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Schizophrenia and Brain Imaging

S.-J. Blakemore

INTRODUCTION: SCHIZOPHRENIA
HAS A BIOLOGICAL AETIOLOGY
It is widely accepted that schizophrenia has a biological aetiology.
However, the shift towards this agreement is recent, and the aetiology of schizophrenia has been the subject of lengthy and intense
debate. The debate has been split between those who propose a biological aetiology and those who postulate a psychodynamic origin
to schizophrenia. In the latter camp, non-biological factors such as
family interaction and stressful life events (Kuipers and Bebbington,
1988) have been proposed to playa causal role in the acquisition of
schizophrenia. However, these theories have received little empirical support. In addition, in the past 50 years two main lines of
evidence supporting a biological role in its aetiology have become
apparent. First, there was the discovery of antipsychotic drugs in
the 1950s (Delay et at., 1952) and, second, the demonstration of a
significant hereditary contribution to the disorder (Gottesman and
Shields, 1982). These observations strongly suggest that schizophrenia has a biological basis.
However, current methodologies present challenges for research
on the genetic and dopamine theories of schizophrenia. As a consequence, research has become increasingly focused on attempts to
elucidate some structural or functional brain abnormality since it is
widely held that schizophrenia is a disease of the brain (e.g. Ron and
Harvey, 1990). The theory that some gross brain lesion characterizes schizophrenia seems unlikely. Instead, it is generally accepted
that schizophrenia is characterized not by structural damage, but
by functional abnormalities. This is supported by the relapsing
and remitting course of the illness, fluctuations in symptoms and
response to pharmacological interventions. Therefore the advent of
functional neuroimaging has been important in the study of mental
illness because it enables brain function and its abnormalities to
be investigated. As stated by Weinberger et at. (1996): 'Functional
neuroimaging in psychiatry has had its broadest application and
greatest impact in the study of schizophrenia.'
A major problem is that images of brain function reflect the
current mental state of the patient (i.e. symptoms) and these are
very variable. Symptoms include disorders of inferential thinking (delusions), perception (hallucinations), goal-directed behaviour
(avolition) and emotional expression. Current thinking generally
distinguishes symptoms that comprise the presence of something
that should be absent (positive symptoms) and the absence of
something that should be present (negative symptoms; Crow,
1980). Factor-analytic studies of symptoms suggest that positive
symptoms should be subdivided further into a psychotic group
(comprising delusions and hallucinations) and a disorganized group
(comprising disorganized speech, formal thought disorder, disorganized behaviour and inappropriate affect; Liddle, 1987). The
diversity of symptoms in schizophrenia makes it unlikely that
the pathophysiology can be accounted for by a single localized
brain dysfunction. Instead, the strategy of attempting to localize

specific symptoms to specific brain regions or connections between
regions is encouraging, and this chapter will evaluate the results of
such studies.

STRUCTURAL STUDIES
Computed Tomography (CT) Studies
The main finding from CT scan studies is that the lateral ventricles
are enlarged in schizophrenic patients compared with normal controls. In the first study using this technique, Johnstone et at. (1976)
found that 17 chronically hospitalized schizophrenic patients had
significantly enlarged ventricles compared to normal controls. In a
review of the CT literature Andreasen et at. (1990) noted that 36
out of 49 subsequent studies have replicated this finding to some
extent. There have also been two meta-analyses of the CT scan data
(Raz and Raz, 1990; Van Horn and McManus, 1992), which supported the finding of enlarged ventricles in schizophrenic patients.
However, the extent of ventricular enlargement in schizophrenia is
often small (e.g. Weinberger et at., 1979) or even non-existent in
some studies (Smith and Iacano, 1986). Positive findings might be
due to the control group having smaller ventricles rather than the
schizophrenic patients having larger ventricles. In support of this
suggestion, Van Horn and McManus (1992) found in their metaanalysis that choice of control group was a contributing factor to
the variability of control ventricle:brain ratio (VBR).
Correlation between CT findings and symptoms has been investigated. Lewis (1990) reviewed 41 CT scan studies that addressed
the issue of heterogeneity of schizophrenic symptoms. Only one
of 18 studies found any association between increased ventricular
area and chronicity of illness. Five out of 18 found evidence of a
relationship with negative symptoms. Poor treatment response was
found to be associated with increased ventricular area in about half
the studies. Chua and McKenna (1995) reviewed the CT literature
and concluded that although the finding of increased ventricular area
in schizophrenic patients is widespread and replicated, the difference between schizophrenic patients and normal controls is clearly
small and depends significantly on the control group chosen.

Magnetic Resonance Imaging (MRI) Studies
MRI improves on CT owing to its better spatial resolution and
ability to differentiate white and grey matter. There have been
several replicated findings using structural MRI scans to investigate
the structure of schizophrenics' brains. A number of studies have
shown evidence for reductions in overall brain size, but most of
these have used poor control groups and/or small numbers of
schizophrenic patients (e.g. Andreasen et al., 1986; Harvey et at.,
1993). In addition this finding has not been replicated by other

Biological Psychiatry: Edited by H. D'haenen. J.A. den Boer and P. Willner. ISBN 0-471-49198-5
© 2002 John Wiley & Sons, Ltd.

they found that volume reductions of the frontal and temporal lobes were present in patients with schizophrenia and in some of their siblings without schizophrenia.. = FUNCTIONAL IMAGING Positron-Emission Tomography (PET) Resting Studies There are many PET metabolism studies in the literature. using the identical twins of schizophrenic patients as controls.1). (1998) . (1998). (1992). 1990. Breier et al. 1996a).. 1992). (l996b) and Fletcher et at.. In a study using a large group of patients and well-matched controls (the patients' nonpsychotic siblings and a group of normal controls). Daniel et al. (1997) found evidence for a decreased left hemispheric volume in frontal and temporal regions in schizophrenic patients. 1990.. relative to posterior. (1998) found that low levels of hemispheric asymmetry in the frontal and temporal areas were associated with early onset of schizophrenia. 1994). 1995). Smith et aI.. Young et al... 1997a. The authors found a significant reduction in paralimbic (bilateral temporal pole and insula).. both schizophrenic groups showed some evidence for reduced blood flow in anterior. Buchanan et al. Whereas the demented patients showed a lower level of overall metabolism. (1986).. (1994) created normal and schizophrenic average brains. 1997). However. with some negative findings in the literature (e. The authors propose that these results support the existence of a relative 'fronto-temporal dissociation' in schizophrenia. 1988. Lack of normal asymmetry has been especially associated with early onset of schizophrenia (Fukuzako et aI. 2001). The signal intensity differences between these average images were consistent with cortical thinning/sulcal widening and ventricular enlargement. There have been many conflicting and negative results in studies attempting to locate clinical correlates with temporal abnormalities. It is a data-led technique in which the brain images are normalized. Yurgelun-Todd et at.. 1998. Weinberger et al. 1997).. Sigmundsson et aI. 1989. (1991). Recently. 1986..g.1 Approximate average localization of hypofrontality found by Liddle et al. Andreasen et aI. this technique was used in a well-controlled study to compare regional grey matter in 42 schizophrenic patients and 52 controls (Wright et al. This has become known as 'hypofrontality'. limbic (right amygdala) and cortical (left dorsolateral prefrontal cortex) regions in patients compared with controls. The main finding from data from PET metabolism studies is that there is less metabolism in the frontal lobes of schizophrenic patients compared to normal controls.g.. Buchsbaum et al. Some studies have found frontal lobe reductions in schizophrenic patients (Harvey et al. who compared 15 normal controls with II patients with dementia. Bilateral reduction in volume of the hippocampal formation has been associated with the severity of disorganization syndrome (Fukuzako et aI. suggesting there might be abnormal connections between these areas. Moreover.. Rossi et aI. Kwon et al. the results are inconsistent... Suddath et al. Kelsoe et al. temporal lobe reductions are equivocal. the association with frontal volume SCHIZOPHRENIA being more marked than with temporal volume. Lieberman et aI. 2(01). the other comprised II younger patients). (1990). 1997. Kelsoe et al. 1990) and formal thought disorder (Shenton et al. The first study using isotope imaging was by Ingvar and Franzen (1974). especially in relation to the precise localization of the frontal abnormalities (Raine et al. These findings are consistent with the hypothesis that failure to develop asymmetry is an important component of the pathology underlying some forms of schizophrenia. the left hippocampus and prefrontal white matter. Andreasen et al. (1997a). found evidence for reductions of the left temporal lobe. compared the latter with the former. 1995). Sharma et al. Reversal or reduction of normal structural cerebral asymmetries may be related to the pathogenesis of schizophrenia (Crow. 2(01). Size of the superior temporal gyrus has been associated with hallucinations (Barta et al. (1998) used linear intersubject averaging of structural MR images to create a single averaged brain for the schizophrenic group (n = 25) and for the control group (n 25).650 CLINICAL SYNDROMES: studies (DeMyer et aI. the results are conflicting.. 1991).g. Temporal lobe reductions in schizophrenia have been reported. 1987. Young et aI. elderly patients. However. 1992).. Many MRI studies provide evidence that schizophrenic patients have larger lateral ventricles than normal controls (e.. and this chapter is not exhaustive. 1997. including the hippocampus. Figure XVII-8. middle. and are especially prominent in the hippocampus (Fukuzako et al. This result was supported by Woodruff et al. see Figure XVII-8. 1990). Cannon et aI. Andreasen et aI. Many studies have found no association between chronicity and temporal lobe size (e. who found that interregional correlations were significantly reduced in schizophrenics between prefrontal and superior temporal gyrus volumes. Voxel-Based Morphometry Voxel-based morphometry is a new approach for looking at structural brain abnormalities using MR!. Woodruff et al. and found decreased thalamus size in schizophrenic patients. (1997). 1999).. although one study found an inverse relationship between these two factors (DeLisi et al. Maher et al. Sigmundsson et aI. then differences between groups anywhere in brain are identified (Wright et aI. and two groups of schizophrenics (one group comprised nine chronic... Wolkin et al. (1992) found that schizophrenic patients. Suddath et aI. inferior and orbital regions and found that patients with schizophrenia exhibited selective grey matter volume reductions in the inferior PFC bilaterally. (1998). DeLisi et al. Cannon et al. 1993. Ragland et at. had reductions in the right and left amygdala. (1998) improved on this by subdividing the prefrontal cortex (PFC) into superior.. (1999) recently replicated the finding of a reduction in volume of the left temporal lobe. the right prefrontal white matter volume in schizophrenic patients was significantly related to right amygdalalhippocampal volume. Coffman and Nasrallah.. Volz et at. 1991). (1998) suggested that frontal and temporal structural changes might reflect genetic (or shared environmental) effects.g... Spence et al... 1991). 1988. 1988. However. 1998.. compared with matched healthy controls. There are some MRI data that provide support for the hypothesis of disconnection between brain areas in schizophrenia. Johnstone et aI. There was no difference between the schizophrenic and control groups in any other region of the frontal lobes. parahippocampal gyrus and the amygdala (Yurgelun-Todd et aI. and there are several negative findings (e. regions (hypofrontality.

Silvestri et aI. in which rCBF increased with increasing severity of psychopathology. In other studies. It is claimed that hypofrontality is not due to the drug status of the patients at scanning (Waddington. Ebmeier et aI.. The reality distortion syndrome.. patients with schizophrenia present a significant but mild elevation of D2 receptor density parameters. 1992). 1994).. 1990). Cognitive Activation Studies Functional neuroimaging is most frequently used to evaluate the regional cerebral responses to a particular cognitive or sensorimotor process. 1999.. 1999. It is widely accepted that the 'typical' anti psychotics (such as haloperidol and perphenazine) bind mainly to the D2 receptor (Kapur. Among those showing a positive relationship with hypofrontality are chronicity (Mathew et ai.. Recent attention has been focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. 1997). and a baseline task. binding of the radioligand to Dl receptors was reduced in the prefrontal cortex of schizophrenics. These task-specific .. and mesencephalic. 1986. other metaanalyses have shown that a significant proportion (up to a third) of schizophrenic patients cannot be discriminated from normal healthy controls in terms of D2 dopamine density (Zakzanis and Hansen. Using data from the same patients. At clinically relevant doses.651 BRAIN IMAGING However. The discrepant results might in part be due to the diversity of PET methodology used in these studies. was associated with decreased perfusion of the dorsolateral prefrontal cortex (DLPFC) at a locus that is activated in normal subjects during the internal generation of words. Although no differences were observed in the striatum relative to control subjects. 1998). The highest correlation was in the left parahippocampal region. but the results are inconsistent. Typically..g.. whereas recently most studies have used absolute frontal flow values with or without correction for mean total brain blood flow rates. 1990). Soares and Innis. Farde et aI. 2001).g. In a meta-analysis of 15 brain-imaging studies comparing indices of dopamine function in drug-naive or drug-free patients with schizophrenia. Researchers have attempted to correlate regional cerebral blood flow (rCBF) levels with symptom severity scores for Liddle's three clinical subdivisions in 30 schizophrenic patients (Liddle et aI. 1993). Studies vary on the frontal areas in which activity was measured. There is also broad agreement that unwanted extrapyramidal (parkinsonian) side effects of antipsychotic drugs result from high striatal D2/D3 receptor blockade by these drugs. Kapur and Seeman. 2oooa). Several studies have looked at clinical correlates associated with hypofrontality. compared to healthy controls.. risperidone and Quetiapine. If the D2 occupancy is too high (it exceeds 80%). such as clozapine. subjects are scanned while performing an activation task. 1987. (1992) examined correlations between rCBF and a measure of psychopathology receiving equal contributions from each of Liddle's three subsystems. (1997) used PET to examine the distribution of D I and D2 receptors in the brains of drug-naive or drug-free schizophrenic patients. Kapur et ai. 1988). Friston and colleagues suggested that disinhibition of left medial temporal lobe activity mediated by fronto-limbic connections might explain these findings. Crawley et ai.g. 2000). 1986.g. Regions that show significantly more activity in the experimental state than in the baseline state are considered to be involved in the cognitive/sensorimotor process of interest. Freedom from motor side effects results from low D2 occupancy. A canonical analysis of the same data highlighted the left parahippocampal region and left striatum (globus pallidus). and the authors proposed that this might be a central deficit in schizophrenia. Pilowsky et aI... 1997). 1998). and in several studies hypofrontality was due to an elevated flow in posterior regions (Mathew et aI.. Other studies using PET have produced contradictory results or only very weak evidence of an abnormality in DA receptor number in schizophrenia (e. Receptor Imaging and Antipsychotic Drug Action PET and SPECT receptor imaging can be used to explore receptor targets for antipsychotic drug action in living patients. The earlier studies tended to use the frontal:occipital ratio as a measure of hypofrontality. others have looked at frontal or prefrontal subdivisions only. which nevertheless seems to be sufficient for mediating an antipsychotic effect (Raedler et ai. Atypical anti psychotics differ widely in their D2 occupancy. However. Breier et ai. However. The D2 occupancy seems to be the important mediator of response and side effects in antipsychotic treatment (Kapur et ai. The majority of studies. 1993) and neuropsychological task impairment (e. was associated with increased perfusion of the right anterior cingulate gyrus at a location activated in normal subjects performing the Stroop test.. thalamic and left striatal structures.. which engages the cognitive/sensorimotor process of interest. which engages all components of the activation task except the cognitive/sensorimotor process of interest. 2001) and only transient D2 occupancy. recently antipsychotic medication has been found to affect brain metabolism (Miller et aI.. in particular D2) receptors is increased in schizophrenic brains (Wong et aI. They demonstrated that the psychomotor poverty syndrome. olanzapine... Laruelle (1998) found that. while that of clozapine is significantly lower (under 60%). in the Stroop test).. which has been shown to involve impaired suppression of inappropriate responses (e. negative symptoms (e. disagreement about the definition of hypofrontality has caused inconsistencies in the results. However. antipsychotics lose some of their 'atypical' properties and produce a higher incidence of extrapyramidal side effects (Kapur et aI. Siegel et aI. have found little evidence for statistically significant hypofrontality.. especially for 'atypical' anti psychotics. the differences between control and schizophrenic frontal cortex metabolism are small. Early PET and single photon emission computed tomography (SPECT) receptor imaging studies focused on striatal D2 receptors.. 1999). which might arise from disordered internal monitoring of activity. The D2 occupancy of risperidone had been found to be within the typical range (over 60%). which has been shown to involve a diminished ability to generate words. Neuroreceptor Dopamine Imaging of Antipsychotics using PET Receptors Many studies have shown evidence that the density of dopamine (DA. using any of these definitions. The degree of psychopathology correlated highly with rCBF in the left medial temporal region. 2001). Friston et ai.. PET receptorbinding studies have found that 60-80% D2 occupancy provides optimal antipsychotic response with little extrapyramidal side effects (Kapur. Okubo et ai. Therefore the abnormalities of brain metabolism underlying each of the three syndromes might be widely distributed over the brain. 1998. not from high 5-HT2 occupancy (Kapur and Seeman. 1988. Some atypical anti psychotics such as Quetiapine have very low (Gefvert et aI. 2001) and negative subjective experiences such as depression (de Haan et aI. was associated with increased perfusion in the medial temporal lobe at a locus activated in normal subjects during the internal monitoring of eye movements. The disorganization syndrome. Some have included all anterior regions. Paulman et aI. 2ooob). 1998. atypical antipsychotics tend to have a higher affinity for 5-HT receptor subtypes than for D2 receptors and are associated with few extrapyramidal side effects (Lieberman et aI.

652 CLINICAL SYNDROMES: activity patterns can then be compared between patients and control subjects to determine how the condition affects brain function. 1996). Weinberger et ai. Again. These functional abnormalities increased with the complexity of the task. whereas patients did not (patient performance was worse than that of the controls). Both patient groups also lacked activation of the right parietal cortex. and is particularly sensitive to damage to DLPFC (Berman et ai. Mattay et ai. remembering the previous responses in order to learn by trial and error. Better WCST performance correlated with rCBF increase in prefrontal regions for controls and in the parahippocampal gyrus for patients in two recent studies (Ragland et ai. Importantly. 1982). the rule is changed and subjects must determine the new rule for matching. However. Daniel et al. Several researchers have investigated brain activity in schizophrenic patients while they perform a version of the WCST. (1991) used SPECT to study the effect of amphetamine (a DA agonist) and a placebo on rCBF in 10 chronic schizophrenic patients while they performed a version of the WCST and a matched control task. (\ 997) used functional magnetic resonance imaging (fMRI) to investigate activity during the WCST in \3 chronic schizophrenics on stable neuroleptic medication. can be varied. They also showed evidence for lack of activation in the right PFC and a trend towards SCHIZOPHRENIA increased left temporal activity during the WCST compared to normal controls. so whether less activation of the PFC was due to poorer performance or vice versa cannot be resolved. but has to made in terms of either colour. This task is known to activate the DLPFC in normal controls. However. The authors suggest that this result shows that the better DLPFC was able to function. decreased activation occurred only in the patients with high scores for negative symptoms. (1992) used SPECT during the Tower of London task in three different groups: 13 neuroleptic-naive schizophrenic patients. On placebo no significant activation was seen during the WCST compared with the control task. Wisconsin Card Sorting Task (WCST) Schizophrenia is largely characterized by impairments in planning and execution and therefore tasks that involve this kind of planning and modification of behaviour have been exploited in the scanner. which facilitated performance? Volz et ai. and 15 healthy normal volunteers. It is impossible to determine whether taskrelated underactivation causes or reflects poor task performance. again the task performance was different between the two groups and therefore the results remain ambiguous. Riehemann et ai. this conclusion is based on an ill-founded assumption. Brain imaging makes it possible to identify the abnormal pattern of brain activity associated with this abnormal performance. 2001). Again this is a finding that is difficult to interpret: did amphetamine facilitate task performance. the better patients could perform the task. so that their positions match a goal arrangement also presented on the screen.. 1998. and so on. They have to determine from trial and error which dimension is correct. but are informed after each choice whether they are right or wrong. The Tower of London task activated the left mesial frontal cortex (probably including parts of the cingulate gyrus) in normal controls. Tower of London Task The Tower of London task involves high-level strategic planning among a number of other processes (Shall ice. In contrast. Patients showed greater ipsilateral activation in the primary sensorimotor and lateral premotor regions and had a significantly lower laterality quotient than normal subjects. in terms of the number of moves necessary to complete the task. Subjects are not informed of how to make the match. The Component Processes Underlying Executive Function One problem with studies that employ complex executive tasks is that these tasks involve many processes. attending to one dimension rather than another. the match is not exact. this study was limited because a one-slice imaging technique was used. representing the circuitry specifically activated by the Tower of London in normal controls. Motor Tasks Even tasks that require no more than the production of a simple sequence of movements can be associated with abnormal patterns of brain activity in schizophrenia. On each of a series of trials the subjects have to match a target stimulus with one of the four standard stimuli. (1986) measured rCBF using Xe133 inhalation SPECT in 20 medication-free patients with chronic schizophrenia and 25 normal controls during the WCST and a number-matching control task. in patients. so no information about the activation pattern in adjacent brain regions was obtained. 1995. which then caused an increased rCBF in the PFC? Or did amphetamine cause PFC activity to increase. In addition. In the absence of a series of carefully constructed comparison tasks it is not possible to relate the various brain regions activated with each of the component processes. For example. significant activation of the left DLPFC occurred on the amphetamine trials. Daniel and colleagues point out that patients' performance improved with amphetamine relative to placebo and that with amphetamine. shape and number. The results suggest that schizophrenia may involve a breakdown in the integration of a fronto-temporal network that is responsive to executive and declarative memory demands in healthy individuals. schizophrenic patients performed poorly on the tasks involved. SchrOder . The authors therefore suggested that hypofrontality is related to negative symptoms and is not a long-term effect of neuroleptic treatment or of chronicity of illness. In the typical computerized version of the WCST subjects view a computer screen that displays a number of stimuli. Andreasen et ai.. These stimuli differ along three dimensions: colour. Several types of task that have been used to evaluate brain function in schizophrenic patients are discussed in this chapter. Furthermore. shape or form. The complexity of the task. Nagahama et al. DLPFC rCBF correlated positively with WCST performance. During the WCST but not during the control task normal subjects showed increased DLPFC rCBF. In the following section studies that employed simpler tasks with far fewer component processes are reviewed. The authors proposed that these results demonstrate a functional disturbance in the cortical motor circuitry of schizophrenic patients. a significant correlation was found between activation of DLPFC and performance on 'the WCST task. Task-Based Studies of Executive Function In behavioural studies the most striking impairments are seen when schizophrenic patients perform the various complex executive tasks associated with the frontal lobes. the WCST involves choosing a strategy. and will be discussed in more detail throughout the chapter. However. This is a crucial issue in cognitive activation studies. 23 non-naive schizophrenic patients who had been chronically ill but were medication free for at least 3 weeks. (1997) studied seven patients with schizophrenia and seven normal subjects while they performed a finger movement task of increasing complexity.. In this task subjects have to rearrange a set of three balls presented on a computer screen. but not with placebo. After subjects have made a series of correct responses. but not in either patient group..

stereotyped (routine) movements in the baseline condition. Friston and Frith suggested that this might represent a failure of the PFC to inhibit the temporal lobes. It might reflect a direct influence of apomorphine on the temporal lobe.. making it more similar to that seen in control subjects. They postulated that the temporal lobes may be required to recognize the consequences of actions initiated by the frontal lobes in order to integrate action and perception. these researchers investigated rCBF of 18 chronic schizophrenic patients and six normal controls matched for age. Verbal Self-Monitoring Patients with schizophrenia with auditory hallucinations and delusions show impairments on tasks that require monitoring selfgenerated actions. 1995). Spence and colleagues concluded that. the response is openended and involves making a deliberate choice. 1992). (1996) used a factorial design in PET to test the effect of apomorphine. The authors noted that the DLPFC was also activated during the stereotyped joystick movement task in schizophrenic patients in remission.. Frith et aI. Both these studies raise the possibility of a fundamental but subtle problem of motor control associated with schizophrenia. (1995) and Fletcher et al. The authors analysed data from 13 schizophrenic patients. Brain systems engaged by a paced verbal fluency task in unmedicated schizophrenic patients and normal controls were studied. In addition. In contrast. subjects had to make voluntary joystick movements in the experimental condition. However. For example. Fletcher and colleagues therefore suggested that schizophrenia is associated with both segregated (anterior cingulate) and integrative (fronto-temporal) functional abnormalities. 2(00) and verbal selfmonitoring tasks (Johns et at. all patient groups failed to show a normal deactivation when verbal fluency was compared with word repetition. 1989.. In normal subjects. In particular. They suggested the reason for previous equivocal hypofrontality results is that schizophrenics with a varying amount and combination of symptoms are being compared with normal controls. odd (wrong words) and unimpaired. or lifting a finger).. which when given in very low doses as in this experiment acts primarily on auto-receptors. The finding of normal prefrontal activation found in this study is in agreement with a study in which task performance was optimized by pacing the task (Frith et aI. were associated with increased blood flow in the DLPFC (Brodmann area 46.BRAIN IMAGING et al. independent of their level of performance. Both groups showed increasing activity with increasing speed in sensorimotor cortex and supplementary motor area (SMA). the abnormal fronto-temporal pattern of activation in schizophrenic subjects was normalized by this neuropharmacological intervention. the lack of frontal activation by cognitive tasks 653 in schizophrenic patients has not consistently been located in the PFC.2). There is a fundamental distinction between actions elicited by external stimuli and actions elicited by internal goals (acts of will). Using PET. Dolan et al.. relative to routine actions. and do nothing in a control rest condition (Spence et aI. In a recent PET study. but they found a failure of task-related activation in anterior cingulate cortex and deactivation of the left superior temporal gyrus in the schizophrenic subjects (see Figure XVII-8. Schizophrenic patients showed reduced left PFC activation and increased left temporal activation relative to control subjects during a verbal fluency task in an fMRI study (Yurgelun-Todd et aI. 2(01). However. intentions of will are no longer properly formed and so actions are rarely elicited via this route. The interpretation of the apomorphine-induced reversal of the deactivation in the left temporal lobe in schizophrenic subjects is unclear. but became activated when their symptoms decreased. Schizophrenic patients typically show abnormalities of willed behaviour. In chronic patients. The differences were most marked in a subgroup of patients who were drug free at the time of testing. thus decreasing the release of endogenous dopamine. a different letter being presented every 5 seconds. This is an important concept. mostly between the left PFC and infero-temporal cortex. poverty of speech and action) (Frith. This is true for motor actions (Frith and Done.g.. especially given the relatively large amount of evidence showing a lack of temporal deactivation in the presence of a lack of frontal activation in schizophrenia. Again this result was interpreted to reflect abnormal functional connectivity between frontal and temporal cortex.. willed acts in two response modalities (speaking a word. comparing two occasions when symptoms were severe and when they had subsided. The authors interpret the absence of the normal reciprocal interaction between the frontal and the superior temporal cortex in schizophrenia (the failure of task-related deactivation of the superior temporal gyrus in the schizophrenic group) as suggesting the presence of impaired functional integration. Activation of the DLPFC was normal. the DLPFC is not necessary for that task. 1991). Willed Action Willed action involves a 'higher' stage in the control of action. in contrast to a control group. However. sex and premorbid IQ. What is the functional significance of DLPFC activation in normal controls and patients without symptoms if schizophrenic patients with symptoms can perform the task without recruiting the DLPFC? Verbal Fluency Verbal fluency tasks involve subjects having to generate words to a given cue. This can be seen as a task that involves willed action since subjects have to choose for themselves precisely which word to say. Cingulate activation was restored by low-dose apomorphine in schizophrenics. while they performed (a) paced verbal fluency. subjects might have to produce a word beginning with a certain letter. Blakemore et aI. They used special analytic techniques to assess cortico-cortical interactions. This gives rise to behavioural negative signs (e. when patients . a non-selective dopamine agonist. Additionally. Willed actions are a fundamental component of executive tasks. (1999) asked 12 patients and 12 healthy controls to produce sequences of movements at three different speeds during fMRI. All patient groups showed the same pattern of left PFC activation as control subjects. The DLPFC was activated by normal controls for the free choice task only. However. 1991). in the left superior temporal cortex.. (b) paced word categorization and (c) paced word repetition. Frith et aI. Verbal fluency tasks engage a distributed brain system similar to that engaged by motor response selection tasks associated with willed action (Frith et aI. and included data from a normal control group to clarify the role of the left DLPFC in volition. Normal controls showed negative fronto-temporal interactions whereas all the schizophrenic patients showed positive interactions. alternatively the reversal could be due to a 'downstream' effect of the change in anterior cingulate function. in willed (or self-generated) acts. 1996b). The schizophrenic patients were split into three groups according to their verbal fluency task performance level. it was not activated by schizophrenics with symptoms. Routine actions are specified by an external stimulus. 1998). Overall. hypofrontality seems to depend on current symptoms. these results provoke another question. Friston and Frith (1995) performed an additional analysis of their data from the same three groups of schizophrenic patients according to the level of task performance: poverty (no words). in schizophrenic subjects the effect of apomorphine was to modify the pattern of brain activity. 2000. since hypofrontality was evident in schizophrenics who can perform the experimental task. the patients showed less overall activation than the controls. However.

1996). Fu et at. but when the memory load increased the patients' performance deteriorated more than did that of control subjects. 1998. 1996. Wiser et at.._ . which was either undistorted or distorted (in several ways). (1996). these findings are difficult to interpret in the context of abnormal task performance in patients. The DLPFC is activated by semantic processing during encoding and retrieval.. Callicott et ai. After removing confounds and matching subjects for signal variance (voxel stability). Memory Tasks Memory impairments are especially enduring symptoms in schizophrenia (Green. Researchers have recently developed an event-related fMRI acquisition sequence to scan patients during verbal self-monitoring paradigms. 1997). Acutely psychotic patients tended to misidentify their own distorted voice as 'other' and did not engage these regions. The DLPFC and the hippocampal formation have been the subject of investigation in schizophrenia. (1998) investigated blood oxygen leveldependent (BOLD) signal changes in 10 patients with schizophrenia and 10 controls performing a novel N-back WM task. The rCBF response to increased WM load was significantly reduced in the patients' right DLPFC.. This supports the notion that abnormal brain activity in schizophrenics may be associated with current symptomatology. Carter et at. with a trend towards patients showing smaller activations than controls in frontal and superior temporal cortical regions (e. 1997. This finding . (1998) used PET to evaluate rCBF associated with the 'Nback' working memory (WM) task. while hippocampal activation is associated with the detection of novelty and the creation of associations during encoding in normal individuals (Schacter et at. 64 _ i~ Transverse (a) (b) Figure XVII-8. Ragland et at. decreased DLPFC activity and a tendency for overactivation of parietal cortex were seen. using a verbal memory task with SPECT.2 (a) Statistical parametric maps (SPMs) showing brain regions where there was a significant (p < 0. 1998)....··. Ganguli et at.~. 1997. These differences may be due to the different type of memory tasks used by each group. This task activates the PFC as a function of WM load in normal subjects. the accuracy of both groups in the N-back task was equal. using a verbal free-recall supraspan memory task).005) difference in drug (apomorphine)-task (verbal fluency) interaction between the schizophrenic group and the control group. (1998) measured rCBF during a long-term recognition memory task for words in schizophrenic patients and in healthy subjects using PET.. the impaired cingulate activation seen during the verbal fluency task in schizophrenic patients was significantly reversed by apomorphine. with permission from the Journal of Neuroscience speak aloud but hear a distorted version of their own voice.. precuneus and cerebellum in patients as much as it did in the control group. (2001) compared brain activation patterns of healthy volunteers.. 1997). This memory retrieval task did not activate PFC. Dolan and Fletcher. Words were read and heard during silent portions of the acquisition sequence to control for the problems of scanner noise.~.. but patients may be failing to select frontally mediated cognitive strategies because of abnormal connectivity between otherwise normal regions. In other words. :I ~-~... Several functional neuroimaging studies have failed to find evidence for abnormal activation of temporal or frontal cortex in schizophrenia during memory tasks (Busatto et ai._ . Other studies have shown rCBF changes that overlapped in the schizophrenic and control groups. However. Other groups have found evidence for hypofrontality during memory tasks. The task was designed so that performance scores were similar in the patient and control subjects. they report hearing someone else rather than themselves. :. . The authors interpret the failure of task-related deactivation of the superior temporal gyrus in the schizophrenic group to suggest the presence of impaired functional temporo-frontal integration. There may be nothing inherently abnormal about the physiology of the frontal cortex in schizophrenia. The area in which there was an augmenting effect of the drug on the task-related activity occurring in schizophrenics compared to controls was the anterior cingulate gyrus. 1994. The hippocampus. . using a Paired Associate Recognition Test with PET).. during which subjects are presented with a sequential series of items and have to press a button when a presented item has already been presented a certain number (N) of items earlier. schizophrenic patients with acute psychotic symptoms and schizophrenic patients in remission while they read adjectives aloud and heard their voice. as these are involved in various aspects of memory (Goldman-Rakic and Selemon. (b) Transverse section showing the verbal fluency task-related deactivation of the superior temporal gyrus that was absent in schizophrenic relative to control subjects._·· . while the pattern of activation in patients in remission was intermediate between the other two groups. using fMRI. cingulate and cerebellum were particularly activated when healthy controls heard their own distorted voice. Under low WM load conditions.g. Reprinted from Retcher el al.654 CLINICAL SYNDROMES: o o E : SCHIZOPHRENIA 64 ! ···'1---!'· •. Arnold. with memory storage particularly affected (Feinstein et at.

They found that DLPFC activity correlates with memory task difficulty and performance in the control group. especially use of poor control tasks such as rest. building on the idea that simple cognitive processes can be localized in discrete anatomical modules (referred to as 'functional segregation'). Alternatively. 1997). Although auditory hallucinations are· more common than any other type. the product of PFC and anterior cingulate gyrus (ACG) activity predicted a bilateral temporal and medial PFC deactivation. findings have been confounded by several factors. and this abnormality is due to a failure of the ACG to modulate the prefronto-temporal relationship (see Figure XVII-8. with no unequivocal evidence for any particular region being involved. Fletcher et ai. Imaging Symptoms Functional neuroimaging is also useful for evaluating neural activity in patients experiencing psychotic symptoms. or activations in A and B might be caused by changes in another area (C).g. perceptions in the absence of external stimuli. are prominent among the core positive symptoms of schizophrenia. The authors therefore suggested that hypofrontality in schizophrenics correlates with task difficulty rather than task performance. 1986). In addition to the task-specific hippocampal underactivation. 1999). However. The schizophrenic patients recruited the PFC during the effort of retrieval but did not recruit the hippocampus during conscious recollection. a finding consistent with previous studies of memory in normals (Schacter et al.. Unlike the control group. activity in A might cause activity in B. and normally consists of spoken speech or voices (Hoffman. This requires a more complex approach in which the anatomical components of a cognitive system are defined.3). Liddle et ai. the majority of positive findings suggest that a disruption of frontotemporal integration is a core feature of schizophrenia. Dolan and Fletcher. Connections between these regions are designated on the basis of empirical neuroanatomy and the connections are allocated weights or path strengths by an iterative least-squares approach in such a way that the resultant functional model of interregional influences best accounts for the observed variance-covariance structure generated by the functional neuroimaging observations (Friston et ai.. 1996. They demonstrated that in control subjects. despite a significant difference in performance between the two schizophrenic groups. since the memory-impaired schizophrenic group performed worse than the non-impaired. In contrast. There is currently little direct evidence in favour of this hypothesis. areas A and B may be effectively connected if their relationship can be shown to be causal. A simplified version of effective connectivity (Friston et ai. even though both groups showed no increase in PFC activity as task difficulty increased. they therefore might represent a core pathology of schizophrenia. Functional neuroimaging studies of auditory hallucinations suggest that they involve neural systems dedicated to auditory speech perception as well as a distributed .. Indeed they suggested that because temporaVparietal activations were not correlated with performance. there was no inferior temporaVparietal deactivation in either schizophrenic group. and hippocampal and parahippocampal activation occurred during successful retrieval in normal control subjects. and non-matched task performance in the schizophrenic and control groups. The authors suggest that the lack of deactivation of these areas might represent a temporofrontal disconnection in schizophrenics. Hypofrontality has not always been found in studies using modified tasks to optimize the performance of schizophrenic subjects. Future cognitive activation studies using improved methodologies should resolve issues such as whether abnormal frontal function causes or reflects poor task performance in schizophrenia. Further evidence for abnormal integration between brain areas in schizophrenia comes from a study that specifically investigated the functional integration (Fletcher et ai. Hallucinations in all modalities tend to be associated with activity in the neural substrate associated with that particular sensory modality. research suggests that the interaction of a distributed cortico-subcortical neural network might provide a biological basis for schizophrenic hallucinations. The authors interpreted these results as showing that in schizophrenia there is an abnormality in the way in which left PFC influences the left superior temporal cortex. but not in the schizophrenic patients. 1992). In this study activation of the PFC correlated with effort of retrieval. Brain areas A and B may be functionally connected if it can be shown that an increase (or decrease) of activity in area A is associated with an increase (or decrease) in area B. and the authors propose that this overactivation represents an 'effort to compensate for the failed recruitment of the hippocampus'. which can be shown empirically by analysis of covariance. Auditory Hallucinations The most common type of hallucination in schizophrenia occurs in the auditory domain. In this case. However. 1997) was employed by Fletcher et al. in which they used PET to evaluate 13 schizophrenic patients and a group of normal control subjects during memory retrieval tasks. Conclusion There is a body of evidence suggesting that schizophrenic patients show abnormal interactions and influences among brain regions (or functional integration) during cognitive tasks. for both schizophrenic groups DLPFC activity levels plateaued as task difficulty increased. The schizophrenic patients showed a more widespread activation of prefrontal areas and parietal cortex during recollection than controls.655 BRAIN IMAGING suggests that there is a dysfunctional cortico-cerebellar circuit in schizophrenia. hallucinations in other sensory modalities occur in a proportion of patients. which projects to A and B. 1993).. This study improves on previous cognitive activation studies in which the confound of non-matched task performance occurs. The authors suggested that high baseline hippocampal activity together with an absence of task-specific activation demonstrates abnormal cortico-hippocampal functional integration in schizophrenia. and several regions have been found to function abnormally. Hallucinations Hallucinations. This interpretation again moves away from the simple notion of dysfunction in isolated brain regions explaining the cognitive deficits in schizophrenia. and towards the idea that neural abnormality in schizophrenia reflects a disruption of integration between brain areas. (1998) used PET to compare rCBF in memoryimpaired and non-impaired schizophrenic patients with normal controls during a parametrically graded memory task.. the authors observed a generally higher overall level of non-specific hippocampal activity. A question of clinical importance is whether different patterns of cortical interaction correlate with or predict schizophrenic symptoms or outcome. (1999) to evaluate effective connectivity between regions in the data from their PET study of a graded memory task in schizophrenia. Hypofrontality was not found in a study by Heckers and colleagues (1998). there is evidence that activation of the sensory cortex particular to the false perception is not in itself sufficient for the perception. supporting previous metabolic studies (e. However. Functional integration considers complex cognitive processes as emergent properties of interconnected brain area. Instead.

The first. especially the right middle temporal gyrus. to external speech.05). limbic structures (especially hippocampus) and paralimbic regions (parahippocampal and cingulate gyri and orbito-frontal cortex). (1995) used PET to study brain activity associated with the occurrence of hallucinations in six schizophrenic patients. Thus. Reprinted from Aetcher et at. This abnormality will be observable even in the absence of current symptoms. and showed activations in visual and auditoryllinguistic association cortices. The regression coefficient of each of the two groups is considered to provide a measure of contribution of PFC x ACC to superior temporal cortical activity. Visual cortical activation to flashing lights remained the same over all four scans. asks what changes in brain activity can be observed at the time hallucinations are occurring. and the particular sensory cortical regions activated in individual patients may affect their specific perceptual content. who used fMRI to study seven schizophrenic patients while they were experiencing severe auditory verbal hallucinations and again after their hallucinations had subsided. Right panel: Graphic representation of the relationship between activity in left superior temporal cortex (STG. called the trait approach. y-axis) and the combination of cingulo-prefrontal activity (PFC x ACG. (1999). On the former occasion. compared to when their hallucinations were mild.3 Left panel: Region of left superior temporal cortex showing a significant difference between control and schizophrenic subjects (p < 0. There are two distinct approaches to the study of the physiological basis of auditory hallucinations. in the controls an increase in PFC x ACC produces an inhibition of superior temporal activity. The authors thus proposed that auditory hallucinations are associated with reduced responsivity in temporal cortical regions that overlap with those that normally process external speech. these patients had reduced responses in temporal cortex.CLINICAL 656 SYNDROMES: SCHIZOPHRENIA 3 (a) 2 Sagittal -5 Transverse 0 -5 (f) -2 ~ 4-1-4 -3I (b) -2 0 62 ~10 '" III '" o 5 10 PFC'ACC 20 Figure XVII-8. The authors propose that activity in deep brain structures seen in all subjects may generate or modulate hallucinations. possibly due to competition for common neurophysiological resources. asks whether there is a permanent abnormality of brain function present in patients who are prone to experience auditory hallucinations when they are ill. called the state approach. The linear best fit is shown for both groups. (l997b). indicating the opposite effect. x-axis in (a) controls and (b) schizophrenic subjects. Importantly this study pointed to the possibility that hallucinations coincide with activation of the sensory and association cortex specific to the modality of the experience. David et al. In the schizophrenic subjects the line slopes upward. and while he was on and off antipsychotic drugs. A similar result was obtained by Woodruff et al. An SPM rendered onto sagittal and transverse section of a stereotactically normalized structural MRI is shown. with permission from Neuroimage network of other cortical and subcortical areas. The BOLD signal in the temporal cortex to exogenous auditory stimulation (speech) was significantly reduced when the patient was experiencing hallucinating voices. The subject was scanned during presentation of exogenous auditory and visual stimuli. State Studies Silbersweig et al. Temporo-parietal auditory-linguistic association cortex activation was present in each subject. a notion that has received support from several further studies. whether the subject was experiencing auditory hallucinations or not. (1996) used fMRI to scan a schizophrenic patient while he was experiencing auditory hallucinations and again when hallucination free. One drug-naive patient had visual as well as auditory verbal hallucinations. The second. . Five patients with classic auditory verbal hallucinations demonstrated activation in subcortical (thalamic and striatal) nuclei. regardless of medication.

4). Zeki et ai. During hallucinations. for example. The authors propose that this reduced activity might contribute to the articulation of the linguistic anomalies that characterize positive thought disorder. A similarly elegant design was employed in a recent fMRI study (Shergill et ai. they differed from both hallucinators and controls in showing reduced activation in the right parietal operculum (see Figure XVII-8. very limited activation in striate cortex could be induced by exogenous visual stimulation. which entails both the generation and monitoring of inner speech. ffytche et ai. They used PET to evaluate the neural correlates of tasks that engaged inner speech and auditory verbal imagery in schizophrenic patients with a strong predisposition to auditory verbal hallucinations (hallucinators). schizophrenic patients with no history of hallucinations (non-hallucinators) and normal controls. However. The authors suggested that these subcortical activations could be due to retrieval from memory of the hallucinated material and emotional reaction to the voices. (1996) (See Colour Plate XVII-8. 1992). Conversely. Dierks et ai.4 Difference in rCBF between schizophrenic patients with a strong predisposition to auditory verbal hallucinations (hallucinators). was associated with the presence of auditory hallucinations. They found that frontal and temporal speech areas and several other cortical and subcortical regions were activated during auditory hallucinations. This was investigated by McGuire et al.4) dedicated to the particular sensory modality in which the false perception occurs and a widely distributed cortico-subcortical system. (1999) used event-related fMRI to investigate three paranoid schizophrenics who were able to indicate the onset and offset of their hallucinations as in the study by Silbersweig et al. temporal lobe and frontal operculum (Broca's area) were also activated during auditory hallucinations. (1997) performed had to make voluntary joystick a PET study in which subjects movements in the experimental . regions activated by both normal subjects and non-hallucinators. (1998) found activity in ventral extrastriate visual cortex in patients with the Charles Bonnet syndrome when they experienced visual hallucinations. Similarly. Using this design they found that primary auditory cortex. For example. regions activated by both normal subjects and non-hallucinators. When imagining sentences spoken in another person's voice. Intersubject variability in the specific location of the sensory activation associated with the hallucination could arise from differences between the patients in the sensory content and experience of their hallucinations. Finally hallucinations were also associated with increased activity in the hippocampus and amygdala. 1991). There were no differences between hallucinators and controls in rCBF during thinking in sentences. which may reflect this region's role in the processing of linguistic anomalies. Trait Studies The finding that auditory hallucinations are associated with activation of auditory and language association areas is consistent with the proposal that auditory verbal hallucinations arise from a disorder in the experience of inner speech (Frith.BRAIN IMAGING 657 Recently. which entails both the generation and monitoring of inner speech. controlling for differences in the total number of words articulated. and normal controls during tasks that engaged inner speech and auditory verbal imagery. hallucinators showed reduced activation of the left middle temporal gyrus and the rostral supplementary motor area. (1997) used fMRI to investigate the visual cortical response to photic stimulation during and in the absence of continuous visual hallucinations. areas implicated in the regulation and monitoring of speech production. including Heschl's gyrus. paralimbic and frontal areas. functional neuroimaging studies suggest that hallucinations involve an interaction between the neural systems Thought Disorder McGuire et ai. When visual hallucinations were absent photic stimulation produced a normal bilateral activation in striate cortex. (1998) scanned six schizophrenic subjects with PET while they described a series of ambiguous pictures. Verbal disorganization was positively correlated with activity in the parahippocampaUanterior fusiform region bilaterally. (1996). At least part of the activity in the brain associated with the experience of visual hallucinations is located in the visual cortex. when imagining sentences spoken in another person's voice.. 2000). which provoked different degrees of thought-disordered speech in each patient. Adapted from McGuire et al.. Visual HallucinatWns The neural correlates of visual hallucinations also seem to be located in the neural substrate of visual perception. cingulate and left superior temporal cortex. Secondary auditory cortex. Moreover. McGuire and his colleagues suggest that the presence of verbal hallucinations is associated with a failure to activate areas concerned with the monitoring of inner speech. when non-hallucinators imagined speech. Figure XVII-S. the content of the hallucinations reflected the functional specialization of the region. Howard et al. respectively. Verbal disorganization (positive thought disorder) was inversely correlated with activity in the inferior frontal. including limbic. The severity of thought disorder was correlated with rCBF across the 12 scans. supporting the notion that auditory hallucinations are related to inner speech. hallucinators showed reduced activation of the left middle temporal gyrus and the rostral supplementary motor area. using SPECT Hoksbergen et al. schizophrenic patients with no history of hallucinations (non-hallucinators). hallucinations of colour activated V4 (the human colour centre. In conclusion. (1996) found that visual hallucinations were associated with hypoperfusion in the right occipito-temporal region. which showed partial normalization after the visual hallucinations had subsided. Passivity Symptoms Spence et ai.

OBSTACLES TO FUNCTIONAL NEUROIMAGING AND SCHIZOPHRENIA STUDIES Subject Matching It is important that patients are matched to the control group on as many factors as possible.it is clearly not necessary for performing the task. there is a conceptual problem with applying the approach of cognitive activation studies to patient groups. Schizophrenic patients with passivity showed hyperactivation of inferior parietal lobe (BA 40). but who do not have a particular symptom. They investigated a group of schizophrenic patients with passivity (delusions of control) and without (the same group in remission).5). A clear advantage of using symptom-specific schizophrenic groups is that the control group can comprise people with a diagnosis of schizophrenia. a reversal of this hyperactivation of parietal lobe was seen. It is not clear whether the control group's education level should be matched to the patient's parental or premorbid education level. However. as reviewed here. It is difficult to distinguish these two alternatives. Therefore. However. there are also problems Tasks As has been discussed at length throughout this chapter. comprising a variety of different symptoms. When patients were in remission. Should they be taking the same medication. the results are inconsistent. replicated finding peculiar either to the syndrome of schizophrenia or to a particular symptom. both of these are superior to matching controls to patients' current IQ level. There is the question of which psychiatric population should be used. It is difficult to interpret patterns of brain activity that differ between control and patient groups when the performance of the two groups on tasks differs in terms of degrees of efficiency and success. the same group of schizophrenic patients can be used as their own control group if and when the symptom evaluated remits (see the study by Spence et ai. as though it were being caused by an external force. However. Since psychiatric patients will be more matched on these factors they may be a preferable control group. to attend or think more or less. Better still. who are thus matched in terms of medication and hospitalization. These include the fact that normal controls are not taking medication. Another question is whether the control group should be normal or psychiatric. may reveal activity specific to depression or to schizophrenia. Hyperactivity in parietal cortex may reflect the 'unexpected' nature of the experienced movement in patients. a clear shortcoming of using symptom-specific groups is that little can be discovered about schizophrenia as a syndrome. and stereotyped (routine) movements in the baseline condition. Normal controls are important in order to establish a baseline model of the neural circuitry involved in an experimental task. PET and SPECT studies have shown that the density .. comparing schizophrenic with depressed patients. A comparison of all schizophrenics with normal controls revealed hypofrontality in the patients. What do differences in brain activity mean in the context of normal task performance? If an area is activated more in the controls than in the patient group during such a task. for example. hospitalized or affect-flattened. Attempts have been made to correlate cognitive brain activity with specific symptoms or clinical signs.. in both resting metabolism and cognitive activation studies.S Diagram of overactivity in right parietal lobe (Bro<!mann area 40) in patients with passivity while making voluntary joystick movements (in the study by Spence et aI. and a group of normal controls. there have been repeated findings of frontal and temporal abnormalities in schizophrenia. which may be considerably impaired by illness. Therefore. Any difference in brain activity between the two groups could represent a critical abnormality in schizophrenia and might cause poor task performance. Experimental Figure XVII-8. The most obvious interpretation is that patients and controls are using different strategies to achieve similar task performance. or alternatively it might reflect poor performance. or is hospitalization the more important factor? They might not be able to perform the experimental task for some reason that is different from that causing impairment in schizophrenic patients. or that might have a direct effect on rCBF. there are several problems with using nonpsychiatric controls. However. but the best way to match IQ and education level is uncertain. Similar results were found when schizophrenic patients with passivity were compared with normal controls. Hyperactivity in parietal cortex might reflect the patient's experiencing the movement as 'unexpected. However.' as if it were being caused by some external force condition. since each symptom may be associated with a different brain pattern or functional abnormality. Using groups of patients defined by diagnosis (schizophrenia) may explain the inconsistent and equivocal results of functional imaging studies. Recent studies have employed tasks on which performance of the patient and control group is matched. interpretational difficulties remain: what is the nature of the relationship between differences in brain activity and behaviour? How do these two variables relate to the schizophrenic state? These problems have not been resolved. 1997). a reversal of the hyperactivation of parietal lobe and cingulate was seen.CLINICAL 658 SYNDROMES: SCHIZOPHRENIA with using psychiatric patients as controls. and do nothing in the rest condition. When patients were in remission. and no longer experienced passivity symptoms. and no longer experienced passivity symptoms. and remain when interpreting data from studies in which task performance of patient and control groups is matched. the cerebellum and the cingulate cortex relative to schizophrenic patients without passivity (see Figure XVII-8. 1998). Symptom-Specific Groups Schizophrenia is a heterogeneous illness. However. factors that might cause the patients to be more or less motivated. there is also a problem with interpreting the results of activation studies in which the task performance of the patient and control group is matched. the functional significance of that activation is difficult to understand . OVERALL CONCLUSION Although there has been no specific.

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