Brain, the general impact of the neurosciences has become a central focus of many ongoing academic and public discussions. Newly developed technologies for the external functional manipulation of the Central Nervous System – as in Parkinson’s disease or the movement disorders – have received primary medical attention in this context (Blake 1999; Farah and Wolpe 2004; Morrisson et al. 2004). In the parallel bioethical debates they came to be viewed as extremely problematic, however, especially when questions of informed consent, individuality, or the patients’ autonomy in decision making were taken into account (Farah et or similarities regarding clinical trials that make use of psychoactive drugs (De Vries 1999).

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al. 2004). When the modern neuromanipulative approaches of deep brain stimulation are related to the now historical methods that sought to change the functional capacity of the human brain – developed after the Second World War –, it shall be argued here that many contemporary neuroethical debates appear problematic in significant respects: As such, a particular argument shall be made against the increasing view of a neuroethical exceptionalism, which is taken to favour a special account of ethical considerations regarding Central Nervous System research – as put forward by Judy Illes and Eric Racine: “[…] with new and still-evolving insights into our neurobiology and previously unquantifiable features of profoundly personal behaviors such as social attitude, value and moral agency, the difficulty of carefully and properly interpreting the relationship between brain findings and our own self-concept is unprecedented. Therefore, while the ethics of genetics provides a legitimate starting point – even a backbone – for tackling ethical issues in neuroimaging, they do not suffice. Drawing on recent neuroimaging findings and their plausible real-world applications, we argue that interpretation of neuroimaging data is a key epistemological and ethical challenge. This challenge is two-fold. First, at the scientific level, the sheer complexity of neuroscience research poses challenges for integration of knowledge and meaningful interpretation of data. Second, at the social and cultural level, we find that interpretations of imaging studies are bound by cultural and anthropological frameworks. In particular, the introduction of concepts of self and personhood in neuroimaging illustrates the interaction of interpretation levels and is a major reason why ethical reflection on genetics will only partially help settle neuroethical issues. Indeed, ethical interpretation of such findings will necessitate not only traditional bioethical input but also a wider perspective on the construction of scientific knowledge.” (Illes and Racine 2005: 5).

There are important philosophical counter-arguments against the exceptionalism thesis of such “a wider perspective on the construction of scientific knowledge” (Bufford and Allhoff 2005; Stahnisch 2008). Also, many clinical similarities between the successive states of stimulation approaches in the neurosciences need to be taken into account, when they impinge upon other classical problems in thera10 peutically oriented medical research. The individual case examples from contemporary and recent history of neuroscience that build the problematic context of this chapter definitely make us aware of its continuation whithin medical progress and patient ethics. In fact, it must

10 This is classical problem is already discussed in an earlier publication by Dieter Birnbacher (Birnbacher 1994).

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be seen as an intrinsically blurred conceptual boundary between clinical research, therapeutic intention, and physiological restitution, which is inherent in modern biomedical progress (Heinrichs 2006: 133-139). This problematic situation shall now be exemplified further by drawing on core applications for invasive surgical treatment (such as Deep Brain Stimulation) during the last two decades: Parkinson’s disease and other dystonic movement disorders (Baltuch and Stern 2007). Such surgical approaches have emerged as an alternative treatment option to neurological practice and are most often used in disease conditions, where – for various reasons – only insufficient progress could be made with pharmacological, physical, or psychological means. For example, in current clinical research projects developed at the neurological centres of the Medical Faculty Charité in Berlin – led by Andreas Kupsch – or the Mount Sinai School of Medicine in New York City – under Charles Warren Olanow – patients suffering from basal ganglia disease have stimulation electrodes inserted into the deeper brain regions, such as the Globus pallidum or thalamus nuclei (Kupsch et al. 2003; Morrison et al. 11 2004). Through the application of periodic high-frequency electric currents, typical tremor and dystonic movements can now be suppressed in conditions, where patients have often lived through very long periods of suffering and decreasing benefit from any pharmacological treatment. In the immediate post-operative phase, often enormous relief from the earlier condition can be solicited, and patients describe a near to normal restitution of their former motor functions and general health condition. In direct comparison to the earlier historical approaches, such therapeutic options today have developed into relatively standardised forms of symptom control and therapeutic management, subsequent to the common knowledge of those clinicians and researchers who already have long-standing experience with such invasive treatment 12 approaches.

11 In Canada, particularly the group around the neurosurgeon Frank LeBlanc and the clinical neurophysiological laboratory of Zelma Kiss at the University of Calgary (Alberta) has gained the most experience with neurostimulatory approaches in various diseases of the basal ganglia system (Kiss et al. 2007). 12 Wolfhard Winkelmueller argues that it was particularly due to the progress in surgical practices and the availability of new technology that such a therapeutic standardisation process has become possible (Winkelmueller 2005: 1078f.).

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Figure 2: CT (2001) with full implantable electrodes in the brain, representing a research step in the scientific programme of Dr. Haelbig

Source: Research project of Dr. Thomas D. Hälbig, formerly at the Department of Neurology, Charité – Berlin

In particular, the advances in stereotactical operations and modern neuroimaging methods have offered better surgical control and reliable handling of the available DBS approaches which can now be accompanied intraoperatively by highly sensitive electroencephalographic methods (see Wichmann and Delong 2006). At the same time, the pressing problem of an increased infectious risk could be addressed through the introduction of fully implantable neuroinvasive stimulation systems. However, although many technical advances in deep brain stimulation have been made over the last decades, a number of contemporary neuroscientists admit that some major epistemic uncertainties remain. For example, there is insufficient knowledge about the functional influence of DBS on sensibility, long-term memory, or complex motor actions in patients (Haelbig 2005). This adds to considerable questions about the long-term effects of deep brain stimulation and the psychological changes that are associated with increased risk particularly in suicidal attempts and depression (Benabid et al. 2005). Recent therapeutic approaches have endeavored to increase the individual autonomous modes of stimulation in patients enabling them to equilibrate and intensify the electrical currents according to their own specific needs. This is most notable in the increased use of hand apparatuses, despite the fact that in the past mostly predefined amplitudes, impulse margins and electrical frequencies were used clinically (Volkmann 2007). It has now been acknowledged that for a long time 158

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the therapeutic approaches in movement disorders had been strictly research-oriented or even research-driven. This is particularly true for the applications that were designed to find out the right locus of stimulation and effectiveness, a modulation of day rhythms, the adaptation of changes of behaviour and emotion, as well as patients’ ‘decision making’ processes (Haelbig et al. 2005). If one takes the foundational dichotomy between therapeutic and nontherapeutic medical science closer into account, the electrostimulatory approaches become more questionable however and worthy of discussion from a number of perspectives. It is argued that this proves to be true especially when one understands that Deep Brain Stimulation formed an integral part of clinical research when electrostimulatory methods were introduced providing common knowledge on the subject – 13 even if performed with primarily therapeutic intention. This perspective makes it quite clear that in historical and recent cases, the research interests of the engaged scientists and medical doctors must be regarded as crucially relevant with the need to be observed in greater detail. Since the beginning of modern clinical neurology, observers and investigators had been interested in the general nature and aetiology of epilepsies, schizophrenias, or dystonic movement disorders, as well as situations in which “their motivation was strictly therapeutic”. Furthermore, the renowned American psychiatrist and neurologist, Robert Galbraith Heath (himself a specialist on seizure and schizophrenia research) articulates the same in his textbook Studies in Schizophrenia (Heath 1954: viii). This essential tension (for the technical notion see Kuhn 1977) between therapeutic treatment options and pressing medical knowledge interests has not gone unnoticed with the recent protagonists of neuroethics (such as Illes and Racine 2005). Reflecting on the structural problems of modern neuroscientific research, they have even identified it as a central research dilemma. This includes major efforts to understand the morphological complexity of the Central Nervous System, in addition to the continuation of epistemic uncertainties by means of experimental surgery approaches, and increased social applications with the potential risks of highly invasive and manipulative neurological methods (ibid. p. 15). When trying to develop a better understanding of 13 The local situations and the constraints of clinical experimentation with therapeutic intentions have been contextualised by Martin Dinges, for example, who broadens the perspective from a narrow medical research perspective to an increased understanding of health conditions (see in Dinges 2004: 209-236).

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these deeper epistemological and methodological issues, I now aim here at comparing the modern developments of electrostimulatory approaches in patients with Parkinson’s disease and in patients with other movement disorders to those trials performed at clinical centres for electrophysiological brain stimulation since the 1930s and 1940s – particularly the Montreal Neurological Institute (MNI) in Canada and the Tulane School of Medicine in the United States of America. It will thus become clear that many of the modern-day approaches (concepts, neurostimulatory procedures, but also ethical concerns) are indeed based on the therapeutic and research foundations that were laid by scientific teams under the Montreal neurosurgeon, Wilder Penfield – who was nominated four times for the Nobel Prize for Physiology or Medicine – and the biological psychiatrist and neurologist, Robert Galbraith Heath in New 14 Orleans. Even now, modern neuroscientists use very similar arguments when legitimising their research approaches, for example by appealing to the ‘critical or incurable condition’ of their patients and pointing out the risks of other alternative healing methods – such as brain tissue transplantation (as discussed in many other chapters of this volume).

A Historical Comparison with the Clinical Trajectories of Brain Stimulation since the 1930s A more in-depth historical scrutiny of the early phase of brain stimulatory approaches is important for the argumentation of this chapter and it is necessary for two specific purposes: Firstly, there is a rhetoric of foundation, reaching back to the 1930s (Penfield 1975: 109114) and the early Post-war Period, becomes visible again in neuroscientific research and therapy today. – Those deeper ethical and historical dimensions however, still remain insufficiently understood. Secondly, only the early 20th century stimulatory developments with their strong clinical orientation were able to generate the knowledge basis so that it could become possible to speak meaningfully of “Implanted Minds” (the topic of this edited conference volume) and a manipulation of the brain; thereby addressing new neuroethical questions of “mind control” or “psychocivilised individuals” as well (Delgado 1969). As I have described above and following the standard ‘self-image’ of scientific workers in the brain stimulation field, there 14 Both have already been the subject of numerous biographical publications, which however discuss their ethical positions only in passing (e.g. Lewis 1981; Winstead 2000; Fradelos 2008).

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seems to be a reluctance to include such individuals as the famous Breslau neurosurgeon, Otfried Foerster or his Montreal pupil, Wilder Penfield among the forebears of neurosurgical DBS programs (e.g. Krauss and Volkmann 2004). Current-day brain stimulation researchers might feel inclined to think that what their predecessors produced was only related to cortical surface stimulation and not to be regarded as deep brain stimulation at all. But, following their own writings and some of the patient records that have come to be published (e.g. Penfield and Jasper 1954; Heath 1961), a picture emerges that sees them instead as pioneers of a new technique of brain manipulation which came to be redefined with the advent of newer deep brain stimulation methods: The Canadian neurosurgeon, Wilder Penfield – who may not be so well known – principally learned his operative technique for neurostimulation during two extensive research periods with Otfried Foerster at the Breslau Clinic for Nervous Diseases and Psychiatry in 1928 and 1931 (Feindel 1998). In the Breslau Clinic, his German mentor used the method of deep brain stimulation basically for treating schizophrenic patients and individuals with posttraumatic epileptic disorders – a therapeutic approach that in the future would be included in Penfield’s programme with its emphasis on research into the functional localisation of the human cerebral cortex: “Foerster’s clinic [in Breslau] is above all a clinic in which therapy takes first place. Syphilis of the central nervous system is treated energetically by the Swift-Ellis endolumbar method in addition to the other usual procedures. Intracarotid injections of salvaranized serum likewise freely used. Physio- and hydrotherapy are carried out vigorously in the special rooms which are well equipped for that purpose. The wards are pleasant but the nursing is not of the highest order and decubitus is too frequently seen. […] Diagnosis is thorough. Encephalography is very frequently used and in the 1500 cases of spinal injection of air there seem to have been very few bad reactions. Direct ventriculography is also frequently used as well as lipiodal and the ventricular injection of dyes. Physiological diagnostic procedures also find a place here in a remarkably well equipped laboratory for chronaxie and other electrical measurements. […] Practically all of [Foerster’s] operating has been done under local anaesthesia. Thus he has used the patient as a witness to pain localisation, has outlined areas of skin innervation and has determined the movements of the body which follow electrical stimulation of various areas of the cerebral cortex. This analysis of the cortical areas has made possible an intelligent advance in the treatment of epilepsy. His study of the pain paths has made it possible to relieve certain types of pain more intelligently. […] Above all, here Neurology is accompanied by therapy. […]. In his almost universal use of local anaesthesia, the patients sometimes suffer acutely, although

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Figure 3: Functional homunculus of the cerebral cortex in man; described by Wilder Penfield (original drawing ca. 1958, Montreal)

Source: Osler Library of the History of Medicine, McGill University, Montreal it must be admitted that the mortality is thereby probably lowered. In general, the diagnosis is accurate, the treatment radical and the results good. In focal epilepsy his fearless radical excisions of the scarred brain area makes a step 15 forward in this treatment of this scourge.”

After his return from the European tour, Penfield began with the successful build-up of a comparable and very modern clinical and research centre at the Montreal Neurological Institute (Feindel 1992). It was there that he and his collaborators stimulated patients in intraoperative settings mainly with surface currents of 1 Volt and a frequency of 60 Hertz (see further in Hagner 2006: 180-187). Penfield closely monitored and recorded the movement effects, sensory perceptions and 15 Penfield’s admiration for Foerster’s institute and neurosurgical work is powerfully manifested in his travel report “Impressions of Neurology, Neurosurgery, and Neurohistology in Central Europe of 1928”, written after returning to Canada from his first research visit to Breslau (Penfield 1928: 6f.).

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psychological changes in his patients who – during the neurosurgical operation – were kept fully conscious to avoid major damages to the brain under intraoperative stimulation conditions. In these circumstances there was special consideration given to spare the language, visual, and somatosensory centres. It is reasonable to argue that his famous cortical cartographic map, which successfully established the functional homunculus of motor and sensory cortical areas of the human brain was thus developed as a side effect of these therapeutic stimulation efforts. Even more precisely evident was the differentiation between the complex patterns of subjective phenomena – such as the emotions of ‘familiarity’, déjà-vu-impressions, or aversive emotions that Penfield’s group identified through stimulating the parietotemporal areas of the cortex, and must not be seen as value-neutral observations. Instead, as will be pointed out here, the collection of all of this data – including stimulation data from deeper brain regions when operating in posttraumatic epileptics or tumour patients – intrinsically depended on the accompanying research programme of the functional brain mapping of the integrative cortex (Penfield 1958: 31-42). It is very remarkable to note that at this time and after agreeing to receive surgical treatments to cure their disease condition, Penfield’s patients had not been specifically instructed about the research intention of the general neuroscientific 16 programme. This internalistic combination of the problématique of neuroscientific investigation, epistemic conjectures and ethical considerations, as minimal as they were, did not really find a transparent representation in the doctor-patient-relationship. Instead, ethical deliberations continued to be confined to the individual consciousness and decision-making of the operating surgeon and some preliminary discussion with expert colleagues or hospital staff – discussions which mainly concerned the feasibility of the operations rather than their 17 immediate ethical implications. These paternalistic stances are omnipresent in Penfield’s writings, although he barely touches on them in an analytical way. He mostly writes of his personal accounts or post hoc legitimisation and such reflections can be found in the Proceedings of the Harvey Cushing Memorial Meetings of the Montreal Neurological Society of November 1939. Here, Penfield clearly embraces the teacher16 On Penfield’s rapport with his neurosurgical patients, see, for example, the Wilder Penfield Collection, WP-Archival Template 10, C/G1 (MNI Accession No. 002) in the Osler Library of the History of Medicine at McGill University (Montreal, Canada). 17 A background description of the doctor-patient relation in psychiatryrelated research fields at the time is provided by Andrea Tone (Tone 2005).

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pupil-relationship in clinical medicine and gives it visible priority vis-àvis over theoretical and philosophical reflections on the changes in the experimental nature of clinical neuroscientific research (Fins 2008): “It was easier for me [Wilder Penfield] to see in [Harvey] Cushing [18691939] the imprint of his masters because of the fact that I was a medical student under [William] Osler [1849-1919] at Oxford and under [William Stewart] Halsted [1852-1922] at [Johns] Hopkins [University]. It is a common experience for all of us to see in a son [!] an unexpected trick of manner or attitude that recalls his father. In a similar way, to see Cushing walk down the corridor of a hospital was sometimes for me as seeing Osler in the same 18 manner – and to hear his banter.”

To this day, not many sources have been identified or patient records declassified which would reveal Penfield’s ethical views in medicine more precisely. Moreover, the paternalistic descriptions from within the exceptionally individualistic position of the Montreal neurosurgeon – such as the ethical considerations of many other neurological pioneers of brain stimulation – are quite typical for the immediate post-war period in medicine (see also Roelcke 2004). In general, Penfield was primarily interested in his individual research programme and investigating the interrelationship of behaviour-dependence and motor responses in his patients, which he traced back to tinkering with complex stimulations of parts of the brain under intraoperative conditions. The Montreal neurosurgeon, however, did ask himself – in his autobiography (Penfield 1977: 168-170) – whether it was legitimate for the operating neurologist to manipulate the individual conscious answers of his patients when applying electrical stimulation currents. Nevertheless, the primary concern of his approach stayed with the surgical treatment of those areas of the brain which were seen as causally relevant in the aetiology of epilepsies and tumour growth. Overall it is quite remarkable that although his programme became so well known and Penfield’s neurophysiological findings made such a strong impression on the scientific community and interested public, not much can be found of an open debate in the media, or of the many critical voices that accompanied those clinical research approaches during this initial period (Lewis 1981: 123). 18 This address to the Montreal Neurological Society can be seen as one of the most explicit statements of Penfield about the importance of the teacher-pupil relationship in medical research and teaching. In opposition, however, the doctor-patient relationship is utterly neglected in this talk and the neurosurgeon did not deem it necessary at all to address the ethical problem more explicitly (Penfield 1939: 342).

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In particular contrast to Penfield’s programme, the social resonance regarding the neurostimulatory working group under Robert G. Heath at the Tulane School of Medicine in New Orleans was quite different and later developed significant media interest and provoked severe public reactions in the United States (Mohr and Gordon 2001: 119-123). At least in this instance, the disciplinary historiography has credited one of the co-workers of the Tulane group, the neurosurgeon, Donald E. Richardson (1919-1969), as one of the pioneers in the development of modern brain stimulation (Alesch and Mullet 2004: 8). The research in Louisiana which commenced in the early 1950s went undetected by the public in its beginning years. It was barely received in the neuroscientific community – probably because, at the time, the communities of psychiatry and neurology were often considered to be separate. Except for their ethical evaluation, it is not insignificant that about one hundred patients were included in the clinical applications of the research programme which extended over a period of thirty years (Baumeister 2000). In 1996, Heath was even awarded the Gold Medal for the American Society of Biological Psychiatry for having “accomplished important work as a pioneer in the field of biological psychiatry” and “strongly enhanced our knowledge about the structural and functional relations of schizophrenic diseases to the 19 brain”. Over the past three decades of this programme, it is possible to discern individual phases of patient access and a changing doctor-patient relationship. The same holds true for the ethical reflections and rhetorical struggles from within the contemporary scientific community, as they ensued from discussions about the usefulness of Heath’s procedure as “a last desperate cure” (Fradelos 2008) in psychiatric and neurological diseases. The contested nature of the Tulane programme further helps to understand the modifications within the bioethical discussion and also the contemporary medical decision-making surrounding deep brain stimulation methods (Slattery 1990-91). Heath, similarly to Penfield’s mentor Foerster, began his investigations within a psychiatric context: In a seventeen year old girl, suffering from schizophrenic episodes since her early adolescence, Heath applied electrical currents by means of deep brain electrodes to the septum region of the diencephalon. Subsequent to the neurobiological understanding at the time, he wanted to “recalibrate” the functional inequality between “primitive brain regions” 19 (CPSC 2000: 33). During his lifetime – in 1993 – the Tulane School of Medicine awarded him the endowed Heath Chair in Psychiatry and Neurology “in recognition of his accomplishments” thus honouring Heath’s scientific achievements (The Times-Picayune, New Orleans, Sept. 23rd, 1999: B-4).

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of human development and the unfolded complex cortical structures. This was, of course, a highly abstract and unspecific view that lead Heath to apply the “method of functional restitution” in many other psychiatric and neurological diseases as well (Heath 1954: 30-8). Although the neurostimulatory approaches of the Heath group were performed with a primarily therapeutic intention, the general effects in man had only been crudely understood at that time. The conceptual underpinnings basically relied on earlier neuroanatomical findings (such as Rolf Hassler’s, 1914-1984, works of the 1950s), on the neuroconnectivity of the thalamus and basal ganglia and on highly exploratory animal experiments which underpinned the clinical approaches (e.g. Dieckmann and Hassler 1972): “One approach consists of investigating the physiological activity of certain brain regions. It necessitated, however, the availability of a technique for implantation and fixation of the electrodes in the brain, first in animals and later in human subjects. In addition, the application of electrical brain stimulation in man was based on the data derived from animal experiments, which suggested a close relation to the electrical activity in specific brain regions with normal and pathological forms of behaviour. But even though the results from animal experimentation suggest that pathological forms of behaviour are changed by a modulating activity in locally circumscribed brain areas, we will only be able to corroborate those results found in cats and rhesus monkeys by continuing with clinical patient investigations. It is obvious, of course, that only human subjects are able to describe their thoughts 20 and emotions in the individual test series.”

Following Heath’s expectations, trials with human subjects had to take precedance over animal research approaches, as he illustrated in his notable and influencial 1957 report on the research conducted at Tulane. This report was then delivered to the National Institutes of Health in Bethesda that funded the Tulane School’s research activities in their “extramural programme” over the entire period. Moreover, Heath acted as the priciple member of a task force, which reported on the current state of neurostimulatory research for the neurological and psychiatric 21 institutes at the NIH. Consequently, the Heath group was able to 20 Along with the neurosurgical and neurophysiological colleagues of his research project, Heath tried to develop a continuous stimulation method, which could be placed in situ for months and even years, over an extended period of time (Heath et al. 1976: 296). 21 (NIH 1958: 259). The other members of the commission included the chair Desmond S. O’Doherty (1901-1971?), professor and chair of the Department of Neurology of the Georgetown University Medical Center;

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advance significantly with their exploratory research and started to increase the electrical currents that were applied in their stimulatory experiments. The brain researchers wanted to understand the margins of unintended adverse reactions under treatment conditions, however these were not very well known at this time and the psychiatric patients were placed at enormous risk when the stimulation methods were applied. As Heath himself admits, the original choice of the stimulatory impulse was 1 msec at the high frequency of 100 Hz and the decision for an in situ application of the electrodes between 13 and 54 hours was only ‘randomly determined’. Even though the Heath group was completely aware of the operative risks they took – such as electrical induction of seizures, the coagulatory destruction of brain tissue or possible intracranial bleeding due to the operative traumas –; those unintended reactions were accepted as ‘necessary’ for advancing the therapeutic protocols. In actual fact, most of the patients had psychiatric disease conditions and were unable to understand the complexity of the clinical trials to give their autonomous consent. For the Heath group, these facts seemed to legitimize such experiments and patients were not specifically informed of the research character of the operations. The relatives and friends of these psychiatric patients often were not aware of the current research practices until decades had passed and the experiments came to the attention of the public, then their interest became quite apparent (Slattery 1990-91; Fradelos 2008). This is also reflected in the judgment of the New York neurosurgeon and neuroanatomist Fred A. Mettler (b. 1907) who criticised Heath’s work right from the beginnings: “There is in the present communication [one of Heath’s publications], I think, some evidence that the theoretical preconceptions have tended to constitute a bed of Procrustes in which the reported data have at least been invited to 22 recline if not made to conform.” the neurologist Robert G. Bickford (1902-1993) of the Mayo Clinic; the neurophysiologist Mary A. Brazier (1904-1995) from UCLA; the UCLA neurosurgeon John D. French (1911-1989); the Oslo neurophysiologist Carl Wilhelm Sem-Jacobsen (1919-1990); as well as the German émigré neurosurgeon Ernest Adolf Spiegel (1895-1980) from Philadelphia, PA. 22 Because of his in-depth neuroanatomical research knowledge, Mettler was well aware of the considerable uncertainties that swayed over the functional and morphological networks of the basal ganglia system. As a bench researcher, he accused the clinical team of a haphazard methodology and exposing their patients to incalculable risk (Mettler et al. 1954: 535). But although he was also well-known academically, Mettler did not have the same weight in the clinical psychiatric and neurological communities and was not a member of the steering committees of the

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Figure 4: Stereotactic operation device from Kopf Inc.

Source: Kopf Inc., based on Ernest A. Spiegel, Henry T. Wycis, Matthew Marks & Arnold Saint-Jacques Lee (1947) “Stereotaxic apparatus for operations on the human brain”, in: Science 106(2): 349-350 (Osler Library of the History of Medicine, McGill University, Montreal)

It seemed that the patients were selected for specific inclusion in this research programme in biological psychiatry, whith preference given to severe cases where no ethical consent could be obtained nor opposition elicited from them. The outcome of the research results from the investigations was thus interpreted in an overtly positive light. It is interesting to note that in the research setting of the Tulane brain surgeons, the electrodes for neurostimulation were no longer confined to the septum region (the place where the investigators had started their program, making use of valuable, known data obtained from Foerster’s research group as well as some others). Nevertheless the Tulane researchers advanced their electrodes into completely new brain regions “of functional interest”, such as the thalamus (Richardson 1980) or the Nucleus caudatus (Heath et al. 1976) hoping to discover what would happen in their clinical patients afterwards. In so proceeding, these clinical researchers sought to derive further knowledge from the intraoperative site at the exact moment the skull of their patients lay open in front of them. In direct comparison, there are no qualitative or National Institutes of Health in this important phase, so his criticisms had almost passed unnoticed.

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structural differences to the contemporary research programme on the human cortex at the Montreal Neurological Institute, and both institutions operated in the same ethically void space of the time: “I [Penfield] had been very astonished, that really every time when I advanced my electrode, an answer of the patient could be elicited. How could this be? It had to do with human consciousness! I now began to perceive such answers 23 as ‘experimental’ in nature and awaited to collect even more data.”

It would be begging the ethical question, however, if the rationally structured programme of Wilder Penfield was simply represented as following a hazardous surgical attempt, which had developed from pure contingency or failure. To the contrary, from the very beginning of the programme, the procedures were specifically designed to allow for an exploratory form of experimentation. This ambivalent nature in surgical treatment and neurophysiological research was strategically built into both programmes at the Montreal Neurological Institute and into Heath’s group at the Tulane School of Medicine. Hence, it is not really comprehensible, why François Alesch (Vienna) and Keith Mullett (Maastricht) – when specifically drawing attention to Heath’s work – came to the following conclusion: “In the research literature, there have been repeated reports on the application of electric currency to the brain and spinal cord. But these were rather of a contemplative nature and without any therapeutic success.” (Alesch and Mullett 2004: 8). The neurostimulatory nature of the programmes at Montreal and New Orleans – spanning more than thirty years – were certainly not just ‘contemplated’ but had been pre-planned in their individual steps. Therapeutic access to the neurological and psychiatric patients was typically used for advancing the exploratory character of their research into anatomically and functionally unknown terrain and, of course, they claimed to having had ‘therapeutic successes’. Furthermore, it was used as a legitimisation against the great risk that these operations carried with them. Consequently, in Heath’s group at Tulane the study design became restricted to psychiatric patients who, in most cases, could not opt out of the research programme (Baumeister 2000). This lasted until the end of the 1970s when public concerns became more tangible vis-à-vis the early neurostimulatory researchers, being mostly due to the impact of the North American civil rights movements (Guerini 2003: 109-135). In widely distributed national print media, 23 This quote from 1975 shows, in retrospect, that Wilder Penfield was himself very well aware of the experimental nature of his clinical research program (Penfield 1975: 27).

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such as Newsweek and Reader’s Digest including local Louisiana news24 papers, the necessity of public discussion and opinion building was increasingly articulated, while stressing the need for a democratic participation in the decision-making process of physicians and brain researchers, especially where public research funding through the National Institutes of Health was concerned (Rushton 1974). The ethical framework of the early brain stimulatory programmes, which led to an inclusion of vast numbers of patients in both Louisiana and Québec, needs to be represented here as being very broad and flexible. It had been almost at the discretion of the operating neurosurgeon that the neurostimulatory investigations were performed, altered, or, on very rare occasions, ordered to be stopped. The brain stimulations in the psychiatric and neurological patients, overall, continued to be pursued in line with the principle of “therapeutic authority” (Rice 1974: 503-506) and even without explicit consent, when in ‘wellfounded cases’ further harm needed to be avoided. As Volker Roelcke has shown in a recent publication on the ethical framework of clinical experiments with psychiatric patients in the European countries, this may be seen as an international benchmark of Western biomedicine from the 1940s to the 1960s (Roelcke 2004). Although public critique was more and more tangible and even gained legal ground, the main impetus for change in the neurostimulatory research programmes came from new technological determinants in medicine: During the course of the 1960s, innovative research methods were developed – such as transportable and transcutaneus stimulation systems –, which now offered the opportunity where electrodes stayed in situ for months and even years (Rzesnitzek 2008). With these technological advances, electroencephalographic recording from deep brain structures now became possible outside of the confines of the surgical operating rooms in major neuroscientific research centres. These new procedures were now placed into the hands of the patients themselves, enabling them to use the devices at home and in their daily life situations. These new technological advances were equally responsible for major changes in physicians’ clinical attitudes, a development that his-

24 See, for example, the reports in Newsweek (July 21st, 1971) or in Readers Digest (August 8th, 1962). Following the influential civil rights movement in the United States, the focus of awareness became particularly oriented towards medical violations of human values – such as the widespread experimentation with prisoners, the black population, and inmates of psychiatric asylums. Civil rights activists in the Medical Committees for Human Rights thus also attacked the research programme on psychiatric patients of the Tulane group (Slattery 1990-91).

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torical introductions in textbooks of deep brain stimulation have often brushed over or blandly ridiculed as a “forgetting of the method” (Alesch and Mullett 2004: 10). With the increasing introduction of psycho- and neuropharmacological substances such as, chlorpromazine in schizophrenias, Valproate in epileptology, or L-dopa in Parkinson’s disease (Pressman 1998: 158f.), Deep Brain Stimulation methods lost their research appeal and medical significance during the 1970s – in the United States and elsewhere. They became further confined to the rather narrow areas of functional restitution in therapy-resistant schizophrenias and intractable thalamic pain disorders. Figure 5: Dorsal view of one of Robert G. Heath’s patients: The deep and surface brain electrodes are visible outside of the patient’s head. The connecting plug devices could be used as interfaces in the context of the electrophysiological research laboratory (photograph, ca. 1970; courtesy of Springfield Publishers)

Source: Baumeister 2000: 270; reproduced with permission of Springfield Publishers, Springfield, IL

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Some Considerations Regarding the Ethical and Epistemological Problématique of DBS In comparing the characterised development in the current neurostimulatory therapies – such as Deep Brain Stimulation of the basal ganglia system with cases from historical electrophysiological stimulation approaches (that targeted the Septum, Thalamus, or Corpus callosum region, etc.), the foundational ambivalence in therapeutic and research strategies of modern biomedicine remains incredibly visible. This essential tension in the research trajectories of deep brain stimulation as well as emerging from the opposition of the therapeutic treatment situation and urging medical interests for knowledge, advances in the neurosciences have previously been dealt with by a number of bioethicists (Synofzik 2005; Illes and Racine 2005; Knoppers 2005). When reflecting upon the structural problems of modern neuroscientific research, Illes and Racine emphasised this problem to be a research dilemma, brought about by the morphological complexity of the Central Nervous System, the pertaining epistemic uncertainties of experimental surgery, and the increased manipulative risks of neurological methods and practices. The individual cases presented in this chapter further expose the conceptual fuzziness of the complex relationship between therapeutic intention, medical research and functional restitution. Since the early days of electrotherapeutic brain stimulation enhances of the 1930s, the boundary between what could be called functionally restitutive medicine and a manipulative bioengineering approach in the clinical neurosciences became increasingly blurred. This general development has been accelerated through research advances which have also been analysed in recent Science and Technology Studies, during which time scholars also began to analyze the parallel development in cybernetics since the 1940s and 1950s (see: Hayward 2001; Andrew Pickering 2004). The technological properties of the neurostimulatory approaches make it perfectly clear that the application-related (‘therapy’) and research-oriented (‘investigation’) perspectives in the invasive and implantative operations on the Central Nervous System must be regarded as two sides of the same coin: Although it has become obvious through the reconstruction of the early history of deep brain stimulation approaches in this chapter, it remains fairly difficult to judge these independently. It must be allowed again at this point to take Illes’ and Racine’s (2005) demand for a stand in neuroethical exceptionalism into account, since the case examples that were described here have shown that the 172

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possibilities and borders of the neurostimulatory approaches (keeping both current and historical research settings in mind) profoundly change the integrity of the biological and mental ‘self’. The approaches of the two North American working groups under Wilder Penfield in Montreal and Robert Galbraith Heath in New Orleans were planned and pursued, although individual consent of their patients was not specifically asked for – even in cases where high-risk research was to be performed, the patients entered the operating rooms trusting to receive treatment for their illnesses. Both programmes must therefore be interpreted as collateral research approaches situated in local clinical settings. It is precisely this amalgamation that adds further questions to the general problem of distinguishing between the lines of therapeutic intention, medical research and functional restitution in highly manipulative and invasive clinical neuroscience (Roskies 2002). At this point, the question needs to be addressed again, whether a principal argument for the exceptionality of neuroethics approaches can indeed be constructed intelligibly and upheld, if the above characterised modern and historical programmes are taken into account. With a specific view to the historical development, it does not appear that such a strong case can be made: Like many other biomedical research approaches in clinical contexts, the historical neurostimulation methods operated on the delicate terrain of insufficient data. Similar cases can be argued for psychosurgery and psychopharmacology when comparing them to early heart surgery or transplantation research (Synofzik 2006). The ethical core conflict between the epistemic reach of neurostimulatory approaches (e.g. the demand pace maker systems) and intended manipulations of invasive functional neurostimulation remains until this day (Haelbig et al. 2005). As was described in the first part of this chapter, the essential tension in the research trajectories of deep brain stimulation persists in many areas of the modern neurostimulation approaches and supervenes over insufficient knowledge, particularly regarding the long-term effects, emotional changes and alterations of decision making behaviour, etc. When closely analysed, neither the historical reconstruction of individual research trajectories nor the modern cases of neurostimulatory research show that the multi-layered relationship between therapeutic intention (medical research) and functional restitution has ever been incontestably upheld. It is nearly impossible to discern practical contexts for the application of a restitutio ad integrum, as was claimed in some bioethical accounts and medical disease theories earlier on (e.g. Rothschuh 1978: 8f.). The integrity of the patient in neuroscientific research settings always appears to be a relative one – inde173

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pendent of whether he or she is subjected to somatic, psychosomatic, or neuroscientific methods. Even if the argumentation of the neuroethical exceptionalists was based on the medical healing task – as it was used by the neuroscientific community in various historical contexts –; this can only describe some of the necessary areas for patient autonomy. It seems nearly impossible to define sufficient markers for neuroethical exceptionalism when analysing the clinical research contexts that often affect patient autonomy and personhood in similar ways (see also Knoppers 2005: 3). It is therefore necessary that the differing problem constellations of future neurostimulatory programmes are closely observed, assuming they will follow similar problematic trajectories which are also typical in other areas of clinical research. Analogous to the cases of Penfield’s and Heath’s research groups, the relationship of neuroscientific research and public opinion, the handling and treatment of their patients, and the fuzzy line between therapeutic intervention and medical research needs to be further discussed from various comparative perspectives in the future. This article has provided one such perspective by contrasting current forms of deep brain stimulation to the specific contexts of their historical precursors.

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Cha nge s in Pers onalit y: Pos s ible Hazards Ar is ing from Chronic Implantation of Electrostimulation De vice s s uc h as Deep Brain Stimulation Systems (DBS) or Ad va nc e d Electronic Ne uroprosthese s ∗ CHRISTIAN P. BÜHRLE

Comparison between Stem Cell Grafts and Dedicated Electronic Neuroprostheses Incapacitated brain or spinal cord functions may be replaced by electronic circuits like anterior root bladder stimulators for controlling dysfunctional micturition in patients with spinal transsection (Brindley et al. 1982; Jünemann et al. 1994; Schmidt et al. 1999); cochlear implants (Niparko and Wilson 2000; Fayad et al. 2008; Gantz et al. 2006), retinal implants (Chow et al. 2004; McMahon et al. 2007). The same is true for other cognitive functions (Berger et al. 2005; Berger 2005; Warwick et al. 2003) or motor disturbances (Schwartz et al. 2006; Santucci et al. 2005; Lebedev et al. 2005; Nicolelis 2003; Nicolelis and Ribeiro 2002; Wessberg et al. 2000). These specialized in silicoreplacements are, for the most part, monofunctional. They constitute a major step towards restoring lost functions or abilities. Thus, the improvement of such ‘dedicated’ neuroprostheses is highly desirable from ∗

The author is most grateful to Dr. Utako B. Barnikol for stimulating and in-depth discussions. Without the secretarial and research help of Ms. Jessica Steinert this essay would not have been possible.

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the medical angle, since neuroprosthesis technology opens up therapeutic perspectives not available so far. However, electronic neuroprostheses are limited in their capacity to restore lost functions since – as yet – following the theory of linear and non-linear systems, they are much less complex than the defunct neural circuitry they are meant to replace. As opposed to their biological counterparts they are absolutely deterministic systems. Nevertheless, there is hope that owing to the rapid progress in electronics and nanotechnology they will eventually come very close to emulating destroyed neuronal circuits. Resting on principles of applied physics and numerical mathematics as well as very innovative and creative engineering, the respective electronic circuits are fully understood. Besides limited complexity as described above, the absence of high-capacity interfaces between electronics and bionics, i.e. biological circuitry, is the main obstacle in this rapidly expanding field. At present, many attempts at designing and constructing such highperformance interfaces are extremely promising. Essentially, the term ‘high performance’ translates into the abilities of such advanced microelectronics to selectively and specifically exchange information between an engineered sensor or effector, the neuroprosthesis proper and the brain (Georgopoulos et al. 1988; Santhanam et al. 2006; Patil and Turner 2008; Liu et al. 2008; Handa 2006; North 2008; Harrison 2008; Velliste et al. 2008; Warwick et al. 2003; Weiland and Humayun 2008). These dedicated neuroprostheses and interfaces have one thing in common: Either they supply the brain with afferent, mostly sensory, information, or they translate efferent brain activity into information properly formatted and readable for electronics or mechatronics that act as replacement systems, enabling the patient to execute motor functions or even speech. Up to that point, we cannot identify any ethical issues, since these systems replace complex sensory and motor functions that are unavailable for the patient, either because the lack of these functions is caused by genetic defects, i.e. inherited, or acquired, meaning caused by neurotrauma, degenerative systems diseases (retinitis), or intracerebral haemorrhage. Likewise, the destruction of the material substrate of these functions may result from a reduced or totally failing supply of oxygen and energy as a consequence of diminished or stopped perfusion of the respective region by brain vessel occlusion such as atherosclerosis or embolism.

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M o n i t o r i n g N e u r o n a l Ac t i v i t y There is indeed an ethical problem when it comes to reading out information from the brain. Already eighty years ago, after the findings of Berger in 1928 (Berger 1929) that electrical brain activity may be recorded either by Ag/AgCl2 silver wires inserted into the cerebral cortex in a patient suffering from skull fraction after a motorcycle accident, or even from the scalp of persons with their skulls intact by surface electrodes, there was the notion that electroencephalography might be able to eventually read human thoughts. This, of course, was either wishful thinking or extreme anxiety, depending on who was concerned at the time. This notion was falsified most elegantly and convincingly by the eminent physiologist Lord Adrian in 1936. For a demonstration of the strong and unbroken resolve of interested parties to read other people’s minds, we would like to quote Knudsen et al. (2008) who maintain that the American Military is funding experiments to isolate from the EEG correlates of words being thought by human subjects under study. It goes without saying that this is pseudo-science, since the EEG (Janjarasjitt et al. 2008; Járdánházy A. and Járdánházy T. 2008) can only record from the most superficial layer the activity of a large number of synchronously firing neurons, thus permitting only the most general statements about brain activity, e.g. characteristic patterns associated with rhythmic discharges during epileptic seizures, and potential changes indicating PD, neurodegenerative disease, neoplasms or intoxication of the brain and similarly unspecific conditions of the cerebral cortex. In this context it is somewhat scaring that the American Military obviously desires so strongly to read other persons’ minds that they believe and massively invest in a hypothesis that has been proved wrong already seventy years ago. Nevertheless, with general purpose neuroprostheses the scientific community has created – with the best of intentions – the tools which might now be put to wrong and unethical uses. Especially, the massive introduction of mathematically-based signal analysis techniques has contributed to a renaissance of the EEG (Janjarasjitt et al. 2008; Járdánházy A. and Járdánházy T. 2008), which had largely become obsolete as a diagnostic tool with the adoption of tomographic imaging (CT, MRI, fMRI, PET, SPECT etc.). For quite some time the EEG’s role was confined to a diagnostic aid in epileptology, a monitoring instrument for assessing the functional state of the brain in disciplines like anaesthesiology and intensive care medicine, and a general neuroscientific research tool. 185

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The nature of the generation of the potential changes picked up by the most sophisticated quantitative EEG (Janjarasjitt et al. 2008; Járdánházy A. and Járdánházy T. 2008) or magnetoencephalographic equipment immediately leads to the well known mathematical question of the ‘inverse problem’ which has been thoroughly studied both theoretically and experimentally. Generally, inverse problems are ill posed. Briefly, the set of equations is underdetermined, making it impossible to find a unique solution. Attacking most inverse problems yields either no or infinitely many solutions (Tarantola 2005; Engl et al. 1996; Natterer 2001; Natterer and Wübbeling 2001; Aster 2004; Khosrow and Sabatier 1977).

General Description of DBS A promising instrument for treating or ameliorating CNS diseases that is still in its infancy is ‘Deep Brain Stimulation’, a serendipity finding by Benabid in the 1980s (cf. Chibirova et al. 2005) which was originally elaborated for the therapy of Parkinson’s disease (PD). Although being still heuristic (Kahnemann et al. 1982) and empirical, this technique is now the therapeutic ‘gold standard’ in cases of PD refractory to pharmacological treatment. Here, in most cases the target is the subthalamic nucleus (STN), a relay within the mutually dependent loops of the extrapyramidal motor system. In both hemispheres, these nuclei (dimension 3 x 2 x 2 mm) are stereotactically impaled with deep brain stimulation electrodes. Both electrodes are connected by subcutaneous leads to a fixed-frequency neurostimulator, essentially a multivibrator circuit with adjustable pulse width, pulse frequency and voltage amplitude. A typical setting for treating PD would be like this: pulse following frequency: 130 Hz, pulse width: 40 - 120 µs, amplitude: 2 - 6.5 V. Presently, however, the indication spectrum for this therapy is rapidly being expanded beyond movement disorders world-wide by neurosurgical groups, often cooperating with neurologists and/or psychiatrists, although one is hard-pressed to identify an universally defendable and scientifically ‘hard’ anatomical or functional rationale for doing so. By contrast to these novel indications, an immense body of experience, circumstantial evidence and know-how has been gained over the last decade with PD and movement disorders. With these particular indications, conventional DBS electrodes are stereotactically inserted into the respective targets. These are mostly selected on the basis of anatomical reasoning, interpretation of imaging

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technique results (functional or non-functional), analogies derived from animal experiments, MEG/EEG measurements, or by conjecture. For PD, the target most often selected is the STN, while there are alternative targets like the Vim and the GPi. To make the STN the ‘standard’ target for PD a large amount of time-consuming work had to be invested to elaborate the pros and cons of STN, Vim and GPi and to weigh them for an efficiency assessment. For the novel indications, this task has largely still to be done. Except for disturbances of extrapyramidal motor disorders, this method has meanwhile been expanded to: • major depression • schizophrenia • Gilles de la Tourette - syndrome • obsessive-compulsive disease (Stein et al. 1992; Stein et al. 1998) • neurodegenerative diseases of the CNS (Hou and Hong 2008; Lazic and Barker 2003) • alcohol abuse and • drug dependency The diversity of the clinical entities above may be taken as an indication that a heuristic, technologically embryonic (Kahnemann et al. 1982) and mechanistic approach, such as stimulating the ‘responsible’ brain structures or volumes on a quasi macroscopic scale, may well be a less than ideal tool for chronic treatment of complex CNS disturbances. Quite naturally, when addressing functional disturbances of the CNS in general and mental disorders in particular, the odds of identifying a successful therapeutic regimen increase, as soon as the neuropathophysiological mechanisms underlying said disorders are at least partially understood. We wish to make one thing quite clear: A diffuse concept or a general idea, why there may be a malfunction and what might be the nature of it certainly does not suffice as a basis for a rational therapeutic approach in this intricate and sensitive field. What, instead, is required are hard neurophysiological and neurobiochemical facts. Where a conceptual and methodological criticism of the DBS technique may set in is the fact that for most indications listed above there are few guidelines pertinent to the respective precise pathomechanisms and etiologies. In the future, these will have to be elaborated to provide a solid foundation for therapy. Classically, such guidelines are derived from animal experiments. Deplorably, for the DBS method there is still no unified theoretical basis, and the efforts to create such a platform for curing or alleviating 187

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CNS disturbances from the psychiatric domain by neuromodulation have to be further intensified. This statement may be countered by arguing that there are no appropriate animal models when it comes to study schizophrenia, major depression and obsessive-compulsive disease (OCD), because the neocortex of commonly used rodent experimental animals is just to primitive for modelling mental disturbances, and that these disturbances do not naturally occur in these species (Stein et al. 1992; Stein et al. 1998). Although this is quite true, it should prompt researchers in the DBS-field to proceed more slowly but also more thoroughly when performing full-scale clinical studies of the technique in human beings. The reason is that – at least for extrapyramidal motor disturbances such as PD and the dystonias – there are indeed such models (6-OHDA in the rat). However, these have been largely not been fully exploited so far by clinical researchers. The same is true for the well-established acral lick-disease (ALD) model (Rapoport et al. 1992), which has been widely used in pharmaceutic/pharmacological research for identifying drugs that may be helpful for application in human beings (Solinas et al. 2008) suffering from OCD. It equally holds for various drug-dependence models in rodents that have been used in elucidating the role of the mesolimibic axis and the intrinsic brain reward system (Rang 2003). These models are particularly valuable, because the mechanisms for drug dependence only marginally involve the neocortex, since they are essentially harboured in mesencephalic and diencephalic structures (Solinas et al. 2008). In addition, we command a host of animal models pertinent to neurodegenerative diseases such as Alzheimer’s syndrome (Lazic and Barker 2003; Adeli et al. 2008). All the above models and the considerable body of results already obtained by using them should more strongly influence the mindset of DBS-researchers when it comes to a theory – as well as quest for curing mental diseases. What is true is the statement that – in the animal domain, including primates – there are no useable models for the hypercomplex mental disorders like major depression, schizophrenia or Gilles de la Tourette’s syndrome. Here, evidence-based medicine (Elstein 2004; Little and Rubin 2000; Sacket et al. 1996; Torpy et al. 2006) comes in: Although the claims of clinical electrostimulation research are enthusiastic, the evidence presented for most of the clinical entities mentioned is mostly level III and IVa information. The only level I studies the author is aware of are those of Deuschl et al. (2006), concerning the beneficial

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action of DBS in Parkinson’s disease and of Witt et al. (2008), dealing with neuropsychologic and psychiatric changes after stimulation for PD. Taken together, at the present state of knowledge the application of DBS for indications beyond Parkinson’s disease and the dystonias, is still somewhat debatable, especially, since, except for case reports and small series, little is published that would support the efficiency of DBS in mental disorders on a large scale. In our opinion the procedure of stating that a given patient with a mental disorder is refractory to all measures of conventional treatment, and that it is therefore justifiable to subject him/her to DBS-treatment as a measure of the last resort, must always be judged according to the most stringent criteria to avoid raising ethical concerns.

Technical Refinement of DBS Although DBS, in its present state, is – from a neurophysiological and neuroanatomical point of view – a still immature concept the methodology of which has to be vastly refined for influencing a hypercomplex system like the brain, this situation may quickly change. If this is for the better or worse, only future can tell. Given the technological advances in microelectronics, nanotechnology, molecular biology etc. it may well be possible to influence higher brain functions in a controlled manner (Warwick et al. 2003; Santhanam et al. 2006; Patil and Turner 2008; Liu et al. 2008; Harrison 2008; Abbott 2006). A glimpse of this may be already be gleaned from the untoward actions of neurostimulation if the target is not hit properly or the excitation current spreads to systems unrelated to those that are intended to be stimulated (Krack et al. 2001). What it takes to do this is not even far beyond the reach of current technology: • Understanding of the function to be influenced on the neuronal circuitry level or better, on the level of the neuronal membrane. The basic functions of e.g. a motor neuron have been simulated mathematically, i.e. numerically, already in the 50ties of the last century (Hodgkin and Huxley 1952; Lorente de Nó 1935, 1938, 1947; Hoppenstead and Cummings 1997; Iansek and Redman 1973; Redman and Walmsley 1983; Jack et al. 1971; Holmes and Rall 1992). • At present, although it takes a last-generation supercomputer, a complex neuron, such as a purkinje cell, may be numerically simulated in real time: i.e. the nonlinear, non-stationary transfer function of this cell (Mendell and Henneman 1971; Miller et al. 189

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•

•

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1985; Sun and Bookman 1994; Zhang 2008; Zhdanov 1988) which translates excitatory and inhibitory synaptic bombardment; i.e. analogous transmembrane voltage changes across the soma-dendrite (SD) membrane into a frequency, phase- or pulse-code–modulated spike train at the axon hillock may be emulated electronically. Although the comparison of the brain with a computer in the sense of a Turing-machine is not or only to a very limited extent applicable and acceptable, both systems consist of certain more or less stereotyped building blocks. In one case, these are transistors or integrated circuits, in the other, they are neurons. As a rule, transistors and ICs are stationary as to their transfer function and act absolutely deterministically, whereas neurons are and do not. Nevertheless, the knowledge of the function of a semiconductor device down to quantum electrodynamics (QED) does not imply even a notion of the circuit, e.g. a computer, it is part of. By analogy, this likewise holds for single neurons in the brain under study or even more so for a SC grafted into the brain that differentiates along the neuronal pathway. Following the analysis of neuronal circuit function and topology, the appropriate inputs of the biological circuits prone to external influences (membrane potential changes, current injection) have to be identified in a next step. Subsequently, multi-channel pulse trains have to be synthesized that put the cerebral subsystem into the desired functional state. This is certainly a very difficult task, since a large number of spatiotemporal stimulus patterns have to be tested. However, using Monte Carlo methods and autonomously learning, self-adapting control units and pulse generators will be essential for solving this problem.

All this is, in principle, already feasible.

General Remarks on Neuromodulation, Brain Stimulation and Neuroprostheses Deplorably, neurostimulation as in DBS exhibits some deficiency in neuroscientific and basic sciences theory. The method also suffers from some practical shortcomings, such as purely technical issues (longevity of the generator, biocompatibility of stimulator and electrodes), problems in identifying the target ‘responsible’ for the respective disorder, precisely localizing and hitting this target and also applying the appropriate stimulus pattern in each individual case. These problems 190

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have to be eliminated in the interest of a specific and selective neuromodulatory treatment: a very basic electronic circuit at the heart of the neurostimulator is a very basic electronic circuit, meaning that a pulse generator with a few degrees of freedom in its settings (pulse following frequency, pulse width and pulse amplitude) is supposed to improve or ameliorate a host of motor- or even higher brain dysfunctions by a more or less precisely focused local application of current pulse trains. This electrical input into the sub-system of the brain to be influenced is nonphysiologic, since stimulation is extracellular, acts by strongly distorting the potential field in the extracellular space, and requires large voltages to evoke an effect. From a formal point of view the ‘data format’ at the output of the stimulator, i.e. rectangular current pulses has little in common with the ‘data formats’ (electrochemical synaptic transmission, transmembrane currents, excitatory (EPSP) and inhibitory (IPSP) analogue potential transients at the dendrites and the soma of the neuron, as well as action potentials resulting from non-linear analogue-to-digital conversion by the initial segment, i.e. the axon hillock) that the brain is able to read under physiological conditions (Lloyd 1943, 1945). Number and bandwidth of information carrying channels, i.e. the brain-machine interface, (contacts of the stimulation electrodes) are, as yet, rather limited. With DBS – as opposed to other approaches – the interface problem between biological and electronic circuitry is still not solved satisfactorily, although much work has been done to create sensory (Weiland and Humayun 2008; Niparko and Wilson 2000; Fayad et al. 2008; Gantz et al. 2006; Warwick et al. 2003; Berger et al. 2005; Patil and Turner 2008; Harrison 2008; Abbot 2006; Liu et al. 2008) and motor interfaces (Velliste 2008; Schwartz et al. 2006; Santucci et al. 2005; Lebedev et al. 2005; Nicolelis and Ribeiro 2002; Nicolelis 2003; Wessberg et al. 2000). Signal translation or reformatting problems have not been addressed as per the time of this writing. Thus, there is an important need of specificity, particularly in small and highly ordered structures, e.g. in somatotopically organized projection fields, or in small, multifunctional deep brain nuclei. In addition, when regarding the dimensions of the stimulation electrodes and those of the excitable cells as well as of the extracellular space, it is clear that the ‘problem of scale’ (miniaturization) still remains to be solved. In other words, the commercial stimulation electrodes presently used are more than an order of magnitude larger at their tips and shanks than is required and tolerable for selective CNS microstimulation. Admittedly, the construction of small-diameter microelectrodes with four spatially different contacts is no easy task when considering that 191

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these electrodes will be implanted permanently and have to work under ‘real world’ rather than under laboratory or OP-room conditions. In addition, with smaller electrodes, stimulation over a µm-size tip or contact point at an impedance of about 1 MΩ would require rather high voltages and a complete redesign of the pulse generator. However, to the author’s knowledge no such work has been done, although the clinically easily manageable commercial are conceptually and technically rather dated. The drawbacks associated with these designs become evident when regarding, for instance, the dimensions of chemical synapses responsible for transferring information from one cell to the other (Eccles 1964). For comparison, the diameter of the synaptic boutons where release, diffusion and interaction of the transmitter with the postsynaptic ligand-activated receptors take place is in the sub-micrometer and that of the clefts in the upper nanometer range. Looking at the dimensions of some targets to be impaled by these electrodes, it is rather disturbing for neuroanatomists and –physiologists that these anatomical structures are of roughly the same order of magnitude as the electrodes. Consequently, the stimulation electrodes may possibly damage their targets partly or entirely.

C r e a t i n g t h e B i o t e c h n i c a l , C yb e r n e t i c , Electronic and Computational Foundations of Mind Control Thus, assuming that the correct structures being the substrates of higher brain functions are identified, the interface problem (stable, multichannel and biocompatible neurobionic connections, North et al. 1991; North 2008; Weinberger 1993) is solved, and the ‘code’ of the spatiotemporal stimulus pattern – to be applied in order to instil externally generated, intricate, target-oriented information into the brain – is broken – which, in principle is applied cryptanalysis and cryptography – it additionally takes the construction of an autoadaptive, multiple-channel signal generator and a huge amount of computing power (Sipser 1998; Zhang 2008; Zhdanov 1988) to actually attempt successful mind control. At the present state of the art, the human brain is still protected by its immense spatiotemporal complexity from being efficiently, repeatably and robustly manipulated, for instance by conducting or transmitting information influencing higher brain functions (Kim 1995) into its circuitry. Here, we mean fake sensory input, fake memories and, consequently, fake thoughts, notions and ideas as well as an in192

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tentionally fake redefinition of the self and a spurious notions thereof, leading to efficient permanent, i.e. hard-wired, irreversible indoctrination. At the moment, DBS is still an emerging but neuroscientifically as well as medically very promising and therefore attractive neurotechnology. However, this apparently harmless situation may quickly change when increasing numbers of researchers become involved into the scientific activities taking place in this field. This is for the good as long as only experienced persons with a sound training in the natural sciences and the neurosciences who are used to act according to very high ethical standards and whose absolute integrity is beyond any doubt are concerned. It can, however, only be for the bad when researchers are admitted to this pivotal but extremely sensitive and ethically most delicate field who lack these prerequisites, especially moral responsibility. Particularly problematic are people whose motives are dominated by satisfying their own ambitions in order to foster their careers while tampering with a system and using sophisticated procedures they are not completely familiar with. For the conscientious neuroscientist, continuous self-reflection about his motives and consideration of the infinite damage that may be done not only to neuroscience alone, but also possibly to the protection of the free will of their patients and – ultimately – to humanity in case of unintentional or intentional scientific misconduct should be mandatory. The history of science has taught us that here neither misconduct, fraud nor rogue behaviour and actions being illegitimate or verging on the criminal can be excluded a priori. We must not forget that scientific work in itself is a privilege. This holds to a high degree for neuroscientific work and there can be little doubt that interventional medical research on the human brain is at the very acumen of the biomedical sciences, as far as the requirements on moral responsibility of the individual researcher are concerned. Suffice it to say that privileges can be granted, but they may equally well and with every justification be withdrawn should any wrongdoing by the privileged person be identified or become obvious otherwise. To be absolutely unambiguous about this: It is by no way the intention or objective of these deliberations to impair freedom or progress of science. However, not only the scientific community but also the public should understand quite clearly that an invisible but decisive line has been crossed by not only surgically intervening in the brain for purely therapeutic reasons, i.e. for aiding the patients, but also by doing research that is either not purpose-free in itself or uses techniques with an 193

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unknown intrinsic potential to harm individuals or society by altering or controlling the mind. One may attempt to refute this argument by pointing out that interventional functional brain research has already been done before by Penfield and Rassmussen in the 1930s - 1950s. Their techniques, however, hardly had the potential to interfere with higher brain functions. Research using experimental lesional techniques in man that may compromise the patients’ mind were heavily debated and finally largely phased out either because of their inefficiency, the presence or development of side-effects or on moral grounds, i.e. for protecting these very ‘higher brain functions’. So, this line of argument is a fallacious one. It is the conundrum with electrical brain stimulation that it has – at least with Parkinson’s disease – an undoubtedly positive effect and is highly efficient. This nourishes the standard argument that even more research has to be done to fully assess this technique’s value and, finally, to extend the indication spectrum to an increasing number of other diseases or disorders. This, however, is faulty logic since DBS was initially elaborated as a therapeutic protocol for movement disorders and not as a research tool. For delivering other than isolated and unspecific data the associated methodology is still lacking sophistication. Likewise, the dysfunctions and pathomechanisms of mental diseases are, in the opinion of the author, extremely complex and, in addition, encompass a large, if not dominating component, i.e. biochemistry. Summing this up, the use of suboptimal research techniques to investigate hypercomplex entities, and their pathomechanisms which are not or only ill understood by underestimating other, maybe more central aspects of these problems such as genetics, developmental biology, systems theory and – last not least – neurobiology, is in the author’s opinion an exercise in futility. On closely examining the entire complex a further conundrum turns up that will be hard to deal with: Given that DBS remains more or less on its technological level and that it is restricted to the known treatment of movement disorders, there will be no problems, except occasional but correctable side-effects due to electrode displacement or current spread to the neuronal circuitry of other, unrelated systems. Should it be attempted – without previously having largely enhanced the knowledge base about the respective indications – to treat other, especially psychiatric disorders at the same level of technology, the outcome will be unpredictable and possibly dangerous, because it large194

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ly depends on the individual case and a variety of free parameters that cannot be kept constant yet. Thus the results of accompanying investigations will neither be systematic nor coherent. As a consequence, treatment can only improved and beneficial outcome increased in movement disorders, if there is at least a pathophysiological framework, and if the techniques for stimulation and recording are refined as to their selectivity and specificity. Again, the argument that further experimentation in humans is needed here does not hold, since methodology can, to a very large extent, be developed under constant laboratory conditions in animal experiments. Whether any successful intervention using neuromodulation alone can be attained at all in the hypercomplex mental disorders without simultaneously addressing other aspects of mental disorders, like the biochemical one, only the future will tell. Little is to be gained with a refined stimulation technology alone, if its optimum targets remain elusive. Here, animal experiments with the possible exception of those done in primates are of little help either, since there is no condition in the animal kingdom that could model the schizophrenias or the bipolar diseases. As with other scientific issues, with DBS there is the classical ‘dualpurpose’- problem: Inventing and refining a technique that may be used – particularly so when sufficiently refined and sophisticated – to both good and evil ends. On the one hand, creating a direct access to the CNS is desirable, since it probably will improve medical treatment and extend our knowledge about neuronal circuitry. On the other hand, this is the first time in medical history that the possibility opens up to immediately influence information flow and processing or even to devise information of exterior origin and to feed it into the system ‘brain’ or into one of its sub-systems for purposes other than purely therapeutic ones, such as altering cognition and conscience or, ultimately controlling the mind of innocent individuals. It is the neuroscientist’s dilemma that – in order to treat dysfunctions so far untreatable – he creates a method along with suitable instruments which he strives to continuously improve and acquires the systemstheoretical knowledge he needs to influence his targets in the brain with the classical scientific mindset that it all will be ultimately to the benefit of his patients. Whether he reflects other, more dire consequences of his research is quite another matter. This should, however, be of great concern to him as well as to his peers and to the public. Today, many research and development activities have the potential to come up with dual-purpose results; deplorably, this is nothing new or special. These results, used with the same instruments and knowledge 195

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may, on the one hand, save lives, if applied in an ethical and morally responsible way, or they may destroy them, if used with a lack of ethical consideration, either negligently or with outright rogue intention. As soon, however, as we will have reached a conceptual and technological level sufficing to manipulate the material correlate of human thought, mind, self, personality or even soul in an intentional and controlled manner, the quality of this problem will shift or be overturned immediately, radically and – worst of all – irreversibly. Accordingly, our paradigms will also have to be altered profoundly and radically. So should we also raise the level of our awareness as morally responsible human beings and especially as neuroscientists to the extreme, when it comes to discussing issues concerning evolutionary steps in medicine automatically being converted into revolutionary events with the most far-flung consequences by the coincidental upcoming of the ‘fitting’ technological developments. Attempting to stop important but critical medical research would be foolish for two reasons: First, freedom of science would be violated and second, undesirable progress in this field would at best, be delayed. The same is true for research and development in the technological sector. Although most readers may believe that the author is overstating his case, he would nevertheless like to point out certain historical parallels: When Otto Hahn experimentally proved that nuclear fission was a reality in 1938, he openly published his findings with the best of intentions as purpose-free scientific results, not considering possible consequences outside science. At this time he had – both unknowingly and unintentionally – opened Pandora’s Box. The possible, and as some researchers believed, probable consequences, however, became clear in nuclear science almost immediately thereafter. At once, politics stepped in and further publication was first restricted and subsequently totally suppressed. Although there was considerable resistance to build a nuclear device by eminent scientists both on the German and the American side, the matter was quickly taken out of the scientists’ hand on both sides of the Atlantic, and the initially purely scientific issue of nuclear fission was converted to an engineering task to be instrumentalized as a weapon. In spite of a number of petitions signed by conscientious scientists directed to the American president, the first nuclear device was built and tested. It took not even 8 years from Hahn’s laboratory-scale proof of principle to the detonation of the Hiroshima and Nagasaki atomic bombs in 1945. Even if America or Germany would have unanimously abstained from building such a weapon, a few years later somebody else would have done it. 196

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It is self-evident that scientific concepts or findings themselves are – from an ethical point of view – neutral. To be held morally responsible are those who convert these concepts into procedures or devices that serve their own selfish or political ends at the cost of others losing their mental liberty. It is still unclear, whether Pandora’s Box is already open in the case of mind control on the basis of neuroscientific findings and as a result of – in the broadest sense – technological achievements. Finally, it all comes down to that: Once the ghost is out of the bottle, there will be nobody who is able to put him back in. Nevertheless, there are case reports on complex reactions that surpass motor control and involve systems still poorly understood, like the limbic. Here, one of the best-known examples is the observation of Krack et al. (2001) who evoked ‘mirthful laughter’ in a patient simply by electrostimulating part of the accumbens nucleus in a patient undergoing stereotactic neurosurgery (Okun et al. 2007). Although being a serendipity finding, this report, among others, should alarm the neuroscientific community about to what extent the brain eventually may be influenced already. This alarm should lead to an assessment of worst-case scenarios for the future, to the definition of pre-emptive measures against such attacks at higher brain functions as well as at the ‘mind’ and the ‘self’, and finally to the drawing up of contingency plans for the case that all regulatory measures, from voluntary ethical reflection to punishment of the perpetrators under penal code, anchored in national and international legislation, should ultimately fail. However, after the fortunately rather unspecific, hardly reproducible and therefore unsuccessful experiences made with psychotropic drugs like LSD, sodium thiopental, mescaline on the one hand, and with a host of Pavlovian and non-Pavlovian psychological conditioning techniques on the other, methods that were systematically tested in persons that were not aware that their minds and their actions were about to be controlled by others. These may be individuals, governmental or military bodies or – best known to the population owing to the information dissemination by the media – religiously or pseudoreligiously oriented communities, the parties involved may well recognize by now that a direct communication with the brain, obviating time-consuming psychological conditioning programs, i.e. direct transfer of the desired content to the brain, may be the future method of choice to achieve their unethical ends. Here, it is important to realize that studying the neural circuitry as the material basis of the higher functions to be controlled, is a dual197

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purpose type of research: On the one hand, there is the overwhelming desire of the medical community, especially the theoretical and clinical neuroscientists, to cure or at least make bearable for the patients certain severe neurological diseases and to understand how this works on a cellular or network level. There can be no doubt that this objective is entirely legitimate in both a juridical and ethical framework, as long as the fundamental guideline of any therapeutically active physicist ‘nil nocere’, meaning: ‘do no harm to the patient’ is strictly adhered to. However, as history, especially that of the 20th century, has taught us, the reverse side of the coin is rather grim. Given the limited conceptual, neuroscientific, and technical means available in the mid 1930’s (during the first wave of mind control done by the NKVD headed by Yeshov on orders of the Prosecutor General Vyshinsky), in 1950 (Korea conflict; with consistent reports of systematic brainwashing done in American soldiers by the North Koreans as well as the Chinese), the MKUltra-program instigated by the American CIA on average, uninformed American citizens and continuing thereafter, there is not even the shadow of doubt that the determination and strong resolve to control other individuals’, groups’, classes’ and minority social groups’ minds has – in millions of instances – gained such a strength, vigour and obsession, that the traditional ethical boundaries set up by philosophy and – ambiguously so by religion – have virtually been swept away at an instant. Here, it is of particular significance that the perpetrators got away with their crimes without being appropriately punished by the respective societies or nations, because laws regulating this were simply non-existent. Only a very few of them were actually put to trial and have been condemned for crimes the definition of which remains more than diffuse (crimes against mankind, violation of the dignity of man). To make this quite clear, none of the perpetrators known for their efforts at controlling the mind with means as crude as torture and as sophisticated as pharmacologically aided operant conditioning, refined interrogation, indoctrination and conditioning techniques, have so far been prosecuted or even condemned for the actual misdeeds they have committed, i.e. for attempting to undermine, infiltrate or simple rob other persons of their most individualist, private and unique personal traits. One of the central problems certainly consists in probably a great many of them securely being embedded in governmental agencies, where they act with the full consent of their superiors and are beyond the reach of parliamentary control or even jurisdiction, be it local, national or international. It goes without saying that any traces of their actions are most easily covered up in such a type of clandestine organization which thrived and continue to do so in virtually any nation on the globe. 198

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It is not unreasonable to assume, that these bodies which may, very simplistically, be termed secret services or secret-service - like agencies, may command the most ample resources. As a rule, they firmly rest on the juridical and legislative basis of the nation they belong to and are protected by. It is unnecessary to discuss here similar clandestine, governmentaligned organisations that are not legalized but condoned or actively supported and funded by nations that have a military or politically interest in their actions, not to forget so called ‘freedom movements’, or openly terrorist entities where group coherence and total obedience are essential. Generally, the public is kept in the dark about their objectives, and there is no coordinated resistance among citizens against the perpetrators’ unlawful actions. This, however, is not always the case with bodies straining to be ‘churches’ such as Scientology, and requesting the protection of ‘freedom of religion’ that is, at least formally, codified in the constitutions of most civilized nations. Many of them are under the constant observation of the press and of the population, since many a family has over the last decades been confronted with the fact that a family member has been brought under the control of these fraudulent religions or cults and accordingly been stably indoctrinated to adhere to the respective ‘codices’ being the social and psychological backbone of these pseudoreligious groups that usually operate in the grey zone at the brink, or even beyond, of the civil code they are under as legal persons or the penal code that is relevant for them as individuals. The most important lesson for the neuroscientist to learn is that these stable indoctrinations have been exclusively achieved with the conventional arsenal of psychological instruments sketched above. In plain language, these ‘successes’ in personality destabilization, group obedience, extinction of individual personality traits, etc. were done without any direct access and therefore with the lack of the possibility to straightforwardly transfer exogenous information and content to the brain by surgical intervention or brain stimulation techniques. Consequently, the danger of altering the original hard-wiring of these brains may be considered to be less severe than probably with direct access. Over the past decades, several ‘deprogramming’ techniques have been developed to rid these victims of the often mentally fatal consequences of these massive assaults at their thoughts and notions. Deplorably, these excellently devised techniques having been developed and advocated by the most reputable scientists in their field, although

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being extremely useful and defining further efforts into this direction have not proven to be successful in a number of cases. DBS may develop from an invaluable therapeutic tool with an immense beneficial potential into an efficient instrument for influencing mood (Castrén 2005) and finally for controlling thought (Russel and Norvig 1995; Turing 1950). Here, DBS would be the technique of choice, since its usage were comparatively easy to justify and to accept socially on the ground that this technique is a rather harmless, since reversible, means of ameliorating or curing a wide spectrum of neurological diseases. This makes this regimen an ideal dual-use technique for applications that are ethically and legally justified while, from a therapeutic point of view, it is an absolutely desirable instrument. On the other hand DBS is also attractive for rogue physicians, doing experiments that serve their own selfish goals or those of the types of organizations described above. Since brain stimulation is deterministic – by contrast to the uncontrollable action of stem cells that, for instance, may evoke psychotic behaviour by electrophysiologically or neurochemically altering normal homeostasis (Mamelak 1998; Freed 2002; Freed et al. 2003, 1990) – this wilful interference from the outside is a much more dangerous instrument for destroying the free will and abolishing the self (Dawkins 1976; Hacker 2003; Price 2005). It would be utterly naïve to believe that a technically feasible line of research will – for ethical reasons – not be exploited to any imaginable extent, even if this had the most severe consequences for mankind. We consider large-scale and routine stable mind control at least morally equal to the annihilation of the human species by thermonuclear, biological or chemical warfare. It is one thing to drive a single individual into insanity using traditional psychological tools or outright torture, but it is infinitely more evil to intentionally and systematically rob a large number of human beings of their personalities by destroying their freedom of choice in order to coax these victims into thinking or doing things they would never have thought or done, if they still were guided by their own ethical code acquired in the course of their normal socialisation. The presence of such an ethical, self-evident code in every conscientious individual is the hallmark of humanism. Although all this may sound dramatic and overdone at the present time, we cannot deny that the wish to control other people’s sensory impressions, the interpretation of those, the ensuing formation of thoughts, notions and ideas, in order to finally determine their actions has been an issue since antiquity. So far, the human brain has proven to be mostly resistant to and able to recover from the more specific 200

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psychological conditioning techniques or pharmacological interventions being sufficiently specific to hold any value to induce its owner to think thoughts that are not his own or to perform actions he would never have consented to if he had had the freedom of choice. Deplorably, it is quite true that anybody’s will may ultimately broken by torture, extreme pain or by most elementary fear, but it remains doubtful, if autonomy and freedom of thought may be eradicated in this way reproducibly and on a large scale. Now, the writing on the wall is clear, even after the horrendous experiences with surgical interventions like lobotomy: Unfortunately, the emerging discipline of neuromodulation has even been denominated ‘Psychosurgery’ (Manjila et al. 2008; Ogren and Sandlund 2005) despite the utterly negative connotation of this term. This does by no means imply or even insinuate that researchers in the field of brain stimulation are evil-minded or criminally inclined persons. It is – on the contrary – the objective of this essay to caution researchers in the DBS-field and to urge them to continuously reflect on their actions and on possible consequences, if the method got into the wrong hands. This may easily be the case since all results are reported in the public domain. However, it takes no training in neurophysiology or psychiatry, to acknowledge that DBS has the potential to indeed turn into a ‘dual purpose’ instrument the more so as this technique will be refined. Since a large number of scientists is currently doing research in this field, it would be irresponsible to stigmatize them as potential perpetrators. However, it would be equally irresponsible or even utterly foolish to ignore or deny the possibility that this technique may be used to amoral and evil ends. Being a neuroscientist myself involved in both SC- as well as DBSresearch and certainly no luddite at all, I maintain that it is only a matter of time, allocation of sufficient resources and the fierce determination to penetrate and neutralize the inherent protective mechanisms of the brain, until the technical questions will be solved, i.e. an interface between electronics and neuronics with sufficient selectivity, specificity and bandwidth created, and the immense computational power made available to convert science fiction into dire reality (Le Doux 2002; McClamrock 1995). As far as we can judge, there is no natural law to automatically prevent this. One possible exception is the mathematical truism that in order to analyze a complex system an even more complex system, i.e. one of higher mightiness, is required. Here, as with stem cells, its own complexity may be the brain’s last intrinsic line of defence. 201

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History tells us that totalitarian but also democratic regimes have gone to great lengths to achieve total obedience via mind control, using comparatively primitive means in brainwashing, such as Pavlovian conditioning, tachistoscopy, hypnosis, psychotropic drugs etc. Although this may be an extremely pessimistic line of thought, the inventory being created at the moment with the best of intentions may prove to be the key to make possible such an irreversible and apocalyptic development.

Ad v a n t a g e s o f B r a i n S t i m u l a t i o n o v e r Stell Grafting However, DBS or electric brain stimulation in general has three invaluable advantages over stem cell grafting: 1) Stimulation may be switched off or neutralized if untoward actions should occur or develop. 2) Developmentally, an electronic circuit is stable, its functions are preconceived, and we can assume its operation to be strictly deterministic. Therefore, we must not fear its autonomy. This is true for single-purpose electronic devices, for future closed-loop systems obeying the general laws of cybernetics (Wiener 1948), as well as for any upcoming computer-aided circuitry, as long as the central processing unit belongs to the class of Turing machines. 3) For Parkinson’s disease refractory to pharmacological treatment DBS is both highly efficient and safe. Since nearly two decades, about 40.000 patients have been implanted. In Germany alone, about 1.000 to 1.300 patients are being operated annually, using minimally invasive stereotactic procedures. In selected centers, the risk of intracranial bleeding is well below 1%. Thus, provided the initial diagnosis is correct, DBS is the method of choice in treating patients with severe PD refractory to pharmacological regimens. The same is true for other movement disorders such as essential tremor and the dystonias. Yet, it has to be pointed out that the efficiency of DBS is a serendipity finding and that its mode of action is not as well understood as would be desirable in spite of considerable research activities. To reiterate this: should the medical need arise, the DBS system, comprising intracranial electrodes and an extracranial pulse generator implanted subcutaneously may be removed at once and the status quo 202

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ante restored. As will be shown later, it is already possible with today’s technology to improve on some shortcomings of DBS and to substantially increase the technique’s spatial selectivity, meaning that the specificity of the stimulation may be improved markedly in the foreseeable future. As sharply opposed to this: stem cells and SC-based grafts are developmental time bombs as has been demonstrated in animal experiments (Erdö et al. 2003). Once implanted, they are no more under the control of the surgeon or physician. Most often, it is quite uncertain what they will do when the boundary conditions change, e.g. when they are exposed to the microenvironment of the host brain. Their actions are not controllable to any reasonable extent. Likewise, their development schedule is unknown and may change, simply because cell cultures, as sources of SC grafts, age and their genome accumulates defects over time. Selecting freshly prepared cells for each implantation case would also not be a realistic option, because the ‘initial conditions’ were not comparable among different SC batches. Under such conditions it would be hard to do meaningful clinical studies about the SC-grafts’ efficiency. In addition, as already lined out, the ‘differentiation schedule’ of SCs does, under no circumstances, match that of the host cells. Except for some of the more general growth or development factors, we may suppose that the grafted cells can neither read nor decipher the messages of the host ‘master clock’, of the timer governing the presentation of developmental key signals, and of diverse developmental pathway selection mechanisms (e.g. neuralizing vs. non-neuralizing). Probably it is not feasible to re-enact local development at 10-50 x the normal speed and expect results that are not only working as intended, but also stably so (Rakic 1998). This is underlined by the observation that most stem cells die after contact with the host medium, particularly, when the cells come from different individuals, or even more so, from different species. Especially in early stem cell work, it is amazing to observe the hopes and expectations, verging on the irrational, put on this novel research field (Hodges et al. 2003; Modo 2004, 2006, 2008; Hoehn et al. 2002). As an example, stem cells were presented by some groups or individual researchers as a virtual panacea for all diseases conceivable. They were popularized accordingly while disregarding facts that did not fit into this positive picture and neglecting openly recognizable conceptual and technical difficulties. As a consequence, there was never a real widespread scientific discussion of the medical, technical and ethical issues that arose from

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their utilization, since any hint at possible failure of the concept was, and partly still is, anathema. At least in Germany, the ethical discussion primarily revolved around questions relating to the source of human stem cells, i.e. whether it was ethically justifiable and forensically legitimate to use aborted embryos for harvesting new stem cell lines. This discussion which was led quite fervently within both the neuroscientific community and the German legislature essentially missed the core of the matter, in neglecting the problem of preserving both physical and mental integrity of future recipients of SC-derived grafts. On the basis of rat and mouse experiments in neurotrauma or stroke models, where predominantly soft data such as elementary behavioural functions were obtained during mostly rather short observation periods (usually 3 months), SCs or progenitor cells were initially considered a treatment modality requiring as little as possible interference from the physician. The observation that in rodent models soft parameters tended to improve prompted the fallacious notion that stem cells have the potential to act as ‘fire and forget’ weapons for combating a wide variety of CNS diseases (Magnus et al. 2008). It was, however, overlooked or ignored that transferring results and conclusions from the rodent CNS with its minute and simple neocortex to the human brain would be more than problematic. It was equally not realized that treatment respecting the boundaries of other – functionally different or disjunct – systems will not be possible as a result of the SCs’s elusive propagation, migration and differentiation properties (Rakic 1990). Self- or microenvironmentally guided migration to the ‘target’ depends on many factors which have not been identified yet and, consequently, are neither predictable nor subject to external attempts at influencing or even controlling them (Rakic 1990). Even worse, for a precise, predetermined migration and end-stage homing on the target area, it is reasonable to assume that for each trajectory describing a specific SC locomotion from the engrafting site to the target area a singular set of temporal, spatial, local and concentration-dependent neuro-humoral factor combinations is required. These sets are presently unknown and only subject to conjecture. Today, we only know or have drawn the conclusion that, for instance, the emission of chemotactically active or otherwise SC-attracting substances is required and that migration of SC is greatly accelerated along preformed anatomical pathways, such as fibre or white matter tracts, a fact that has for a long time been known to be true for the dissemination of glioma or 204

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glioblastoma cells. The developmental and differentiation problems have been treated in depth by Rakic (1998, 2002a, 2002b, 2005); especially neocortical problems have been addressed by Bystron (2008).

Conclusion With regenerative medicine in the form of stem cell therapy for neurorepair (Kaslin et al. 2008; Kessaris et al. 2008; Li 2008; Reynolds and Weiss 1992; Zhang et al. 2008) and with deep brain stimulation for altering certain cerebral functions in order to ameliorate or abolish various ‘functional’ CNS diseases, we are regarding two techniques that are comparable to only a very limited extent. What they have in common is the following: • Both have a considerable potential to fulfil their tasks once they are sufficiently mature • In spite of considerable work, their theoretical basis is still rather unstable • Both may have severe side-effects which possibly cannot be countered for the lack of sufficiently understanding the method, its mode of operation and its consequences • The application of both is discussed in a highly emotionalized manner as a result of the therapeutical benefit hoped for • From the point of view of evidence-based medicine (Sacket et al. 1996; Torpy et al. 2006; Little and Rubin 2000; Elstein 2004), the benefits claimed for both techniques are debatable, in view of the fact that mostly single cases or studies in small cohorts are reported (this does not hold for the positive effect of DBS in PD refractory to pharmacotherapy which is well-documented) • To stay within the context of this essay, SC-grafting as well as DBS most probably have the capacity for mind-altering, since they strongly interact with the brain as the material basis of thought, mind, self and other emanations thereof. Therefore, in both cases, a large number of ethical issues will arise, before these techniques may be clinically applied on a large scale; again with the exception of PD treatment by DBS. In a simplified manner, SC-therapy is a technique that comes from the bench, i.e. is based largely on animal experimentation, whereas DBS has emerged from the lucky finding that stimulation of certain deepbrain nuclei resulted in the cessation of resting tremor during a neurosurgical-stereotactic operation. That means that this particular kind 205

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of neuromodulation does not come from the bench, but rather from the operation room. This may be the reason why there is less animal experimentation – as far as it is justified to compare this – than with SCtherapy. Thus, DBS lacks or has circumvented the stage at which most undesirable effects of innovative techniques are identified and eliminated. Both from a scientific as from an ethical position, this is a major concern which, as of the time of this writing, is not discussed openly as has been the case in SC-work. Now the differences: • DBS has the invaluable advantage of being completely reversible, meaning that the stimulator may be switched off at any time and even the entire system removed from the patients’s body. The only consequence is the return of the symptoms which – if possible – have to be coped with otherwise. The value of the reversibility of this method cannot be overestimated. • SCs become uncontrollable once they are implanted, and, as yet, their further interaction with the recipient’s brain is absolutely unpredictable. There is no conceivable means of removing them from the CNS, except to engineer them with a redundant and therefore fail-safe suicide mechanism that may be activated from the outside. However SC-therapy must be considered irreversible, at least, inactivating them as outlined above is only a theoretical option which has never been practiced. In opposition to that, electronically controlled neurostimulation is entirely deterministic. • SC-grafting and DBS-therapy, for instance with PD or neurodegenerative diseases (Lazic and Barker 2003), indications that are addressed by both methods, are conceptionally widely different: Whereas the rationale for SC-treatment as part of Regenerative Medicine is apparently rather straightforward in assuming – correctly or not – that defunct telogenic brain cells may be replaced by pluri- or totipotent cells that differentiate in a way to eventually take over their functions. DBS, on the other hand, does not aim at replacing destroyed tissue, thus restituting the latter’s previous functions, but rather at correcting ‘dysfunctional’ subsystems of the brain by supplying the brain with information (stimulus trains) being intended to re-convert a dysfunctional subsystem into a functional one. It must be reiterated, that the rationales behind SC or DBS-therapy remain incomplete, mechanistic and maybe over-simplified, since

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neither the mode of action of the therapies themselves, nor the targets’ structure and function are understood well enough. This is particularly true for DBS when attempts are made to expand the spectrum of indications beyond extrapyramidal motion disorders like PD, essential tremor and the dystonias. It is unclear what clinical entities like major depression, obsessive-compulsive disorders, drug dependence, alcohol abuse, Gilles de la Tourette-syndrome, neurodegenerative diseases and even the schizophrenias might have in common to make them suitable for DBS treatment. To put it simply, Parkinson’s disease and the neurodegenerative disorders do have a morphological correlate (Arias-Carrión et al. 2006, 2007; Lazic and Barker 2003), depending on the progress of the disorder, alcohol abuse and drug dependence may also be associated with morphological alterations, but major depression, schizophrenia, or Gilles de la Tourette generally are not. For all these disturbances, a positive effect of DBS is claimed. However, one is hard-pressed when it comes to forwarding a hypothesis, how disorders with a large biochemical and cell-biological component like Alzheimer’s disease should profit from essentially the same kind of neuromodulation as may be efficient in presumed network phenomena like PD or other extrapyramidal motion disorders (Adeli et al. 2008). Here the level of epistemology, i.e. ‘Erkenntnistheorie’ appears to be rather low and urgently needs to be raised. The present practice of selecting a CNS disease or disorder and to apply electrostimulation to the structure held responsible is a trial and error approach, which may become potentially dangerous for the patient, if higher brain functions are affected (Lakoff and Nuñez 2000). Owing to the connection of most deep brain targets with the limbic system (Weinberger 1993), the thalamus, and fronto-basal cortical areas, the likelihood of inducing personality changes (cf. Krack 2001) must not be neglected. Before attempting to treat functional CNS disorders, a thorough understanding of the neuronal circuitry involved should be mandatory, ideally well in advance of feeding any ‘information’ even if it is as simple as a fixed-frequency pulse train or a barely more complex stimulation sequence into the structure or network held responsible for the dysfunction. Here, we identify a major ethical issue, when a therapeutic regimen is carried out using a technique the foundation of which is weak in regions the circuitry (active elements like neurons or impulse propagation structures like axons) of which is only assessed on a neuroanatomical basis with conjectures derived from there and not additionally on a functional one. The classical analysis would consist in

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Mapping the area using its resting and – as far as possible – evoked activity as a criterion Reconciling the results with neuroanatomical and neurochemical data Identifying neuronal circuits within this area and identifying their inputs and outputs which may be done by microstimulation in association with microrecording By feeding white noise or Dirac’s δ-function into a presumed ‘input’ and measuring the resulting potential changes at the presumed ‘output’, it may be possible to reconstruct the impulse response or transfer function of this circuit. However, we have to assume that even simple biological circuits have more than one input and one output. Therefore, the circuit under study probably has a set of transfer functions which have to be determined individually. In addition, neuronal circuitry is both instationary and non-linear. Therefore, the appropriate non-linear dynamic algorithms have to be chosen, if meaningful insights into this circuit’s workings are to be obtained. In nuclei such as the subthalamic or the accumbens, there is neuroanatomical evidence that they are composed of a multitude of such circuits. These have to be analyzed and the data compared to the anatomical maps of that area. It is well known that such deep brain nuclei often are multifunctional, i.e. that they may consist of a sensory-, a motor- and a limbic, i.e. higher function part. These parts which may be considered as subsystems of a subsystem have to be discerned from each other and mapped accordingly. Again, cytoarchitectonical data have to be factored in. Based on histological results, the connections of this nucleus to other structures in its vicinity, but also to distant brain areas, i.e. its projections, have to be studied functionally, for instance by putting in a test signal at the target and by recording the evoked response at the projection site(s). Since such connections very often operate bidirectionally, input and output have to be exchanged. As an ancillary approach, diffusion tensor imaging (DTI) may be helpful, especially with long fibre tracts. One should also study, whether a given nucleus shows a prevailing ‘standard circuit’ or functional unit.

This is the standard procedure in neurophysiological animal experimentation. It goes without saying that functional mapping of the human brain or parts thereof is a tremendous task requiring determination, 208

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skill, imagination and – first of all – time. The dilemma is that these measurements can only be done intraoperatively and must be limited in their duration for avoiding harm to the patient. Therefore, functional mapping is a venture much more complex and demanding than anatomical mapping with cytoarchitecture and fibre staining as the essential techniques (Brodmann 1909). However, there is no way to obviate this, if real hard information that may be quantified, has to be obtained, because imaging techniques like fMRI or PET cannot provide the required resolution in space as well as in time. Even with a high static field MRI scanner (> 3 T) with optimum gradient coils it is doubtful, whether voxel size in the fMRI mode may be narrowed down to a submillimeter scale. The temporal resolution, however, is absolutely insufficient for the task. With PET, the situation is even worse. The temporal resolution of the EEG would not allow identifying a spike; in addition, the technique’s spatial resolution is bad from the outset and becomes worse the deeper the observed structure is embedded in the brain. With MEG, the situation is not much better. Applying low resolution tomographic methods like sLORETA resolves current sinks and sources only in the centimeterrange (Pascual-Marqui 2002; Pascual-Marqui et al. 1994; Janjarasjitt et al. 2008; Járdánházy A. and Járdánházy T. 2008). Nonetheless, a combination of the above-mentioned methods may at least give a general idea about functional dependencies which may facilitate microelectrode recording. To put it somewhat ironically, treating CNS-disorders with DBS at its present state is like repairing a complex electronic instrument with a sledgehammer. It is the firm belief of the author that selective stimulation techniques will eventually be of very great value for the treatment of cerebral dysfunctions.

The Bottom Line The techniques for selectively stimulating and recording will have to be developed. Before, however, the researcher or surgeon has the proper tools at hand, it is ethically not without problems to treat with DBS any indication other than motion disorders. The damage that might be done is possibly irreversible and may well outweigh the therapeutic benefit one hopes for. Only with solid knowledge about how and what we are treating when addressing a condition in the brain, can we hope for efficient and reproducible therapeutic benefits. Therefore, this technique must absolve the step omitted so far, i.e. return to the bench, and undergo all tests usually absolved before a novel therapeutic tool is 209

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positively sanctioned by the authorities. Even if the desired selective multi-channel stimulation hardware as well as stimulation protocols resting on a firm neurophysiological basis and on functional brain mapping as well as thorough circuit analysis of the target are completed, addressing mental disorders has to be done with utter caution until there is sufficient evidence for elucidating the pathomechanisms for major depression, schizophrenia and related disorders on a cellular and biochemical basis. The same is true for neurodegenerative diseases (cf. Hou and Hong 2008). One could, however, argue that it is unethical to deny a superior therapy to the ailing patients. In the author’s opinion none of the different stem cell techniques and treatment protocols is sufficiently mature to justify its application in humans. Stem cells have to remain a scientific tool until the information and knowledge permit to state with a high degree of certainty that the ‘safety’ and ‘technical’ issues are well controlled, that the method is efficient in neurorepair in primates – corroborated by histologically, ultrastructural and electrophysiological as well as clinical evidence – and that for the respective indication mind, thought or personality alterations may be excluded according to the most stringent criteria. In addition, the engineering into stem cells for therapeutic use in humans of two independent programmable suicide mechanisms that may be armed and triggered from the outside should be mandatory.

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Pe rs onalit y C ha nge s through Dee p Brain Stimulation of the Subthalamic Nucleus in Parkinsonian Patients – An Ethic al Disc us sion SABINE MÜLLER

Introduction Parkinsonian patients are suffering from a chronic neuropsychiatric disorder with severe motor dysfunctions (tremor, rigor and dyskinesia) as well as cognitive, affective and behavioral symptoms. All known treatment of Parkinson’s disease (PD) are only symptomatic and do not prevent disease progression. The treatment of PD both via drugs and via deep brain stimulation of the subthalamic nucleus (STN DBS) implies the risk of psychological and behavioral symptoms (Saint-Cyr and Albanese 2006). Affect can be dramatically modulated by the selective manipulation of deep brain structures (Bejjani et al. 2002). Although the beneficial effects of STN DBS on motor functions have been well described, its consequences on the associative and limbic circuits and associated neuropsychological functions have received relatively little attention until recently (Woods et al. 2002; Temel et al. 2005: 395). Personality changes through DBS are discussed since 1998 in the medical press, but until now it is barely communicated with the patients. Whether or not these psychic alterations are unwishful side-effects or welcome, depends on many factors, and they are difficult to predict for the individual patient. 223

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In this paper, firstly the scientific literature about psychic changes through STN DBS is summarized, and secondly an ethical analysis of this therapy is performed.

Parkinson’s Disease and its Treatment Histopathologically PD is characterized by selective, chronic and progressive degeneration of the Dopamin producing cells of the nigrostriatum. This leads to a continuous abnormal bursting mode of activity of the nucleus subthalamicus (STN). This STN hyperactivity increases the activity of the basal ganglia output nuclei, and, consequently, excessively inhibits their targets. This mechanism is held responsible for at least part of the cardinal PD symptoms such as hypokinesia and rigidity (Temel et al. 2005: 394). Administration of dopamine agonists reduces firing rates in the internal globus pallidum and STN and thus alleviates motor symptoms (Schneider et al. 2003: 296). Most PD patients can be effectively treated with levodopa and other medications. In spite of the drugs the disease progresses. Some patients develop variability in their response to treatment, so-called motor fluctuations. During an ‘on’ period, a person can move with relative ease, often with reduced tremor and stiffness, but during an ‘off’ period the person has difficulties with movement. Another form of motor fluctuation is dyskinesia (choreiform movement) (National Parkinson Foundation 2008). Parkinson’s disease is associated with a wide range of cognitive and psychiatric symptoms which can be even more challenging than its motor manifestations. Most frequent are apathy, depression, and psychosis. Besides that, symptoms of impulse control disorder, such as pathological gambling, addiction to levodopa, or hypersexuality have been reported. These symptoms are associated with dysfunction of reward processing systems (Pagonabarraga et al. 2007). When wearing off and dyskinesias cannot be managed with adjustments of medication anymore, or when the drugs cause significant side-effects, surgical treatment may be considered. The first surgical procedures developed were brain lesioning procedures (thalamotomy and pallidotomy) (National Parkinson Foundation 2008). Chronic stereotactic deep brain stimulation (DBS) of the subthalamic nucleus has the same clinical effects as a lesion with respect to the motor functions, but the additional advantages of adjustability and reversibility (Temel et al. 2005: 394).

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DBS surgery involves placing a thin metal electrode (about the diameter of a piece of spaghetti) into one of several possible brain targets and attaching it to a computerized pulse generator, which is implanted under the skin in the chest (much like a heart pacemaker). All parts of the stimulator system are internal. The stimulator can be adjusted by a physician using a programming computer held next to the skin over the pulse generator. Instead of lesioning brain tissue, DBS reversibly alters the abnormal function of the brain tissue in the region of the stimulating electrode. DBS does not act directly on dopamineproducing cells and does not affect brain dopamine levels. Instead, it compensates for one of the major secondary effects of dopamine loss, the excessive and abnormally patterned electrical discharge in the globus pallidus (GPi) or the STN. There are three possible targets for placement of stimulating electrodes: the GPi, the subthalamic nucleus (STN), and the ventro-intermediate nucleus (Vim) in the thalamus. These structures play critical roles in the control of movement. Thalamic stimulation (Vim) is only effective for tremor, whereas stimulation of the GPi or STN may benefit also rigidity (muscle stiffness), bradykinesia (slow movement), and gait problems (National Parkinson Foundation 2008). Stimulation of the Vim or of the GPi seems not to produce behavioral changes as stimulation of the STN (Temel et al. 2006: 268). An advantage of DBS over ablative procedures is the opportunity to vary the parameters of stimulation (frequency [Hz], pulse width [µs], and amplitude [V]) (Woods et al. 2002). Typically these operations are performed with the patient awake, using only local anesthetic and occasional sedation. The surgery is performed stereotactically: A rigid frame is attached to the patient's head just before surgery, after the skull is anesthetized with local anesthetic. Through a small skull opening, deep brain structures can be reached. MRI is obtained with the frame in place. The images of the brain and frame are used to calculate the position of the desired brain target and guide instruments to that target with minimal injury to the brain. To maximize the precision, fine microelectrodes are used to record brain cell activity in the region of the intended target to confirm that it is correct, or to make very fine adjustments of 1 or 2 mm. The brain mapping produces no sensation but patients must be calm, cooperative, and silent during the mapping. The brain’s electrical signals are played on an audio monitor so that the surgical team can hear the signals and assess their pattern. The neurological status of the patient (such as strength, vision, and improvement of motor function) is monitored frequently during the operation. Once the target site has been confirmed by microelectrode recording, the permanent electrode is inserted. It is 225

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anchored to the skull with a plastic cap, and the scalp is closed with sutures. The patient then receives a general anesthetic for the placement of the pulse generator in the chest and for positioning of connecting wires between the brain electrodes and the pulse generator unit (National Parkinson Foundation 2008). The most serious potential risk of the surgical procedures is bleeding in the brain, producing a stroke. The average risk is about 2%. The effects of stroke can range from mild weakness that recovers in a few weeks or months to severe, permanent weakness, intellectual impairment, and death. The second most serious risk is infection, which is about 4%. An infection is usually not life-threatening, but it may require removal of the entire DBS system. In most cases, a new DBS system can be re-implanted when the infection is eradicated. In the first few days after surgery, it is normal to have some temporary swelling of the brain tissue around the electrode. This can produce mild disorientation, sleepiness, or personality change that lasts for up to 1 - 2 weeks (National Parkinson Foundation 2008). DBS of the STN mostly leads to a significant improvement of motor functions (50% - 60%) (Schneider et al. 2003) and to a reduction of antiparkinsonian drugs by approximately 60% (Temel et al. 2006). Often affective processing and subjective well-being are enhanced (Funkiewiez et al. 2003; Funkiewiez et al. 2004; Schneider et al. 2003; Houeto et al. 2006; Woods et al. 2002). Some patients report about posttraumatic stress disorders after DBS surgery. Especially the drilling of the skull with only local anesthesia seems to be traumatic. Helmut Dubiel, a known sociologist at Frankfurt University, reported that during his DBS surgery he felt like a dog that undergoes an attack with a chain saw on his doghouse (Dubiel 2006: 94). Afterwards he suffered from nightmares and severe depressions. Meanwile, several surgeons (e.g. H.-W. Bothe, University Hospital Muenster, Germany) operate under full anesthesia in order to prevent the psychic traumatisation. Possible long-term side-effects are speech and swallowing disorders (Ehlen 2007). Besides this, more and more studies report about psychiatric side-effects.

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P s yc h i c S i d e - e f f e c t s o f D B S o f t h e Nucleus Subthalamicus (STN DBS) The first clinical findings of neurobehavioral outcomes of STN DBS were published in 1998 by Limousin et al. In 2002, a review of Woods et al. which evaluated 16 papers about STN DBS provided “preliminary support for the cognitive and behavioral savety of this treatment”. The most common findings of the studied reviewed by Woods et al. (2002) were (1) improvements in self-reported symptoms of depression and (2) a diminished verbal (lexical and categorical) fluency. Postoperative changes in global cognitive abilities, memory, attention, and frontal/executive functions were inconsistently reported and of questionable persistence and clinical significance. Since 2001, more and more studies report side-effects such as personality changes, disinhibition, depression, anxiety, mania, hypersexuality, and reduction of symptoms of obstructive compulsive disorder, respectively. Reported are also changes in cognitive functions: general cognitive decline, impairments in executive functioning, attention, working memory, mental speed, response inhibition, verbal memory and verbal fluency. Animal experiments had similar effects: Rats showed impaired response inhibition, and marmosets had attentional deficits after STN stimulation (Temel et al. 2005: 406). Only a minority of the studies have found no or only mild negative effects on the behavioral performance (Ardouin et al. 1999; Funkiewiez et al. 2003; Jahanshahi et al. 2000; Perozzo et al. 2001; Schneider et al. 2003) and on cognitive functions (Witt et al. 2004). A meta-analysis of 82 studies published up until June 2004 (1,398 patients) shows that the majority of the patients experience cognitive impairment (41%); the second most commonly observed behavioral complication is depression (8%), and thirdly, (hypo)mania (Temel et al. 2006). The authors conclude that it is actually the modulation of the STN, not drug reduction or surgery that has a substantial effect on behavioral parameters. A search was conducted on MedLine on 30. December 2008. The search yielded 1,900 citations about DBS, and 128 about “apathy or depression and DBS”. The latter were further examined to find those papers which met also the criteria STN DBS for the treatment of Parkinson disease and clinical study. The result is 65 articles, from which 12 are reviews, comparative studies or meta-analyses. The following sections summarize their findings about psychic side-effects of STN DBS.

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Improvements of Quality of Life (QoL) and of (Neuro-) Psychological Parameters The meta-analysis of Temel et al. (2006) found that the activities of daily living (ADL) score improved by 52% in the off and by 10% in the on phase (1,398 patients). Houeto et al. (2006) found that the global QoL score was improved by 28% (20 patients). Martinez-Martin et al. (2002) report a significant benefit in mood, mobility, and activities of daily living and a modest benefit in emotional well-being, stigma, and bodily discomfort (17 patients). Smeding et al. (2006) also found an increase of QoL, but that was related only to physical aspects, not to mood. Several studies report improvements of depression and anxiety disorders after STN DBS (Ardouin et al. 1999; Funkiewiez et al. 2003; Funkiewiez et al. 2004; Schneider et al. 2003; Houeto et al. 2006; Witt et al. 2006; Smeding et al. 2006). The review of Woods et al. (2002) lists 10 studies which assessed mood changes after DBS: Six studies documentated improvements, and four no significant changes. Bandini et al. (2007) report about two Parkinson patients who started pathological gambling within two months of dopaminergic dosage increasement. Both men were financially ruined and had severe private problems. Although they regretted the consequences of gambling, they could not resist it. One patient was declared mentally incompetent by a court, and a legal guardian was appointed. Both patients were treated with STN DBS, and the dopaminergic drugs were reduced. In both cases there was a dramatic improvement of the gambling. The patient who had been declared mentally incompetent was rehabilitated by court. The authors admit that whether DBS or the reduction of dopaminergic treatment was the cause of the behavior improvement remains unclear. Pathological gambling related to dopaminergic treatment in Parkinson’s disease is part of the so-called dopamine dysregulation syndrome. Ardouin et al. (2006) describe seven PD patients with pathological gambling due to dopaminergic treatment, intolerant to reduction in medication. After surgery, the dopaminergic treatment was reduced below the dosage of gambling onset. In all patients, pathological gambling resolved postoperatively after 18 months on average. Improvement paralleled the time course and degree of reduction in dopaminergic treatment. Pagonabarraga et al. (2007) found out that the decision-making of PD patients is altered as examined by the IOWA Gambling Task; it is similar to patients with lesions restricted to ventromedial prefrontal

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cortex and in pathological gamblers. For an overview of the decisionmaking of PD patients see Sinz et al. (2008). Frank et al. (2007) compared PD patients treated with dopaminergic medication and patients treated with DBS. They found that dopaminergic medication prevents learning from negative decision outcomes; this mechanism may explain pathological gambling. In contrast, DBS patients sped up their decisions under high-conflict win-win conditions. Frank and colleagues guess that the STN provides a control-signal that temporarily prevents the execution of any response, depending on decision conflict. The impulsive behavior of DBS patients may be explained by an inability to self-modulate decision times as a function of conflict. There seem to be two different mechanisms that lead to distinct forms of impulsivity in treated PD patients.

Impulse Control Disorder On the other hand, several papers report about impulse control disorders resulting from STN DBS. Sensi et al. (2004) report about a 64 year old man suffering from Parkinson disease for 8 years who underwent STN DBS. The patient had no systematic diseases, alcohol or other substance abuse, and both the psychiatric interview and the neuropsychiatric test showed that he had no prior personal or family history of psychiatric disorders. On the 2nd day postoperative, after device was activated with continuous monopolar current at 2.6 V on the left and 2.4 V on the right electrode, the patient showed spontaneous unprovoked, aggressive outbursts, mostly verbal directed toward the medical staff. In the following days he had explosive aggression with physical attacks directed at people and patients in the hospital, and violent behavior with family members. When asked about his excessive conduct, the patient denied being aggressive. On three occasions he displayed kleptomania. The physicians investigated whether DBS alone was responsible for the behavioral changes, and therefore tested the patient with the combination of the four basic therapeutic settings: on and off stimulation and on and off the dopaminerg drugs. These tests showed that the behavioral disturbance was independent of the drugs, and that there was a clear correlation with the stimulation and the aggressive behavior. Consequently a bilateral analysis of each electrode for the four contacts by changing DBS parameters (voltage, pulse width, and frequency stimulation) was done. The result was that an acute increase of the stimulation amplitude of the left electrode to 4 V produced the aggressive bouts. By increasing the voltage amplitude gradually, the patient became progressively more nervous, agitated and restless, and he 229

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refused any changes in the stimulation parameters. When the stimulation of the left electrode was turned off, his parkinsonian signs reappeared on the right side, whereas the hostility toward medical staff receded within few minutes. The patient never felt that his actions were irrational either during activation nor after inactivation of the device. The voltage intensity of 2.6 V on the left electrode which was necessary to control the motor symptoms was permitted after institution of a new atypical antipsychotic drug (quetiapine). At 6 months follow up all parkinsonian features were improved, and the dopaminergic drugs were reduced and the antipsychotic drug withdrawn without reappearance of the behavioral disorder.

Aggressive Behavior Bejjani et al. (2002) report that a patient showed acute transient aggressive behavior during intra-operative test stimulation. The electrode responsible for the aggressive burst was located between the medial STN and the posteromedial hypothalamic region (triangle of Sano). This area used to be selectively lesioned to treat medically intractable aggressive behaviors in severely affected psychiatric patients. Aggressive behavior after STN DBS is also reported from Funkiewiez et al. (2004): 2 out of 77 patients (2.6%) showed transient aggressive impulse episodes. The meta-analysis of 82 studies by Temel et al. (2006) found that less than 0.5% developed aggressiveness, personality changes, hypersexuality or apathy.

Mirthful Laughter Induced by DBS Krack et al. (2001) report about two PD patients in whom acute stimulation of an electrode located in the STN using high stimulation parameters (50% higher than therapeutic) induced funny associations, leading to infectious laughter and hilarity. The laughter attacks were associated with mirth, in contrary to pathological laughter. In both patients, the therapeutic parameters induced increases in mood, motivation, libido, and hedonia.

Mania and Hypersexuality Romito et al. (2002) report that among 30 Parkinson’s disease patients who received STN DBS 5 developed remarkable disorders of mood or sexual behavior. Two male patients showed mania and hypersexuality a 230

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few days after the implant that lasted for some months and then gradually disappeared spontaneously. One patient developed a manic syndrome, characterised by inflated self-esteem and grandiosity, marked increase in goal-directed activities (this led to the purchase of unneeded items), decreased need for sleep, planning of hazardous business investments, and flights of ideas. Furthermore he began to spend much of his time writing religious poems, despite a lack of interest in religion, and he began driving his car in a reckless manner. The other patient developed inflated self-esteem, labile mood, increased sexual desire and non-customary sexual behavior (inappropriate seductive behavior towards female medical staff). For the first time in several years he resumed work and went on a journey with his wife. He wrote a manuscript about his experience with PD and resumed his university course in astrophysics which he had abondoned 15 years previously. Kulisevsky et al. (2002) tell that three PD patients developed manic behavior after bilateral implantation of electrodes, and that the manic symptoms did not remit after levodopa reduction or stimulation ‘off’, but resolved with stimulation through higher electrode contacts. Herzog et al. (2003) report about a patient who gradually developed a first episode of mania with psychotic symptoms after STN DBS. She lost normal social inhibitions, and engaged in unrestrained buying of cloths. Her judgment was impaired, and she became suspicious, hostile and paranoid. Stimulation arrest led to a rapid deterioration of her mood without any improvement in mania. The psychotic symptoms disappeared under clozapine therapy, but then both mania and depression were present at the same time. With the combination of clozapine and the mood stabilizer carbamazepine (which is not recommended because of a higher incidence of agranulocytosis) the affective disorder remitted within 3 months. In the study of Funkiewiez et al. (2004) four patients out of 77 developed psychoses (5%) (one permanent) and five hypomania (6.5%) (one permanent). Houeto et al. (2002) report about two patients who showed after STN DBS an abnormal sexual behavior with exhibitionism or paedophilia and leisure tourism, respectively. Another interesting case of changed sexuality after STN DBS and a consequent change in artistic expression is presented by Witt et al. (2006): A 65-year-old architect with a 16-year history of PD was treated with STN DBS. Before stimulation he was frequently painting; his themes were exclusively architectural. Since surgery he painted exclusively female acts, although he had never painted nudes before.

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Apathy and Depression STN DBS may have an antidepressive effect (Schneider et al. 2003; Witt et al. 2006; Houeto et al. 2006) and may ameliorate anxiety (Houeto et al. 2006). On the other hand cases of apathy, depression, and even suicide are documentated. Berney et al. (2002) studied a series of 24 consecutive PD patients prospectively prior to and within 6 months postoperatively for mood, motor, and cognitive status to investigate the effects on mood of STN DBS. In six patients (25%), mood state worsened significantly despite clear motor improvement. Funkiewitz et al. (2004) report one case of permanent apathy and one case of transient severe depression after STN DBS (77 patients). Bejjani et al. (1999) report a case of transient acute depression that was reproducibly caused by DBS (with an electrode in the substantia nigra). The meta-analysis of 82 studies by Temel et al. (2006) found that 8% developed a depression. Usually it resolved after a pharmacological treatment. STN stimulation may be less effective than a domaminergic treatment to control the parkinsonian apathetic state; apathy therefore could be a consequence of drug reduction instead of stimulation (Funkiewiez et al. 2004; Schneider et al. 2003; Witt et al. 2006).

Suicide Several studies report suicides after successful deep brain stimulation for movement disorders. Burkhard et al. (2004) observed a high rate of suicide (6/140 patients, 4.3%). This prevalence is much higher than that of the general population and dramatically contrasts with the suicide rate in PD patients which is estimated to be 10 times lower than in the general population. Apparent risk factors included a previous history of severe depression and multiple successive DBS surgeries, whereas no relationship was found with the underlying condition, DBS target, electrical parameters, or modifications of treatment. Burkhard et al. (2004) guess that DBS should be considered as an independent facilitating factor for suicide attempts in at-risk patients and as a possible risk factor for suicide completion. Therefore they propose to exclude patients at high risk for suicide from DBS surgery. Other studies also report suicides and suicide attempts, even though less than the Burkhard study. Funkiewiez et al. (2004) report 5.2% suicide attempts plus 1.3% suicides (77 patients); Houeto et al. (2002) 232

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3.6% suicides (28 patients); Witt et al. (2008) 1.3% suicides (78 patients); Soulas et al. (2008) 1% committed and 2% attempted suicides (200 patients); Smeding et al. (2006) 1% attempted suicides (99 patients); Berney et al. (2002) 12.5% transiently suicidal patients (24 patients). The meta-analysis of Temel et al. (2006) found a suicide (attempt) rate of 0.4% (1,398 patients). Not only postoperative depression is a risk factor for suicidal behavior, but also increased impulsivity and an inability to control emotions (Soulas et al. 2008).

Neuropsychological Changes Smeding et al. (2006) performed a prospective study with a control group of nonimplanted PD patients. They found that DBS induced an executive dysfunction, characterized by a larger decline of verbal fluency, naming speed, selective attention and verbal recall. Nine percent of their STN patients (vs. 3% of controls) had psychiatric complications. Witt et al. (2008) randomly assigned 123 PD patients to (1) STN DBS (60 patients) or (2) the best medical PD treatment according to the German Society of Neurology guidelines (control group) (63 patients). They found that STN DBS does not reduce overall cognition, although there is a selective decrease in frontal cognitive functions (verbal fluency and Stroop test) and an improvement in anxiety. These changes did not affect improvements in quality of life. Schüpbach et al. (2006) assessed 29 Parkinson patients prospectively for two years. They found that the patients often had subtle intellectual and psychic problems that became apparent only in unstructured interviews. The patients had more difficulty ordering complex actions and thoughts, anticipating and planning; they had problems with attention, and were distractible. Several were logorrheic, irritable and impatient; they expressed their opinions more freely.

Adjustment Disorders, Psychiatric Disorders and Personality Changes Witt et al. (2008) found that 16.7% of the DBS patients and 12.7% of the controls had severe psychiatric adverse events. In the DBS group depressions and apathy occurred (8.3%), and one suicide (1.3%) happened, whereas in the control group one patient died in a psychotic

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episode. The incidence of psychoses was higher in the control group (11.1%) than in the DBS group (6.7%). Houeto et al. (2002) have evaluated 24 Parkinson patients retrospectively for adjustment disorders (social adjustment scale, SAS), psychiatric disorders (comparison of the results of psychiatric interview and the mini international neuropsychiatric inventory) and personality 1 changes (IOWA scale of personality changes). They found that social adjustment was moderately or severely impaired by 62.5%. Psychiatric disorders consisted of amplification or decompensation of previously existing disorders that had sometimes passed unnoticed, such as depression, generalised anxiety, and behavioral disorders with drug dependence. Personality traits were improved by 35%, unchanged by 30%, and aggravated by 35%. A recent retrospective study of the same research group (Houeto et al. 2006) came to quite different results. This time, 20 Parkinson patients were rigorously selected regarding psychiatric criteria. The authors found that the patients’ personality traits were unmodified, and scores for social adjustment remained stable. The meta-analysis of 82 studies by Temel et al. (2006) found that less than 0.5% developed aggressiveness, personality changes, hypersexuality or apathy.

Deterioration of Sociomoral Judgment after STN DBS Brentrup et al. (2004) and Bothe (2003) report that 2 out of 15 patients were socially maladjusted after STN DBS for more than one year. The average value of the personality trait ‘novelty seeking’ of these two patients rose from 1.50 to 2.25 (normal range: 2.21 - 3.18), whereas their ‘conscientiousness’ value decreased from 2.41 to 1.66 (normal range: 1.94 - 3.18). Their power of sociomoral judgment decreased on the 6-

1

“The IOWA scales of personality change (ISPC) give a quantitative estimate of the affective, behavioural, and social disturbances that may occur after brain lesions, and assess the extent of changes from premorbid levels. The information is elicited from the spouse or other family member who has had the best opportunity to watch the subjects in daily life. Behavioural guidelines with examples are provided with each scale to enhance reliability. Twenty six ‘clinical scales’ assess disturbances in behavioural control, goal directed behaviour, decision making, emotional expression, interpersonal relations, and insight. The spouse first rates the current level of the item on a scale of 1 to 7. The patient’s behaviour during the 6 months preceding surgery was also evaluated with the same scale. The difference between the two ratings provides a measure of the extent of the changes.” (Houeto et al. 2002: 703)

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level Kohlberg scale from level 4 (adhering to social system and conscience) to level 2 (serving one’s own interests and letting others do the same) (Kohlberg 1984).

Marital Situation and Family Life Schüpbach et al. (2006) found that after STN DBS marital life worsened more often than it improved. Marital problems occurred in 71% of the couples (50% were in a crisis before the operation). 12.5% were divorced within 2 years after the operation. There are two types of marital conflicts after surgery: First, the patients rejected their spouse, because they had regained autonomy and wanted to recover a social life, whereas the spouse did not want to give up the role of caregiver. 33% of the spouses became depressed after their partner was successfully operated. Second, the patient still wanted to be recognized as sick, whereas the spouse expected that they would resume a normal life and therefore refused the patient. On the other hand, the social life, relations with their children, and family life improved more often than worsened. Modified familiar relations are also reported by Perozzo et al. (2001). They found in psychological interviews that many patients felt a sense of impotence and passivity regarding their clinical condition because the stimulation parameters can be varied only by physicians. Whereas the patients had difficulty to give up the benefits deriving from the illness condition, the caregivers did not feel inclined to sustain a caregiver role again. Houeto et al. (2002) found frequent deteriorations of conjugal relationships (0.25%), too. They attribute the marital conflicts after surgery to the patients’ regained autonomy and to their spouses’ loss of function after years of care.

Professional Activity Schüpbach et al. (2006) found that after STN DBS professional activity worsened more often than it improved. Out of 16 patients who had a professional activity before surgery, five did not want to work any more, because they gave priority to leisure activities; five did not feel able to work any more after surgery. 44% gave up working after surgery in spite of an excellent motor improvement. The authors assume that the slight intellectual and psychic symptoms which they found in the unstructured interviews could degenerate into maladjustment at work. Another reason may be an increased hedonism and in some cases the belief, that society owed the patients compensation for their suffering. Gisquet (2008) also 235

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found that several patients no longer wanted to work after DBS: Before surgery, the job meant control over their life; after surgery, when the struggle against the disease was over, also work lost its meaning.

Patient’s Experience Schüpbach et al. (2006) found that many patients suffered from an altered body image or even from a feeling of strangeness. Many uttered regret about the damages to their lives by the disease and had negative anticipations. Many suffered the loss of aim in the life: Fighting against the disease was an aim in itself. After surgery, it was as if life had lost all meaning (see also Gisquet 2008: 1849). Gisquet (2008) reports that several patients feel that their identity has been affected; this feeling results from mood changes, irritability or apathy.

S u m m a r y: P s yc h i c C h a n g e s t h r o u g h S T N D B S Although the DBS treatment of patients suffering from Parkinson disease does not intend psychic changes, they occur relatively often, and they are not always unwanted for the patient. In many cases, DBS influences the mood, some cognitive functions, and personality traits as novelty seeking, risk willingness, conscientiousness, social conformance, and moral competence. The psychic effects of STN DBS are not predictable, and sometimes seem to be paradox. Social problems (partnership and job) occur often in spite of a good clinical outcome. Minimal modifications of the stimulation parameters or the positions of the electrodes can influence the psychic outcome enormously. Frequent positive changes are increased power of concentration, motivation, alertness, and verbal memory, and decrease of depression, anxiety, strain, fatigue, and OCD. This often allows for the re-activation of social activities. Sometimes the changes are evaluated positively by the patients, but negatively by their social surrounding. That is true especially for an increased energy, novelty seeking, risk willingness, and sexual drive as well as for decreased social conformance. Negative changes are decreased frontal cognitive abilities (verbal fluency and memory), decreased moral competence, mania, kleptomania, levity, apathy, depression, anxiety, emotional hyperreactivity, and suicidal tendencies.

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In most cases, the psychic changes are transient or can be managed through the adaptation of the stimulation parameters, so that a good outcome can be reached. But in some patients, psychic changes after STN DBS are permanent and sometimes even persist after deactivation of the stimulation. Gisquet (2008) concludes that DBS is a unique form of biographical disruption of which neither patients nor physicians measure the impact.

P o s s i b l e C a u s e s o f t h e P s yc h i c E f f e c t s of STN DBS The amount of reports about psychic effects of the stimulation of the nucleus subthalamicus (STN) raises the question whether this nucleus is directly involved in emotional regulation or whether its stimulation has only indirect effects on structures of the limbic system. Once it was believed that the STN was no more than a relay station serving as a gate for ascending basal ganglia thalamocortical circuits which has only an inhibitoring function on the motor circuit (Temel et al. 2005). If that would be true, the psychic effects of STN DBS could be explained as side-effects of current spread to passing fibers and/or neighbouring structures which are relevant for mood and emotions (Sensi et al. 2004), especially to the hypothalamus (Bejjani et al. 2002). Brentrup et al. (2004) suppose that STN stimulation sometimes causes an increase of the glucose metabolism of the frontomedial cortex which produces a deterioration of sociomoral judgment and social maladjustment. This thesis could be supported by findings of Nyffeler and Regard (2001): They report the case of a patient who developed kleptomania and pathological gambling behavior in the course of a right frontolimbic behavior syndrom after the resection of a craniopharyngioma. STN DBS also causes occasionally kleptomania, pathological gambling behavior and further symptoms of impulse control disorder, possibly because of negative effects on the frontal lobes. But since more and more cases of psychiatric effects of STN DBS are reported, this hypothesis is argued by several authors: Woods et al. (2002) point out that STN axons have significant collaterals to almost all basal ganglia structures, suggesting that the STN is a part of a widely distributed network and not just an indirect circuit. Temel et al. (2005) conclude that the STN which was classically regarded as a mere relay station should be considered as the pacemaker not only of the basal ganglia motor circuit but also of associative and limbic circuits. The 237

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current data from animal studies and clinical studies is in favor of the hypothesis that the STN itself and not neighbouring structures are responsible for the behavioral consequences of STN DBS and lesions (Temel et al. 2005: 406). The STN is situated on a central position of each of the five cortico-basal ganglia-thalamocortical circuits through which higher and lower regions of the brain communicate with the basal ganglia. This communication involves motor, associative and limbic functions represented by the specific circuits. The STN has anatomically three subdivisions: the somatomotor part (dorsolaterally located), the limbic part (medial), and the associative part (ventromedially) (Temel et al. 2005: 397). Krack et al. (2001) note that the three main components (motor, associative and limbic) of the cortical-basal ganglia-cortical circuits pass through the STN. Therefore, they guess that the STN is not only involved in motor, but also in psychomotor regulation; then the STN stimulation might also influence the limbic loop. Funkiewiez et al. (2003) summarize that several lines of evidence (PET studies in PD patients with STN DBS, lesion experiments with rats, and clinical observations) indicate that STN activity modulates sensorimotor, limbic, and cognitive functions. A high STN activity (off-drug or off STN stimulation in PD patients) causes low motor activity (bradykinesia, rigidity, tremor, off dystonia), few spontanous thoughts, impaired executive function and working memory, poor motivation, depression, anxiety, and apathy. By contrast, a low STN activity (on drug or on STN stimulation) leads to high motor activity, possibly dyskinesia, rich associations, possibly delusions and hallucinations, and enhanced mood, eventually mania or impaired emotional control. The STN seems to work as a powerful amplifier, regulating motor, cognitive, affective, and behavioral functions. Funkiewiez et al. (2003) found that both levodopa and STN DBS induce acute amphetamine-like psychotropic effects, in which the psychotropic effect of levodopa is higher. It is likely that the psychotropic effects are indeed specific to the STN, and stimulation of such a small target as the STN is unlikely to selectively influence its motor part, without affecting its associative and limbic parts. The STN has a potent regulatory function in the processing of associative and limbic information towards cortical and subcortical regions. Therefore changes in STN activity immediately result in behavioral changes, without being corrected by regional compensatory mechanisms. Such a potent influence on associative, limbic and motor functions has not been observed with other targets. In almost all clinical studies improvement of motor disability was accompanied by unexpected behavioral changes. STN DBS seems not to be selective for the motor parts of the STN, but generally involves its associative and 238

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limbic parts. With the current technique of chronic stimulation and current dimensions of electrodes, it is very unlikely to influence selectively the motor part of the STN (Temel et al. 2005: 406).

Ethical Discussion of Personality Changes t h r o u g h B r a i n I n t e r ve n t i o n s The current data allows the conclusion that STN DBS sometimes causes personality changes with regard to the influential ‘Big Five’ personality model of Lewis Goldberg. This five-dimension personality model contains the following basic personality traits: 1. Extraversion, 2. Neuroticism, 3. Agreeableness, 4. Conscientiousness, 5. Openness to experience (International Personality Item Pool). All these personality traits have been influenced by STN DBS in some patients. On the first glance one could draw the conclusion from these data that STN DBS is unethically. But to defend this conclusion, one would need a strong argument why personality changes are generally negative. This argument is hard to defend because a person’s personality alters anyway during lifetime, not only because of experiences, but also through biological processes such as brain disease or degeneration. Nevertheless, with regard to artificially induced psychic changes, two different points of views are often uttered (Müller 2007: 190-193): 1. Technical changes of psychic properties are generally inacceptable; the only acceptable methods are education and psychotherapy. 2. Improvements and deteriorations of psychic properties have to be differentiated. To aim for the first is ethically correct, also by artificial means. The first point of view is based on an is-ought equalization. This position implies that naturally occurring psychic changes (e.g. by disease) have to be accepted, even when they cause severe suffering. This position is a legitime personal opinion, but is not convincing in general, because it is dogmatic. If this position is taken serious, the whole medicine becomes obsolete because it uses technical means to cure diseases and disabilities. According to the second point of view it is not relevant whether psychic changes happen by natural processes or by medical interventions; only the result counts. This position differentiates good and bad psychic conditions. Therefore it requires an evaluation of psychic changes in order to differentiate between improvements and deteriorations. That raises the difficult question: What are good psychic 239

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properties? Is subjective well-being the relevant criterium? Does morality belong to a good personality? A consensus about criteria for good psychic properties obviously is illusionary, since the evaluation of many psychic properties depends on culture. Examples are homosexuality, paedophilia, and religiousness. Nevertheless, medicine, especially psychiatry, cannot avoid to evaluate psychic properties, because otherwise neither diagnoses nor therapy of psychic diseases would be possible. Therefore the ethically decisive question is not whether DBS alters personality or not, but whether it does so in a good or bad way (Synofzik and Schläpfer 2008). The possibility to modify a personality through DBS is indeed a qualitatively new type of moral dilemma (Gharabaghi et al. 2005: 67). In this context it is important to differentiate between not-intended psychic changes and intended ones: 1. Not-intended psychic changes may happen as side-effects or complications of microsurgery, radiosurgery, radiotherapy or chemotherapy, e.g. as a consequence of bleeding, liquor accumulation, radiation necrosis or inflammation. 2. Intended psychic changes are aspired when a brain lesion or disease is supposed to be the cause of a mental sickness. In severe cases, functional micro- or radiosurgery is used for the treatment of psychiatric disorders. Deep brain stimulation also is tested for the treatment of psychiatric disorders, especially obsessive compulsive disorder and severe depression (e.g. by Mayberg, Nuttin, Schläpfer, Sturm, Greenberg). Besides that, psychic changes also occur without brain surgery, through (1) experience, (2) neurodegeneration, (3) eventually brain disease or brain trauma, (4) effects of (psychotropic) drugs. These changes often are unwanted by the patient and/or his social surrounding. One example may illustrate this thesis: Burns and Swerdlow (2003) report the case of a 40-year-old married schoolteacher who became obsessed with child pornography and started to frequent prostitutes. His wife evicted him from the family home after discovering his sexual advances to children. He was found guilty by the court of molesting children. One day before he was due to go to prison, he went to hospital because of a headache and indomitable sex drive. An MRI scan revealed an egg-sized brain tumour in the frontal lobe. The tumour was removed. The paedophiliac drive vanished completely, and the man went home to his family. But several months later, he secretly started to collect pornography again. An MRI scan showed a tumor remission. After reresection his abnormal sexual drive vanished again. 240

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That leads to the conclusion: Not only interventions into the brain, but also their abnegation can be ethically problematic (Müller 2007).

E v a l u a t i o n o f S T N D B S Ac c o r d i n g t o t h e Principles of Biomedical Ethics I agree with Synofzik and Schläpfer (2008) who have argued that the concept of personality is not useful to gain normative orientation in the issue of DBS in psychiatric patients. Instead, the bioethical principles of beneficience, non-maleficence, and autonomy should be used for the ethical evaluation because they allow a clinically applicable, highly differentiated context- and case-sensitive approach. Additionally, I will apply the principle of justice because for the evaluation of psychic and behavioral changes the patient’s wishes and well-being cannot be the only criterium, when other people are also concerned. From the principles of biomedical ethics (Beauchamp and Childress 2009) can be deduced at first that an intervention into the brain which could change psychic properties is unethically, if • it is performed against the (not delusive) patient’s will (patient’s autonomy), • it has effects which the patient does not accept (patient’s autonomy), • reduces the patient’s biological prerequisits of autonomy, e.g. reduces the mental capacities or downgrades the moral competence (patient’s autonomy), • causes suffering of the patient (nonmaleficence), • deteriorates the social behavior of the patient so severely that rights of other persons will be concerned (justice). Autonomy: On the one hand, STN DBS can increase the autonomy of PD patients because it improves their mobility, makes them (more) independent of care, and often restores their ability to work. Furthermore, it often reduces depression, anxiety, obsessive compulsive disorder or pathological gambling, so that more autonomy can be gained. On the other hand, STN DBS can decrease the patient’s autonomy, namely if it reduces the moral competence or induces mania, depression, or apathy. Furthermore, the experienced autonomy is decreased in patients who feel telecontrolled by the physicians, feel a sense of impotence and passivity regarding their clinical condition or who suffer from self-alienation (Perozzo et al. 2001; Gisquet 2008). In general, it is difficult to predict whether STN DBS will enhance the individual patient’s autonomy or not. Therefore, the patient should 241

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be informed about this dilemma in extenso. If a patient experiences a decreased autonomy after stimulation, its parameters should be adapted so that the (experienced) autonomy is maximized. The stimulation parameters should be chosen so that the autonomy will become as high as possible. The autonomy could also be increased if the patient is enabled to adjust the stimulation parameters himself in a certain range. Nonmaleficence: STN DBS fulfills the principle of nonmaleficence in so far as it is (largely) reversible and minimal-invasive. But on the other side there are risks of complications (bleeding, inflammation) and consecutive disability and even death, and furthermore there are relatively large psychic risks including the risk of suicide. Therefore the possible harm of DBS has to be weighted against its possible benefits. Beneficence: DBS promises to restore mobility, manual abilities and independence, to enhance the mood and to allow for more participation in social life. Although the majority of patients experience an improvement of their quality of life, the beneficence for the individual patient is not predictable. Since the aim of DBS is the improvement of the quality of life and it is neither the treatment of a life-threatening condition nor a cure, it is an elective treatment which requires especially strict criteria for its indication and a sophisticated individual risk-benefit analysis (Gharabaghi et al. 2005: 67). Justice: Because STN DBS is an effective treatment of a severe, hindering disease, patients have the right to be treated. Even from the societal point of view, the treatment would be justified, because it reduces costs for the social system, when patients become independent of care and regain the ability to work. On the other hand, there is a small risk that the treated patient develops an antisocial or even violent behavior. The principle of justice requires that the stimulation is adapted so that not only the patient’s beneficence, but also his compatibility with his surrounding and with the society are preserved or restored. From the principle of justice does not follow necessarily that an intervention with a high incidence of marital problems is not allowed, because a right for the continuation of a partnership does not exist. But it forbids interventions which cause kleptomania, paedophilia, loss of control over sexual drive, drug abusage, criminal behavior etc. The evaluation of STN DBS according to the principles of medical ethics is non-uniform because this therapy offers great chances for improving the quality of life which are contrasted with (small) risks of complications and subsequent disabilities and with relevant risks of severe psychiatric complications. In individual cases, a careful evaluation is required. 242

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Recommendations Based on the mentioned studies and the ethical analysis, I conclude with concrete recommendations: Physicians should counsel patients and their relatives extensively about the risks of psychic changes (Gharabaghi et al. 2005: 69; Temel et al. 2006: 269), including the risk of partnership problems. They should evaluate the risks and the expectable benefits together with the patient and his/her relatives. Caregivers and patients should be educated about the potential impact of STN DBS on mood and the risk for suicide (Berney et al. 2002). Predictors for the risk of cognitive or emotional decline after STN DBS should be established (Smeding et al. 2006; Temel et al. 2006: 269). A careful psychological and psychiatric examination should be performed before surgery (Houeto et al. 2002; Saint-Cyr and Albanese 2006). Patients with high risks for psychiatric disorders should be excluded from STN DBS. Cognitive deficits and dementia appear to be contraindications for STN DBS (Woods et al. 2002: 120; Saint-Cyr and Albanese 2006). Patients should be informed about alternatives to STN DBS: either GPi DBS (in the case of disabling motor fluctuations) or VIM DBS (in the case of therapy resistant disabling tremor) (Temel et al. 2006: 269). A psychological follow up is necessary to ensure the best possible outcome (Houeto et al. 2002), especially to prevent suicides. Continuated long-term evaluation of DBS patient is indicated to further track the persistence of neuropsychological findings (Woods et al. 2002: 122). (Bio-)Medical scientists should intensify research on the electrophysiological properties of the basal ganglia-thalamocortical circuits and of the functional parts of the STN and their possibly different thresholds of electrical stimulation (Temel et al. 2005: 407). Furthermore, the surgical procedure to modulate only the motor part of the STN should be technically improved (Temel et al. 2005: 407). The research on desynchronisised DBS (developed by Peter Tass and collegues in Jülich) should be supported, because it probably has less side-effects. Research on psychic side-effects of STN DBS should be intensified.

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Devices should be developed and made available to the patients which allow for modifying the stimulation parameters in a certain range autonomously. Last but not least, (medical) ethicists should develop tests for moral agency in order to document and evaluate changes of moral competency through DBS. (This desideratum is tackled by Markus Christen in Zürich.) Furthermore, a debate should be initiated about the issue which changes of personality can be accepted or are even desirable (Gharabaghi et al. 2005: 69).

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Houeto, J.L., L. Mallet, V. Mesnage, S.T. du Montcel, C. Béhar, M. Gargiulo, F. Torny, A. Pelissolo, M.L. Welter & Y. Agid (2006) “Subthalamic stimulation in Parkinson disease: behavior and social adaptation”, in: Archives of Neurology 63(8): 1090-1095. International Personality Item Pool (IPIP), http://ipip.ori.org/newBigFive5broadKey.htm. Accessed Nov 10, 2008 Jahanshahi, M., C.M. Ardouin, R.G. Brown, J.C. Rothwell, J. Obeso, A. Albanese et al. (2000) “The impact of deep brain stimulation on executive function in Parkinson’s disease”, in: Brain 123(6): 1142-1154. Kohlberg, L. (1984) The psychology of moral development (San Francisco: Harper and Row). Krack, P., R. Kumar, C. Ardouin, P.L. Dowsey, J.M. McVicker, A.L. Benabid & P. Pollak (2001) “Mirthful laughter induced by subthalamic nucleus stimulation”, in: Movement Disorders 16(5): 867-875. Kulisevsky, J., M.L. Berthier, A. Gironell, B. Pascual-Sedano, J. Molet & P. Parés (2002) “Mania following deep brain stimulation for Parkinson’s disease”, in: Neurology 59: 1421-1424. Limousin, P., P. Krack, P. Pollak, A. Benazzouz, C. Ardouin, D. Hoffmann & A.L. Benabid (1998) “Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease”, in: New England Journal of Medicine 339A: 1105-1111. Martinez-Martin, P., F. Valldeoriola, E. Tolosa, M. Pilleri, J.L. Molinuevo, J. Rumià & E. Ferrer (2002) “Bilateral subthalamic nucleus stimulation and quality of life in advanced Parkinson’s disease”, in: Movement Disorders 17: 372-377. Müller, S. (2007) „Dilemmata bei operativen Eingriffen in das Gehirn“, in D. Groß & S. Müller (eds.), Sind die Gedanken frei? Die Neurowissenschaften in Geschichte und Gegenwart. (Berlin: Medizinisch Wissenschaftliche Verlagsgesellschaft): 229-268. National Parkinson Foundation (2008) “Treatment options”, www.parkinson.org/NETCOMMUNITY/Page.aspx?pid=227&srci d=201. Accessed Dec 28, 2008 Nyffeler, T. & M. Regard (2001) “Kleptomania in a patient with a right frontolimbic lesion”, in: Neuropsychiatry, Neuropsychology, and Behavioral Neurology 14 (1): 73-76. Pagonabarraga, J., C. García-Sánchez, G. Llebaria, B. PascualSedano, A. Gironell & J. Kulisevsky (2007) “Controlled study of decision-making and cognitive impairment in Parkinson’s disease”, in: Movement Disorders 22(10): 1430-1435. 247

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Perozzo, P., M. Rizzone, B. Bergamasco, L. Castelli, M. Lanotte, A. Tavella, E. Torre & L. Lopiano (2001) “Deep brain stimulation of subthalamic nucleus: behavioural modifications and familiar relations”, in: Neurological Sciences 22: 81-82. Romito, L.M., M. Raja, A. Daniele, M.F. Contarino, A.R. Bentivoglio, A. Barbier, M. Scerrati & A. Albanese (2002) “Transient mania with hypersexuality after surgery for high frequency stimulation of the subthalamic nucleus in Parkinson’s disease”, in: Movement Disorders 17(6): 1371-1374. Saint-Cyr, J.A. & A. Albanese (2006) “STN DBS in PD. Selection criteria for surgery should include cognitive and psychiatric factors”, in: Neurology 66: 1799-1800. Schneider, F., U. Habel, J. Volkmann, S. Regel, J. Kornischka, V. Sturm & H.-J. Freund (2003) “Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease”, in: Archives of General Psychiatry 60(3): 296-302. Schüpbach, M., M. Gargiolo, M.L. Welter, L. Mallet, C. Béhar, J.L. Houeto, D. Maltete, V. Mesnage & Y. Agid (2006) “Neurosurgery in Parkinson disease: a distressed mind in a repaired body?”, in: Neurology 66: 1811-1816. Sensi, M., R. Eleopra, M.A. Cavallo, E. Sette, P. Milani, R. Quadrale, J.G. Capone, V. Tugnoli, M.R. Tola, E. Granirei & P.G. Data (2004) “Explosive-aggressive behavior related to bilateral subthalamic stimulation”, in: Parkinsonism Related Disorders 10: 247-251. Sinz, H., T. Benke, W. Poewe & M. Delazer (2008) „Entscheiden bei Morbus Parkinson – eine Übersicht“, in: Zeitschrift für Neuropsychologie 19(4): 235-251. Smeding, H.M.M., J.D. Speelman, M. Koning-Haanstra, P.R. Schuurman, P. Nijssen, T. Van Laar & B. Schmand (2006) „Neuropsychological effects of bilateral STN stimulation in Parkinson disease“, in: Neurology 66: 1830-1836. Soulas, T., J.M. Gurruchaga, S. Palfi, P. Cesaro, J.P. Nguyen & G. Fénelon (2008) “Attempted and completed suicides after subthalamic nucleus stimulation for Parkinson’s disease”, in: Journal of Neurology, Neurosurgery, and Psychiatry 79(8): 952954. Synofzik, M. & T.E. Schlaepfer (2008) “Stimulating personality: ethical criteria for deep brain stimulation in psychiatric patients and for enhancement purposes”, in: Biotechnology Journal 3(12): 1511-1520.

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Temel, Y., A. Blokland, H.W.M. Steinbusch & V. Visser-Vandewalle (2005) “The functional role of the subthalamic nucleus in cognitive and limbic circuits”, in: Progress in Neurobiology 76: 393413. Temel, Y., A. Kessel, S. Tan, A. Topdag, P. Boon & V. VisserVandewalle (2006) “Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: a systematic review”, in: Parkinsonism Related Disorders 12(5): 265-272. Witt, K., U. Pulkowski, J. Herzog, D. Lorenz, W. Hamel, G. Deuschl & P. Krack (2004) “Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease”, in: Archives of Neurology 61(5): 697-700. Witt, K., P. Krack & G. Deuschl (2006) “Change in artistic expression related to subthalamic stimulation”, in: Journal of Neurology 253(7): 955-956. Witt, K., C. Daniels, J. Herzog, D. Lorenz, J. Volkmann, J. Reiff, M. Mehdorn, G. Deuschl & P. Krack (2006) “Differential effects of L-Dopa and subthalamic stimulation on depressive symptoms and hedonic tone in Parkinson’s disease”, in: Journal of Neuropsychiatry and Clinical Neurosciences 18(3): 397-401. Witt, K., C. Daniels, J. Reiff, P. Krack, J. Volkmann, M.O. Pinsker, et al. (2008) “Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease: a randomised, multicentre study”, in: Lancet Neurology 7(7): 605-614. Woods, S.P., J.A. Fields & A.I. Tröster (2002) “Neuropsychological sequelae of subthalamic nucleus deep brain stimulation in Parkinson’s disease: a critical review”, in: Neuropsychology Review 12 (2): 111-126.

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Manipulating the Brain – An Ethical Challenge? Lessons from Deep Brain Stimulation in Mo ve me nt Disorders ∗ THOMAS D. HÄLBIG

Introduction Major advances in the neurosciences uncovered basic principles of central nervous functions that underlie human perception, cognition, action and motor control. The assumption that psychological functions and mental states depend on the brain is nowadays shared between both scientists across various disciplines and folk psychology. Stronger claims even reduce mental states to neural states or identify the self with the brain. At the same time, the understanding of pathophysiological mechanisms of various neurological diseases has been furthered, and, in parallel, medicine has begun to establish techniques that manipulate brain functions for therapeutic purposes. These techniques comprise the surgical implantation of technical devices such as electrodes for deep brain stimulation (DBS) or – still at the experimental stage – the implantation of stem cells or other biological substrates. Related to the assumption that our mental life depends on the brain, ethical concerns ∗

Many thanks for helpful comments on earlier versions of this manuscript to Antje S. Bonhage (Berlin, Germany), Michael Schüpbach (Paris, France), and Winona Tse (New York, NY, USA).

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have been raised regarding the possibility that these new therapies might affect negatively personality, personal identity and autonomy. The following statement by a patient with Parkinson’s disease (PD), who is treated with DBS in order to achieve better control over his motor symptoms, illustrates that the ethical concerns might be justified (Hummel 2008): “[…] The battery is placed in a box under my skin in my right chest […] coming out of this box are two cables. These connect to two electrodes inserted deep in my brain, which deliver electrical pulses. This helps me a lot. The whole thing is called deep brain stimulation […] When the battery runs out of power, they open my chest to replace it. The new one will last about five years. Five good years. The best for quite a while […] Recently, one electrode was defect. They reopened my head again and replaced the electrode. Afterwards, I was a different person: I spent too much money - for a new bike and for electronic gadgets. My wife was devastated, yet I was merely stating: “That is what I need, that is what I am going to buy.” Compulsive shopping is a possible side-effect after that kind of surgical intervention. In fact, I was lucky. The electrodes had been immediately implanted at the right target. A friend of mine, also suffering from Parkinson’s, jumped out of the 1 window and died, one day before his birthday […]”.

In parallel with a transfer of his control over mind and body to mechanical devices and to the treating physicians, the patient suffered a personality change with a partial loss of his personal autonomy. In the following, the question will be discussed, if it is ethically responsible to use DBS in order to treat patients with chronic movement disorders, although this therapy may compromise psychological and personality status. This essay, however, might serve to elucidate ethical problems that arise in relation to therapeutic brain manipulations in the non2 psychiatric domain in general. As an evaluation of the ethical implications of DBS requires at least a basic understanding of its clinical indications, mechanisms of action and effects, these will be subsequently outlined.

1 2

Author’s translation. Brain manipulative interventions such as DBS are currently tested also for the treatment of various other neurologic and psychiatric disorders such as depression, obsessive-compulsive disorder and Tourette’s syndrome (Mallet et al. 2008; Mayberg et al. 2005; McNeely et al. 2008; Welter et al. 2008). Whereas DBS in psychiatric diseases aims at changing psychological functions, DBS for the treatment of movement disorders tries to avoid psychological side-effects. Ethical concerns against DBS in both areas therefore differ considerably.

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Deep Brain Stimulation – Mechanisms and Effects DBS for disabling chronic and often progressive movement disorders is considered when medical therapy is insufficient to treat symptoms such as slowness of movements, muscle stiffness and tremors or other severe 3 involuntary uncontrollable movements. DBS requires the neurosurgical implantation of usually two electrodes that are inserted via cranial burrholes into the basal ganglia, which are neural nuclei located in the depth of the brain hemispheres. The electrodes are connected via subcutaneously placed cables to one or two electrical impulse generators at the chest wall that carry a battery, similar to those that are known as cardiac pacemakers. Via the electrodes, the electrophysiological activity of the neural target can be modified. Despite its widespread use, the mechanisms of action of DBS are not well understood (Volkmann and 4 Deuschl 2007). DBS does not provide a cure nor does it slow down the disease progression. However, it has been shown to be a powerful and efficient symptomatic therapy that dramatically reduces motor symptoms (see 5 below). Since its introduction about 20 years ago, more than 75,000 patients worldwide have been treated with DBS (personal communication Medtronic, Germany, 03/2010). DBS side-effects are classified as being related to the surgical intervention and as effects of stimulation. The frequency of surgery related side-effects varies between centers and consists in hemorrhage (1-4%) and infection (3-4%) (Volkmann and Deuschl 2007), which in 3

4

5

DBS is also considered when medications that are used to treat movement disorders are not tolerated for mental or other important side-effects (see below). It is thought that the modulation of abnormal activation patterns or a depolarization block mediates the therapeutic effects. On the other hand, DBS probably has both excitatory as well as inhibitory effects depending on the distance between the active electrode contact and the cell membrane, the specific location where a neuron is stimulated (soma vs. dendrites) and the type of neuron. Further, it is debated whether DBS affects the action of neurotransmitters and whether it has effects on the molecular level. Moreover, multiple of these effects may interact such that effects on different structures, depending on the distance to the electrode are mediated in a different fashion and differ with respect to their functional consequences (Johnson et al. 2008; McIntyre et al. 2004; Volkmann and Deuschl 2007). This has been appreciated by the Food and Drug Administration in the US and its European counterparts who approved DBS for the treatment of different movement disorders and by major European health insurance programs and Medicare in the US that cover its costs.

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most instances can be managed with full recovery in the majority of patients. However, permanent neurological deficits are observed and even devastating irreversible sequels (paralysis, loss of language or memory, etc.) are possible. Transient acute psychiatric symptoms such as confusion, delirium, psychosis or manic states may develop postoperatively (Voon et al. 2006). Stimulation effects and side-effects are reversible and remit after a variable delay once stimulation parameters are re-adjusted or stimulation is set off. Side-effects of stimulation consist in sensory (paresthesias), motor (involuntary muscle contractions) or autonomic (sweating, vertigo) symptoms. On the other hand, personality change and psychiatric side-effects may develop insidiously after a variable delay and may not immediately be recognized as being DBS related. Interestingly, the likelihood of the development of personality changes and psychiatric side-effects varies considerably across different individuals, diseases and the neural targets that are chosen for DBS. In conditions such as essential tremor or dystonia, these changes usually do not occur.

D B S i n M o ve m e n t D i s o r d e r s s u c h a s E s s e n t i a l T r e m o r o r D ys t o n i a Although essential tremor (ET) is one of the most frequent movement disorders, it is far less known by the public than PD. ET may begin in early adulthood and affects nearly 5% of persons over the age of 60 (Louis 2005). ET is generally considered a pure motor disorder presenting with tremor of the extremities, the head or the voice. It is often called ‘benign’ but may be extremely disabling and may interfere with 6 feeding, dressing, hygiene, etc. ET often responds only to a limited degree to pharmacological treatments. Further, drug treatment frequently is limited by side-effects consisting for example in sedation or vertigo. DBS for ET has been established in the 1980s for upper limb tremor and targets the ventral intermediate thalamic nucleus (VIM). DBS has been performed in about 7,500 patients worldwide (personal communication Medtronic, Germany, 03/2010) and various studies with follow up durations of up to 7 years confirmed its efficacy in ET with lasting tremor reduction of 60-90%. Overall, VIM DBS is considered 6

Although ET today in general is considered a ‘pure’ motor disease, recent clinical and neuropathological findings suggest different subtypes of the disease with and without cognitive and other non-motor impairments (Louis and Vonsattel 2008).

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neutral with respect to mental status and psychological functioning (Fields et al. 2003; Troster et al. 1999). Another movement disorder that is treated with DBS is dystonia (Jankovic 2006). Dystonia is less frequent than ET and PD and has a prevalence of 40/100,000. It is characterized by sustained involuntary muscle contractions frequently causing twisting and repetitive movements or abnormal postures. Dystonia may develop in children. In particular generalized forms of the disease may lead to extreme difficulties in virtually all motor-related activities of daily life. Injections with botulinum toxin and pharmacological treatment may be useful (Jankovic 2006) but often are limited when multiple body parts are affected or by psychiatric and other medical side-effects, respectively. DBS has been performed in more than 10,000 patients with dystonia (personal communication Medtronic, Germany, 03/2010) and targets usually the posteroventrolateral motor part of the globus pallidus internus (GPi), which belongs to the basal ganglia. GPi DBS in dystonia has been shown to improve motor symptoms significantly by 50-71%. In controlled prospective studies no psychiatric or neuropsychological adverse effects were found (Hälbig et al. 2005; Kupsch et al. 2006; 7 Vidailhet et al. 2005). The observation of improved motor function and unaffected neuropsychological status is compatible with recent research suggesting a neuroanatomical and functional subdivision of the GPi with a mediodorsal part mediating cognitive functions and the posteroventrolateral motor portion being sufficiently large to allow a precise electrode placement. A trivial first conclusion from DBS in movement disorders such as ET and dystonia is that stimulation of structures that mediate motor functions and that are sufficiently large to allow a precise targeting in general does not affect psychological functions. This may be different in PD, as suggested by the introductory case report.

The Case of Parkinson’s Disease PD is one of the most common neuro-degenerative diseases and has a prevalence of 100-200/100,000 (Kasten et al. 2007). The mean age at onset is between 50 and 60 years and it is estimated that about 1% of the population ≥ age 60 suffers from PD. Its classical motor symptoms 7

There are single reports of suicides after thalamic or pallidal deep brain stimulation for the treatment of dystonia or ET. These, however, do not allow supporting a clear causal relation with DBS (Burkhard et al. 2004; Foncke et al. 2006).

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consist in resting tremor, muscle stiffness and slowness and inability to initiate movements (Shahed and Jankovic 2007). PD is a progressive condition and advanced stages of the disease may interfere significantly with virtually all motor-related activities of daily living. In contrast to ET and dystonia, PD is characterized to a varying frequency and degree by non-motor symptoms. These include cognitive impairments sometimes developing into full-blown dementia, psychiatric problems such as depression and anxiety, autonomic symptoms with unstable blood pressure, sexual dysfunctions or incontinence as well as sleep disorders, pain and sensory symptoms (Chaudhuri et al. 2006). Symptomatic PD therapy consists in supplementation of endogenous dopamine, which is diminished in PD. This allows for a more or less sufficient motor symptom control during the first years. After 4 - 8 years of disease progression, however, ‘motor complications’ develop with often unpredictable worsening of PD symptoms or overshooting, involuntary movements (dyskinesias). When these fluctuations become uncontrollable by dopaminergic or other medical drugs, or when psychiatric and other side-effects of the dopaminergic medications become a serious problem, DBS is considered as a therapeutic option (Olanow et al. 2009; Volkmann and Deuschl 2007). More than 50,000 PD patients worldwide have been treated with DBS (personal communication Medtronic, Germany, 03/2010). Most centers nowadays use the subthalamic nucleus (STN) as a target 8 (Benabid et al. 2009). The STN is functionally part of the basal ganglia. STN DBS allows a significant reduction of dopaminergic medication, which may be important for patients with medication induced sideeffects such as psychiatric symptoms (Ardouin et al. 2006), arterial hypotension or gastro-intestinal and sleep problems. Well-controlled prospective studies demonstrated that STN DBS lastingly improves motor functions and ameliorates in particular motor fluctuations (for an overview, see Benabid et al. 2009). These effects have been shown to translate into significant improvements of activities of daily living and health-related quality of life (Deuschl et al. 2006; Schüpbach et al. 2007).

8

Another target is the GPi (see above; Volkmann et al. 1998). In contrast to GPi DBS in dystonia, GPi DBS in PD has been reported to be associated with neuropsychological changes. Few studies compared the effects of GPi DBS to STN DBS in PD (Okun et al. 2009). There is some evidence that neuropsychological changes in PD are found less frequently with GPi DBS (Hariz et al. 2008). However, as STN DBS has advantages over GPi DBS, such as the possibility to decrease dopaminergic medication, it became the preferred DBS target in PD (Volkmann and Deuschl 2007).

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Neuropsychological Effects of STN DBS in PD Although neuropsychological functions have been evaluated in DBS patients, the available data are from studies that vary in methodology and often lack control groups. However, there is converging evidence that STN DBS in PD leads to mild frontal executive deteriorations and most frequently to verbal fluency deficits, even in carefully selected patients without preoperative cognitive deficits (Witt et al. 2008). It is questionable whether these deteriorations are clinically relevant and in most patients they do not translate into daily life problems. On the other hand, even modest changes can shift patients with borderline or mild cognitive impairment into severe cognitive dysfunctions (Saint-Cyr et al. 2000).

Psychiatric and Neurobehavioral Effects of STN DBS in PD Psychiatric and behavioral effects only recently became a research focus and only few major clinical prospective trials assessed them. On a group level, psychiatric measures appear to remain stable. Although data suggest mild improvements in anxiety or mood (Witt et al. 2008), often only physical aspects of quality of life improve (Drapier et al. 2005). On the other hand, and despite major motor improvements, Witt et al. (2008) report an incidence of 13% of serious neuropsychological and psychiatric adverse events in STN DBS patients (versus 10% in the medical control group), not all of them present only in the immediate postoperative period. Various smaller, non-controlled studies report severe psychiatric 9 side-effects. These include major depression, manic states and instances

9

Most of the reports on psychiatric effects are derived from uncontrolled trials with small sample sizes, from single case studies, retrospective chart reviews or smaller open case series. A considerable number to studies did not involve control groups or have other important methodological limitations. For example, the vast majority of patients with behavioral abnormalities are poorly characterized. Further, it usually is not reported where exactly the active electrode contact was located. It therefore is not clear whether the reported side-effects resulted from a misplaced electrode or if they were induced rather by stimulation via an optimally placed electrode contact. Further, psychological and personality changes are notoriously difficult to measure and experimental neuropsychological and psychiatric testing – if done at all – may be insensitive to clinically meaningful psychological changes. A full appreciation of psychological effects presumably would require qualitative assessments including psychosocial factors. The true incidence of psychiatric complications due

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of impulse control disorders such as compulsive shopping, gambling or hypersexuality (Table 1; see also Voon et al. 2006). Further, PD patients with STN DBS do have a significantly higher risk for suicide. As determined in an international multicenter survey on suicide outcomes following STN DBS in 5,311 patients with PD, their postoperative suicide rates were significantly higher than the age- and gender-matched country-specific rates (which are in general similar or higher than baseline suicide rates in PD patients who are not treated with DBS): The overall suicide rate in PD patients treated with STN DBS was 0.45% and the rate for attempted suicide 0.90% (Voon et al. 2008). The mean delay between completed suicide and the surgical intervention was 17.8 months. Table 1: Postoperative psychiatric and neurobehavioral symptoms in PD patients with STN DBS. For references, see main text. Depression Apathy Hypomania / Manic episodes Transient postoperative confusion Impulse control disorders (ICDs) • Hypersexuality • Pathological gambling • Compulsive shopping Impulsivity / Irritability Attempted or completed suicide Emotional processing deficits and alterations • Deficient recognition of emotional facial expressions • Enhanced emotional reactivity Psychosocial difficulties Lack of appreciation of motor benefits

to STN DBS may therefore be under- or overestimated and the significance of the reported effects often is not clear.

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Emotional, Psychosocial and Personality Changes after STN DBS in Parkinson’s Disease Apart from major psychiatric symptoms, STN DBS may induce more subtle emotional, behavioral or personality changes, see Table 1. As revealed by qualitative interviews, patients have been found to be more direct in their approach to others, more irritable and impatient (Schüpbach et al. 2006) and expressing opinions more freely as if being disinhibited. Schüpbach et al. (2006) in their report on 29 patients describe that despite significant motor improvements and ameliorations in their activities of daily living, in 17 out of 24 couples, marital conflicts developed or worsened, and 7 out of 16 patients gave up work. They finally observed a lack of appreciation of the often dramatic motor benefits. Data from quantitative evaluations add to this picture. For example, we recently were able to show that STN DBS patients score higher on impulsivity questionnaires than PD patients without DBS (Hälbig et al. 2009). This observation is compatible with data from neurocomputational models of the basal ganglia (Frank 2006) and with experimental neuropsychological evidence in humans (Frank et al. 2007). The data further are compatible with STN lesion effects in a rat model (Baunez et al. 1995) suggesting that stimulation of the STN results in pre-mature behavioral responses. Moreover, emotional processing such as the recognition of facial emotional expressions has been shown to be impaired (Le Jeune et al. 2008). On the other hand, STN DBS may enhance emotional processes such as emotional memory (Schneider et al. 2003). Although the clinical relevance of these findings is far from clear, it is conceivable that even mild changes in impulsivity or emotional reactivity may have impact on psychological status and wellbeing and may explain psychosocial maladjustment.

A Distressed Mind in a Repaired Body? The true incidence of relevant psychiatric complications due to STN DBS may be under- or overestimated due to the considerable methodological limitations of the published studies. Nevertheless, the available psychological and psychiatric data are largely sufficient to support the assumption that at least in a subset of patients, despite successful motor symptom reduction, STN DBS may affect psychological status negatively: STN DBS in PD may induce changes ranging from mild personality alterations to more devastating psychiatric symptoms compromising autonomy, free will and moral responsibility 259

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and may even lead to suicide. This prompted leading investigators in the field to raise the possibility that STN DBS in PD may result in “distressed minds in repaired bodies” (Schüpbach et al. 2006) and makes “the doctors happy, the patient less so” (Agid et al. 2006). Were these provocative statements adequate descriptions of the outcome of STN DBS in PD, it would indeed be irresponsible to expose PD patients to the risks of this therapy.

Multiple Risk Factors for Psychological and P s yc h i a t r i c S i d e E f f e c t s o f D B S Various causal factors for the development of side-effects have been identified. This explains, on the one hand, why in most instances it is possible to prevent side-effects and why only a minority of patients with DBS develops them. On the other hand, it becomes clear why it may be difficult to anticipate and avoid side-effects in the individual case. See Figure 1. First of all, the neural target determines the effects of DBS. Stimulation of pure motor structures, as in DBS for the treatment of ET or dystonia, may be neutral with respect to non-motor functions. Yet, the understanding of the functional role of many brain structures is limited and it is not always clear which structures are ‘pure’ motor structures. For example, there is evidence that the STN despite its indisputable implication in motor processes is involved in the integration of 10 cognitive-associative, limbic-emotional and motor information. That the concern of a limited understanding of the targeted structures is not merely academic is supported by the fact that STN DBS, which is used to improve motor functions in PD, has been established as a valuable research tool to explore the psychological functions of the STN. In other words, only because the functions of the STN – and a fortiori the effects of its stimulation – are unclear, it makes sense to use DBS as a research tool. For example, various studies tested scientific hypothesis regarding the functional role of the STN by ascertaining stimulation effects while patients performed cognitive tasks or during 10 There is some evidence that the STN is composed of different subterritories that mediate motor, cognitive or limbic-emotional functions. Whether these operate in a dissociated manner or whether the STN is a site of integration of motor and non-motor information is an open question. Were this latter hypothesis true, than it would be possible that even focused stimulation of what we consider the ‘motor’-part of the STN affects non-motor functions, as suggested by recent data (Mallet et al. 2007).

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brain imaging procedures or by recording changes of electrophysiological activity via the implanted electrodes while patients were exposed to specific stimuli (e.g., Hälbig et al. 2004; Hershey et al. 2004; Kuhn et al. 2005; Mallet et al. 2007; Schneider et al. 2003; Witt et al. 2004). Related to the role of the neuroanatomical site of stimulation is the precision of surgical targeting. In the case of inadvertent deviations from the targeted neural structure, DBS may induce spectacular psychological effects such as severe sadness or mirthful laughter (Bejjani et al. 1999; Krack et al. 2001). The likelihood of electrode misplacements depends on the precision of the neuro-radiology based target localization, the experience of the surgeon, the quality of the intra-operative electrophysiological target confirmation and the experience and availability of the neurologist (Okun et al. 2005). Another important factor determining the effects of DBS is the type of disease that is being treated. In rather pure motor diseases such as dystonia or ET, usually no psychiatric side-effects are observed. This is different in multi-systemic diseases such as PD, even when the same neural target is chosen (See Footnote 8). Moreover, the surgical procedure may have irreversible effects. This can be explained by permanent lesions of neural tissue that result from repeated insertion of electrodes that are intra-operatively used to explore the adequate electrode position. These effects are difficult to quantify and depend probably on the vulnerability of the individual brain and on differences in surgical and electrophysiological procedures. Few studies prospectively evaluated psychological functions before DBS surgery and post-operatively on and off stimulation. The impact of lesion effects therefore might be over- as well as underestimated. Further, DBS parameters and modes of stimulation (polarity, contact, voltage, frequency, pulse width, total energy) necessary to achieve sufficient symptom reduction vary considerably between patients and certain parameters are more likely to induce current spread to bypassing non-motor fiber tracts or non-motor areas than others. One factor determining the choice of DBS parameters is the precision of the targeting. Although there are expert opinion guidelines for DBS programming, the parameter selection is a matter of individual choice. Further, disease independent individual patient vulnerabilities such as a positive history for psychiatric conditions and cognitive baseline performance have been identified as risk factors for psychological outcome and psychiatric complications (Schadt et al. 2006; Voon et al. 2008).

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Although STN DBS may alleviate medication induced psychiatric side-effects via a significant reduction of dopaminergic drugs, postsurgical medication changes may also induce major psychiatric problems such as apathy or severe depression (Voon et al. 2006). On the other hand, it is conceivable that dopaminergic medications in conjunction with DBS may contribute to the development or maintenance of impulse control disorders (Hälbig et al. 2009). The psychological outcome of DBS in movement disorders is presumably also affected by individual psycho-social and environmental factors. ‘Being a single’ has been identified as one independent factor associated with the variance for attempted suicide risk (Voon et al. 2008). Further, coping and adaptation on the part of the spouse, in response to the post-DBS often dramatically changed psychosocial role, may impact the patients’ own dealing with the new situation. Unmet unrealistic expectations regarding the therapeutic effects of DBS that are potentially based on insufficient presurgical counseling 11 may be a source of deep disappointment and frustration. Further, the burden of normality (Wilson et al. 2001, 2007), the reframing of expectations and normative standards and the loss of secondary gain may induce psychological distress, even in patients without psychiatric 12 risks. This list of factors potentially impacting the psychological outcome in PD patients treated with DBS is non-exhaustive and the different factors may act synergistically or outweigh one another. However, the 11 Often it is not sufficiently appreciated that DBS, though highly efficient for the treatment of certain motor symptoms, is neither providing a cure nor has therapeutic effects on non-motor symptoms or motor symptoms that do not respond to levodopa. 12 The often dramatic improvements in motor functions and in activities of daily living after long-term disability in patients with STN DBS may be challenging for both the patient and his spouse or family. It may in fact be difficult for the patient returning to a normal life. This domain of possible psychosocial problems is not well examined. Various problems may emerge as a function of the ‘burden of normality’ and the loss of secondary gain. Whereas before DBS, patients framed their expectations and objectives taking into account limitations by the disease, regained motor functions not only increase physical independence but also social or professional expectations and obligations. Not having to take care of disease management any longer may even be experienced as a loss. Paradoxically, diminished disease burden may be a problem, as adaptation to a chronic condition may have caused new facets of identity, meaning and personality to emerge (Gisquet 2008). Further, a regain of personal autonomy may create important psychosocial problems. For example, the redefinition of roles shaped for both partners of a couple according to the needy person may fail and induce important relational problems.

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limited understanding of the functions of the neural structures that are manipulated in conjunction with the limited control and understanding of the mechanisms of DBS make clear why the effects of DBS may be difficult to predict in the individual patient. Figure 1: Multiple factors for psychological and psychiatric side-effects of DBS

S h o u l d w e b e t t e r Av o i d D B S S T N i n P D ? Let us imagine introducing surgically an electrode of a diameter of 1.5 mm into a brain structure of a size of about 6 x 3.5 x 5 mm (Richter et al. 2004) which is thought to mediate crucial psychological functions that are yet far from fully understood. Let us further assume that we apply via the electrode electrical pulses that affect the target structure and potentially surrounding tissue in a way that is not understood and that the induced effects depend on various only partially known and controllable co-factors. Let us further suppose that these interacting factors potentially result in negative and sometimes devastating psychiatric side-effects including suicide. Considering this scenario, shouldn’t we better renounce STN DBS in PD, which is a merely 263

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symptomatic therapy of only a subset of symptoms in a condition that in contrast to, for example, brain tumors, is neither life threatening nor significantly limiting life expectancy? A balanced, ethically responsible answer to this question would have to reconsider the treatment indication as well as treatment alternatives.

The Indication for STN DBS in PD Reconsidered To date, the established indication for STN DBS in PD is the presence of severe motor fluctuations with often alternating episodes of hypo- and hyperdopaminergic states. The former may be characterized by painful muscle stiffness and cramps, inability to move, to stand up, to walk, to turn around in bed, to eat without help or to perform basic activities of hygiene. These symptoms often are associated with anxiety, depressed mood and may lead to social withdrawal. The medication-induced hyperdopaminergic states, however, manifest themselves by uncontrolled, involuntary movements, which may also interfere considerably with motor activities. Dyskinesias, despite their pure motor character, may give the non-informed observer the impression that the person suffers from a psychiatric condition or other mental debilitation, which in turn may create a severe psychosocial burden contributing to psychological distress. It is important to appreciate that the often high doses of dopaminergic medication used to symptomatically treat PD (Hälbig and Koller 2007; Rascol et al. 2007), not only may have autonomic and gastrointestinal side-effects but may also induce severe psychological and psychiatric side-effects such as vivid dreaming, night mares, hallucinations, confusion, cognitive deficits, mania or impulse control disorders (e.g. pathological gambling, hypersexuality, compulsive shopping, internet addiction or binge eating; Potenza et al. 2007; 13 Weintraub et al. 2006). The effects of dopaminergic and other

13 All these effects are possibly induced by dopaminergic medications (thought to restore deficient dopaminergic neurotransmission in motor loops of the brain) via overstimulation or dysregulation of other dopaminergic systems that are involved in non-motor functions. Psychiatric side-effects such as hallucinations are among the most frequent reasons for institutionalization in advanced PD (Goetz and Stebbins 1993). There is some preliminary evidence that the lowering of dopaminergic medication in PD patients treated with STN DBS may be associated with major decrease if not ceasing of medication-induced psychiatric side-effects such as impulse control disorders (Ardouin et al. 2006). Medication induced psychiatric side-effects therefore are not necessarily contra indications for STN DBS. Their presence may be even an indication for STN DBS.

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psychotropic medications on psychological functioning reminds us of the trivial fact that no mechanical or electrical manipulation of the brain 14 is needed in order to interfere with the mental status.

What Are the Treatment Alternatives? Not to treat advanced PD with STN DBS implicates high dose dopaminergic therapy with potentially continuous motor fluctuations and side-effects. To abstain from STN DBS in PD therefore does not necessarily protect the patient from psychiatric deficits. This has been clearly demonstrated in a recent study on the effects of STN DBS in PD that enrolled a control group of patients who were managed with best medical treatment. In this study, which demonstrated that DBS was associated with superior health-related quality of life scores compared to best medical treatment, ten patients in the DBS group (13%) and eight patients in the medical control group (10%) had severe psychiatric adverse events. The distribution of complications differed between both groups with higher rates of psychosis in the medical group and a higher incidence of depression in the DBS group (Witt et al. 2008). Alternatives to STN DBS and standard oral dopaminergic drugs consist in non-oral modes of administration of dopaminergic agents via tubes that allow the direct administration into the gastro-intestinal tract, which may have a beneficial effect on motor fluctuations. Apart from the practical daily life constraints due to the PEG-tube, side-effects may consist in skin irritations or necrosis, infections, challenges during the complex technical management of the delivery system and psychiatric dopaminergic side-effects. Finally, administration of dopamine agonists may be realized via a subcutaneously placed needle, again carrying the risk of infections, skin irritations and psychiatric side-effects.

14 Actually, other interventions affecting the central nervous system may also lead to acute and lasting personality change. For example, various medications, including several non-prescription drugs are well known to have psychological side-effects. Further, alcohol, nicotine and other illegal and legally available drugs, as well as educational, psycho-therapeutic or brain-washing procedures may induce psychological and personality change. It is not surprising that for many of the behavioral consequences of these interventions, it is already possible to demonstrate changes of their neural correlates.

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Would it Be Unethical NOT to Provide DBS? Based on the current clinical indication and its treatment alternatives, it would be unethical not to suggest appropriately selected and wellinformed patients to undergo DBS for the treatment of PD and to deprive them of the often dramatic motor benefits. This conclusion is strengthened by the assumption that rigorous clinical patient management considering the above listed factors can probably help avoiding most complications. Acknowledging our current limitations in the understanding of the functions of the STN and of the effects of STN DBS, the clinical procedures during the selection of PD patients for surgery require, however, maximal effort (a) to identify those patients who may best profit from the motor benefits of DBS, (b) to avoid DBS surgery in those who run the risk of important side-effects, (c) to communicate thoroughly all possible consequences of the procedure assuring a fully informed consent and (d) to monitor and follow up on the possible induction of side-effects and treatment outcome on both the psychological and somatic levels. If these requirements are met, DBS is a complex and time consuming procedure and can only be realized by well-trained multidisciplinary teams involving neuro-radiologists, neuro-surgeons, neurologists, neuropsychologists, psychologists, psychiatrists and social workers and, on the part of the patients, peers, relatives, spouses and primary care physicians. The fact that is not always ensured has already been demonstrated by research on “DBS failures” in inappropriately selected or managed patients (Okun et al. 2005). Apart from these practical implications for patient care, experimental and clinical research on the psychiatric and psychological effects of DBS needs to be reinforced and further improvement of surgical, electrophysiological and imaging procedures are urgent requirements.

W h a t Ar e C r i t e r i a f o r ‘ E t h i c a l l y R e s p o n s i b l e ’ Brain Manipulations? As was demonstrated so far, therapeutic brain manipulations not necessarily affect psychological functioning. However, depending on the target and the technical approaches, DBS may lead to mild or even severe mental changes. These are not always predictable and thus cannot always be avoided.

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Due to technological progress and demographic change in western societies, there is an increasing demand for DBS and other powerful brain manipulative therapies in neurology and psychiatry. Currently, clinical trials are already testing whether the indication for STN DBS should be extended to early PD and other neural structures are being evaluated as potential DBS targets. At the same time, we are facing vast epistemological deficits regarding the neural correlates of our mental life. We further lack a full understanding of the mechanisms and effects of therapeutic brain manipulations, a problem that is even more relevant with regard to brain manipulation techniques that are under development (e.g., stem cell transplantation). It is not obvious what kind of outcome criteria – apart from the intended symptom reduction – DBS and other therapeutic brain manipulations should satisfy in order to qualify as ethically responsible therapies. This issue will be addressed in the remainder of this essay. Traditionally, the evaluation of treatment outcome in clinical therapy research focused on ‘objective’ disease characteristics such as the presence or absence of symptoms (e.g., tremor, slowness of movements, muscle stiffness) or symptom severity. Only more recently ‘health related quality of life’ (HRQoL) as a patient focused outcome measure was introduced. HRQoL measures the impact of disease and treatment on patients’ activities of daily living (such as dressing, feeding, hygiene, mobility, etc.) as well as on physical, emotional and social well-being (Kaplan 1985). However, in general, HRQoL measures the impact of disease more in terms of physical, social and psychological functions than in relation with internal experiences. The PDQ-39 is the questionnaire that is most frequently used in PD to assess the effects of DBS on HRQoL (Peto et al. 1998). Although it considers up to a certain extent non-motor items such as emotional, cognitive or social functions, it is a rather descriptive instrument that is dominated by items focusing on motor-related functions and neglects the patients’ subjective perspective on his functioning. It therefore does not come as a surprise that quality of life as measured by the PDQ-39 has been shown to improve in most studies on the effects of STN DBS in PD (Martinez-Martin et al. 2002) in parallel with motor symptoms (as measured by the physician employed motor rating scale UPDRS; Unified Parkinson’s Disease Rating Scale; Fahn and Elton 1987). In relation to the earlier discussed possible direct and indirect effects of DBS on psychological functioning and psychosocial status, it is conceivable that despite significant objective motor improvement and even improved HRQoL, the patients’ subjective well-being deteriorates leading to significant dissatisfaction and “distressed minds in repaired 267

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bodies” (Schüpbach et al. 2006). The evaluation of the effects of brain stimulation in general, and of STN DBS in PD in particular, on the 15 patients’ subjective well-being (or: global quality of life) therefore is an urgent need. Quality of life is a complex construct which according to the definition by the World Health Organization (WHO 1995) considers the 16

“[...] individual’s perception of his/her position in life in the context of the culture and value systems in which he/she lives and in relation to his/her goals, expectations, standards and concerns. It is a broad ranging concept incorporating in a complex way the person’s physical health, psychological state, level of independence, social relationships, personal beliefs and their 17 relationship to salient features of the environment [...]”

There is evidence that positive states of subjective well-being correlate with better physical health (e.g., Hilleras et al. 1999; Murrell et al. 2003; Ostir et al. 2000) and potentially life threatening illnesses such as congestive heart failure (Verbrugge et al. 1994) as well as other illnesses that are not life threatening (Celiker and Borman 2001) such as fibromyalgia and rheumatoid arthritis or the co-existence of multiple conditions may lower subjective well-being (Mehnert et al. 1990; Stewart et al. 1989). However, recent quality of life research in the realm of neurological disorders also suggests that there is often a remarkable lack of correlation between subjective well-being and disease severity (Brief et al. 1993; Robbins et al. 2001; Rothwell et al. 1997). For example, the subjective well-being in patients with most severe progressive motor disability, as in amyotrophic lateral sclerosis (ALS), often remains stable (Hays et al. 1995; Kubler et al. 2005; Simmons et al. 2000). In line with this, there is evidence that the quality life of PD patients is much more determined by psychological, psychiatric and psychosocial factors than by their motor abilities (Koplas et al. 1999; Schrag 2006) and, as shown for multiple sclerosis, diminished subjective well-being correlates with social support and awareness of disease and not only with disease severity (Ryan et al. 2007).

15 Global quality of life (or: subjective well-being) is here contrasted with health related quality of life (HRQoL). 16 Author’s emphasis. 17 Although this has never been formally assessed (Den Oudsten et al. 2007), all these aspects may be affected in PD and might contribute to lower levels of subjective well-being.

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The reasons for the rather limited impact of even severely disabling neurological symptoms on subjective well-being are not fully understood. The adaptation to the chronic condition, the reframing of normative standards and the presence of meaningful personal relations and values possibly help to outweigh the importance of the disease burden (Rapkin and Schwartz 2004). However, the probably most important predictors of subjective well-being are basic psychological and personality factors (Diener et al. 1999) such as positive affect / extraversion and negative affect / neuroticism (Costa and McCrae 1980; Watson and Clark 1984), self-esteem, self-efficiency and sense of coherence (Lucas et al. 1996; for an overview, see Herschbach 2002). This ‘psychological and personality framework‘ of which several factors have been associated with genetic predispositions, is mediated by the central nervous system (CNS) and is supposed to be rather stable. One might therefore argue that the often seen discrepancy of physical disease severity and subjective well-being disqualifies subjective well-being as an outcome measure for the evaluation of a somatic treatment. However, as therapeutic CNS interventions may compromise (or 18 improve) emotional processing, impulse control or mood, these therapies might affect major psychological and personality factors that determine subjective well-being (irrespective of improved ‘objective’ health status and performance level in activities of daily living).

18 Actually, STN DBS in PD may have inadvertent positive neuropsychological and psychological effects (Hälbig et al. 2004; Schneider et al. 2003; Witt et al. 2004). This likely results from stimulation ‘side-effects’ in non-motor and in particular ‘limbicemotional’ territories of the STN rather than as indirect consequences of improvements of motor-related activities of daily life. A recent own clinical observation in a PD patient treated with STN DBS illustrates this phenomenon: According to the patient – and confirmed by his spouse – he had always been a little too anxious, cautious, even a little boring in his demeanour. He had been rather passive and hesitant than novelty seeking or outgoing. Yet, he never suffered from any psychological distress nor had he psychiatric diseases. Several months after initiation of successful STN DBS he described himself – again confirmed by his spouse and family – as being more joyful, spontaneous, and curious, as showing more sexual initiative, as being all together a little more ‘risk’ taking although never acting irresponsibly. The patient and his family were fully satisfied by the overall DBS outcome. DBS in this case clearly had an inadvertent positive impact on a ‘healthy’ personality. What was observed here as an inadvertent positive DBS side effect, however, points to a separate, important ethical phenomenon: namely the possibility of an ‘enhancement’ of ‘normal’ psychological and behavioral capacities using brain manipulative therapies. (See chapter by Dominik Groß.)

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Applying these considerations to the main topic of this essay – i.e., whether STN DBS in PD in particular, and therapeutic brain manipulations in general, represent an ethical problem – leads us to the empirical question of whether a given therapy results in lower levels of subjective well-being. Were this the case, it likely would be difficult to justify the respective therapy. To the best of my knowledge, the effects of DBS on subjective well-being have never been examined. When framing the general perspectives for research programs and for criteria 19 interventional brain therapies have to satisfy, subjective well-being should be evaluated in addition to health-related quality of life and current standard neurological, cognitive and neuropsychiatric measures. Given the complexity of the concept of subjective well-being with its numerous determining factors, it appears to be too strong a requirement for most brain manipulative therapies that they would have to improve subjective well-being. Given the possibility of “distressed minds in repaired bodies”, they should, however, not lead to inferior levels of subjective well-being when compared to best medical treatment or no treatment.

Conclusions Regarding the Ethical C o n c e r n s As s o c i a t e d w i t h D B S a n d O t h e r B r a i n M a n i p u l a t i ve T h e r a p i e s i n t h e Neurological Domain DBS for the treatment of movement disorders is a powerful therapeutic tool. It may dramatically reduce symptoms and improve health-related quality of life. At the same time, DBS may have psychological and psychiatric side-effects in individual patients. Whether DBS leads to side-effects or not, depends on the specific disease, the neural target, the mechanisms of intervention and the vulnerability of the individual patient. The concern that DBS might affect personality, personal identity and autonomy is legitimate and has to be taken seriously. However, medical and other non-invasive therapies can also have substantial negative psychological and psychiatric consequences. The probability of side-effects induced by DBS (or other brain manipulative therapies) therefore has to be weighed against treatment benefits and 19 There are established instruments that would allow these evaluations. For example, in order to ascertain the effects of brain manipulations on the ‘cognitive’ component of subjective well-being, the SWLS (Diener et al. 1985) could be employed and to measure effects on the ‘affective’ component, the PANAS (Watson et al. 1988) is available.

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potential side-effects of therapy alternatives, before a conclusion regarding the superiority of one treatment modality over another can be drawn. With regard to the individual decision for or against a therapy, a given patients’ specific risk-benefit ratio should be taken into consideration. Finally, we face vast epistemological deficits regarding the neural basis of our mental life and it is possible that brain interventional therapies may negatively impact subjective well-being. It therefore is an urgent need to include subjective well-being as outcome measure, when designing clinical trials examining the effects of brain manipulative therapies.

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Welter, M.L., L.Mallet, J.L. Houeto, C. Karachi, V. Czernecki, P. Cornu, S. Navarro, B. Pidoux, D. Dormont, E. Bardinet, J. Yelnik, P. Damier & Y. Agid (2008) “Internal pallidal and thalamic stimulation in patients with Tourette syndrome”, in: Arch Neurol 65/7 (Jul): 952-957. WHO (1995) “The World Health Organization Quality of Life assessment (WHOQOL): position paper from the World Health Organization”, in: Soc Sci Med 41/10 (Nov): 1403-1409. Wilson, S., P. Bladin & M. Saling (2001) “The ‘burden of normality’: concepts of adjustment after surgery for seizures”, in: J Neurol Neurosurg Psychiatry 70/5 (May): 649-656. Wilson, S., P. Bladin & M. Saling (2007) “The burden of normality: a framework for rehabilitation after epilepsy surgery”, in: Epilepsia 48 Suppl 9: 13-16. Witt, K., U. Pulkowski, J. Herzog, D. Lorenz, W. Hamel, G. Deuschl & P. Krack (2004) “Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease”, in: Arch Neurol 61/5 (May): 697-700. Witt, K., C. Daniels, J. Reiff, P. Krack, J. Volkmann, M.O. Pinsker, M. Krause,V. Tronnier, M. Kloss, A. Schnitzler, L. Wojtecki, K. Botzel, A. Danek, R. Hilker, V. Sturm, A. Kupsch, E. Karner & G. Deuschl (2008) “Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease: a randomised, multicentre study”, in: Lancet Neurol 7/7 (Jul): 605614.

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Ques tions on Dee p Bra in Stimula tion on Childre n and J uve niles w ith Ne urops yc hia tr ic Dis or de rs w it h Ex tre mel y Ad ve rse Course JÖRG M. FEGERT

Introduction Besides known neurological applications Deep Brain Stimulation has also become an applied treatment alternative in neurosurgery of adulthood for neuropsychiatric disorders with extremely adverse courses in the past years. It is predominantly put to use when medicinal treatment attempts have been exhausted and a longlasting unsuccessful disease course with considerable and actual impairment of quality-of-life and functionality exists. As juveniles themselves and in particular the custodian parents increasingly seek information on treatment alternatives for serious diseases via the internet, pediatricians as well as child and adolescent psychiatrists are occasionaly approached on neurosurgical treatment alternatives not only with respect to epilepsy treatment but also with respect to severe depressive disorders, obsessive disorders and most severe therapy refractory Tic-disorders (TouretteSyndrom). Until now the author has been exceedingly reserved due to various considerations and rather advised the affected juveniles and their families to await the 18th birthday before taking such a decision. In an actual case, which years ago was treated initially under my responsibility a surgery has been conducted during adolescence in a 281

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suitable neurosurgical center and results have not been satisfactory so far. This clinical case report is depicted in detail someplace else (compare Dueck et. al. 2009). The topic of this contribution is to develop a direction for dialogue with affected families with respect to other grave decisions on treatments outside of medical standards. At the same time development in child and adolescent psychopharmacology plays a special role as reference, as during the past 10 years considerable changes emerged and the subject on treatment of so called incompetent or consent incapable children and juveniles was discussed in a much more systematic manner.

F r a m ew o r k s f o r a W e l l - b e i n g At t e m p t w i t h C h i l d r e n a n d J u ve n i l e s Since, until a few years ago, most treatment forms approved for adulthood have not been scientifically investigated on children and juveniles, the practicing pediatrician or child- and adolescent psychiatrists are well familiar with therapeutic attempts and so called off-label-use and unlicensed-use of substances for which absolutely no approval exists in Germany. The analogy to Off-Label-Use is thus relevant as during the so called Off-Labe-Use on children and juveniles a treatment method established mostly for adults and for which an indication (Label) for adults exists is used outside this indication (OffLabel) on children and juveniles. Assumptions on a comparable effect are often deceptive. Children and juveniles are not little adults. The child body and the infantile and juvenile brain react in part differently to comparable interventions in an adult. This insight, which had to be gained from to some extent heavy treatment incidents in medicine such as the Grey syndrome etc. finally led to new procedures after painful research disasters on antidepressants in children and adolescents. Latest antidepressants, so called serotonine- uptake inhibitors (SSRIs) and combined reuptake inhibitors (SNRI) have been used increasingly during childhood and adolescence due to positive experiences in adulthood all over the world as these medications showed considerably less side-effects than the old tricyclic antidepressants. Based on individual cases publicized by the media, BBC published “The secret of seroxat”, noting that the British regulatory agencies had not sufficiently considered corresponding risks in children and juveniles based on manufacturer statements on Paroxetine on studies in children and juveniles. This led to a worldwide reanalysis of published and unpublished studies on children and adolescents (see Fegert 2004, Fegert et al. 282

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2006) which ultimately resulted in the formulation of a general warning on the use of antidepressants for children and juveniles initially by the FDA and later by the European regulatory bodies as well. Subject of this warning was the increased appearance of suicidal ideation and behavioral activation during the antidepressant treatment in children and juveniles. At the same time it turned out that numerous studies with negative results had not been published and were only known to the regulatory authorities and manufacturers while physicians relied on anecdotal observations, analogies to adulthood and on some small successful studies in their Off-Label-Use. In the end, an overview of the research results at that time showed that only Fluoxetin could be approved as an antidepressant for treatment of depression in childhood and adolescence. Other SSRIs such as Fluvoxamin were approved in Germany for treatment of obsessive-compulsive disorders in childhood and adolescence due to sufficiently positive data. A critical examination of the literature showed that the younger the children involved were, the more frequently somatic side-effects such as nausea etc. appeared. As a rule, the anti-depressive effect decreased with child age while the number of the side-effects increased. Several medications appeared to be effective during adolescence but could not show sufficient efficacy in children (11 years and younger). It became apparent that many of these studies had been conceived very fast and without sufficient pharmacokinetic investigations during childhood and adolescence. Differences in age-dependent metabolism of the substances were often not considered and eventually studies have been conducted with inadequate dosages for children and juveniles. The warning signs and the shock over the concealed negative results resulted in a general cautiousness by many physicians. The prescription of antidepressants for children and juveniles abridged substantially mainly in the USA and psychiatric less experienced specialty groups such as pediatricians or general practitioners, who previously had been frequent first prescribers of these substances, suddenly abandoned this practice in a relatively short time. At the same time an increase of suicide rates was observed in the United States and the Netherlands and discussions emerged whether the regulatory intervention for the protection of children and youth went too far and whether the warnings resulted in higher side-effects and social costs than the side-effects of the medication. In the end, this so called SSRI-disaster left children, juveniles, their families and treating physicians as well as approval authorities helpless in a way. Simultaneously, many activities were initiated however, which are also important for our problem. An international study register was introduced for example, in which all planned studies with their design 283

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and relevant target size must be named. In the United States such register is publically accessible. The European EUDRACT-Register can only be accessed by regulatory authorities and participating scientists. Scientific publishers agreed on standards whereby only studies are published which have been enrolled before and whose primary endpoints have been determined before the start of the study, such that the time is not so long until a positive result appears after a study has been finalized. Similar to preceding American legislation an EUdirective demands that all substances which potentially can be used in children and youth must have a pediatric investigation plan at the time of their investigation and market introduction for adults. This plan on investigation during childhood and adolescence must be submitted to the European Medicines Agency (EMA) already during the course of investigations on adults.

W h a t D o e s t h i s An a l o g y a n d O t h e r E q u i va l e n t S i t u a t i o n s M e a n f o r t h e U s e o f Deep Brain Stimulation during Childhood a n d Ad o l e s c e n c e ? Deep Brain Stimulation is a method whereby many indications can be considered experimental also for neurosurgery in adults. Apart from indications which primarily or most frequently appear during childhood and youth, such methods as with medication should be investigated first on consenting adults. Adults with corresponding diseases do not decide primarily on this treatment method but based on massive everyday life impairment, often during year-long treatment course (see Merkel et al. 2007: 168 ff.). Cases from the Nuttin team, which we discussed in this interdisciplinary team in detail, are adult patients with compulsive disorders, who showed both a high symptom load, and a strong impairment which became obvious by low values in the global detection of managing everyday life (Global Assessment of Functioning). It was expected that this level of impairment existed for at least five years. Most patients described there, had spend more than ten years with massive impaired quality-of-life and their psychiatric disease could be actually considered as therapy-refractory. Therefore, one may conclude that if similar conditions of adulthood were applied to childhood and youth, a corresponding intervention, if at all, can only be seriously considered during adolescence at this time and excluded during childhood for psychiatric diseases. Various and severe compulsive- or Tic-disorders of childhood and adolescence show a wave-like course of 284

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disease. Some remit after several years, such that in a growing and developing organism the criterion of disease chronicity and deficiency in therapy response (“therapy-refractory”) must once again be evaluated differently from adulthood where substantially less remissions are known in the course of the disease. On the other hand, a severe chronically debilitating disease impairs child development in general and in particular reduces chances for participation such that certain integration measures can either not or only insufficiently be performed. Therefore one could argue that it is unethical to wait too long during a decisive stage of development. One should also consider the higher suicide rate and the higher willingness of youth to take risks in general. While generally a systematic detection of side-effects from single observations and studies exists with respect to medication, side-effects and complications of electrical brain stimulation for treatment of psychiatric disorders, which are of central importance for parents and juveniles for treatment decisions, are not sufficiently systematically recorded. The research team in Leuven and Antwerp, where Bart Nuttin participated in the interdisciplinary team intervening in the brain (Merkel et al. 2007), describes side-effects as technical problems and problems which go along with limited battery lifetime, surgical complications and other complication such as changes in autonomous functions, changes in weight, sleepiness, nervousness etc. Kuhn et al. (2010) discriminate complications associated with surgical procedures, purely technical problems and side-effects by the actual stimulation in a similar manner. For equivalent evaluation of OR-risks neuro-surgical experiences of movement disorders are considered. Intracerebral hemorrhages can result in focal herds or even lethal outcome, moreover a risk for perioperative infections by the introduced material exists. The extent of these risks is different depending on the center. The technical development leads to a reduction of “hardware problems” described in the literature such as cable splits and malfunctions etc. Of the undesirable stimulation-dependent side-effects specifically changes of the psycho-pathological condition and character modifying attitude changes are relevant (e.g. sexual disinhibition during stimulation of an otherwise extremely controlled patient). Based on the experiences with antidepressants described above one cannot assume that the indicated rates of suicidality (under 1% after Kuhn et al.) also apply to youth. In order to qualify for use in adolescents more information about age dependent effects and side-effects must be gathered and published in a standardized form. Similar to medications it may be useful to make such representations in surveys age-dependent as patients between 18 and 25 285

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years of age have been described in adult literature and a subgroup analysis of positive results and limitations in this age group may eventually facilitate treatment decisions for adolescents. Presently, for all patients a despairing situation precedes such an operation whereby many patients are also acutely suicidal due to the consequences of illness. A restriction and lack of perspective often go along with suicidality which leaves doubt if the patient alone is in the position to make such a far reaching decision with adequate consideration at all. In any case, a thorough test of understanding of their own problematic nature in youth, their prognosis and finally their capability of consent, is necessary. At the same time it must be considered that in clinical studies on children and youth the custodians must always give their consent. However, a well-being youth, with full mental capacity, can also conclusively consent alone in treatment decisions but not in research. Nevertheless, nobody would want to rely on this and thus sufficiently inform both parents and youth. In such a situation a continuous yearlong standardized documentation of the condition and psycho-social impairment in preparation of an eventual treatment decision is highly recommended. Even if one generally decides as a treating physician to delay corresponding decisions into adulthood, the course (of the disease) should be conclusively documented during childhood and adolescence in a way that all decision relevant criteria exist in adulthood. Clinical ethics committees can be of great help in discussion of such hopeless developments and also support therapists, which often for years treat and support at first the children, then growing adolescents in their desperation along with their parents. In any case, the request for an second opinion is urgently recommended outside of the system of parents, youth, physician. In child and adolescent psychiatry, it often happens that patients and individual parents or both parents have a different view on treatment decisions. In view of such an experimental method, an intervention with approval of custodian parents without informed consent of the youth must be rejected based on ethical grounds because in an attempt for treatment the recognizable, even not verbally articulated will of the child or youth must be considered. This recognition is also important because again and again, more or less like in science fiction novels imaginations on behavior control by surgical interventions are discussed especially for impulsive aggressive offenders or so called “psychopaths”. In view of the totally unknown risks and the far reaching decisions, an indication other than the improvement of symptoms and the quality-of-life must be absolutely rejected. Experiments which primarily serve the improvement 286

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of legal prognosis of juveniles and young adult offenders are therefore completely excluded.

Conclusion – Recommendation for the Discussion of Deep Brain Stimulation as U l t i m a R a t i o f o r S e ve r e N e u r o p s yc h i a t r i c Disorders of Juveniles Above all, potential neuropsychiatric indications during adolescence, severe chronically occuring Tourette syndromes (cave remission rate up to 40% to adulthood) with a high compulsive component or most severely impairing obsessive-compulsive disorders must be named. Severe, non-remitting depressions respond quite well to EcT. One can hardly understand in Germany that in general for historic reasons extreme fear of EcT exist in the professional world as well as in parents. Transcranial Magnet-stimulation is increasingly discussed as alternative treatment for the indication ‘depression’ amongst the usual medicines for non sufficiently remissive (disease) courses. Here as well, the present indication (Schläpfer et al. 2005) does not show advantages of RTMF over EcT. Fortunately, corresponding terrible and severe child- and juvenile diseases are relatively rare. Children with severe progression of obsessive-compulsive disorders and Tourette syndromes are frequently treated by several physicians in the course of their young lives, because the unsatisfactory disease development encourages parents again and again to seek a way out or hope in new treatments, methods or therapists. Thus, parents with such heavily burdened children are extremely tempted not only by experimental treatment methods in medicine but by all sorts of charlatans and miracle healers which are often sought out. Thus, a thorough medical history of the treatment pre-history (also the non medical and non lege artis practised treatment attempts) belongs to the regular preparation of corresponding decision-making processes. Patients with such difficult (disease) courses should be looked after in specialized centers, for example during special Tourette consultation hours. It is useful to introduce such patients to corresponding neurosurgical centers already at a young age whereby a close collaboration with physicians for adults is absolutely necessary as adequate experiences in child- and juvenile psychiatry do not exist. As attractive as the idea of a successful surgical intervention may be in a hopeless situation, a state of the art pharmacotherapy over a longer period of time with course documentation should be conducted in a specialized center. 287

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It would be fundamentally important and in my opinion also ethically justifiable, to record such severe developments of obsessivecompulsive disorders or combined obsessive-compulsive disorders with Tourette syndrome in a register and investigate prospectively. The neuropsychiatric investigation methods, especially those with documentation of motor phenomenons etc., should occur in a standardized manner in consultation with specialized neurosurgical centers such that we can learn from the few individual cases worldwide in a coordinated way. In general, the present task of the treating child- and youth psychiatrist is to conduct a profound course documentation, to discuss all considerations in detail with the respective youths and the parents, but to delay a respective decision into adulthood. Often, it will be necessary to regularly examine such patients with respect to suicidal tendencies because of their apparently hopeless situation and to protect them in some cases by admission to an acute psychiatry ward.

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References Dueck, A., A. Wolters, K. Wunsch, S. Bohne-Suraj, J.-U. Müller, F. Haeßler, R. Benecke & J. Buchmann (2009) “Deep brain stimulation of globus pallidus internus in a 16-years-old boy with severe Tourette syndrome and mental retardation”, in: Neuropediatrics Oct; 40(5): 239-242. Fegert, J.M. (2004) „Depressionsbehandlung mit SSRI in der Kinderund Jugendpsychiatrie – Ein Forschungs- oder ein Informationsdebakel?“, in: Nervenheilkunde 23(1): 60-64. Fegert, J.M., K. Jahnsen & I. Böge (2006) „Medikamentöse Behandlung der Depression im Kindes- und Jugendalter“, in: Psychopharmakotherapie 13(3): 84-94. Kuhn, J., T.O.J. Gründler, D. Lenartz, V. Sturm, J. Klosterkötter & W. Huff (2010) „Tiefe Hirnstimulation bei psychiatrischen Erkrankungen“, in: Deutsches Ärzteblatt International 107(7): 105-113. Merkel, R., G. Boer, J.M. Fegert, T. Galert, D. Hartmann, B. Nuttin & S. Rosahl (eds.) (2007) Intervening in the brain. Changing psyche and society (Springer). Schläpfer, T.E. & K. Lieb (2005) “Deep brain stimulation for treatment of refractory depression”, in: The Lancet 366(9495): 1420-1422.

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Traditional vs. Modern Neuroenhancement: Note s from a Me dic o-ethical a nd Societal Pe rspective DOMINIK GROSS

Introduction Neuroenhancement generally designates measures taken for the improvement of cognitive abilities or emotional sensitivity in people who evidence no signs of illness. Yet which mental phenomenon and behaviors do we consider illnesses? Which of these pathological conditions seems to us in need of therapy and what criteria do we apply? Which mental conditions and behaviors do we include under the attribute ‘healthy’? Even these initial questions indicate that objective involvement with the field of neuroenhancement requires a differentiation between therapy and enhancement and thus also clarification of the terms health and illness. Therefore this clarification is made at the beginning of this contribution (chapter 1). I begin by briefly describing psychopharmacological enhancement treatment as prelude to a more detailed description of invasive neurobionic forms of enhancement (chapter 2). In chapter 3 these two modern, controversial forms of neuroenhancement will be compared to ‘traditional’, socially acceptable or at least tolerated enhancement methods. These are followed by some conclusions concerning the ethical and societal perspective on traditional and modern neuroenhancement methods.

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H e a l t h o r I l l n e s s , E n h a n c e m e n t o r T h e r a p y? The answer to the question as to where the dividing line between enhancement and therapy lies is largely context dependent, that is, it is subject to prevailing socio-cultural and political values. Essential to this are the prevalent concepts of health and illness in a society at any given time (Groß and Müller 2007). This can be seen, for example, in how some cultures evidence highly disparate attitudes toward addictive drugs and the closely correlated, situation-specific different attitudes regarding addiction-related illnesses. In other words, the difference between enhancement and therapy is not something that can be scientifically determined beyond any doubt. Practically demarcating between these termini is correspondingly difficult. Even if for a moment we assume categorical definitions for ‘illness’ and ‘health’, the problem of a missing differentiation of the terms ‘enhancement’ and ‘therapy’ remains as indicated by the following four examples: (1) There is the chance that the same medical results will be considered pathological at one point and later categorized as nonpathological. One might think here of a (relative) shortage of growth hormones; in a child whose parents are of slight build this would be normal, while in a child whose parents are stoutly built this would make one consider that there might be an imbalance. (2) It appears that a condition can be classified as pathological, but not as requiring therapy, that is to say that the character of an illness and its therapy requirements of a medical situation are determined differently depending on the culture and/or the social environment. Thus the use of antidepressants such as fluoxetine (Fluctin®, Prozac®) to combat depression and dysthymia is hardly disputed. While absent or deficient self-confidence in some is taken as an indication for treatment with fluoxetine, meaning that it calls for therapy, in others this treatment 1 would be understood as enhancement. Also controversial is the use of medical enhancement by means of nootropics for those suffering from light cognitive disturbances which are predominantly taken as the 2 normal signs of old age but are defined by some as pathological. (3) There is a chance that certain conditions are seen socially as needing therapy although their classification as an illness is nevertheless 1 2

It is the Anglo-American world that generates the greatest demand for fluoxetine. See Foster (2006) as well as en.wikipedia.org/wiki/Fluoxetine. The availability of options (nootropics) does influence the yardstick here as to what is seen as (still) normal or in need of treatment. See also the contributions by Sabine Müller and Mareke Arends & Heiner Fangerau in this volume.

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questionable. Thus deafness is construed by most as a physical dysfunction in need of treatment although some of those effected would not agree with that evaluation. This illustrates some of what has been happening with cochlear implants (Bentele 2006): in some cases deaf parents refuse to permit the procedure to be carried out on their deaf children because they do not see this condition as pathological but merely as ‘different’. The prospect of cochlear implants in children initiated a discussion about the classification of neuro-prosthetic procedures: is neuro-prosthetic treatment for a ‘disability’ a therapy, an enhancement, a strange mutilation due to social pressure or the forced adjustment of people? (4) Finally, we must consider that the social definition and comprehension of mental and neurological diseases can shift based on the availability of new technologies and interventions. What was perceived yesterday as merely functional and structural deviations from a ‘cerebral standard’ could be interpreted tomorrow as a defect which should be treated. In sum, we know that there are definitional vaguenesses which complicate an unambiguous classification of a measure as ‘enhancement’ or ‘therapy’. Keeping this in mind, for purposes of comprehension intervention will here be understood as enhancement and at present enhancement is not (primarily) seen by the majority of our society as requiring medical intervention.

Neuroenhancement: Modern Forms and Possible F i e l d s o f Ap p l i c a t i o n Psycho-pharmacological Enhancement Psycho-pharmacological enhancement, also known (disparagingly) as 3 ‘cosmetic psycho-pharmacology’, ‘pharmacologic neuroenhancement’ (Schäfer and Groß 2008) or (abbreviated) ‘brain doping’, refers to the administration of medicines developed for patients with dementia (e.g., donepezil), depression (e.g., fluoxetine), attention disorders (e.g., methylphenidate) or narcolepsy (e.g., modafinil) when not medically indicated. Since the 1980s we have witnessed an increasing ‘extra-medical’ use 4 of psycho-pharmacology. Such uses include memory improvement, the 3 4

This well-known term can be traced back to Kramer (1993). This is described by Peter Kramer in the framework of a prescription for the anti-depressive fluoxetine (Prozac®) (1993).

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heightening of attention, mood enhancers, the ‘modulation’ of personality characteristics and the reduction of the need for sleep. In order to improve cognitive abilities principally at school, at university and at work anti-depressives such as fluoxetine are prescribed which are sometimes taken in order to liberate oneself from unwanted personal traits such as (what is subjectively perceived to be) a lack of selfconfidence or simply to feel ‘better than good’. Whether such an expectation can actually be met by taking fluoxetine will not be discussed 5 here. The reduction of the need for sleep can also be seen as a desirable and attractive option within educational and professional fields. It is however also and especially of interest in military fields where the sleep needs of soldiers in defensive or attack situations can play a decisive role (Bielefeld and Eurich 2005). Likewise attempts have been described of using psycho-pharmaceuticals to heighten receptivity for religious 6 experiences. In sum it can be said that the demand for chemical neuroenhancement is often oriented toward socially and personally desired character qualities as well as mental states. While within the field of neuro-pharmacology concrete extratherapeutic possibilities for the modulation of mental conditions with the goal of increasing performance or an improvement in (subjective) wellbeing already exist, enhancement via brain-computer interaction (neurobionic enhancement) is still largely in the experimental stage. Yet here too concrete options are indicated which deserve more detailed inspection.

Technical Enhancement and Brain Engineering Technical enhancement, which also operates under the terms ‘brain 7 engineering’ (Foster 2006) or technical ‘brain enhancement’, is generally speculative in nature. By this is meant the application of neuro-technological, invasive procedures for the enhancement and/or augmentation of human abilities beyond their generic functions (Rötzer et al. 1996; Cochrane 2000; Brooks 2002; Farah 2002). In many areas it is based on implants from the ICT sphere, that is, ‘information and 5

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Nevertheless it should be mentioned at this point that the effectiveness of fluoxetine as a ‘happy pill’ is questioned by many experts (see Farah 2005: 36; Einemann 2003). See Muggenthaler (2004) who reports on corresponding activities of the World Transhumanist Association (WTA). The latter demand the freedom to customize their bodies at their own discretion with any available technology. Efforts to increase receptivity to religious experiences can also be found among primitive peoples. See also www.ics.uci.edu/~granger/

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communication technology’. The procedures described in the literature are essentially in the developmental phase or – according to some – are 9 visionary or even fictional. Developmental possibilities and future fields of application are anticipated principally in the following fields: a) Expansion of sensory perception This has to do with endeavors to provide people sensory functions via neurobionic implants which nature had not made available. The neologism ‘neurobionic’ refers to a field of research which originated at the interface of the neurosciences, biology and technology; it deals with the integration of neural prostheses into the human nervous system (Bothe and Engel 1998; Rosaler 2003; Rossmann and Tropea 2005; Berger and Glanzmann 2005; Groß 2007a, 2007b, 2009a, 2009b; Müller et al. 2009). The goal is to tap into worlds of experience which normally are not accessible to the human ‘mesocosmos’, that is to the human 10 range of sensory perception. The point of departure for these efforts is knowledge about the superiority of some senses among certain 11 animals. We roughly extrapolate the olfactory world of the dog, the auditory world of the field mouse, the colored world of the bee and the spatial orientation of the cetacean at best with theoretical knowledge or with the aid of technical tools (e.g., night vision goggles), but not as unmediated, concrete perception. Proximate possibilities for these kinds of functional enhancements consist of the further development of the current procedure for cochlear implantation and retina implantation, the latter being in the pilot stage, and the expansion of the range of available sensory perception. One possible goal thus concerns the neurobionic extension of the spectrum of audible frequencies. Others consider research into improved optical perception (‘supersensory seeing’ [Cochrane 2000; McGee and Maguire 2001; Brooks 2002]), via infrared or ultraviolet light, chemical spectra, gamma radiation or the further development of eye functions to create a

8 9

See here the exemplary Hamburg (2005), p. 71f, www.commece.org. The question as to how realistic the technical implantation is among those who envisage neurobionic procedures in theory cannot be dealt with here as must the question regarding demand for such operative procedures. 10 For details on the term ‘human mesocosmos’ see Engels and Hildt (2005), passim, as well as Engels (2005: 230-236). The term explicitly refers to the field of human sensory perception. It describes the unity of physical reality which humans are able to experience and process exclusively via our sensory organs. Thus UV and infrared rays and sound waves outside the 16-20,000 Hz range, for example, are ruled out. 11 On the perceptive world of animals see Varju (1998).

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‘night vision unit’, worthwhile (Muggenthaler 2004). Enhancements to the olfactory and gustatory senses are also envisaged. An attractive goal of these efforts is the transcendence of the normal limits of human experience and full exploitation of the optical, auditory and flavor worlds of animals (Engels 2005: 230-236). The goal is thus an enhancement of human consciousness and human experience which could lead to experiencing, organizing and structuring the world anew. Yet there are indications that these kinds of performance enhancements could be used to equip and field soldiers (Foster 2006: 191; Bielefeld and Eurich 2005). b) Memory enhancement Neurosurgery in the human brain is today part of standard medical treatment in the industrialized world. It can restore lost or damaged functions or prevent their loss. In so doing these operations do not restrict themselves to the removal of pathological deformities, rather certain procedures are designed to implant technical elements (e.g., electrodes for stimulation). With this assistance those functions which have been lost or pathologically altered can be restored or improved. Furthermore, the advancement of neurobionic implantation could in the future be adapted for the brain to deal with certain situations or for the enhancement of cognitive performance in private or everyday workrelated use. In a 1995 study the ‘Office of Technology Assessment at the German Parliament’ drew the conclusion that by means of microchips the brain could learn to directly receive certain kinds of information 13 (e.g., computational ability) or that databanks could be accessed directly in the brain without recourse to a computer (Büro für Technikfolgenabschätzung 1995: 14f.). A single glance at the relevant literature reveals considerable interest in the visionary possibilities of an implant-based direct link between the human brain and computers. Expectations are that this will provide speedier and more efficient handling of what has become in recent decades a steadily increasing flood of information. An example of this are ‘memory chips’ which enable quick access to encyclopedic databanks thereby accelerating the

12 See National Science Foundation, Converging Technologies for Improving Human Performance (Report) (www.wtec.org/ConvergingTechnologies/). 13 It has been noted that computational ability represents not information, but an ability, as the term indicates. It precedes a learning process independent of whether a ‘calculator’ will be integrated into the brain or, for example, one uses a pocket calculator.

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acquisition of new languages, for example (Cochrane 1999a, 1999b, 2000; Brooks 2002). More realistically, we are presently witnessing the further development and more widespread extra-therapeutic application of 14 ‘transcranial magnetic stimulation’ (TMS). In contrast to the procedures described above, this is a non-invasive technology which stimulates specific regions of the brain with the aid of strong magnetic 15 fields. TMS too is expected to increase cognitive and mnemic abilities. Like a modern version of the ‘Nuremberg Trichters’, in the popular press a ‘brain cap’ has been propagated as an ‘IQ cap’ and as the path to ‘hyper-intelligence’. The tenor of these pieces is that with long-term use 16 TMS can tune your brain to peak efficiency. c) Personality modification via electrode implantation Techniques which are already in clinical use such as deep brain stimulation (DBS) (Wolf 2005: esp. 356f.) with Parkinson’s patients or vagus nerve stimulation (VNS) with epileptics and those suffering from pharmaco-therapy resistant depression are new fields of therapeutic as well as conceivably extra-therapeutic application (Deuschl et al. 2002; Andrews 2003). Thus the implantation of electrodes into certain parts of the brain could serve to bring about or strengthen desired behaviors as well as break undesired aspects of the patient’s personality (e.g., dysthymia). The 1995 study by the Office of Technology Assessment at the German Parliament cited above also considered that the brain could be stimulated via implanted electrodes which would distribute the body’s own sedative and mood enhancing substances. This would give rise to completely new fields of application in, for example, anesthesiology, pain therapy and the treatment of depression. This kind of artificially induced distribution of these kinds of bodily substances could potentially also be used in drug addiction treatment as well (Büro für Technikfolgenabschätzung 1995: 14f.). In 2005, a patient in Mexico City with ‘therapy-resistant’ depression, borderline personality disorder and an eating disorder was given deep brain stimulation in their pedunculus thalami inferior (Jiménez et al.

14 For the origins of TMS see Barker et al. (1985: 1106-1107). 15 In contrast to the measures described in this chapter, TMS has already been clinically proven. The most common side-effects are temporary headaches. Yet most feared is the rare onset of an epileptic fit when repeatedly subjected to TMS. For that reason strict usage regulations were developed in 1998. 16 See for example the September issue of P.M. 2006, Editorial, p. 9, as well as Lackerbauer (2006: 12-20).

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2005). This case history strikingly shows the complex ethical problem of this, less invasive method. First, it is not known whether the patient in 17 question was actually ‘therapy-resistant’. Furthermore, it is not clear whether she was capable of giving consent given her severity of her depressive symptoms (informed consent). More importantly, as this patient had already attempted suicide twice and had persistent suicidal ideation it was ethically questionable to have taken her off anti18 depressive medication before surgery. Finally, the termination of chronic electrode stimulation despite it having improved her symptoms 19 out of scientific curiosity alone is problematic at best. The publication documents a paternalistic treatment. The implantation of electrodes 20 increased the probability of micro-lesions of healthy brain tissue. Apart from that, neuro-stimulation demonstrated no positive effect on the eating and borderline disorders. 21

d) Creating ‘CyberThink’ Others are trying to creating ‘cyberthink’: invisible, direct communication with others or sources of information, for example, in decision-making processes based upon brain implants (McGee and Maguire 2001). And, if needed, this kind of communication could likewise provide easier access to all kinds of data. Some proponents of neurobionic measures have expressed visionary ideas: direct 17 They are treated pre-operatively with various anti-depressants, however only in mild dosages. The duration of the particular medicinal treatment is not stated. Classic tricyclic anti-depressives or MAO-inhibitors were not employed. The psychotherapeutic options were also not exhausted. Thus merely 20 sessions of cognitive therapy took place. The psychotherapy was not continued for financial reasons. Instead after two unsuccessful series of electro-convulsive therapy (EKT) the neuro-surgical operation was carried out which, however, may be more expensive than psychotherapy (see Jiménez et al. 2005). 18 Discontinuing the medication lead promptly to an increase in the Hamilton Depression Scores from 33 to 42 (Jiménez et al. 2005). 19 It does not become clear from the publication that this took place after a protocol with defined success and abort criteria explained beforehand and signed by both the patient and investigators. We are dealing here with much more than a double-blind design which ensured that the patients also did not know that the stimulation had been switched off. Even after the stimulation was turned off the condition remained stable to begin. On account of the exacerbation of the depressive symptoms after 20 months the treatment was repeated; ibid. 20 The term micro-lesion refers merely to not traceable neuro-radiologically lesions, whereas even small, invisible lesions can be of considerable relevance to functionality. 21 Cited in Orlowski (2004).

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communication with others over the internet as well as radio, beeper and telephone functions being integrated into the brain (Cochrane 1999b, 2000; Brooks 2002). In this way neuro-technological procedures should ease adaptation to the fast-moving, technological world of the present and the future (Rötzer et al. 1996; Kurzweil 1999; Cochrane 1999a, 1999b, 2000; Brooks 2002; McGee and Maguire 2001). e) Behavioral governance and control The implantation of electrodes could also facilitate a particular adaptation of the brain to certain situations. This could have applications in the working world as well as in military realms. Similar efforts have already been seen initial success in animal testing. For example, ‘roborats’ are rats stimulated by brain electrodes to move according to the three dimensional commands (right, left, forward, etc.) of a researcher (Talwar et al. 2002). Possible fields of application (Boyce 2002) for animals so modified include the exploration of inhospitable terrains, searching for injured people in collapsed buildings and the 22 detection of landmines. Most of the ideas mentioned here are considered visionary by current standards of knowledge. Until now it has not been possible to utilize neurobionics to generate fundamentally new capabilities or to transmit data directly to the brain. This would require a far better understanding of how the human brain functions than we possess today. 23 Despite this, research initiatives in this field are increasing. Incidentally, it should be emphasized that the multi-use term ‘neuroprosthetic’ does not appear to be appropriate for most of the scenarios sketched here. When prostheses serve therapeutic purposes within a 22 Ray Kurzweil’s vision - plotting the brain from inside out in order to generate a copy of the human brain for transfer into a computer - can be regarded as purely speculative. His idea is that the computer would then have an exact copy of the memories, that is, ultimately a human personality. In this vision after ‘transferring’ the brain into a computer the person in question continues to exist as PC software. In this way the person in the computer could attain a kind of immortality - a vision which especially within the ‘transhumanist’ movement has found a few adherents. All the same, this appears particularly unrealistic. Apart from that, following the customary definition this would no longer be defined as ‘enhancement’. For details see Kurzweil (1999); Muggenthaler (2004). See National Science Foundation, Converging Technologies for Improving Human Performance (Report) (www.wtec.org/ConvergingTechnologies/). 23 Since 1971 Foster has advocated a ‘neural prosthesis’ program at the National Institutes of Health. Between 1994 and 2003 19 such aids were developed (Foster 2006).

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human body and replace or relieve organs in some of the examples above we are then dealing with (visionary) cases of ‘organ 24 enhancement’. Here the intent is to create capabilities which do not exist in the human body. Considering the attempt to extend the extent of natural human sensory perception Eve-Marie Engels recently suggested that instead of the label ‘neuro-prostheses’ the more pointed term 25 ‘neuro-transmitter’. Proponents of this kind of neuro-transmitter point to the advantages in comparison with the prior need by means of the knowledge of physical regularities as well as by immersing oneself in one’s own imagination in such an (animal) experiential world. They proceed from a long-term enhancement of consciousness because given new sensory perceptions and the experiences they will provide it will make the restructuring of our world possible and a new reality accessible (Engels 2005: 230-236).

Traditional Forms and Parameters for the Social Ac c e p t a n c e o f N e u r o e n h a n c e m e n t While the given examples of neuroenhancement are predominantly critically discussed, there are (conscious as well as unconscious) traditional forms of ‘enhancement’ which are overwhelmingly socially tolerated, accepted or even desired. I shall present below a number of examples which in our current socio-cultural environment are considered as accepted ‘enhancements’. Thereafter I shall analyze the underlying reasons for the social distinction between ‘good’ and ‘bad’ enhancement and question just how compelling the arguments which underlie such a differentiation are. a) (Pedagogic) Early intervention One classical method to increase children’s intellectual ability is pedagogic early intervention for whether in the form of early musical instruction, learning foreign languages in childhood (e.g., multilingual, 24 Cited in Engels (2005: 234). 25 See Engels (2005), ibid. “Therefore we shall not speak here of neuroprosthetics, as prosthetics compensate or reestablish lost functions or those changed by illness in the human body. Exceeding our species-specific perception is not about compensation or reestablishment, however, but has to do with the establishment of ancillary functions which moreover exceed human experience and are particularly, even utterly strange to it. By way of identification of this goal, these implants shall be termed ‘neurotransmitters’.”

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private education, attendance at a multilingual kindergarten), or targeted (professional) encouragement they all promote early individual skills and proficiencies. This form of cognitive ‘enhancement’ is indisputably effective. Many infant prodigies experienced a systematic, early intervention of this kind. Social acceptance of pedagogic early intervention is comparatively high. Although there are egalitarian voices who fear the formation of an elite, early intervention is now predominantly seen as necessary for highly gifted children. This approach has a long tradition especially among the middle class and particularly with early musical 26 education. b) ‘Classic’ learning The improvement of one’s naturally achievable cognitive performance takes place not only by means of methylphenidate (Ritalin®) or nootropics, but also via ‘classic’ learning. Our society tends to particularly cherish those skills acquired in educational realms, within the framework of professional or advanced training, or through one’s own private efforts while simultaneously looking askance at increases in cognitive performance achieved via medicine or neuro-transmitters even when both produce eminently comparable results. Yet given the changing conditions and feasibility of pharmacology and technology, should we not review our standards? Is what we traditionally learn still appropriate? Considered normatively, is it really without alternatives? For example, does it make sense to teach raw (historical) facts at school although it has now become possible that call up that kind of factual data in just a few seconds almost anywhere? Why must students have names of the Roman Emperors drummed into their heads when it could be equally or even more easily recalled electronically? What is the difference if I solve a complicated mathematical equation expertly in my head, with a pocket calculator, a laptop or a built-in chip? If I want to acquire an expert’s knowledge in a special field what does it matter whether I read a book or download the requisite knowledge onto an implanted chip? Is the classical acquisition of knowledge a desirable goal in modern everyday life? Some neuroenhancement proponents would answer these last two questions in the negative, many ‘traditionalists’ counter this by referencing the fundamental importance of the learning process for the comprehension of context and the opportunity to gain an over-all perspective on certain issues.

26 See The President’s Council on Bioethics (www.bioethics.gov/).

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c) Feedback mechanisms and psychotherapy Another form of accepted ‘enhancements’ concern procedures have to do with emotional stress. This includes, for example, various forms of biofeedback. Using the biofeedback method, a subject ‘communicates’ via his own neuro-physiological correlates. EEG biofeedback procedures are particularly far-reaching for with their aid a marked increase in concentration can be achieved. Other examples include Jacobson’s 27 28 progressive muscle relaxation (PMR), Autogenic Training, 29 meditation, ‘coaching’ and various forms of psychotherapy. Common to these methods is that when carried out professionally they all represent interventions with potential neuroenhancement. Whether I increase my (cognitive) efficiency in testing situations based on the acquisition of professional tools from Autogenic Training, via psychotherapy or by virtue of psycho-pharmacological enhancement, ultimately in all of these cases I would have artificially helped my performance. d) ‘Natural’ psychopharmaceuticals For centuries people in the orient as well as the occident have – deliberately and unwittingly – sought substances to influence their consciousness. Historical descriptions of plants and victuals possessing these qualities have helped spawn their own historical discipline: the history of pharmacology. Then as now, these kinds of ‘natural’ psychopharmaceutics are important (Finzen 1994). Particularly salient and credible examples include cerebral stimulants such as caffeine and its analogues (coffee, black tea, cola), sedatives such as alcohol, mood 30 enhancers such as chocolate and nutraceutics, and psychotherapeutics such as cava and ginkgo biloba (Gold et al. 2002) which are part of a billion dollar market and are already considered acceptable by modern 31 society. 27 Edmund Jacobson’s (1938) Progressive Muscle Relaxation (PMR) (aka Muscle Relaxation (PR)) is a procedure in which voluntary, conscious tensing and relaxing of specific muscle groups leads to a state of deep relaxation of the entire body. 28 Autogenic Training is a relaxation technique based on autosuggestion. 29 Depending on the form of psychotherapy a contest with the unconscious takes place in order to explain the origins of the illness (e.g., dream interpretation); alternatively it can plumb and examine conscious thought and perception (e.g., conversational therapy). 30 Neutraceuticals are nutritional products rumored to effect one’s health. 31 While enhancement via psycho-pharmaceuticals is discussed with particular verve and accessibility to psycho-pharmaceuticals and anesthetics is liable to strict regulation, the human body - and thus also the human brain – ‘rejects’ this and struggles constantly against the Controlled

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e) Non-cerebral enhancement When we examine general, non-cerebral forms of enhancement here too we find noteworthy neuroenhancement procedures. A medicinal and operative example of non-cerebral enhancement is instructive here: as stated above, for some time growth hormones have been given to children of below average sized parents in order to facilitate a normal body size for the child in adulthood. This is clearly an extra-therapeutic measure, one justly considered enhancement, which is seriously discussed, but is essentially accepted (Runkel 2005). A long-established operative enhancement variant represents cosmetic surgery as well as non-surgical cosmetic enhancement measures (e.g., botulinum toxin treatments). Despite continuing discussions particularly regarding the extreme forms of these measures, they enjoy increasing popularity and – given the client’s autonomous decision and allowing for informed consent – one could hardly conceive of everyday life without them (Stark 2006). This might in this respect be surprising as the interventions are potentially very invasive, carry considerable health risks and the danger of complications. It has also been argued that invasive cosmetic interventions have side-effects on the mental life and self-confidence of the person affected such that here too – like the above-mentioned psychotherapeutic measures – we find similarities with neuroenhance32 ment.

Conclusions We have thus established that there are unquestionably forms of (neuro-) enhancement which are socially accepted. Thus enhancement as a procedure per se is not socially discredited. Consequently the (normative) discussion is not sparked by the goal, but by the possible paths that lead to it. Yet why are the paths to neuroenhancement sketched above socially Substances Act (CSA). The brain produces not only benzodiazepine-like substances and endorphin, but also opiates and, as has been recently discovered, cannabis-like substances. Apart from that, contrary to its actual title, the CSA manages not only all trade in controlled substances, but also-counter-active-stimulants. See the CSA (http://www.usdoj.gov/dea/pubs/csa.html) and the German equivalent (www.gesetze.2me.net/btmg/). 32 The motives for a cosmetic operation remain largely unknown. In some cases it stems from a low feeling of self-worth or from the uncritical acceptance of a putative ideal of beauty. Also worthy of mention is the fact a pre-operative psychiatric-psychotherapeutic evaluation is not standard procedure.

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accepted while psycho-pharmacologic and neurobionic approaches actuate a medico-ethical debate on principles? To what extent do these last two procedures go beyond the anthropological framework of accepted enhancement procedures? Although there is no clear, indubitable or universal answer to these 33 questions, it may be possible to formulate a few assumptions: As a rule people want to determine their own behavior and be held responsible for their actions particularly (assuming a positive connotation) when it has anything to do with the enhancement of cognitive capabilities. Accordingly, it makes a difference whether I can ascribe changes which concern my own person to my own conduct, in as much as I acquired them myself (by learning them at school, by completing a potentially protracted psychotherapy, or by acquiring mechanisms of self-control) and thus credit them to an autonomous plan and execution, or whether these changes were accomplished outside of my control. The feelings of personal success and pride at having achieved something when learning also play a role here (Hildt 2005: 105). Thus there is a particular value to being able to credit oneself for this success rather than merely owing cerebral achievements to a piece of technology or psycho-pharmaceuticals. Ultimately, neuro-implants and medicines also represent external determination and a loss of control. Here particular cerebral accomplishments and skills are not achieved by one’s own work, but are produced artificially. There is a certain analogy with the evaluation of achievements in sports: legitimate performance is only based on natural ability and hard work, not pharmacological or genetic manipulation. From this perspective ‘brain doping’ is consequently similarly fraudulent and morally dubious as doping in general. This attitude essentially relies on a distinct way of thinking about autonomy and on concepts such as self-efficacy. Besides, enhancement via neuro-implantation or psychopharmaceutics may engender feelings of alienation and depersonalization. Some of those affected find it difficult to take possession of an ‘improvement’ in whose origin and development they had nothing to do, which ‘just happens’, as if it were the result of one’s own effort. This way of thinking correlates with a conservative, protective attitude as well as a rather critical view of technology. Both tend to result in seeing technical or even psycho-pharmacological ‘manipulations’ negatively and to separate these types of performance enhancer from the person who possess them. 33 An ethical valuation of the following thesis sketches ways of seeing things and attitudes cannot be undertaken here; in so far as medico-ethically relevant, this topic will be covered in the other contributions of this volume (e.g. by Sabine Müller).

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Moreover, for certain portions of the population enhancement via neuro-implant or psycho-pharmaceuticals interferes at the very least 34 with their understanding of ‘nature’. Technically effected increases in performance are seen as unnatural and consequently unacceptable. This kind of perspective can be based upon natural philosophy, for example. Representatives of this point of view do not hold the goal of performance increase as dubious, but the unnaturalness of the medium – that is to say, the path one must take to achieve it. An example of this is the use of fluoxetine as an enhancer for people with pronounced low self-confidence. If a patient’s feeling of self-worth is successfully strengthened by means of self reflection and ‘maturation’ or alternatively via a long and deep psychotherapy this satisfied the criteria of being natural and would consequently be acceptable in principle while taking fluoxetine would be seen as an unnatural short cut past these kinds of treatments (Degrazia 2000: esp. 34f.). In addition to their known dangers, psycho-pharmacologic and neurobionic enhancement methods hide other risks which have still to be discovered. On the other hand, the three examples described at the beginning of this chapter of ‘accepted’ enhancement procedures (early intervention, learning, feedback and psychotherapy) are either free of side-effects or, as in example four (enhancement via ‘natural’ psychopharmaceuticals), whose side-effects are (partly incorrectly) believed to be ‘controllable’ or unthreatening. Accordingly the presumed risk aspects of the application of psycho-pharmaceuticals and neurobionics shrink. Finally, the division of enhancement methods into ‘good’ and ‘less good’ demonstrates considerable shortcomings of knowledge and misjudgments, that is to say, it is also a result of inadequate clarification. It provides a glimpse into the social appraisal of the various medicines subsumed under ‘psycho-pharmaceutical’. Thus anti-psychotics and especially anti-depressive medications – that is, the medicinal groups which represent potential neuroenhancers – were viewed much more critically by Angermeyer (1993) than benzodiazepine (Finzen 1994: 256). Curiously, the first of these assumes an addictive potential, a quality which in reality corresponds to benzodiazepinene. Here too we find that the frequency of the actual reception of psychopharmaceuticals is greatly underestimated: five of the ten best selling drugs are psychopharmaceuticals, thus they represent a group of medications which society handles with the greatest ambivalence. The misjudgments 34 For a fundamental discussion of the term ‘naturalness’ and the implications for philosophical ethics and everyday morality see Birnbacher (2002: 167-171).

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detailed here concerning psycho-pharmaceuticals correspond with an uncritical and/or unreflective use of ‘natural’ neuroenhancers. It could be shown that the distinction made between social acceptance and rejection of enhancement is due to our present-day socio-cultural setting. It is not generally valid, but is linked to its particular context and time; it is thus relative. In the prevailing social setting the use of some of the mentioned natural neuroenhancers is unquestioningly accepted. In contrast, tobacco and coffee consumption in the early modern period was widely frowned upon and as a consequence was partly liable to prosecution. On the other hand, at the end of the last century heroin had been touted for decades as absolutely free of side-effects as an antitussive. Cocaine too had been long used as an ingredient in CocaCola®. Yet in our current socio-cultural setting both heroin and cocaine are highly controversial. Then again, Prohibition in the USA during the 1920s, the ban on alcohol in Islamic cultures and the deliberately highpriced alcohol in Scandinavian countries all indicate a repressive handling of alcohol which is not in accord with our continental European practice. Thus, it is not neuroenhancement as such that is subject to criticism; the discussion concentrates much more on how it is accomplished.

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CONTRIBUTORS

Mareke Arends (Dr. med.) is a psychiatrist and psychotherapist. Until 2009 she worked as a clinical researcher at the Psychiatric Hospital of the University of Düsseldorf, Germany. Since 2010 she works in her own medical practice and teaches Neuroscience at the University of Düsseldorf. Her research interests include brain stimulation methods, neuroimaging techniques and ethical topics/considerations. Paula Budde (Dr. med.) is clinical researcher and clinician at the Neurological University Hospital Bergmannsheil at the Ruhr-University Bochum, Germany. Her research interests include neurodegenerative diseases, especially Amyotrophic Lateral Sclerosis. Christian P. Bührle (Priv.-Doz. Dr. med.) is head of the Laboratory of Electrophysiology and Computational Neurosciences at the Department of Stereotactic and Functional Neurosurgery at Cologne University. His current interests focus on integrative neurophysiology and neuropathology, especially the mode of operation of Deep Brain Stimulation on the cellular / brain subsystem scale and the functional analysis of the associated neuronal circuitry. Jens Clausen (Dr. rer. nat) is senior researcher at the Institute for ethics and history in medicine, Tübingen University, Germany. His current research interests include neuroethics, anthropology and ethics, technology and ethics, ethics of brain machine interfacing.

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Heiner Fangerau (Prof. Dr. med.) is the director of the Institute of the History, Philosophy and Ethics of Medicine, Ulm University, Germany. His current research interests include History and Ethics of Biomedicine of the 19th and 20th Centuries, Neuroethics, Regenerative Medicine. Jörg M. Fegert (Prof. Dr. med.) is the director of the Department for Child and Adolescent Psychiatry/Psychotherapy of the University Hospital Ulm. His main fields of interests comprise child abuse and neglect, early intervention programs, child protection and questions of public health related to Child and Adolescent Psychiatry. Jan Goldstein is a graduate student of medicine and philosophy at the Düsseldorf University, Germany. His interests include philosophy of mind, cognitive science and personal identity as well as issues of practical ethics. He is currently working on a medical dissertation on the subject of “personal identity and intracerebral stem-cell transplants” under the guidance of Heiner Fangerau. Torsten Grehl (Dr. med.) is clinical researcher and clinician at the Neurological University Hospital Bergmannsheil at the Ruhr-University Bochum, Germany. His research interests include neurodegenerative diseases, especially Amyotrophic Lateral Sclerosis. Dominik Groß (Prof. Dr. Dr. Dr.) is the director of the Institute for History, Theory and Ethics of Medicine at the RWTH Aachen University and president of the Clinical Ethics Committee of the University Hospital of Aachen. His current research interests include medical history and medical ethics, especially neuroethics, clinical ethics, dealing with human corpses and distributive justice in health care. Thomas D. Hälbig (Dr. med.) is at the Centre d’Investigation Clinique Neurosciences, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France. His research interests include the neuropsychology of the basal ganglia with special emphasis on emotional processes, the mechanisms and effects of deep brain stimulation, and the impact of the neuroscientific progress on our understanding of psychological concepts. Samia Hurst (M.D.) is assistant professor at the Institute of Biomedical Ethics, Geneva University, Switzerland. Her current research interests include fairness in clinical practice, and the protection of vulnerable persons in research and health care. 314

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Alexandre Mauron (Ph.D.) is full professor at the Institute of Biomedical Ethics, Geneva University, Switzerland. His current research interests include the ethics of embryonic stem cell research, as well as the technological transformation of human nature, for instance in sports doping. Sabine Müller (Dr. phil. Dipl.-Phys./Ph.D. M.Sc.) is scientific employee (Wissenschaftliche Angestellte) at the Department for Psychiatry and Psychotherapy, Charité University Medicine, Berlin, Germany. Her current research interests include ethical issues of interventions into the brain and of functional imaging. Josef Quitterer (Prof. Dr.) is head of the Department of Philosophy at the Theological Faculty of the University of Innsbruck, Austria. His current research interests include Philosophy of Mind, Philosophy of Science and Bioethics. Mirjam Rupp (Dipl.-Psych.) is working as a researcher at the Neurological University Hospital Bergmannsheil at the Ruhr-University Bochum, Germany. Her research interests include psychological phenomena related to neurodegenerative diseases. Frank W. Stahnisch (Dr. med., M.Sc.) holds the AMF/Hannah Professorship in the History of Medicine and Health Care at the University of Calgary, AB, Canada. He is an Associate Professor in the Department of Community Health Sciences and the Department of History at the UofC. His current research interests include the historical epistemology of the biomedical sciences in the 19th and 20th century; questions of the interdisciplinary organisation of the morphological neurosciences in the early 20th century; historical and theoretical relations between the brain sciences and the philosophy of mind; the forced-migration of German-speaking neuroscientists after 1933; as well as issues in the history of public mental health in North-America in the 20th century. Martin Tegenthoff (Prof. Dr. med.) is director of the Neurological University Hospital Bergmannsheil at the Ruhr-University Bochum, Germany. His research interests include neurodegenerative diseases, and plasticity in human sensorimotor and visual cortex. Thorsten Trapp (Dr. med.) is senior researcher at the Institute of Transplantation Diagnostics and Cell Therapeutics, Düsseldorf 315

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University, Germany. His research interests include molecular neuropathology, transplantation biology, stem cell biology.

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