Neuropsychological and ocular motor studies of schizophrenia

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Neuropsychological and Ocular Motor Studies of Schizophrenia

Dissertation zur Erlangung des Doktorgrades

Eingereicht an der mathematisch-naturwissenschaftlichen Sektion der Universität Konstanz

von

Dipl. Psych. Johanna Kißler aus Regensburg im Dezember 2001

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Acknowledgements

In a way, this thesis is the result of a number of lucky coincidences. Having mistaken the

‘Clementz lab’-meeting that had been announced as ‘topics in experimental psychopathology’

in the list of courses at UCSD, for a regular course, I walked into one of these meetings.

Somehow I got to stay, and this is how I started to learn about the psychophysiology of schizophrenia. I am greatly indebted to Brett Clementz and Jennifer McDowell for supporting me at every stage of the way!

Another fortunate coincidence brought me to Konstanz: Brett Clementz introduced me to Brigitte Rockstroh and Thomas Elbert who accepted me as their student. Here, I benefited greatly from their expertise and guidance, and from the know-how of all members of the group. The friendly atmosphere in this group and the social events helped to overcome the lows that I at times went through as part of the normal ‘graduate student experience’.

Many people helped me realize this dissertation: Without Claudia Catani it would have been impossible to collect and analyze all the data. What’s more: It was fun to have you around!

Hope, I did not make you suffer. Thank you so much and all the best with your own dissertation! Anniek Vaessen, too, helped to collect some of the data. Many thanks! Isabella Paul segmented the MRs for the boundary element models and started me off on Curry.

Thanks for your help! It was fun to work together and I hope we will have the opportunity to continue some of this stuff.

Without the support of the physicists in the group, I would not have been able to even begin to understand MEG-technology and data analysis. Patrick Berg, Markus Junghöfer and Christian Wienbruch (strictly in alphabetical order!) patiently helped. Thank you!

Brigitte Rockstroh helped me to structure my work and my writing and patiently read, commented and corrected large parts of this dissertation even at times when she herself was extremely busy. Thank you, and I hope I have learned a few things!

Jennifer McDowell has read huge proportions of this manuscript, made suggestions, comments and corrections. Above all: Jen, you have been such a great source of personal support and encouragement! Thanks so much!

Brett Clementz has helped me in very many ways. Practical, theoretical, personal. I think the most important thing is teaching me to think about science. I hope I have learned!

Nathaniel Pihama has commented and corrected parts of this manuscript. Thanks! And: It’s all in space and spaghetti!

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Aditi Lahiri and Carsten Eulitz gave me the time to finish this dissertation. Thank you.

Lastly and most importantly: A special thanks to all the patients who have participated in my studies! I am sure it was not always easy to do and not always a pleasant experience in spite of our best efforts! I hope that some time patients will be able to benefit from the insights gained from studies like the present ones!

Konstanz, December 2001.

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0. Zusammenfassung

Die vorliegende Arbeit beschäftigt sich mit Informationsverarbeitungsdefiziten bei Schizophrenie unter den Gesichtspunkten der Aufgaben- und Störungsspezifizität, klinischer Korrelate und der Gehirn(dys)funktion. Dazu wurden paradigmatisch sieben Untersuchungen aus dem Bereich der Neuropsychologie (Studien 1-3) und der Okulomotorik (Studien 4-7) durchgeführt.

In Studie 1 wurde das neuropsychologische Profil schizophrener mit dem depressiver Patienten verglichen. Die neuropsychologischen Profile bei Schizophrenie und Depression ähnelten sich, jedoch wiesen die schizophrenen Patienten die schwerwiegenderen und generalisierteren Defizite auf. In beiden Gruppen waren die Defizite bei Tests der linkshemisphärischen fronto-temporaler Funktionen am deutlichsten, jedoch erstreckten sie sich bei schizophrenen Patienten auch auf räumliche Aufgaben, die eher rechtshemisphärische und parietale Verarbeitung erfordern.

In Studie 2 ergab sich ein Zusammenhang zwischen Negativsymptomatik bei Schizophrenie und reduzierter Wortflüssigkeit und Intelligenz, sowie zwischen Positivsymptomatik und der Tendenz falsch-positive Reaktionen zu generieren. Dieses Muster ist konsistent mit der Vorstellung, daß Negativsymptomatik mit reduzierter Reaktionsbereitschaft aufgrund reduzierter Frontalhirnaktivität einhergeht. Positivsymptomatik dagegen könnte aufgrund von Überaktivität der Assoziationskortices zu der Tendenz führen, inadäquate Reaktionen zu generieren (Frith, 1991, 2000).

Anhand von Spektralanalysen des Magnetoenzephalogramms (MEG) wurde in Studie 3 die Gehirnaktivität gesunder Probanden und schizophrener Patienten in Ruhe und bei Belastung des Arbeitsgedächtnisses verglichen. Gesunde Personen wiesen bei mentaler Beanspruchung eine Erhöhung schneller MEG-Aktivität (Gamma-Band) über links fronto-temporalen Arealen auf. Bei Patienten fehlte diese Aktivitätserhöhung entweder oder es zeigte sich eine umgekehrte Lateralisierung mit erhöhter Aktivität über rechts fronto-temporalen Arealen.

Dies ist konsistent mit Berichten über reduzierte Frontalhirnaktivität (Goldman-Rakic, 1999) und reduzierter oder umgekehrter Lateralisierung bei Schizophrenie (Crow, 1997).

Die okulomotorischen Untersuchungen ergaben normale Fixationsstabilität und normale Generierung reflexiver Sakkaden bei Schizophrenie, was für eine adäquate Funktionsweise des Cerebellums und des Hirnstammes spricht (Studien 4 und 5). Allerdings wiesen schizophrene Patienten deutliche Inhibitionsdefizite und Störungen des visuellen Arbeitsgedächtnisses (Studie 5) auf. Bei Depression zeigten sich moderate Anomalien bei der

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Generierung primärer Sakkaden, die für cerebelläre Dysfunktionen sprechen, ebenso wie ein Inhibitionsdefizit im Vergleich zu Gesunden, das aber weniger ausgeprägt war, als bei Schizophrenie. Depressive Patienten hatten zwar keine signifikanten Defizite des Arbeitsgedächtnisses, jedoch korrelierten schlechtere Leistungen im visuellen Arbeitsgedächtnis bei beiden Gruppen mit höherer Negativsymptomatik. Frontale Defizite liegen also bei beiden Gruppen vor, sind aber bei Schizophrenie deutlich ausgeprägter und teilweise wohl auch durch andere neurophysiologische Prozesse bedingt. Belege für Dysfunktionen des Cerebellums zeigten sich nur bei Depression.

Studie 6 ergab, daß bessere Aufmerksamkeitsleistungen und besseres auditorisches Arbeitsgedächtnis mit besserer Inhibition und besserem visuellen Arbeitsgedächtnis korrelieren.

Ein Vergleich der neuronalen Vorbereitung von Pro- und Antisakkaden bei Gesunden und schizophrenen Patienten mittels realistischer magnetoenzephalographischer Quellmodellierung (Studie 7) demonstrierte frontale Inhibitionsdefizite sowie rechtshemisphärische Defizite bei der Aktivierung des dorsalen Aufmerksamkeitssystems vor Antisakkaden bei Schizophrenie. Die Defizite bei schizophrenen Patienten waren besonders deutlich vor Antisakkaden ins linke Halbfeld, was zusätzlich als Evidenz für eine Störung der hemisphärischen Dominanz bei dieser Aufgabe gewertet werden kann.

Die Befunde zeigen, daß kognitive Auffälligkeiten bei Schizophrenie domänenübergreifend und nicht störungsspezifisch sind, daß sie aber bei Schizophrenie in gravierenderer Form auftreten als bei affektiven Störungen. Bei Aufgaben, deren neuronales Substrat weniger komplex ist als das kognitiver Tests, etwa bei okulomotorischen Aufgaben, zeigen sich aufgaben- und störungsspezifische Unterschiede. Die Verwendung weniger komplexer Aufgaben könnte daher für wissenschaftliche Zwecke vorteilhafter sein.

Neurophysiologisch ergaben sich klare Belege für Störungen des Frontalkortex und der hemisphärischen Lateralisierung bei Schizophrenie. Außerdem waren schizophrene Patienten nicht in der Lage das dorsale Aufmerksamkeitssystem bei schwierigeren Aufgaben adäquat zu mobilisieren.

Die Ergebnisse werden im Hinblick auf ihre Kompatibilität mit gängigen Modellen zur Informationsverarbeitung bei Schizophrenie diskutiert, und es werden Perspektiven für die weitere Forschung entwickelt.

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Summary

In the present thesis information processing deficits in schizophrenia are investigated with respect to task and disorder specificity, clinical correlates and brain (dys)function. To this end neuropsychological (studies 1-3) and oculomotor studies (studies 4-7) were conducted.

Study 1 compared the neuropsychological profiles of patients with schizophrenia and depression. Both groups had similar, wide-spread cognitive deficits, primarily affecting left hemispheric fronto-temporal functioning, but schizophrenia patients’ deficits were more pronounced and generalized to spatial tasks putatively more dependent on parietal and right hemispheric functions.

In study 2, negative symptoms of schizophrenia were associated with reduced word fluency and intelligence, while positive symptoms were correlated with the tendency to generate false positive responses. This pattern is consistent with the notion that negative symptoms result in a general response failure due to reduced frontal lobe functioning whereas positive symptoms are related to a tendency to generate inappropriate responses as a result of overactivation in association cortices (Frith, 1997, 2000).

Magnetoencephalographic (MEG) spectral analyses (study 3) revealed an increase in high- frequency brain activity (gamma band) over left fronto-temporal areas in healthy subjects. In schizophrenia patients this increase was either absent or reversed in laterality with the maximum over right fronto-temporal areas. This finding is consistent with previous reports of reduced frontal lobe activity (Goldman-Rakic, 1999) and reduced or reversed lateralization (Crow, 1997) in schizophrenia.

The ocular motor studies revealed normal fixation stability and normal generation of refixation saccades in schizophrenia, implying adequate cerebellar and brainstem functioning (studies 4 and 5). But schizophrenia patients had considerable inhibition deficits and deficits in visuo-spatial working memory (study 5) indicating inadequate frontal lobe functioning.

Mild cerebellar dysfunction evident from the generation of reflexive saccades was found in depressed patients who also showed inhibition deficits which were, however, less pronounced than in schizophrenia. Depressed patients did not have significant deficits in visuo-spatial working memory but in both groups ‘negative’ symptoms were related to poorer visuo-spatial working memory performance. Thus, frontal lobe dysfunctions are present in both disorders but more pronounced in schizophrenia and are, at least in part, due to different neurophysiological mechanisms. Evidence for cerebellar dysfunction was specific to depression.

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Better attention and auditory working memory is correlated with better visuo-spatial working memory (study 6).

Finally, the preparatory activity before pro- and antisaccades in healthy people and schizophrenia patients was investigated using realistic MEG-source modelling (study 7).

Here, frontal inhibitory deficits and deficits in right hemispheric activation of the dorsal attentional system were observed in schizophrenia patients prior to antisaccades. This lack of activation was particularly evident before antisaccades to the left, pointing to a hemispheric abnormalitiy in inhibitory and attentional control.

Together, the results demonstrate that cognitive impairment in schizophrenia is generalized and neither task nor disorder specific but that it is more severe than in affective disorder. For tasks that rely on less complex neural substrates than cognitive tests, such as ocular motor tests, there are task- and disorder-specific differences, suggesting that the use of such tasks would be more revealing. Neurophysiologically evidence was produced for inadequate frontal cortex functioning in schizophrenia, altered hemispheric lateralization and difficulties in allocation of additional attentional resources in the dorsal stream.

The results are discussed with respect to their compatibility with currently influential models of information processing in schizophrenia and suggestions for further research are made.

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I. Introduction

Many differences in information processing between schizophrenia patients and healthy comparison subjects have been reported. But surprisingly few studies have investigated to what degree such deficits are generalized consequences of the disorder that extend across virtually every aspect of cognitive or psychomotor functioning or to what extent only certain aspects of information processing are impaired. Likewise, it is unclear whether the deficits are specific to schizophrenia or occur in other disorders as well. Similarly, some of the wide range of symptoms that occur in schizophrenia may be unspecific consequences of psychiatric disorders while others may be associated with specific information processing deficits.

In the present thesis, the specificity of abnormalities observed in schizophrenia will be investigated and conclusions about underlying brain (dys-)functions will be drawn. Specificity of performance patterns will be addressed with regard to task specificity, with regard to disorder specificity and with regard to symptom specificity. To this end, data from two domains of information processing where abnormalities in schizophrenia have repeatedly been reported, namely neuropsychological and ocular motor studies, are integrated. The issue of underlying brain functioning will be addressed both based on inference from existing knowledge about brain-behavior dynamics and by measuring brain activity with magnetoencephalography.

Of the seven chapters presented, three focus on neuropsychological performance, three on ocular motor functioning and one addresses the relationship between neuropsychological and ocular motor variables.

Neuropsychological functioning in schizophrenia is examined in three studies:

Neuropsychological performance in schizophrenia patients is compared to depressed and non- psychiatric subjects. The relationship between neuropsychological profiles and clinical symptoms of schizophrenia is studied. Using magnetoencephalography, high frequency brain activity (gamma) in schizophrenia and healthy subjects is investigated in a complex working memory task. High frequency activity may index both cognitive activity and psychotic symptoms.

The ocular motor studies focus on the saccadic system. First, fixation stability is investigated in schizophrenia patients and normal people. Second, the generation of prosaccades, antisaccades and memory guided saccades is compared across schizophrenia patients, patients with depressive disorders and healthy subjects. Third, the relationship between ocular motor

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and neuropsychological variables and symptom scores is explored in sub-samples of patients with schizophrenia and depression who participated in both previous studies. Fourth, the neural processing underlying saccadic system functioning in healthy subjects and schizophrenia patients is studied and the origin of neuromagnetic activity in the brain is modeled by means of magnetic source imaging (MSI).

I.1. Schizophrenia: A specific brain disease with a discrete behavioral outcome?

Schizophrenia is a mental illness that affects about 1% of the population worldwide (Jablensky et al., 1992). The illness is characterized by a wide variety of symptoms:

Hallucinations, delusions, loosening of associations, formal thought disorder, thought withdrawal or thought insertion, poverty of speech or incoherent speech, flattening of affect and emotional withdrawal, psychomotor agitation or poverty, are among the most commonly observed symptoms (see DSM IV, 1994) that characterize the disorder. Not all of these symptoms are seen in every patient and symptoms can vary in the course of the illness but the presence of a number of them over a period of time will suffice for a person to be diagnosed under the syndromal definition of schizophrenia.

The origins of schizophrenia are unclear. This is true in several respects: Historically, although it would appear likely that mankind has always known forms of ´madness´ that would meet today’s classification critieria, there is a lack of documents indicating the clear- cut existence of a group of disorders characterized by hallucinations, delusions, loosening of associations and withdrawal beyond the 19^th century. This is surprising in view of the numerous descriptions of depression (melancholy) or mania that go back to ancient Rome or Greece. Phenomenologically, the definition of symptoms that constitute schizophrenia as an illness is changing and subject to refinement over time. This state of flux affects the incidence and prevalence numbers of schizophrenia, although modern classification systems have partly succeeded in narrowing down the definition of schizophrenia and enhancing the reliability and stability of the nosological classification.

Causally, the mechanisms that lead to schizophrenia are still debated. Suggested causes include genetic, viral factors and environmental and experiential factors or interactions of these.

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In spite of numerous problems encountered in schizophrenia research, considerable progress has been made: While historically psychiatric disorder has been viewed as distinct from somatic illness, in recent years evidence has accumulated for somatic and, more specifically, neural correlates of mental states. Brain processes both guide behavior and are modified by experiential and environmental factors (Elbert and Heim, 2001). This fuels the hope that neuroscientific methods could prove to be helpful tools for the study of psychopathology both in terms of dynamic and in terms of cause. Psychological and neuroscience methods have already uncovered a number ways in which information processing in schizophrenia patients differs from psychiatrically normal people.

Effort has been made to reduce the behavioral complexity by finding simpler models that could account for some of the symptoms in cognitive terms and make testable behavioral predictions that eventually could be investigated neuroscientifically. While none of these models strictly speaking qualifies as a ‘theory’ yet (in spite of some proponents’ contrary claims), such models have helped to structure research on schizophrenia.

The present thesis will discuss, to what extent neuropsychological and psychophysiological characteristics support models of the neurocognitive aspects of schizophrenia.

Therefore, in the following, an overview of four different but currently very influential models of schizophrenia will be given in order to introduce some of the basic contemporary lines of thinking about and conducting research on schizophrenia. From this, some commonly held views but also the vast conceptual differences between various explanatory models on the same subject matter and the underlying methodological problems will become apparent.

Although for some of the studies mentioned below conflicting evidence exists, a detailed discussion of each study would be beyond the scope of the present thesis. The goal here is to outline general lines of reasoning and differences in general approach.

A) Attentional Dysfunction in Schizophrenia – A Faulty Filter at the Core of Information Processing Deficits?

The so-called ‘faulty filter’ models provide an example for a cognitive approach:

These theories take as a starting point the clinical observation that patients often report a feeling of being overwhelmed by a multitude of external stimuli (McGhie and Chapman, 1970). This feeling is thought to result from a faulty attentional filter. Normal people are able to screen out irrelevant information and focus on information that is relevant to a given situation (Broadbent, 1958). Schizophrenia patients, by contrast, seem to lack this attentional

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filter (Braff, 1993), that is, they are unable to ‘gate out’ irrelevant sensory information (see figure I.1.1. for a schematic illustration) and have, moreover, difficulties in allocating attention to relevant information. These attentional problems, then, result in the misinterpretation of situations, the misattribution of sources of information (internal versus external) and general cognitive disturbances. The clinical outcome can be delusions, hallucinations and thought disorder but also negative symptoms as patients are unable to make sense of the world around them and efficiently communicate their thoughts leading to withdrawal from their social environment.

Figure I.1.1.: A faulty stimulus filter is postulated to account for the information processing deficits observed in patients with schizophrenia (from Braff, 1989).

Experimentally, patients’ ´gating` deficits have been shown in the prepulse inhibition paradigm, where the presentation of a warning stimulus shortly prior to the startle stimulus results in a reduced startle response in healthy subjects whereas no such attenuation is evident in schizophrenia patients. Likewise, in event related cortical potential P50 gating paradigms where series of two paired short click stimuli are presented to the subject, presentation of the first stimulus usually leads to a smaller brain response to the second of a pair of stimuli. In schizophrenia patients, however, the brain response to the second stimulus is basically unaffected (Adler, Pachtman, Franks, Pecevich, Waldo and Freedman, 1982). In eye movement research, the observation that schizophrenia patients are less able to suppress reflexive saccades to a visually presented target when instructed to look to the target’s mirror location (antisaccade paradigm) is consistent with faulty filter theories of schizophrenia.

Increased numbers of saccadic intrusions during smooth pursuit tracking in schizophrenia

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patients have also been explained in terms of attentional dysfunction (Olincy et al., 1998;

Ross et al., 1998).

Generally, theories focusing on attentional dysfunction in schizophrenia stress a deficit in the automatic suppression of stimuli as key to understanding the illness and as a cause of many physiological and cognitive abnormalities present in schizophrenia. Noradrenergic mechanisms have been shown to be involved in faulty sensory gating, at least for the P50 paradigm (Adler et al., 1986; 1988). Increased norepinephrine release results in loss of auditory sensory gating in animals, probably through activation of a projection that acts on hippocampal neurons that have been identified as contributing to the P50 potential (Freedman et al., 1994). In schizophrenia, abnormal expression of the alpha-7 nicotinic receptor has been suggested as the cause of both the patients’ inhibition problems and the increased rate of smokers among the patients (e.g. Leonard et al. 2000). Experimental blockage of this receptor in animals results in increased adrenergic activity and un-attenuated P20 (the equivalent of P50 in the animal model) in a paired click paradigm. Genetic linkage analysis indicates that in humans this problem is genetically linked to a locus on chromosome 15 suggesting that this locus plays a role in developing schizophrenia (Adler, Freedman, Ross, Olincy and Waldo, 1999; Leonard, 2000).

B) The Neuropsychology of Schizophrenia – A Deficit in ‘Theory of Mind’?

Frith (1992, 2000) has taken the symptoms of schizophrenia as a starting point for his model of the cognitive neuropsychology of schizophrenia. The symptoms, in his view, can be grouped into three complexes: First, disorders of initiation of ‘willed action’ as reflected in symptoms such as alogia and avolition (essentially the group of symptoms referred to as

‘negative’ by other authors). Second disorders of self-monitoring where own actions and thoughts are attributed to external sources which are clinically observable as hallucinations and delusions of alien control. And third, disorders of ‘mentation’ or ‘theory of mind’, i.e. in monitoring the intentions and mental states of other people. Disorders of mentation can show as formal thought disorder, delusions of persecution or flattened affect. Together, these three aspects are conceptualized as signs of a general underlying disorder of consciousness.

Evidence for this model comes for instance from experiments using ‘source monitoring’ were participants are required to decide whether presented material has previously been read to them or read by them. Here, schizophrenia patients with hallucinations have been

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demonstrated to have a tendency to attribute their own ‘actions’ to external sources (Baker and Morrison, 1998; Johns et al., 2001) consistent with the notion of a ‘disorder of self monitoring’. Disordered mentation in schizophrenia has been observed in studies, where schizophrenia patients were found to be more likely to refer to physical features rather than mental states when describing people (Pilowsky and Bassett, 1980). Moreover, disordered speech is viewed as a result of patients’ failing to take into account their counterparts’

knowledge of the conversation topic, i.e. having an inadequate theory of mind (Rutter, 1985).

Failure or inability to make inferences about other people’s mental states would result in impoverished social interactions (negative symptoms).

A) B)

Figure I.1.2: Faulty intention monitoring as a source of delusions of control. On the left (A) normal action planning, monitoring and sensory perception are shown schematically. On the right (B) failure of accurate movement prediction results in the perception of an anomaly when the result of an unpredicted action is perceived. As a consequence, the intentions behind own actions are attributed to others, a feeling (delusion) of external control results (from Frith, Blakemore and Wolpert, 2000).

Figure I.1.2. illustrates how disordered action planning, initiation and execution can give rise to schizophrenic symptoms: In the healthy individual (A), actions are planned and the consequence of the action is predicted by a feed-forward mechanism. After an action is carried out the actual consequence is compared to the predicted state of the system. If a mismatch between the perceived state of the system and the predicted state of the system occurs, for instance because no prediction was made, actions may be attributed to external sources to explain this unexpected mismatch (B).

According to Frith, the gross misrepresentations of both own and other people’s goals and actions arise from a disconnection of frontal and posterior-parietal or frontal and temporal systems of the brain. (McGuire and Frith, 1996; Frith, 2000). In both cases prefrontal

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structures fail to suppress activity generated in the parietal or temporal lobes. Failure to suppress activity in temporal cortex leads to the experience of thought insertion or hallucinations. Failure to inhibit parietal activity leads to the feeling of actions being generated by external forces, i.e. results in delusions of control.

C) Schizophrenia - The Price Homo Sapiens Pays for Language?

The two previous accounts of schizophrenia both took observable behavior in schizophrenia patients as a starting point for their theorizing about the disorder. The model most notably championed by Crow (e.g. 1997, 2000) has a phylogenetic focus. Crow reasons that if a disorder prevails that is under considerable genetic influence, is ostensibly universal and has universally a stable incidence rate of about 1%, although likely gene carriers have a considerably lower reproduction rate than normal, it must be linked to a phylogenetic advantage that causes the particular gene or set of genes to persist. Sex differences in schizophrenia (the illness affects males more often¹ and at an earlier age than females) would make it likely that the illness is linked to a feature that is differentially expressed in the two sexes. It is argued that the phylogenetic advantage that schizophrenia is linked to is the human capacity for language and that this capacity for language is due to hemispheric lateralization.

Hemispheric lateralization is unique to humans, reflected in the organization of language in the brain and in handedness and is expressed differently in men and in women. Indeed, schizophrenia patients are less strongly right-handed than a non-psychiatric population (Gur, 1977) and some of the positive symptoms of schizophrenia can be viewed as signs of abnormal language processing. Delusions and hallucinations contain meaning that is mediated through language. A misattribution of the sources of language that causes these symptoms is in turn thought to stem from disordered communication between the two hemispheres (Crow, 1997). Schizophrenia is viewed as a result of a failure of hemispheric dominance for language (although evidently not the only possible consequence of reduced lateralization), such that the division of labor between the dominant and non-dominant hemispheres goes awry.

In normal individuals language functions are localized primarily in the left hemisphere. Atypical lateralization, especially ‘hemispheric indecision’, i.e. a lack of hemispheric dominance in either hemisphere, has been linked to reduced academic ability, particularly in language related tasks (Crow, Crow, Done and Leask, 1998). There is evidence

1 Traditionally, both sexes were thought to be affected with equal frequency but it is increasingly acknowledged that the sex distribution found in most larger studies, where about 60% of the patients are male, reflects reality and not a sampling bias (e.g. Waldo, 1999).

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that suggests that some of the asymmetries that typify the human brain are at least attenuated in schizophrenia. In some morphometric studies of schizophrenia patients’ brains, loss of asymmetry of the planum temporale, a structure critically involved in language processing, has been reported (Falkai et al., 1995; Shenton et al., 1993). Functionally, MEG studies have demonstrated that in some cases normal lateralization is absent or even reversed in schizophrenia (Reite et al., 1997; Rockstroh et al., 1998), although compensatory mechanisms appear to exist (Rockstroh et al. 2000). A recent meta-analysis by Sommer et al. (2001) found evidence across studies for a decreased proportion of right-handers and reduced asymmetry of the planum temporale and the sylvian fissure in schizophrenia. On dichotic listening tasks and the proposed reduction of cerebral torque (i.e. greater right frontal and left occipital lobes in healthy adults) in schizophrenia the evidence was inconsistent.

While a plausible argument for a special role of language functions and language related brain areas in schizophrenia can be made, the mechanisms that give rise to these abnormalities according to Crow’s theory are less clear. Importantly, the mode of transmission of schizophrenia remains sketchy. It is argued that ‘some advantage’ must be conferred upon the gene carrier and that transmission occurs most likely through gene translocation from homologous areas on the X to the Y chromosome. Male carriers of the gene would be preferred as mates, thus the gene would be preferentially selected for but carriers of two replicas of the gene would be at an increased risk for schizophrenia. While the adverse effects are made clear, the account leaves open the crucial question of what exactly the advantage is that is conferred by this gene. There are reports that circumstantially link psychosis-proneness to exceptional intellectual abilities (Andreasen and Canter, 1974; Andreasen, 1976) but this possibility is not explored in Crow’s account. If indeed there is an evolutionary link between the relatively recent development of language and increased lateralization, characterization of the so far hypothetical ‘right-shift factor’ (Annett, 1999; Crow, 1999) may provide an avenue for identification of the ‘psychosis factor’.

D) Working Memory Impairment as Cause of Disordered Cognition in Schizophrenia

Using a low level physiological approach, Goldman-Rakic and collaborators (e.g.

Goldman-Rakic, 1987; Goldman-Rakic, 1999) have mapped out some of the functions of the prefrontal neural circuitry in non-human primates and in man. From this knowledge and from studies with schizophrenia patients, this group draws conclusions about the mechanisms that

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underlie schizophrenia. Primarily drawing on evidence from various versions of delayed response tasks, Goldman-Rakic et al. identified specialized groups of neurons in the prefrontal cortex. In its simplest form, the ocular motor delayed response task, subjects must remember the location of a briefly presented target over a delay period before a cue indicates that a motor response should be generated towards the remembered location. Other commonly used tasks include delayed location or object matching tasks, where animals or human subjects are required to remember the position of a target item and after a delay period indicate whether a probe display matches the initial stimulus with regard to spatial configuration and/or identity.

The results of such studies indicate that there are specialized location-specific neurons in areas 8 and 46 of the dorsolateral bank of prefrontal cortex that hold the visuo-spatial coordinates of presented objects on-line for subsequent recall. In schizophrenia, studies show reduced regional cerebral blood flow in these regions (Berman et al., 1986; Goldberg et al., 1996; Weinberger et al., 1996) and behavioral studies have demonstrated schizophrenia patients to be impaired at tasks mediated by these regions (Park and Holzman, 1992, 1993;

Gold et al., 1996; Goldberg et al., 1996). By inference, a central information processing deficit in schizophrenia could be associated with holding desired information on-line for appropriate use and connection with other information. Such a deficit can have two consequences: First, it can result in unavailability of desired information if neurons that should hold information on-line fail to fire. Second, if these neurons fail to turn off perseverative behavior can be the consequence.

Schizophrenia patients’ symptoms and cognitive impairments can vary considerably. To account for this variability, Goldman-Rakic proposes that the common underlying deficit is a failure in the prefrontal central executive that allocates attentional resources and is responsible for the sequential ordering of cognitive processes. Domain specificity within prefrontal cortex then can account for the variable symptom presentation. A number of experiments indeed demonstrate that groups of cells in monkey prefrontal cortex display object-specific firing patterns during working memory tasks (Wilson et al., 1993; O Scalaidhe et al., 1997). With regard to schizophrenia, there is evidence that schizophrenia patients have a verbal but not a tonal working memory deficit (Wexler et al., 1998) and that this verbal working memory deficit is reflected in reduced activation of area 44 of prefrontal cortex (Stevens et al. 1998).

During the tonal working memory task patients have normal activation in area 44 (Stevens et al., 1998). This provides evidence for both domain specificity in working memory functions in humans and a disturbance of certain working memory dysfunctions in schizophrenia.

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In order to relay and sequence information, frontal cortex is connected with a great many other cortical and sub-cortical areas such as parietal and temporal lobes, the cingulate gyrus and the hippocampus. Experimental evidence shows that a disturbance of the normally observed correlated activity between association cortices and frontal cortex is present in schizophrenia (Weinberger et al., 1992; Friston and Frith, 1995). This is taken to indicate that disordered communication in a distributed neural network in which prefrontal cortex acts as a relay station is the core problem in schizophrenia. Brain morphometric studies support this view in that schizophrenia patients’ brains, while containing the same number of neurons as brains of unaffected people, contain less ‘interneuronal neuropil’, i.e. dendritic trees and cortical afferents (Selemon and Goldman-Rakic, 1999). ‘Neuropil reduction’ is especially apparent in prefrontal cortex (Rajkowska, Selemon, Goldman-Rakic, 1998; Selemon and Goldman-Rakic, 1999)

E) Scientific Psychopathology?

The outlined models all emphasize a) the cognitive disturbances in schizophrenia uncovered by experimental psychopathology and b) a disorder of interaction between brain regions at the core of the disturbances in schizophrenia. However, beyond these similarities a number of considerable differences emerge. A comparison of the above models quickly reveals some of the problems that vex schizophrenia research. Since schizophrenia is so multifaceted, different scientists focus on different aspects of the illness and the common entity under investigation is hardly recognized. In the case of schizophrenia, it is not even entirely clear what the entity is or the entities are. In spite of modern classification systems (DSM IV, ICD10) it is thought permissible or plausible to redefine criteria to suit a model, relying on the common assumption that the illness is complex and heterogeneous. The cleverly thought out constructs are supported by a body of selectively interpreted evidence, often without taking into account alternative interpretations. Moreover, the complex nature of both the illness and the theoretical constructs make it difficult to translate the theoretical constructs into predictions testable in experiments.

On the other hand, the results of well designed, controlled experiments, even when they yield clear results cannot readily be translated into the terms of any model and theory and it is sometimes not clear how they bear on the phenomenon under investigation. Why should an abnormal neuromagnetic response to a tone tell us anything about the patients’ capacity for language? How do single cell recordings in monkeys relate to thought disorder in schizophrenia? Conversely, what exactly is the operational definition of theory of mind inside

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a PET scanner? Occam’s razor and the logic of research leads us to prefer simple and unitary explanations over more complicated ones. But when does a simple explanation amount to oversimplification?

In view of the problems inherent to ‘grand theories’ of schizophrenia, many researchers do not adhere to any particular model but prefer a data driven approach. This, indeed, circumvents many problems inherent to large-scale ‘theories’. On the other hand such an approach can fuel the rapid accumulation of unmotivated studies with un-interpretable results

Scientific working hypotheses may provide a compromise between purely data driven research and eclectic theories and thus guide research. Such working models could be used at multiple levels of research into the illness. One very broad working model is suggested by Andreasen (2000). This working model is illustrated in figure I.1.3.

Working Model

Etiology:

(multifactorial)

DNA Gene Expression Viruses Birth Injury Psychological Experiences

Pathophysiology:

Brain development

(e.g. neuron formation, migration, synaptogenesis, pruning, apoptosis, activity dependent changes

Anatomic and functional disruption in neuronal connectivity and communication

Impairment in a fundamental cognitive process

Impairment in one or more second-order cognitive processes (e.g. attention, memory, language, emotion)

Symptoms of schizophrenia (e.g. hallucinations, delusions, negative symptoms, disorganized, speech)

___________________________________________________________________________

Figure: I.1.3. A multi-level working model for schizophrenia research (adapted from Andreasen, 2000).

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Andreasen’s model draws attention to the fact that schizophrenia research is needed at multiple levels and therefore is a multidisciplinary enterprise. Eventually evidence from these various levels should be integrated to expand our understanding of the illness and thereby contribute to the development of better treatments at various levels.

For the present thesis a narrower working model that focuses on pathophysiology and cognitive processes, similar to the one outlined by Clementz (1998), is adopted. If schizophrenia is related to aberrant information processing in the brain, it would be useful to determine

• which domains of information processing (broadly conceived) are affected,

• which domains are unaffected.

• whether information processing deficits observed in schizophrenia occur more commonly in schizophrenia than in other psychiatric disorders, i.e. are relatively specific to schizophrenia.

• how information processing problems observed in the laboratory relate to symptomatology.

• neural processes that sub-serve an investigated behavior both during adequate functioning and in psychiatric states.

These questions will be addressed by examining similarities and differences in neuropsychological and ocular motor tasks between schizophrenia patients and normal comparison subjects on the one hand and between schizophrenia patients and patients with depression on the other hand. The relationship of the neuropsychological and ocular motor variables with schizophrenic symptoms will be addressed and the neural correlates of neuropsychological and ocular motor performance in healthy subjects and schizophrenia will be studied.

Accordingly, the empirical part of the present thesis comprises two main chapters. First neuropsychological studies, second ocular motor studies. For both of these chapters, a separate introduction into the area and rationale of the studies is provided. Finally, the implications for future research will be discussed against the background of the introduced models. Since all studies employ similar methods, a general introduction to the methodology is given at the outset.

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I.2. General Method

The present thesis utilizes three methodological strategies, neuropsychological testing, infrared reflectometry and magnetoencephalography which will be briefly introduced in the following. For specific details of data reduction and analysis used in individual experiments, please see the respective chapters.

A) Neuropsychological Testing:

The observation that people who had suffered injuries to their heads were subsequently rendered unable to perform certain cognitive tasks provided the first strong evidence for a brain-behavior relationship (Broca, Wernicke, Hughlings-Jackson). Since then, a great number of elaborate tests have been developed to investigate cognitive functioning in neurological patients. Using neuropsychological tests researchers have successfully identified a number of double dissociations, where subjects were shown to perform poorly on one test against the background of normal performance on other tests within the same general cognitive domain. Examples are object class specific memory impairments (Warrington and Shallice, 1984; Shallice and Warrington, 1970), spared implicit but impaired explicit learning (Scoville and Milner, 1957 ) or class specific recognition deficits, e.g. for faces as in prosopagnosia (Tranel, Damasio and Damasio, 1988a, b). This general logic has led theorists to propose a modular organization of the mind/brain (Shallice, 1988) but the proposal has met with criticism from proponents of the parallel distributed processing approach who stress the fact that in the normally functioning brain a multitude of systems simultaneously interact to produce behavior (Elman et al., 1996).

For neurological patients the logic that impairments in certain areas of cognition result from localized brain dysfunction has worked reasonably well. Neuropsychological testing in psychiatric patients follows a similar rationale: By administering a number of tests that have been shown to be sensitive to circumscribed brain injury and that cover various cognitive domains, a specific ‘profile’ or ‘signature’ of an illness is sought that points to abnormalities in certain brain structures and should provide a more objective measure of dysfunction than clinical classification.

Two general approaches to neuropsychological testing exist: On the one hand, performance of an individual subject can be compared to the performance of a normative sample of probands that match the person with regard to demographic features. On the other hand, the performance of groups of subjects, usually a patient group and a ‘normal’ comparison group, that should be matched to the patient group with respect to as many attributes as possible, can

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be compared quasi-experimentally on a number of neuropsychological tests and with the aim to identify tests that are most indicative of patient-comparison group differences. Here, the quasi-experimental approach is chosen. Neuropsychological tests can be either administered by trained personnel or adapted for computerized testing. Computerized testing is more standardized but proper administration of tests by the investigator may achieve similar reliability with the advantage of greater control over motivational factors. The tests described in a later chapter were all individually administered by a trained investigator.

B) Infrared Reflectometry:

Infrared reflectometry is a method for objectively measuring eye movements (e.g.

Reulen et al. 1988a, b). It relies on the reflection of infrared radiation by the iris-sclera boundary of the eye. An infrared light-emitting unit that sends infrared light into the eye is mounted below and a photodiode unit, that picks up the reflected light, is mounted above the eyes (see figure I.2.1).

B)

A)

Figure I.2.1.: Infrared eye movement recording device. Photodiodes (A, B) that emit and pick up infrared light are mounted on spectacle-like frames. The device can be adjusted to fit individual eye position and head size and is connected to an amplifier and AD converter unit.

Both the light emitting and the detecting photodiode units consist of arrays of light emitting diodes and of arrays of pick-up phototransistors. As the eye moves, for instance in the horizontal direction away from the center of the screen, the light that is emitted from more central and more peripheral portions of the light-emitting unit is differentially reflected because the iris-sclera boundary also moves. Subtraction of the central from the peripheral signals and subsequent low pass filtering and amplification yields information on eye position at each individual sample point (100 Hz). Eye movement tracings are digitized and stored on

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computer disk. They can be subsequently displayed off-line for parameterization and analysis.

Commonly used parameters are eye position, accuracy, velocity, acceleration, saccadic reaction time and saccade duration. Eye velocity and acceleration are calculated as the first and second derivative of eye position. Figure I.2.2. provides an example of an saccadic eye movement and eye velocity tracing over time.

Figure I.2.2. Eye movement tracings. Eye position (left) and eye velocity (right) for a leftward going saccade at 150 ms. The saccade is elicited by a visual target at time 0. The eye movement is typically executed 100-250 ms after target presentation, depending on experimental manipulation.

Infrared reflectometry has several advantages over the use of the electro-oculogram (EOG): It is not susceptible to muscular noise and signal drift and results in a much cleaner signal.

Individual eye position can be directly measured for both eyes separately, with a linear range of about 25° for horizontal eye movements and 20° for vertical eye movements and a excellent spatial resolution of 1’ of arc. In practice spatial resolution can be somewhat compromised by the quality of initial calibration and by subjects’ head movements, but these factors never have as severe an impact on infrared reflectometry as they have on EOG and the method is less obtrusive as it does not require directly attaching electrodes to a person’s skin.

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C) Magnetoencephalography:

Magnetoencephalography (MEG) measures the synchronized activity of cortical pyramidal cells over the scalp. Any electrical current flow generates a surrounding magnetic field. Thus, intracellular current flow is surrounded by a magnetic field oriented around the dipolar current flow following the right hand rule (see Figure I.2.3.). Cohen (1968, 1972) was first able to measure the magnetic equivalent of the electroencephalographic alpha rhythm.

Since then, a number of technological advances have allowed for more widespread use of the technology. Although there are a number of different electrical phenomena in the brain that generate electrical currents, only a small proportion of these events can be measured over the scalp.

Figure I.2.3.: Intracellular current flow in apical dendrites of a pyramidal cell and resulting magnetic field. The magnetic field around the cell(white circles) is oriented perpendicular to the electrical current flow inside the dendrite (red arrows).

In some cases, such as the magnetic fields generated by action potentials, the dipole configuration is such that the magnetic fields mostly cancel out (two dipoles of opposite direction). Similarly, fields generated by astrocytes have a so-called closed field symmetrical configuration that causes the magnetic fields to cancel out beyond the immediate vicinity of the dendrites. Closed field configurations are also present in some other brain structures such as the hippocampus or the cerebellum. Although these brain structures contain pyramidal cells, their configuration makes it unlikely that their activity considerably contributes to

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magnetic fields measurable on the scalp (for a dissenting view see Tesche, 2000). Moreover, because the magnetic fields generated by individual cells in the brain are minute, the synchronized activation of about 40,000 cells with similar orientation is necessary to produce measurable fields. Such cells are the pyramidal cells which are organized in columns mostly found in layers IV and V of the cortex.

The MEG only picks up magnetic fields generated by structures that are oriented tangentially to the scalp, other fields cancel out (see figures I.2.4. and I.2.5.). The EEG, by contrast, picks up mainly the activity of radially oriented sources. Thus, the MEG is most sensitive for activity generated by columns of neurons in cortical sulci (see figure I.2.4.).

Figure I.2.5: Schematic depiction of a portion of the head containing a cortical fold with groups of pyramidal cells (A, B, C). A strong radial field is generated by (A). It cannot be detected with the MEG but the underlying current flow can be seen in the EEG. (B) has both radial and tangential components and (C) produces a strong tangential magnetic field that is well detected by the MEG. (from Orrison, Lewine, Sanders and Hartshorne, 1995)

Even measurable magnetic fields are typically 8 orders of magnitude smaller than the geomagnetic field, thus requiring the use of a magnetically shielded room to minimize the influence of magnetic noise from the environment and the use of a special measuring technology, the SQUID (Super Conducting Quantum Interference Device). At very low temperatures (-269°C) the SQUID picks up minute currents induced in pick up coils close to the scalp by the magnetic fields generated in the brain and converts them to voltage.

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Unlike the EEG signal, the MEG signal is essentially inert to different conductivities of biological tissue, which offers some advantages when the sources of magnetic activity in the brain are modeled. MEG-technology allows the measurement of the timing of neural events with essentially unlimited temporal resolution (hardware limitations being the only restrictions) and, theoretically with very good spatial resolution. Thus, methods applicable to EEG data analysis, such as analysis of timing and amplitude of events or analysis of frequency content (Fourier Transform, Wavelet Analysis) can be applied to MEG.

Furthermore, estimation of the origin of activity in the brain can be undertaken with greater ease than in EEG research. (see Box I.2.1. for a summary of commonly used analysis methods in MEG research).

Magnetic Source Imaging:

a) Focal Source Models

• Equivalent Single Moving Dipole • Spatio-Temporal Modelling b) Distributed Source Models • Minimum Norm Estimate • MUSIC

• Loreta, Vareta

MEG Data Analysis:

Analysis of Scalp Distributions

•Time course

•Amplitude

•Spectral Analysis

(Fast Fourier Transform, Wavelet Analysis)

Box I.2.1 Overview of commonly used MEG Data analysis techniques.

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As mentioned before, the magnetic fields generated by the brain are not distorted by the volume conduction properties of different types of tissues but decrease uniformly with distance from the generator. For somatosensory or auditory evoked magnetic fields a localization accuracy of about 8mm has been reported (e.g. Gallen et al., 1995 ; Pantev et al., 1998;). But unlike in, functional magnetic resonance imaging or positron emission tomography, in both MEG and EEG the locations of sources of activity in the brain cannot be directly observed but have to be inferred from the scalp distribution of the activity. This poses a serious computational problem, the so-called inverse problem. For any field distribution on the scalp an infinite number of possible source constellations can be found. Additional constraints, either physiological (a priori assumptions about the rough location of sources of activity) or mathematical (e.g. restrictions on the information given to the model; limits on the number of sources, signal decomposition methods), are necessary to restrict the number of plausible solutions. There are approaches that allow for the simultaneous use of the entire information in the data using linear inverse modeling (e.g. Minimum Norm approach or LORETA-low resolution tomography). These techniques allow for the simultaneous estimation of generators of complex fields but these methods generally have to sacrifice spatial accuracy and result in ‘smeared’ solutions. However, such methods may be more appropriate for modeling generators of complex cognitive activities.

MEG source localization accuracy can be further improved by making realistic assumptions about head geometry. Normally, a spherical shell is used to model the volume conductor (i.e.

the brain) but in reality the shape of the brain and head deviate considerably from spherical.

Especially for deeper sources and sources in frontal structures, localization accuracy considerably improves when realistic head-models are used as volume conductors (Crouzeix, Yvert, Bertrand, Pernier; 1999; Fuchs et al., 1998). Such realistic head models can be obtained by segmenting different structures of the head from individual magnetic resonance images (MRIs) and computing ‘Boundary Element Models’ (BEM, e.g. Fuchs et al., 1998) or

‘Finite Element Models’ (FEM, e.g. Haueisen et al., 1997).

For BEM the head is divided into triangularized compartments with non-intersecting surfaces (e.g. skin, skull, liquor, cortex, white matter) and homogeneous conductivities. FEM allows modeling of a considerably more individual volume elements to which different conductivities can be assigned. Both methods, especially FEM, are computationally intensive.

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In the two MEG experiments presented in this thesis, the following methods for MEG data analysis are used: In study three the frequency content of the MEG signals at rest and under mental activation is analyzed using FFT (fast Fourier Transform). The Fourier transform allows decomposition of any signal in the time domain into its frequency and phase components as a series of sine and cosine functions with

] sin

cos [ 2

/ )

(

⁰ ⁰

0

a k x b k x

a x

f

^k

k

ω + ω

+

= ∑

^∞

=

and ak T f x k xdx; bk

T

0 0

cos ) ( /

2

∫

= ω T f x k xdx

T

∫

=

0

sin 0

) ( /

2 ω

In study seven the origin of neuromagnetic activity preceding pro- and antisaccades is modeled on the surface of a realistically segmented (BEM) standard brain (Montreal Brain) using the Minimum-Norm-Least-Square-Solution implemented in Curry (Neurosoft, Inc.

1999). In general, source modeling attempts to minimize the variance between a set of measured data m and forward calculated data mf given a certain source configuration which, in the case of minimum norm, is fixed a priori. The relationship between source configuration and forward calculated data is expressed through a so-called lead-field matrix L. Thus mf

=L*j where j is a dipole component vector. For computation, the regularization term λ is added to the data. Thus, minimum norm is a least square minimization of the term D(j)=║Lj- m║² using the model M(j)=║Wj║²where W is a weighting matrix that consists of the model term M multiplied by a regularization parameter λ.

MEG Data presented in the following were acquired with a 148 channel whole-head magnetometer system (Magnes 2500; 4D Neuroimaging, San Diego, CA).

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II. Neuropsychological Functioning in Schizophrenia

II.1. Neuropsychological Findings in Schizophrenia Research

Many studies have attempted to map out cognitive performance in schizophrenia (see e.g Goldstein, 1991; Flor-Henry, 1991; Gold and Weinberger, 1995; Kolb and Whishaw, 1983). Neuropsychological deficits have been found across a wide variety of tasks and domains. Deficits in verbal memory (Saykin et al., 1994; Gold et al., 1997), attention and speed of information processing (Braff, 1993), divergent thinking, problem solving and abstract reasoning (Morris et al., 1995; Abbruzzese et al., 1997) have consistently been reported across many studies. Some studies also revealed problems with perceptual discrimination, motor performance, spatial memory and face perception (Blanchard and Neale, 1994).

In view of the numerous impairments found, the question of whether these deficits are generalized or task specific has attracted considerable interest. Blanchard and Neale (1994) interpret the results of their study of motor, sensory, perceptual, memory and frontal lobe functioning in 28 un-medicated schizophrenia patients as evidence for generalized deficits in schizophrenia. A study by Zihl, Grön and Brunnauer (1998) where 100 patients were examined also suggests a generalized deficit, although a prominent executive deficit appears to exist against the background of general impairment. Results from Kolb and Whishaw (1983), however indicate a domain specific deficit. In this study, patients displayed a neuropsychological profile of executive and memory impairment against a background of relatively spared performance on spatial tasks relying on parietal functioning, consistent with bilateral frontal and temporal dysfunction. Braff et al. (1991) reach a similar conclusion.

Whether cognitive deficits represent side effects of neuroleptic medication or other non-specific consequences of chronic illness, whether they progress in the course of the illness or whether they result from the underlying schizophrenia-associated neuropathology has been the focus of several studies. Extant evidence supports the view that cognitive deficits are not an unspecific consequence of the illness, for instance related to reduced motivation or as a consequence of neuroleptic treatment. Cognitive deficits are present in unmedicated first- episode patients (Mohamed, Paulsen, O’Leary, Arndt, and Andreasen, 1999; Saykin et al.

1994) and appear as risk factors among people who later develop schizophrenia (Jones, Rodgers, Murray, and Marmot, 1994). Cognitive deficits are also present in clinically unaffected relatives of schizophrenia patients who perform more poorly than matched

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comparison subjects without a familial history of schizophrenia (Cannon et al., 1994;

Goldberg et al., 1990). More severe deficits are found in unaffected members of families with several affected members (‘multiplex families’), than in unaffected members of families with just one ill person, indicating an influence of genetic loading (Faraone et al., 2000). However, diagnosed subjects always perform more poorly that their unaffected siblings (Cannon et al., 1994; Kremen et al., 1994).

Antipsychotic medication does not cause cognitive deficits in schizophrenia patients but it does not appear to greatly remedy neuropsychological dysfunction either. While there are some reports indicating that novel antipsychotics help to improve cognitive functioning in schizophrenia (Goldberg et al., 1993; Hagger et al., 1993; Keefe, Silva, Perkins, Liberman, 1999) these effects are nowhere nearly as pronounced as the effect of such medication on psychotic symptoms. In general, cognitive performance seems relatively unaffected by antipsychotic treatment (Cassens, Inglis, Appelbaum, and Gutheil, 1990).

It is debated whether cognitive deficits progress in the course of the illness: Heaton and colleagues (1994) found no relationship between duration of illness and cognitive status.

Likewise, Hoff et al., (1999) report a stable cognitive deficit in schizophrenia at least for the first five years after onset of the illness. On the other hand Fucetola et al. (2000) observed an accelerated decline of executive functions possibly attributable to a degenerative process.

Harvey et al. (1999) found a disproportionate cognitive decline in older schizophrenia patients that was mirrored in a decline of social adjustment.

The relationship between symptom patterns and cognitive functioning has repeatedly been addressed. Here again, the evidence is somewhat equivocal, although currently the presence of negative symptoms is viewed as perhaps more closely related to cognitive impairment than the presence of positive symptoms (Frith, Leary, Cahill and Johnstone, 1991; O’Leary et al.

2000). A number of studies also report an association between the presence of negative symptoms, cognitive impairment and frontal lobe dysfunction in schizophrenia (Baare et al., 1999; Heckers et al., 1999). Conflicting results are reported, for instance, by Zakzanis (1997) who found a correlation between measures of frontal lobe dysfunction and positive symptoms of schizophrenia.

Although the cognitive deficits found in schizophrenia patients are not caused by medication or hospitalization, the usefulness of neuropsychological measures would still be limited if the deficits were generalized and widespread: As mentioned above, this view has been held by a number of authors and is perhaps best represented by Meehl (1989) who concluded: ‘I conjecture that whatever is wrong with the schizotaxic CNS is ubiquitous, a functional

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aberration present throughout, operating everywhere from the sacral cord to the frontal lobes’

(p.14). Similarly, Zihl (1996, 1998), following Cayne and Joynt (1986) emphasizes not so much the usefulness of neuropsychology in psychiatry research as an indicator of specific circumscribed neuropathology but rather as an evaluative tool. In his view, the cognitive deficits associated with mental disorder are notoriously unspecific such that the contribution of neuropsychology to psychiatry should lie more in individual assessment, early intervention and training that aims at remediation of existing deficits and rehabilitation for independent living. Nevertheless, research into the most common neuropsychological dysfunctions in schizophrenia and their relationship to symptom status or social functioning is needed in order to accomplish such goals. Blanchard and Neale (1994) who, too, advocate the view of a generalized cognitive dysfunction in schizophrenia raise the possibility that psychometric limitations of currently available tests may obscure differential impairments. If indeed there is more than one circumscribed and localizable problem in schizophrenia, a further complicating factor would be that deficits are likely to interact. Attentional impairment, for instance, is likely to influence performance on virtually all other tests. Attentional deficits are well documented in schizophrenia (e.g. Braff, 1993) but their influence on performance on other tasks is rarely explicitly taken into account.

Although there is some disagreement about the implications of the reported neuropsychological deficits for the functional neuropathology underlying schizophrenia, two recent reviews (Gold and Weinberger, 1995; Kuperberg and Heckers, 2001) reach a favorable conclusion with regard to neuropsychological measures as indicators of neuropathology in schizophrenia. They summarize the available evidence as consistent with disturbances of a fronto-temoporo-limbic network and stress the usefulness of neuropsychological investigations as indicators of specific brain dysfunction. Similar conclusions were reached in studies by Flor-Henry (1990) or Taylor and Abrams (1984). Kuperberg and Heckers (2001) also emphasize the value of cognitive variables as predictors of social functioning.

In summary, the perhaps most commonly held, but by no means unanimously accepted, view on the neuropsychological signature of schizophrenia is that deficits are primarily seen in tests of executive functioning, verbal tasks and attention, consistent with dysfunction of fronto- temporal cortex and interconnecting sub-cortical circuitry.

Unanimously accepted facts are that schizophrenia patients display considerable cognitive deficits which are ostensibly not the consequence of neuroleptic treatment. The cognitive dysfunctions must somehow relate to inadequate brain functioning. Deficits are mostly, but not exclusively, seen in areas of executive, verbal and attentional performance consistent with

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fronto-temporal deficits of the dominant hemisphere. There is reason to believe that cognitive dysfunction is related to the clinical presentation of schizophrenia, both probably the consequence of the same underlying brain dysfunction, but the nature of this relationship is not clear. Likewise, the diagnostic specificity of cognitive deficits is at issue.

Against this backdrop, the following hypotheses were tested in three studies:

• There exists a neuropsychological profile that differentiates schizophrenia patients from depressed patients.

• Cognitive impairment in schizophrenia relates to specific symptoms.

• Brain functioning during the performance of a verbal working memory task differs between schizophrenia patients and comparison subjects.

Neuropsychological and ocular motor studies of schizophrenia