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Schizophrenia and Brain Imaging

S.-J. Blakemore

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.

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.




studies (DeMyer et aI., 1988; Andreasen et aI., 1990). Many MRI

studies provide evidence that schizophrenic patients have larger
lateral ventricles than normal controls (e.g. Coffman and Nasrallah,
1986; Kelsoe et al., 1988; Suddath et aI., 1990; Andreasen et aI.,
1990; Woodruff et al., 1997a; Sharma et al., 1998; Lieberman et aI.,
2(01). However, the results are conflicting, and there are several
negative findings (e.g. Smith et aI., 1987; Johnstone et aI., 1989;
Rossi et aI., 1994).
Temporal lobe reductions in schizophrenia have been reported,
and are especially prominent in the hippocampus (Fukuzako et al.,
1997; Sigmundsson et aI., 2(01), parahippocampal gyrus and the
amygdala (Yurgelun-Todd et aI., 1996a). Suddath et al. (1990),
using the identical twins of schizophrenic patients as controls, found
evidence for reductions of the left temporal lobe, including the
hippocampus. Kwon et al. (1999) recently replicated the finding
of a reduction in volume of the left temporal lobe. Cannon et al.
(1998) suggested that frontal and temporal structural changes might
reflect genetic (or shared environmental) effects. In a study using a
large group of patients and well-matched controls (the patients' nonpsychotic siblings and a group of normal controls), 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. However, temporal lobe reductions are equivocal,
with some negative findings in the literature (e.g. Young et aI.,
1991). There have been many conflicting and negative results
in studies attempting to locate clinical correlates with temporal
abnormalities. Many studies have found no association between
chronicity and temporal lobe size (e.g. Kelsoe et al., 1988; Young
et al., 1991), although one study found an inverse relationship
between these two factors (DeLisi et al., 1991). Size of the superior
temporal gyrus has been associated with hallucinations
et al., 1990) and formal thought disorder (Shenton et al., 1992).
Bilateral reduction in volume of the hippocampal formation has
been associated with the severity of disorganization
(Fukuzako et aI., 1997).
Some studies have found frontal lobe reductions in schizophrenic
patients (Harvey et al., 1993; Cannon et aI., 1998; Sigmundsson
et aI., 2001). However, the results are inconsistent, especially in
relation to the precise localization of the frontal abnormalities
(Raine et al., 1992). Buchanan et al. (1998) improved on this by
subdividing the prefrontal cortex (PFC) into superior, middle, inferior and orbital regions and found that patients with schizophrenia
exhibited selective grey matter volume reductions in the inferior
PFC bilaterally. There was no difference between the schizophrenic
and control groups in any other region of the frontal lobes.
There are some MRI data that provide support for the hypothesis
of disconnection between brain areas in schizophrenia. Breier et al.
(1992) found that schizophrenic patients, compared with matched
healthy controls, had reductions in the right and left amygdala,
the left hippocampus and prefrontal white matter. Moreover, the
right prefrontal white matter volume in schizophrenic patients was
significantly related to right amygdalalhippocampal
volume, suggesting there might be abnormal connections between these areas.
Buchsbaum et al. (1997) found evidence for a decreased left hemispheric volume in frontal and temporal regions in schizophrenic
patients. This result was supported by Woodruff et al. (1997a), who
found that interregional correlations were significantly reduced in
schizophrenics between prefrontal and superior temporal gyrus volumes. The authors propose that these results support the existence
of a relative 'fronto-temporal dissociation' in schizophrenia.
Reversal or reduction of normal structural cerebral asymmetries
may be related to the pathogenesis of schizophrenia (Crow, 1995).
Lack of normal asymmetry has been especially associated with
early onset of schizophrenia (Fukuzako et aI., 1997; DeLisi et al.,
1997). Maher et al. (1998) found that low levels of hemispheric
asymmetry in the frontal and temporal areas were associated with
early onset of schizophrenia, the association with frontal volume

being more marked than with temporal volume. These findings are
consistent with the hypothesis that failure to develop asymmetry is
an important component of the pathology underlying some forms
of schizophrenia.

Voxel-Based Morphometry
Voxel-based morphometry
is a new approach for looking at
structural brain abnormalities using MR!. It is a data-led technique
in which the brain images are normalized, then differences between
groups anywhere in brain are identified (Wright et aI., 1995).
Andreasen et al. (1994) created normal and schizophrenic average
brains, compared the latter with the former, and found decreased
thalamus size in schizophrenic patients. Wolkin 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). The signal intensity differences between
these average images were consistent with cortical thinning/sulcal
widening and ventricular enlargement. Recently, this technique was
used in a well-controlled study to compare regional grey matter in
42 schizophrenic patients and 52 controls (Wright et al., 1999).
The authors found a significant reduction in paralimbic (bilateral
temporal pole and insula), limbic (right amygdala) and cortical
(left dorsolateral prefrontal cortex) regions in patients compared
with controls.



Positron-Emission Tomography (PET) Resting Studies

There are many PET metabolism studies in the literature, and this
chapter is not exhaustive. 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. This
has become known as 'hypofrontality'. The first study using isotope
imaging was by Ingvar and Franzen (1974), who compared 15
normal controls with II patients with dementia, and two groups
of schizophrenics
(one group comprised nine chronic, elderly
patients; the other comprised II younger patients). Whereas the
demented patients showed a lower level of overall metabolism,
both schizophrenic groups showed some evidence for reduced blood
flow in anterior, relative to posterior, regions (hypofrontality; see
Figure XVII-8.1).

Figure XVII-8.1 Approximate average localization of hypofrontality

found by Liddle et al. (1992), Weinberger et al. (1986), Daniel et al.
(1991), Volz et at. (1997), Ragland et at. (1998), Spence et al. (1998),
Yurgelun-Todd et at. (l996b) and Fletcher et at. (1998)


However, disagreement about the definition of hypofrontality has
caused inconsistencies in the results. Studies vary on the frontal
areas in which activity was measured. Some have included all anterior regions; others have looked at frontal or prefrontal subdivisions
only. The earlier studies tended to use the frontal:occipital ratio as
a measure of hypofrontality, whereas recently most studies have
used absolute frontal flow values with or without correction for
mean total brain blood flow rates. The majority of studies, using
any of these definitions, have found little evidence for statistically significant hypofrontality, and in several studies hypofrontality
was due to an elevated flow in posterior regions (Mathew et aI.,
1988; Siegel et aI., 1993). In other studies, the differences between
control and schizophrenic frontal cortex metabolism are small. It
is claimed that hypofrontality is not due to the drug status of
the patients at scanning (Waddington, 1990). However, recently
antipsychotic medication has been found to affect brain metabolism
(Miller et aI., 1997). Several studies have looked at clinical correlates associated with hypofrontality, but the results are inconsistent.
Among those showing a positive relationship with hypofrontality are chronicity (Mathew et ai., 1988), negative symptoms (e.g.
Ebmeier et aI., 1993) and neuropsychological task impairment (e.g.
Paulman et aI., 1990).
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., 1992). They demonstrated that the psychomotor poverty
syndrome, which has been shown to involve a diminished ability
to generate words, 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.
The disorganization syndrome, which has been shown to involve
impaired suppression of inappropriate responses (e.g. in the Stroop
test), was associated with increased perfusion of the right anterior
cingulate gyrus at a location activated in normal subjects performing
the Stroop test. The reality distortion syndrome, which might arise
from disordered internal monitoring of activity, was associated
with increased perfusion in the medial temporal lobe at a locus
activated in normal subjects during the internal monitoring of
eye movements. Therefore the abnormalities of brain metabolism
underlying each of the three syndromes might be widely distributed
over the brain.
Using data from the same patients, Friston et ai. (1992) examined correlations between rCBF and a measure of psychopathology
receiving equal contributions from each of Liddle's three subsystems. The degree of psychopathology correlated highly with rCBF
in the left medial temporal region, and mesencephalic, thalamic
and left striatal structures. The highest correlation was in the left
parahippocampal region,. and the authors proposed that this might
be a central deficit in schizophrenia. A canonical analysis of the
same data highlighted the left parahippocampal
region and left
striatum (globus pallidus), in which rCBF increased with increasing severity of psychopathology. Friston and colleagues suggested
that disinhibition of left medial temporal lobe activity mediated by
fronto-limbic connections might explain these findings.


of Antipsychotics

using PET


Many studies have shown evidence that the density of dopamine

(DA; in particular D2) receptors is increased in schizophrenic
brains (Wong et aI., 1986; Breier et ai., 1997). Early PET and
single photon emission computed tomography (SPECT) receptor
imaging studies focused on striatal D2 receptors. However, Okubo
et ai. (1997) used PET to examine the distribution of D I and D2
receptors in the brains of drug-naive or drug-free schizophrenic

patients. Although no differences were observed in the striatum

relative to control subjects, binding of the radioligand to Dl
receptors was reduced in the prefrontal cortex of schizophrenics.
Other studies using PET have produced contradictory results or
only very weak evidence of an abnormality in DA receptor number
in schizophrenia (e.g. Crawley et ai., 1986; Farde et aI., 1987;
Pilowsky et aI., 1994).
In a meta-analysis of 15 brain-imaging studies comparing indices
of dopamine function in drug-naive or drug-free patients with
schizophrenia, Laruelle (1998) found that, compared to healthy
controls, patients with schizophrenia present a significant but mild
elevation of D2 receptor density parameters. However, 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,
1998; Soares and Innis, 1999). The discrepant results might in part
be due to the diversity of PET methodology used in these studies.
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. It is widely
accepted that the 'typical' anti psychotics (such as haloperidol and
bind mainly to the D2 receptor (Kapur, 1998).
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. PET receptorbinding studies have found that 60-80% D2 occupancy provides
optimal antipsychotic
response with little extrapyramidal
effects (Kapur, 1998).
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, especially for
'atypical' anti psychotics, such as clozapine, olanzapine, risperidone
and Quetiapine. At clinically relevant doses, 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., 1998; Silvestri et aI., 2001). Atypical
anti psychotics differ widely in their D2 occupancy. The D2
occupancy of risperidone had been found to be within the typical
range (over 60%), while that of clozapine is significantly lower
(under 60%). Some atypical anti psychotics such as Quetiapine
have very low (Gefvert et aI., 2001) and only transient D2
occupancy, which nevertheless seems to be sufficient for mediating
an antipsychotic effect (Raedler et ai., 1999; Kapur et ai., 2oooa).
The D2 occupancy seems to be the important mediator of
response and side effects in antipsychotic treatment (Kapur et ai.,
2ooob). Freedom from motor side effects results from low D2 occupancy, not from high 5-HT2 occupancy (Kapur and Seeman, 2001).
If the D2 occupancy is too high (it exceeds 80%), antipsychotics
lose some of their 'atypical' properties and produce a higher incidence of extrapyramidal side effects (Kapur et aI., 1999; Kapur
and Seeman, 2001) and negative subjective experiences such as
depression (de Haan et aI., 2000).



Functional neuroimaging is most frequently used to evaluate the

regional cerebral responses to a particular cognitive or sensorimotor
process. Typically, subjects are scanned while performing an
activation task, which engages the cognitive/sensorimotor
of interest, and a baseline task, which engages all components of the
activation task except the cognitive/sensorimotor
process of interest.
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. These task-specific




activity patterns can then be compared between patients and control

subjects to determine how the condition affects brain function.
Several types of task that have been used to evaluate brain function
in schizophrenic patients are discussed in this chapter.

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. Brain imaging makes it possible
to identify the abnormal pattern of brain activity associated with
this abnormal performance.

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.
Several researchers have investigated brain activity in schizophrenic
patients while they perform a version of the WCST. This task is
known to activate the DLPFC in normal controls, and is particularly
sensitive to damage to DLPFC (Berman et ai., 1995; Nagahama
et al., 1996). In the typical computerized version of the WCST
subjects view a computer screen that displays a number of stimuli.
These stimuli differ along three dimensions: colour, shape and
number. On each of a series of trials the subjects have to match a
target stimulus with one of the four standard stimuli. However, the
match is not exact, but has to made in terms of either colour, shape
or form. Subjects are not informed of how to make the match, but
are informed after each choice whether they are right or wrong.
They have to determine from trial and error which dimension is
correct. After subjects have made a series of correct responses,
the rule is changed and subjects must determine the new rule for
Weinberger et ai. (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. During the WCST but not during the control task
normal subjects showed increased DLPFC rCBF, whereas patients
did not (patient performance was worse than that of the controls).
Furthermore, in patients, DLPFC rCBF correlated positively with
WCST performance. The authors suggest that this result shows
that the better DLPFC was able to function, the better patients
could perform the task. However, this conclusion is based on an
ill-founded assumption. It is impossible to determine whether taskrelated underactivation causes or reflects poor task performance.
This is a crucial issue in cognitive activation studies, and will be
discussed in more detail throughout the chapter.
Daniel et al. (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. On placebo no significant activation
was seen during the WCST compared with the control task. In
contrast, 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, but not with placebo, a significant correlation was found between activation of DLPFC and performance on
'the WCST task. Again this is a finding that is difficult to interpret:
did amphetamine facilitate task performance, which then caused
an increased rCBF in the PFC? Or did amphetamine cause PFC
activity to increase, which facilitated performance?
Volz et ai. (\ 997) used functional magnetic resonance imaging (fMRI) to investigate activity during the WCST in \3 chronic
schizophrenics on stable neuroleptic medication. They also showed
evidence for lack of activation in the right PFC and a trend towards

increased left temporal activity during the WCST compared to
normal controls. However, again the task performance was different
between the two groups and therefore the results remain ambiguous. In addition, this study was limited because a one-slice imaging
technique was used, so no information about the activation pattern
in adjacent brain regions was obtained.
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., 1998; Riehemann
et ai., 2001). 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

Tower of London Task

The Tower of London task involves high-level strategic planning
among a number of other processes (Shall ice, 1982). In this task
subjects have to rearrange a set of three balls presented on a
computer screen, so that their positions match a goal arrangement
also presented on the screen. The complexity of the task, in terms
of the number of moves necessary to complete the task, can be
Andreasen et ai. (1992) used SPECT during the Tower of London
task in three different groups: 13 neuroleptic-naive schizophrenic
patients; 23 non-naive schizophrenic patients who had been chronically ill but were medication free for at least 3 weeks; and 15
healthy normal volunteers. The Tower of London task activated
the left mesial frontal cortex (probably including parts of the cingulate gyrus) in normal controls, but not in either patient group.
Both patient groups also lacked activation of the right parietal cortex, representing the circuitry specifically activated by the Tower
of London in normal controls. Importantly, decreased activation
occurred only in the patients with high scores for negative symptoms. 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. Again, schizophrenic patients
performed poorly on the tasks involved, so whether less activation
of the PFC was due to poorer performance or vice versa cannot be

The Component Processes Underlying Executive Function

One problem with studies that employ complex executive tasks is
that these tasks involve many processes. For example, the WCST
involves choosing a strategy, remembering the previous responses
in order to learn by trial and error, attending to one dimension rather
than another, and so on. 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. In
the following section studies that employed simpler tasks with far
fewer component processes are reviewed.

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.
Mattay et ai. (1997) studied
seven patients with schizophrenia and seven normal subjects while
they performed a finger movement task of increasing complexity.
Patients showed greater ipsilateral activation in the primary sensorimotor and lateral premotor regions and had a significantly lower
laterality quotient than normal subjects. These functional abnormalities increased with the complexity of the task. The authors
proposed that these results demonstrate a functional disturbance
in the cortical motor circuitry of schizophrenic patients. SchrOder

et al. (1999) asked 12 patients and 12 healthy controls to produce
sequences of movements at three different speeds during fMRI.
Both groups showed increasing activity with increasing speed in
sensorimotor cortex and supplementary motor area (SMA). However, the patients showed less overall activation than the controls.
The differences were most marked in a subgroup of patients who
were drug free at the time of testing. Both these studies raise the
possibility of a fundamental but subtle problem of motor control
associated with schizophrenia.
Willed Action
Willed action involves a 'higher' stage in the control of action.
There is a fundamental distinction between actions elicited by
external stimuli and actions elicited by internal goals (acts of
will). Routine actions are specified by an external stimulus. In
contrast, in willed (or self-generated) acts, the response is openended and involves making a deliberate choice. Willed actions are
a fundamental component of executive tasks. In normal subjects,
willed acts in two response modalities (speaking a word, or
lifting a finger), relative to routine actions, were associated with
increased blood flow in the DLPFC (Brodmann area 46; Frith
et aI., 1991). Schizophrenic patients typically show abnormalities
of willed behaviour. In chronic patients, intentions of will are no
longer properly formed and so actions are rarely elicited via this
route. This gives rise to behavioural negative signs (e.g. poverty of
speech and action) (Frith, 1992).
In a recent PET study, subjects had to make voluntary joystick
movements in the experimental condition, stereotyped (routine)
movements in the baseline condition, and do nothing in a control
rest condition (Spence et aI., 1998). The authors analysed data
from 13 schizophrenic patients, comparing two occasions when
symptoms were severe and when they had subsided, and included
data from a normal control group to clarify the role of the left
DLPFC in volition. The DLPFC was activated by normal controls
for the free choice task only. However, it was not activated by
schizophrenics with symptoms, but became activated when their
symptoms decreased. The authors noted that the DLPFC was
also activated during the stereotyped joystick movement task in
schizophrenic patients in remission, in contrast to a control group.
Spence and colleagues concluded that, since hypofrontality was
evident in schizophrenics who can perform the experimental task,
the DLPFC is not necessary for that task. In addition, hypofrontality
seems to depend on current symptoms. 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. However, these results provoke
another question. 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. For example, subjects might have to produce a word
beginning with a certain letter, a different letter being presented
every 5 seconds. This can be seen as a task that involves willed
action since subjects have to choose for themselves precisely which
word to say. Verbal fluency tasks engage a distributed brain system
similar to that engaged by motor response selection tasks associated
with willed action (Frith et aI., 1991).
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.,
1996b). However, the lack of frontal activation by cognitive tasks


in schizophrenic patients has not consistently been located in the

PFC. Dolan et al. (1995) and Fletcher et al. (1996) used a factorial
design in PET to test the effect of apomorphine, a non-selective
dopamine agonist, which when given in very low doses as in
this experiment acts primarily on auto-receptors, thus decreasing
the release of endogenous dopamine. Brain systems engaged by
a paced verbal fluency task in unmedicated schizophrenic patients
and normal controls were studied. Activation of the DLPFC was
normal, 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-8.2).
Fletcher and colleagues therefore suggested that schizophrenia is
associated with both segregated (anterior cingulate) and integrative (fronto-temporal)
functional abnormalities. Cingulate activation was restored by low-dose apomorphine in schizophrenics.
Additionally, the abnormal fronto-temporal pattern of activation in
schizophrenic subjects was normalized by this neuropharmacological intervention. Overall, in schizophrenic subjects the effect of
apomorphine was to modify the pattern of brain activity, making
it more similar to that seen in control subjects. The interpretation
of the apomorphine-induced
reversal of the deactivation in the left
temporal lobe in schizophrenic subjects is unclear. It might reflect a
direct influence of apomorphine on the temporal lobe; alternatively
the reversal could be due to a 'downstream' effect of the change in
anterior cingulate function. 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. This is
an important concept, 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.
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., 1995). Using PET, these
researchers investigated rCBF of 18 chronic schizophrenic patients
and six normal controls matched for age, sex and premorbid IQ,
while they performed (a) paced verbal fluency, (b) paced word
categorization and (c) paced word repetition. The schizophrenic
patients were split into three groups according to their verbal
fluency task performance level. All patient groups showed the same
pattern of left PFC activation as control subjects, independent of
their level of performance. However, in the left superior temporal
cortex, all patient groups failed to show a normal deactivation when
verbal fluency was compared with word repetition. Again this result
was interpreted to reflect abnormal functional connectivity between
frontal and temporal cortex.
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), odd (wrong
words) and unimpaired. They used special analytic techniques
to assess cortico-cortical
interactions. Normal controls showed
negative fronto-temporal interactions whereas all the schizophrenic
patients showed positive interactions, mostly between the left PFC
and infero-temporal cortex. Friston and Frith suggested that this
might represent a failure of the PFC to inhibit the temporal
lobes. 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.
Verbal Self-Monitoring
Patients with schizophrenia with auditory hallucinations and delusions show impairments on tasks that require monitoring selfgenerated actions. This is true for motor actions (Frith and Done,
1989; Blakemore et aI., 2000; Frith et aI., 2(00) and verbal selfmonitoring tasks (Johns et at., 2(01). In particular, when patients







'1---!' .,._

. :, :I

...~.. ..

._ ....




Figure XVII-8.2 (a) Statistical parametric maps (SPMs) showing brain regions where there was a significant (p < 0.005) difference in drug
(apomorphine)-task (verbal fluency) interaction between the schizophrenic group and the control group. 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. In other words, the
impaired cingulate activation seen during the verbal fluency task in schizophrenic patients was significantly reversed by apomorphine. (b) Transverse
section showing the verbal fluency task-related deactivation of the superior temporal gyrus that was absent in schizophrenic relative to control subjects.
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. Reprinted from Retcher el al. (1996), with permission from the Journal of Neuroscience

speak aloud but hear a distorted version of their own voice, they
report hearing someone else rather than themselves. Researchers
have recently developed an event-related fMRI acquisition sequence
to scan patients during verbal self-monitoring
paradigms. Fu
et at. (2001) compared brain activation patterns of healthy volunteers, schizophrenic patients with acute psychotic symptoms and
schizophrenic patients in remission while they read adjectives aloud
and heard their voice, which was either undistorted or distorted
(in several ways). Words were read and heard during silent portions of the acquisition sequence to control for the problems of
scanner noise. The hippocampus, cingulate and cerebellum were
particularly activated when healthy controls heard their own distorted voice. Acutely psychotic patients tended to misidentify their
own distorted voice as 'other' and did not engage these regions,
while the pattern of activation in patients in remission was intermediate between the other two groups. This supports the notion that
abnormal brain activity in schizophrenics may be associated with
current symptomatology.


Memory impairments are especially enduring symptoms in schizophrenia (Green, 1996), with memory storage particularly affected
(Feinstein et at., 1998). The DLPFC and the hippocampal formation
have been the subject of investigation in schizophrenia, as these are
involved in various aspects of memory (Goldman-Rakic and Selemon, 1997; Arnold, 1997). The DLPFC is activated by semantic
processing during encoding and retrieval, while hippocampal activation is associated with the detection of novelty and the creation of
associations during encoding in normal individuals (Schacter et at.,
1996; Dolan and Fletcher, 1997).
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., 1994, using a
verbal memory task with SPECT; Ragland et at., 1998, using a

Paired Associate Recognition Test with PET). Other studies have

shown rCBF changes that overlapped in the schizophrenic and
control groups, with a trend towards patients showing smaller
activations than controls in frontal and superior temporal cortical
regions (e.g. Ganguli et at., 1997, using a verbal free-recall
supraspan memory task). These differences may be due to the
different type of memory tasks used by each group. Other groups
have found evidence for hypofrontality during memory tasks. Carter
et at. (1998) used PET to evaluate rCBF associated with the 'Nback' working memory (WM) task, 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. This task activates the PFC as a function of
WM load in normal subjects. Under low WM load conditions, the
accuracy of both groups in the N-back task was equal, but when
the memory load increased the patients' performance deteriorated
more than did that of control subjects. The rCBF response to
increased WM load was significantly reduced in the patients' right
DLPFC. Callicott et ai. (1998) investigated blood oxygen leveldependent (BOLD) signal changes in 10 patients with schizophrenia
and 10 controls performing a novel N-back WM task, using fMRI.
After removing confounds and matching subjects for signal variance
(voxel stability), decreased DLPFC activity and a tendency for
overactivation of parietal cortex were seen. However, these findings
are difficult to interpret in the context of abnormal task performance
in patients. There may be nothing inherently abnormal about the
physiology of the frontal cortex in schizophrenia, but patients may
be failing to select frontally mediated cognitive strategies because
of abnormal connectivity between otherwise normal regions.
Wiser et at. (1998) measured rCBF during a long-term recognition memory task for words in schizophrenic patients and in healthy
subjects using PET. The task was designed so that performance
scores were similar in the patient and control subjects. This memory retrieval task did not activate PFC, precuneus and cerebellum
in patients as much as it did in the control group. This finding


suggests that there is a dysfunctional cortico-cerebellar
circuit in
Hypofrontality has not always been found in studies using
modified tasks to optimize the performance of schizophrenic
subjects. Hypofrontality was not found in a study by Heckers
and colleagues (1998), in which they used PET to evaluate 13
schizophrenic patients and a group of normal control subjects
during memory retrieval tasks. In this study activation of the
PFC correlated with effort of retrieval, and hippocampal and
parahippocampal activation occurred during successful retrieval in
normal control subjects, a finding consistent with previous studies
of memory in normals (Schacter et al., 1996; Dolan and Fletcher,
1997). The schizophrenic patients recruited the PFC during the
effort of retrieval but did not recruit the hippocampus during
conscious recollection. In addition to the task-specific hippocampal
underactivation, the authors observed a generally higher overall
level of non-specific hippocampal activity, supporting previous
metabolic studies (e.g. Liddle et ai., 1992). The authors suggested
that high baseline hippocampal activity together with an absence of
task-specific activation demonstrates abnormal cortico-hippocampal
functional integration in schizophrenia. The schizophrenic patients
showed a more widespread activation of prefrontal areas and
parietal cortex during recollection than controls, and the authors
propose that this overactivation represents an 'effort to compensate
for the failed recruitment of the hippocampus'. 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.
Fletcher et ai. (1998) used PET to compare rCBF in memoryimpaired and non-impaired schizophrenic patients with normal
controls during a parametrically
graded memory task. They
found that DLPFC activity correlates with memory task difficulty and performance in the control group. In contrast, for both
schizophrenic groups DLPFC activity levels plateaued as task difficulty increased, despite a significant difference in performance
between the two schizophrenic groups. The authors therefore suggested that hypofrontality in schizophrenics correlates with task
difficulty rather than task performance, since the memory-impaired
schizophrenic group performed worse than the non-impaired, even
though both groups showed no increase in PFC activity as task
difficulty increased.
Unlike the control group, there was no inferior temporaVparietal
deactivation in either schizophrenic group. The authors suggest that
the lack of deactivation of these areas might represent a temporofrontal disconnection in schizophrenics.
Indeed they suggested
that because temporaVparietal activations were not correlated with
performance, they therefore might represent a core pathology of
schizophrenia. This study improves on previous cognitive activation
studies in which the confound of non-matched task performance
Further evidence for abnormal integration between brain areas in
schizophrenia comes from a study that specifically investigated the
functional integration (Fletcher et ai., 1999). Functional integration
considers complex cognitive processes as emergent properties of
interconnected brain area, building on the idea that simple cognitive
processes can be localized in discrete anatomical modules (referred
to as 'functional segregation').
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, which can be shown empirically by analysis
of covariance. In this case, activity in A might cause activity
in B, or activations in A and B might be caused by changes
in another area (C), which projects to A and B. Alternatively,
areas A and B may be effectively connected if their relationship
can be shown to be causal. This requires a more complex approach
in which the anatomical components of a cognitive system are

defined. 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., 1993).
A simplified version of effective connectivity (Friston et ai.,
1997) was employed by Fletcher et al. (1999) to evaluate effective
connectivity between regions in the data from their PET study
of a graded memory task in schizophrenia. They demonstrated
that in control subjects, but not in the schizophrenic patients,
the product of PFC and anterior cingulate gyrus (ACG) activity
predicted a bilateral temporal and medial PFC deactivation. 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, and this abnormality is due to a
failure of the ACG to modulate the prefronto-temporal
(see Figure XVII-8.3).
There is a body of evidence suggesting that schizophrenic patients
show abnormal interactions and influences among brain regions (or
functional integration) during cognitive tasks. There is currently
little direct evidence in favour of this hypothesis, and several
regions have been found to function abnormally, with no unequivocal evidence for any particular region being involved. However, the
majority of positive findings suggest that a disruption of frontotemporal integration is a core feature of schizophrenia. However,
findings have been confounded by several factors, especially use of
poor control tasks such as rest, and non-matched task performance
in the schizophrenic and control groups. Future cognitive activation
studies using improved methodologies should resolve issues such
as whether abnormal frontal function causes or reflects poor task
performance in schizophrenia. A question of clinical importance is
whether different patterns of cortical interaction correlate with or
predict schizophrenic symptoms or outcome.


Functional neuroimaging is also useful for evaluating neural activity

in patients experiencing psychotic symptoms.

Hallucinations, perceptions in the absence of external stimuli, are
prominent among the core positive symptoms of schizophrenia.
Although auditory hallucinations
are more common than any
other type, hallucinations in other sensory modalities occur in a
proportion of patients. Hallucinations in all modalities tend to be
associated with activity in the neural substrate associated with
that particular sensory modality. However, there is evidence that
activation of the sensory cortex particular to the false perception
is not in itself sufficient for the perception. Instead, research
suggests that the interaction of a distributed cortico-subcortical
neural network might provide a biological basis for schizophrenic

Auditory Hallucinations
The most common type of hallucination in schizophrenia occurs
in the auditory domain, and normally consists of spoken speech
or voices (Hoffman, 1986). Functional neuroimaging studies of
auditory hallucinations suggest that they involve neural systems
dedicated to auditory speech perception as well as a distributed









(f) -2

~ 4-1-4
-3I (b)






Figure XVII-8.3 Left panel: Region of left superior temporal cortex showing a significant difference between control and schizophrenic subjects (p < 0.05).
An SPM rendered onto sagittal and transverse section of a stereotactically normalized structural MRI is shown. Right panel: Graphic representation of
the relationship between activity in left superior temporal cortex (STG; y-axis) and the combination of cingulo-prefrontal activity (PFC x ACG; x-axis in
(a) controls and (b) schizophrenic subjects. The linear best fit is shown for both groups. 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. Thus, in the controls an increase in PFC x ACC produces an
inhibition of superior temporal activity. In the schizophrenic subjects the line slopes upward, indicating the opposite effect. Reprinted from Aetcher et at.
(1999), with permission from Neuroimage

network of other cortical and subcortical areas. There are two

distinct approaches to the study of the physiological basis of auditory hallucinations. The first, called the state approach, asks what
changes in brain activity can be observed at the time hallucinations are occurring. The second, called the trait approach, asks
whether there is a permanent abnormality of brain function present
in patients who are prone to experience auditory hallucinations
when they are ill. This abnormality will be observable even in
the absence of current symptoms.

State Studies
Silbersweig et al. (1995) used PET to study brain activity associated with the occurrence of hallucinations in six schizophrenic
patients. Five patients with classic auditory verbal hallucinations
demonstrated activation in subcortical (thalamic and striatal) nuclei,
limbic structures (especially hippocampus) and paralimbic regions
and cingulate gyri and orbito-frontal cortex).
Temporo-parietal auditory-linguistic
association cortex activation
was present in each subject. One drug-naive patient had visual
as well as auditory verbal hallucinations, and showed activations
in visual and auditoryllinguistic
association cortices. The authors
propose that activity in deep brain structures seen in all subjects may generate or modulate hallucinations, and the particular
sensory cortical regions activated in individual patients may affect

their specific perceptual content. 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, a notion that has received support from several further studies.
David et al. (1996) used fMRI to scan a schizophrenic patient
while he was experiencing auditory hallucinations and again when
hallucination free. The subject was scanned during presentation of
exogenous auditory and visual stimuli, and while he was on and
off antipsychotic drugs. The BOLD signal in the temporal cortex to
exogenous auditory stimulation (speech) was significantly reduced
when the patient was experiencing hallucinating voices, regardless
of medication. Visual cortical activation to flashing lights remained
the same over all four scans, whether the subject was experiencing
auditory hallucinations or not.
A similar result was obtained by Woodruff et al. (l997b), who
used fMRI to study seven schizophrenic patients while they were
experiencing severe auditory verbal hallucinations and again after
their hallucinations had subsided. On the former occasion, these
patients had reduced responses in temporal cortex, especially the
right middle temporal gyrus, to external speech, compared to when
their hallucinations were mild. 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, possibly due to competition for common



Recently, Dierks et ai. (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. Using this design they found that primary auditory
cortex, including Heschl's gyrus, was associated with the presence
of auditory hallucinations. Secondary auditory cortex, temporal lobe
and frontal operculum (Broca's area) were also activated during
auditory hallucinations, supporting the notion that auditory hallucinations are related to inner speech. Finally hallucinations were also
associated with increased activity in the hippocampus and amygdala. The authors suggested that these subcortical activations could
be due to retrieval from memory of the hallucinated material and
emotional reaction to the voices, respectively. A similarly elegant
design was employed in a recent fMRI study (Shergill et ai., 2000).
They found that frontal and temporal speech areas and several other
cortical and subcortical regions were activated during auditory hallucinations.

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, 1992). This was investigated by McGuire et al. (1996). 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)
normal controls. There were no differences between hallucinators
and controls in rCBF during thinking in sentences. However, when
imagining sentences spoken in another person's voice, which entails
both the generation and monitoring of inner speech, hallucinators
showed reduced activation of the left middle temporal gyrus and the
rostral supplementary motor area, regions activated by both normal
subjects and non-hallucinators. Conversely, when non-hallucinators
imagined speech, they differed from both hallucinators and controls
in showing reduced activation in the right parietal operculum (see
Figure XVII-8.4). 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.

Figure XVII-S.4 Difference in rCBF between schizophrenic patients with

a strong predisposition to auditory verbal hallucinations (hallucinators),
schizophrenic patients with no history of hallucinations (non-hallucinators),
and normal controls during tasks that engaged inner speech and auditory
verbal imagery. When imagining sentences spoken in another person's
voice, which entails both the generation and monitoring of inner speech,
hallucinators showed reduced activation of the left middle temporal gyrus
and the rostral supplementary motor area, regions activated by both normal
subjects and non-hallucinators. Adapted from McGuire et al. (1996) (See
Colour Plate XVII-8.4)

dedicated to the particular sensory modality in which the false perception occurs and a widely distributed cortico-subcortical
including limbic, paralimbic and frontal areas. 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.

Visual HallucinatWns
The neural correlates of visual hallucinations
also seem to be
located in the neural substrate of visual perception. At least part
of the activity in the brain associated with the experience of visual
hallucinations is located in the visual cortex. For example, using
SPECT Hoksbergen et al. (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. Howard et al. (1997) used fMRI to investigate the visual cortical response to photic stimulation during and
in the absence of continuous visual hallucinations. When visual
hallucinations were absent photic stimulation produced a normal
bilateral activation in striate cortex. During hallucinations,
limited activation in striate cortex could be induced by exogenous visual stimulation. Similarly, ffytche et ai. (1998) found
activity in ventral extrastriate visual cortex in patients with the
Charles Bonnet syndrome when they experienced visual hallucinations. Moreover, the content of the hallucinations reflected
the functional specialization of the region, for example, hallucinations of colour activated V4 (the human colour centre; Zeki
et ai., 1991).
In conclusion, functional neuroimaging
studies suggest that
hallucinations involve an interaction between the neural systems

Thought Disorder
McGuire et ai. (1998) scanned six schizophrenic subjects with
PET while they described a series of ambiguous pictures, which
provoked different degrees of thought-disordered
speech in each
patient. The severity of thought disorder was correlated with
rCBF across the 12 scans, controlling for differences in the
total number of words articulated. Verbal disorganization (positive
thought disorder) was inversely correlated with activity in the
inferior frontal, cingulate and left superior temporal cortex, areas
implicated in the regulation and monitoring of speech production.
The authors propose that this reduced activity might contribute
to the articulation of the linguistic anomalies that characterize
positive thought disorder. Verbal disorganization
was positively
correlated with activity in the parahippocampaUanterior
region bilaterally, which may reflect this region's role in the
processing of linguistic anomalies.

Passivity Symptoms
Spence et ai. (1997) performed
had to make voluntary joystick

a PET study in which subjects

movements in the experimental




with using psychiatric patients as controls. There is the question
of which psychiatric population should be used. Should they be
taking the same medication, 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. Therefore, comparing schizophrenic
with depressed patients, for example, may reveal activity specific
to depression or to schizophrenia.

Figure XVII-8.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., 1997). When patients were in
remission, and no longer experienced passivity symptoms, a reversal of this
hyperactivation of parietal lobe was seen. Hyperactivity in parietal cortex
might reflect the patient's experiencing the movement as 'unexpected,' as
if it were being caused by some external force

condition, and stereotyped (routine) movements in the baseline

condition, and do nothing in the rest condition. They investigated a
group of schizophrenic patients with passivity (delusions of control) and without (the same group in remission), and a group
of normal controls. Schizophrenic patients with passivity showed
hyperactivation of inferior parietal lobe (BA 40), the cerebellum
and the cingulate cortex relative to schizophrenic patients without
passivity (see Figure XVII-8.5). Similar results were found when
schizophrenic patients with passivity were compared with normal
controls. A comparison of all schizophrenics with normal controls revealed hypofrontality in the patients. When patients were in
remission, and no longer experienced passivity symptoms, a reversal of the hyperactivation of parietal lobe and cingulate was seen.
Hyperactivity in parietal cortex may reflect the 'unexpected' nature
of the experienced movement in patients, as though it were being
caused by an external force.



It is important that patients are matched to the control group on

as many factors as possible, but the best way to match IQ and
education level is uncertain. It is not clear whether the control
group's education level should be matched to the patient's parental
or premorbid education level. However, both of these are superior
to matching controls to patients' current IQ level, which may be
considerably impaired by illness.
Another question is whether the control group should be normal
or psychiatric. Normal controls are important in order to establish
a baseline model of the neural circuitry involved in an experimental task. However, there are several problems with using nonpsychiatric controls. These include the fact that normal controls are
not taking medication, hospitalized or affect-flattened, factors that
might cause the patients to be more or less motivated, to attend or
think more or less, or that might have a direct effect on rCBF. Since
psychiatric patients will be more matched on these factors they may
be a preferable control group. However, there are also problems


As has been discussed at length throughout this chapter, there

is a conceptual problem with applying the approach of cognitive
activation studies to patient groups. 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. Any difference in brain activity
between the two groups could represent a critical abnormality
in schizophrenia
and might cause poor task performance, or
alternatively it might reflect poor performance. It is difficult to
distinguish these two alternatives. Recent studies have employed
tasks on which performance of the patient and control group is
matched. However, 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. 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, the functional significance of that activation is difficult
to understand - it is clearly not necessary for performing the
task. The most obvious interpretation is that patients and controls
are using different strategies to achieve similar task performance.
Therefore, 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, and remain when interpreting
data from studies in which task performance of patient and control
groups is matched.


Schizophrenia is a heterogeneous illness, comprising a variety of

different symptoms. Using groups of patients defined by diagnosis (schizophrenia) may explain the inconsistent and equivocal
results of functional imaging studies, since each symptom may be
associated with a different brain pattern or functional abnormality.
Attempts have been made to correlate cognitive brain activity with
specific symptoms or clinical signs. However, as reviewed here, the
results are inconsistent.
A clear advantage of using symptom-specific
groups is that the control group can comprise people with a
diagnosis of schizophrenia,
who are thus matched in terms of
medication and hospitalization, but who do not have a particular
symptom. Better still, 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., 1998). However,
a clear shortcoming of using symptom-specific groups is that little
can be discovered about schizophrenia as a syndrome.



Although there has been no specific, replicated finding peculiar

either to the syndrome of schizophrenia or to a particular symptom,
there have been repeated findings of frontal and temporal abnormalities in schizophrenia, in both resting metabolism and cognitive activation studies. PET and SPECT studies have shown that the density

of OA (in particular 02) receptors is increased in schizophrenic
brains, and that typical antipsychotic drugs bind mainly to 02 receptors whereas atypical anti psychotics bind mainly to 5-HT receptors.
It is becoming increasingly evident from PET and fMRI studies that
schizophrenic patients show abnormal interactions between brain
regions during cognitive tasks. There is currently little direct evidence in favour of the hypothesis of functional disconnection, and
several regions have been found to function abnormally, but with no
unequivocal evidence for the consistent involvement of any particular region. However, the majority of positive findings suggest that a
disruption of cortico-cortical (and corti co-subcortical) integration is
a core feature of the schizophrenic syndrome. Future studies would
do well to investigate this possibility, using methods of evaluating
functional or effective connectivity to evaluate the influence of one
brain region over another.

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