Language lateralization in schizophrenia Taal lateralisatie bij schizofrenie (met een samenvatting in het Nederlands) PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Universiteit van Utrecht op gezag van de Rector Magnificus, Prof. Dr. W.H. Gispen Ingevolge het besluit van het College voor Promoties In het openbaar te verdedigen op Dinsdag 27 januari 2004 des middags te 12.45 uur Door Iris Else Clara Sommer Geboren op 31 augustus 1970 te Roermond Promotor: Prof. Dr. R.S. Kahn Co-Promotor: Dr. N.F. Ramsey Aan Robert, Julie en Simon The studies described in this thesis were performed at the Department of Psychiatry, Universitary Medical Center Utrecht Printing of this thesis was financially supported by: Eli Lilly Nederland b.v., Pfizer b.v., Janssen-Cilag b.v., GlaxoSmithKline en AstraZenica ISBN: 90-9017730-2 Copyright © 2004 Iris Sommer Printed in the Netherlands by: Ridderprint Offsetdrukkerij B.V. 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No part of this publication may be reproduced in any form by any electronic or mechanisal means (including photocopying, recording, or information storage and retrieval) without the prior written permission of the author. “The truth is discovered by scepticism and disbelief” Nietzsche CONTENTS Aims and scope 3 Part 1 Language lateralization in the healthy brain 11 Chapter 1: Cerebral lateralization (introduction) 11 Chapter 2: Lateralization and evolution 39 Behavioural Brain Sciences 2003 Chapter 3: The fMRI method to measure language lateralization 47 NeuroImage 2001 Chapter 4: Sex differences in language lateralization, meta-analysis 83 Submitted Chapter 5: Language lateralization in monozygotic twin pairs 97 Lancet 1999, Brain 2003 Chapter 6: Pharmacological aspects of language lateralization 119 Submitted Part 2 Language lateralization in schizophrenia 137 Chapter 7: Schizophrenia (introduction) 137 Chapter 8: Cerebral lateralization in schizophrenia, a review of the literature 153 British Journal of Psychiatry 2001 Chapter 9: Language lateralization in men with schizophrenia 177 Schizophrenia Research 2001 Chapter 10: Language lateralization in women with schizophrenia 201 Schizophrenia Research 2003 1 Chapter 11: Language lateralization in monozygotic twin pairs discordant for schizophrenia 217 British Journal of Psychiatry 2004 Chapter 12: Lateralization of hallucinations 237 Journal of Psychiatry and Neuroscience 2003 Summary and Discussion 243 Nederlandse samenvatting 255 Curriculum vitae 263 List of publications 265 Dankwoord 269 2 Aims and outline 3 4 Aims and outline “The ancient man, who had no concept of self-fulfilment, was virtually autonomous. He heard voices inside his head and called them gods. These gods told him what to do and how to act. Their minds were divided into two parts: an executive part called ‘god’ and a follower part called ‘man’. When writing and other complex language activity started weakening the authority of the auditory hallucinations, this ‘bicameral mind’ slowly broke down. The voices of the gods fell silent, and what we call consciousness was born.” (Jaynes 1976) At the time Jaynes formulated his ideas about cerebral lateralization of lan- guage, it was not possible to study the representation of cerebral functions in vivo. Twenty years later, when the studies described in this thesis were performed, an elegant, non-invasive technique; functional magnetic reso- nance imaging (fMRI), had become available to study cerebral functions in healthy and diseased subjects. In this thesis, fMRI was applied to study the representation of language functions in patients with schizophrenia. Schizophrenia is a complex syndrome, incorporating a wide range of symp- toms that may occur in individual patients at certain stages of the disease. Schizophrenia is also a severe psychiatric disorder, which generally has major impact on affected subjects. Most patients are not able to maintain a paid job, and approximately half of them are unable to live independently (Green 1996). Considering the severe, debilitating course, one would expect to find major brain abnormalities in schizophrenia. The paradox of schizophrenia is that on post-mortem investigation the brains of individual patients can generally not be distinguished from healthy brains (Harrison 1999). When groups of patients are compared to control groups in Magnetic Resonance Imaging (MRI) or post-mortem studies, some abnor- malities, such as enlarged ventricles, may become apparent. Still, for all reported brain abnormalities a large overlap between healthy and affected subjects exists (Harrison 1999). Given this relative absence of clear structural pathology in the schizophrenic brain, one would expect that functional MRI may shed more light on the brain processes underlying the symptoms of schizophrenia, as assessment of actual brain functioning represents a closer correlate of abnormal behaviour. The symptoms of schizophrenia can largely be divided into positive and neg- ative symptoms. In short, the positive symptoms are the signs of psychosis, 5 and the negative symptoms represent the defect syndrome. Functional MRI studies may focus on cerebral correlates of both positive and negative symptoms and various imaging groups have done so. To my opinion, fMRI is more apt to study positive symptoms, since it is difficult to interpret cere- bral activity of a function that is decreased or absent. If a patient is not able to perform a function as well as a control subject, fMRI is likely to reveal decreased cerebral activity in the patient as compared to the control. However, it remains unclear whether decreased cerebral activity results from decreased performance or vice versa. Therefore, we decided to focus on the psychotic symptoms. Hallucinations are among the most intriguing and characteristic symptoms of schizophrenic psychosis. In 65% hallucina- tions are auditory verbal in nature, i.e. “hearing voices” (Slade and Bentall 1988). Thus, a frequent positive symptom of schizophrenia concerns lan- guage activity. Other prominent positive symptoms in schizophrenia, such as thought insertion and formal thought disorder can also be considered to be a disorder of language functioning. Language is one of the few cognitive functions of which the cerebral anatomy is relatively well known. This is an important advantage when a function is studied with fMRI. There are three main theories that try to explain auditory verbal hallucina- tions in schizophrenia. First, the mental imagery hypothesis states that pronounced linguistic expectations can generate a perceptual experience (David 1999). In other words, hallucinations are thought to arise from abnormally vivid mental imagery. A second model was proposed by Frith (1992). According to this theory, hallucinations arise from a failure in the self monitoring of own intentions during inner speech. In healthy subjects, language reception areas are inhibited to respond to language that is derived from covert inner speech. This inhibitory system may be malfunctioning in schizophrenia. Thirdly, Nasrallah (1985) proposed that verbal hallucinations and other language- related positive symptoms arise from inappropriate language activity of the non-dominant hemisphere. This was partly based on reports of more bilat- eral language lateralization in schizophrenia (Chaugule and Master 1981). The malfunctioning inhibition system proposed by Frith may coexist with the increased right hemispheric language activity proposed by Nasrallah. Considering these three models of hallucinations, we choose to focus on the theory of Nasrallah, since it proposes a central role for language processing in the aetiology of hallucinations. This central position appears to be justified since the great majority of hallucinations in schizophrenia are auditory verbal 6 Aims and outline in nature. Furthermore, it is a very testable model, especially when fMRI can be applied. One way to test the hallucination model would be to make functional scans of schizophrenia patients at the time they are actually experiencing auditory hallucinations. However, this is a very demanding design. It requires a group of subjects that experience clear-cut periods of hallucinations alternated with periods without hallucinations, all during the time span of a scanning session. These patients have to be able to indicate exactly when the halluci- nations are present and when not. It would also demand a long scanning period, with a complex fMRI protocol. At the time that I started my PhD work, such a protocol was considered unrealistic. Besides, several other groups had already succeeded to obtain scans of schizophrenia patients during auditory verbal hallucinations. A meta-analysis of these studies is provided in chapter 12. For this thesis, another approach was chosen. Functional MRI scans were obtained from patients and control subjects during the performance of language tasks, yielding a language activation map. From these language activation maps, the degree of lateralization can directly be measured. If Nasrallah’s hypothesis on the basis of language-related psychotic symp- toms is right, we would expect a more bilateral language representation