Schizophrenia Research 53 (2002) 45±56

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De-coupling of cognitive performance and cerebral functional response during working memory in schizophrenia. Garry D. Honey a,b, Edward T. Bullmore b, Tonmoy Sharma a,* b

a Section of Cognitive Psychopharmacology, Institute of Psychiatry, London SE5 8AF, UK Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK

Received 14 July 2000; accepted 15 December 2000

Abstract Working memory dysfunction is considered to be fundamental to the cognitive and clinical features evident in schizophrenia. Functional neuroimaging studies have begun to elucidate the neurobiological basis of such de®cits, however, interpretation of these studies may be confounded by performance impairment, when the cognitive load exceeds the limited response capacity of patients with schizophrenia. In this study, patients were pre-selected on the basis of intact performance on a relatively low-load verbal working memory task, in order to mitigate against performance confounds. Subjects included 20 right-handed male subjects with chronic schizophrenia, and 20 right-handed, age-matched, male healthy controls, without personal or familial psychiatric history. All subjects underwent fMRI scanning whilst performing a verbal n-back task. There were no signi®cant between-group differences in target identi®cation; the patient group showed a signi®cantly increased mean response latency. Both groups demonstrated robust fronto-parietal activation. In the control subjects, the power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex, however, this coupling of behavioural performance and cerebral response was not evident in the patients. This de®cit, apparent within the performance capacity of the patients, may represent a fundamental abnormality in schizophrenia, and may compromise performance at higher cognitive loads. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Reaction time; Phonological storage; Working memory; Cognition; Functional magnetic resonance imaging (fMRI)

1. Introduction Working memory is conceptualised as a dynamic information processing system, which is central to numerous higher cognitive processes (Jonides, 1995). Dysfunction of working memory is therefore thought to have important implications for the * Corresponding author: Institute of Psychiatry, Section of Cognitive Psychopharmacology, Department of Psychological Medicine, De Crespigny Park, London, SE5 8AF, UK. Tel.: 144-20-78480528; fax: 144-20-7848-0646. E-mail address: [email protected] (T. Sharma).

conceptualisation of disparate cognitive de®cits, and has been associated with several pathological conditions involving impaired cognitive processing, including Alzheimer's disease (Morris, 1994), Parkinson's disease (Dalrymple-Alford et al., 1994) and schizophrenia (Green, 1996; Goldman-Rakic, 1990). De®cits of working memory have been shown to be prevalent in schizophrenia (Weinberger and Cermak, 1973; Goldberg et al., 1987; Park and Holzman, 1992, 1993; Fleming et al., 1995, 1997; Gold and Weinberger, 1995; Gold et al., 1995; Keefe., 1995; Condray et al., 1996; Green, 1996; Morris et al., 1997; Granholm et al., 1997; Park and McTigue, 1997; Spindler et al.,

0920-9964/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(01)00154-2

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G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56

1997), and also ®rst-degree asymptomatic relatives (Conklin et al., 2000. There is also evidence of disproportionate impairment of working memory in the context of other domains of cognitive dysfunction (Saykin et al., 1991, 1994), and prognostic implications of such de®cits in psychosocial rehabilitation programs (Green, 1996). The physiological basis of working memory is therefore considered to be fundamental to pathophysiological mechanisms of schizophrenia (Goldman-Rakic, 1987, 1994; Cohen and Servan-Schreiber, 1992; Weinberger, 1993). Functional neuroimaging has been utilised to characterise the neurobiological basis of working memory de®cits in schizophrenia, and several studies have demonstrated functional hypofrontality during the performance of working memory tasks (Carter et al., 1998; Callicott et al., 1998; Stevens et al., 1998). However, using parametric grading of cognitive load, Fletcher et al. (1998) and Manoach et al. (1999) have shown that patients exhibit normal frontal activation in response to working memory tasks, until the physiological capacity of the prefrontal cortex to respond to task-related requirements is exceeded by the cognitive load. Parametric studies of working memory may therefore reconcile discrepant ®ndings of hypofrontality in schizophrenia, indicating that the hypofrontal response variably reported in schizophrenia is not a static phenomenon, but dynamically related to task requirements. However, interpretation of functional de®cits at cognitive loads which exceed performance capacity is unclear, as one cannot determine whether the abnormal functional response represents an intrinsic de®cit related to physiological dysfunction associated with the illness, or is more simply a consequence of impaired task performance (Price and Friston, 1999). We have previously demonstrated in healthy volunteers, that prolonged response latency to a verbal working memory task, and as a corollary, increased temporal duration of active storage of the memoranda, correlates with functional activation of the posterior parietal cortex bilaterally (Honey et al., 2000). This is compatible with previous work which has localised phonological storage to this region (Paulesu et al., 1993; Jonides et al., 1998). In this study, we have applied this approach to investigate the neural correlates of working memory performance in patients with schizophrenia. Patients were selected on the basis of

intact working memory performance at a relatively low level of cognitive load, in order to mitigate against problems of interpretation in the context of impaired performance. Patients were predicted to show increased response latency, as this is strikingly replicated across cognitive studies (Nuechterlein, 1977; Nuechterlein and Dawson, 1984), thus facilitating investigation of the relationship between phonological storage and cognitive activation in schizophrenia. 2. Methods 2.1. Subjects and study design A group of 20 right-handed male patients with chronic schizophrenia were recruited for the study, selected on the basis of high percentage of correct target identi®cation during a verbal working memory task. Symptoms were rated at the time of the experiment using the Positive and Negative Symptom Scale (PANSS;Kay et al., 1987); mean scores of the PANSS positive, negative and general psychopathology subscales were 10.2 (^1.1), 15.0 (^7.9) and 26.9 (11.2). Mean duration of illness was 11.8 (^7.3) years, with a mean age of onset of 22.7 (^5.91) years. All patients were receiving stable doses of typical antipsychotic drugs for at least one month prior to participation (299.4 ^ 177.63 chlorpromazine equivalent mg/day); they had no history of neurological disease or alcohol or other substance abuse in the preceding 6 months. Recent substance use was additionally excluded by urine analysis. A group of 20 right-handed males with no history of neurological or psychiatric disease, were recruited by advertisement from the local community in South East London (previously reported in Honey et al., 2000). There was no signi®cant difference between patient and comparison groups in age (group means ˆ 34.6 (^6.6) and 39.3 (^13.6) respectively (t-test: t ˆ 1.41; df ˆ 38; P . 0.05). Written informed consent was obtained from all participants. The study was approved by the Bethlem Royal and Maudsley Hospital (Research) Ethical Committee. 2.2. Verbal working memory task We used a blocked periodic BA design to activate brain regions specialised for executive and active maintenance components of verbal working memory,

G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56

as originally described by Cohen et al. (1994). Two contrasting conditions were visually presented in 30 s epochs to subjects via a prismatic mirror as they lay in the scanner. During each epoch of the baseline (B) condition, subjects viewed a series of 13 letters, which appeared one at a time with inter-stimulus interval (ISI ˆ 2.3 s), and were required to press a button with their right index ®nger when the letter `X' appeared. During each epoch of the activation (A) condition, subjects again viewed a series of 13 letters (ISI) ˆ 2.3 s, and were required to press a button with their right index ®nger if the currently presented letter was the same as that presented two trials previously (e.g. G-D-G, but not R-L-F-R or TT). The two conditions were matched for number of target letters presented per epoch ˆ 2 or 3. Five cycles of alternation between conditions were presented in the course of each 5 min experiment; the baseline condition was always presented ®rst. Subject performance on both tasks during scanning was monitored in terms of reaction time to target letters and accuracy (number of target letters correctly identi®ed). All subjects received identical training in task performance prior to scanning. Subjects also participated in two other 5 min experiments during the scanning session (to be reported elsewhere); in order to minimise the potential confounding effect of task order, the tasks were pseudo-randomised. 2.3. Functional MRI 2.3.1. Image acquisition Gradient-echo echoplanar MR images were acquired using a 1.5 Tesla GE Signa System (General Electric, Milwaukee WI, USA) ®tted with Advanced NMR hardware and software (ANMR, Woburn MA, USA) at the Maudsley Hospital, London, UK. In each of 14 non-contiguous planes parallel to the intercommissural (AC-PC) line, 100 T2*-weighted MR images depicting BOLD contrast were acquired: TE ˆ 40 ms, TR ˆ 3 s, in-plane resolution ˆ 3.1 mm, slice thickness ˆ 7 mm, slice skip ˆ 0.7 mm. 2.3.2. Activation mapping Following estimation and correction of movementrelated effects in each fMRI time series (Bullmore et al., 1999a), the power of periodic signal change at the (fundamental) BA frequency of stimulation was

47

estimated by sinusoidal regression (Bullmore et al., 1996). The standardised power of functional response at BA frequency (or fundamental power quotient, FPQ) was estimated at each voxel and represented in a parametric map. Each observed fMRI time series was then randomly permuted 10 times, and FPQ reestimated after each permutation. This resulted in 10 parametric maps (for each subject at each plane) of FPQ estimated under the null hypothesis that FPQ is not determined by experimental design. All parametric maps of FPQ were registered in the standard space of Talairach and Tournoux (1988) and smoothed with a 2D Gaussian ®lter (full width half maximum ˆ 7 mm). Voxels demonstrating signi®cant power of response over all 20 subjects were then robustly identi®ed by computing the median value of FPQ at each intracerebral voxel of the observed parametric maps (total search volume V ˆ 19,858 voxels) and comparing it to the permutation distribution of median FPQ obtained from the permuted parametric maps (Brammer et al., 1997). The voxelwise one-tailed probability of false positive activation was P ˆ 0.00005; the expected number of false positive test was less than 1. Generically activated voxels were coloured and superimposed on the grey scale Talairach template, to create generic brain activation maps (GBAMs). To estimate the difference between the comparison and schizophrenic groups in the mean power of response to the working memory condition, we ®tted the following analysis of variance (ANOVA) model, at the ith voxel generically activated by the activation condition in one or both of the groups: FPQi;j;k ˆ mI 1 b1 Gj 1 ei;j

…1†

where FPQI,j,k is the standardised power of response in the kth individual in the jth group; G is a factor coding group membership for each subject, and e i,j is an error term. The null hypothesis of zero between-group difference in the mean fundamental power quotient was tested by comparing the observed coef®cient to critical values of its nonparametrically ascertained null distribution. To do this, the elements of G were randomly permuted 10 times at each voxel, b 1 was estimated after each permutation, and these estimates were pooled over all intracerebral voxels in standard space to sample the permutation distribution of b 1. Critical values for a two-tailed permutation test of

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G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56

Fig. 1. Generic brain activation maps. The four maps to the left show the main brain regions activated by the verbal working memory task. The map at far right shows the linear relationship between functional response and reaction time observed bilaterally in posterior parietal cortex (BA 40). The distance above the intercommissural line in the standard space of Talairach and Tournoux is given in millimetres below each map; following radiological convention, the right side of the brain is shown on the left side of each map.

size a ˆ 0.01 were the 100 £ (a /2) and 100 £ (1 2a / 2)th percentiles of this distribution (Edginton, 1980; Bullmore et al., 1999b). Note that this uncorrected probability threshold was used to identify differentially activated voxels only within the restricted search volume of voxels generically activated by the activation condition of each task in one or both groups. To examine the relationship between power of functional response and mean reaction time (RT), we ®tted the following linear model at each intracerebral voxel of the observed FPQ maps: FPQi;j ˆ mi 1 b1 RT1j 1 b2 RT2j 1 b2 A j 1 ei;j …2† Here FPQi,j is the power of response by the jth

subject at the ith voxel; mi is the overall mean at the ith voxel; RT1j, and RT2j are, respectively, the mean reaction times for the activation (working memory) condition and baseline (`look for X') conditions; Aj is the age of subject j, and e i,j is an error term. The null hypothesis that b 1 ˆ 0 was tested by permutation at all generically activated voxels with two-tailed P ˆ 0.005 (Bullmore et al., 1999b; Edginton, 1980. To examine the form of the relationship between functional response and reaction time in greater detail, we also estimated regional mean power, by averaging FPQ observed at an index voxel and its eight nearest neighbours in 2D, for the following ®ve regions (with x, y, z co-ordinates (mm) in standard space in

G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56

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parentheses): right and left posterior parietal cortices (35, 24,37 and 243, 253,37) and supplementary motor area (SMA) (0,6,48), (co-ordinates identi®ed on the basis of localisation of regions demonstrating a correlation between reaction time and functional response, as shown in Fig. 1), and bilateral dorsal prefrontal cortices (48,8,37 and 2 43,17,26) (coordinates identi®ed from prefrontal regions generically activated by the task in the healthy volunteers; see Table 1). Locally weighted regression lines were superimposed on scatterplots of these data against reaction time to assess possible non-linearities in the form of the reaction time-response relationship.

P ˆ 0.006). For the control condition, reaction times ranged from 0.34 to 0.72 s (mean ˆ 0.48 (^0.1)) in the control group, and 0.44±0.76 (mean ˆ 0.57 (^0.1)) in the patient group, which was signi®cantly different between groups (t-test: t ˆ 23.36; df ˆ 38; P ˆ 0.002). For both the experimental and control conditions, there was no correlation between age and reaction time or task accuracy, or between task accuracy and reaction time in either the patient or control groups (P . 0.05).

3. Results

3.2.1. Generic brain activation map A signi®cant response during the working memory condition was observed in a distributed cortical network similarly in both patient and control groups, comprising bilateral parietal and occipito-parietal cortex (extending through the supramarginal gyrus (Brodmann's area (BA) 40), angular gyrus (BA 39) and precuneus (BA 7)), bilateral (predominantly left sided) dorsolateral prefrontal cortex (BA 9, 10 and 46), inferior frontal gyrus (BA 44, 45), lateral premotor cortex (BA 6), pre-central gyrus (BA 4), ventral occipital cortex (fusiform, lingual and inferior/middle occipital gyri (BA 18, 19, 37)) and the cerebellum. Midline structures showing signi®cant response included the SMA (BA 6), and anterior cingulate gyrus (BA 24, 32). Signi®cant responses during the

3.1. Verbal working memory performance All subjects correctly identi®ed all target stimuli in the control task, and performed the working memory task with a high degree of accuracy; there was no signi®cant difference in the mean number of targets correctly identi®ed by patients and control groups (10.2 (^1.1) and 10.65 (^0.67) targets respectively) (t-test: t ˆ 21.6; df ˆ 38; P . 0.05). For the working memory condition, reaction times ranged from 0.36 to 0.72 s (mean ˆ 0.56 (^0.11)) in the control group, and 0.44±0.93 (mean ˆ 0.67(^0.14)) in the patient group, which was signi®cantly different between groups (t-test: t ˆ 22.92; df ˆ 38;

3.2. Functional MRI

Table 1 Main regional foci of generic brain activation in control subjects Region

Posterior parietal cortex/ Precuneus Dorsolateral prefrontal cortex and Inferior frontal gyrus

BA

40/39/7/19 9/44 46/10 6/32 6 4

SMA/anterior cingulated Lateral premotor cortex Pre-central Gyrus Extrastriate cortex Cerebellum

L/R

±

18 18

No. of voxels

Talairach co-ordinates x

y

470

235

253

37

L

48

243

17

26

R Med L R L L R R

5 54 16 23 19 40 16 7

35 0 243 32 220 235 235 26

47 8 26 28 214 272 264 269

15 48 42 53 53 213 213 218

L/R

z

50

G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56

Table 2 Main regional foci of generic brain activation in patients Region

BA

L/R

No. of voxels

Talairach co-ordinates x

Posterior parietal cortex/ Precuneus Dorsolateral prefrontal cortex and Inferior frontal gyrus

40/39/7/19 9/44

SMA/anterior cingulate Lateral premotor cortex Extrastriate cortex Cerebellum

L/R

±

46/10 6/32 6 18 18

y

z

259

26

264

42

L

22

249

11

31

R Med R L R R

35 24 16

52 6 46

14 7 8

26 42 37

7 5

3 35

269 267

26 218

baseline condition were observed in the medial frontal lobe (BA 8, 10) and the left post-central gyrus (BA 43). Talairach co-ordinates and other details for these regional foci of activation are given in Tables 1 and 2; selected slices of the GBAM are shown in Fig. 1. 3.2.2. Between-group comparison of power of periodic response Analysis of variance was used to test the null hypothesis of zero between-group difference in the mean fundamental power quotient at each voxel generically activated in one group or both. The null hypothesis was tested at 948 voxels that were signi®cantly activated in one or both of the generic brain activation maps, with probability of type I error for each test at a ˆ 0.01. For a test of this size, and with an assumption of independent, we expect no more than 10 false positive voxels over the search volume

under the null hypothesis. In total, only three voxels demonstrated a signi®cant difference in mean FPQ, thus demonstrating no statistically signi®cant difference between the groups. 3.2.3. Reaction time-response relationship In the control group, there was a signi®cant linear effect of reaction time for the working memory condition on power of functional response at 55 voxels in total: search volume ˆ 1060 voxels, P ˆ 0.005, expected number of false positive tests ˆ 5. This relationship between reaction time and functional response was evident in posterior parietal cortex bilaterally (BA 40), (x, y, z co-ordinates: 35, 2 44,37 and 243, 2 53,37), and SMA (0,6,48); (see Fig. 1). There was no evidence from this voxel level analysis for a signi®cant reaction time-response relationship in the patient group. A signi®cant linear effect of reaction time for

Table 3 Multiple regression values for regional analysis of behavioural-functional relationships. **P , 0.01; *P , 0.05 Independent variables 1

Dependent variable

2

Twoback RT Twoback RT Twoback RT a Twoback RT a Twoback RT a a

3 a

Control condition RT Control condition RT a Control condition RT a Control condition RT a Control condition RT a

a

Age Age a Age a Age a Age a

Right posterior parietal cortex Left posterior parietal cortex Supplementary motor area Left prefrontal cortex Right prefrontal cortex

Model goodness of ®t statistics F

df

Adjusted r 2

P-value

6.64 10.895

1,19 1,19

0.229 0.342

0.019* 0.004** n.s n.s n.s

Excluded by stepwise regression; n.s., non-signi®cant (all variables excluded by stepwise regression); RT ˆ reaction time.

G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56 51

Fig. 2. Scatterplots of regional mean power of activation against working memory reaction time in bilateral posterior parietal cortex, dorsolateral prefrontal cortex and SMA in the control group. A linear effect of reaction time on the power of functional response is observed bilaterally in posterior parietal cortex (dotted line); solid lines show results of locally weighted regression.

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the working memory condition in the control group on the power of functional response in bilateral posterior parietal cortex was con®rmed at a regional level, whereas reaction time for the control task was excluded in a stepwise multiple regression model (Table 3). There was no signi®cant linear effect of reaction time for either condition on regional measures of frontal fMRI response. Scatterplots of regional mean power of activation against reaction time (Fig. 2) con®rm the lack of a strong relationship between prefrontal response and reaction time. The dif®culty-response relationship for posterior parietal cortex bilaterally is linearly signi®cant, but locally weighted regression highlights a degree of nonlinearity: power of parietal response is disproportionately increased in subjects with mean reaction times greater than 0.5 s. Fig. 3 illustrates the absence of a relationship between RT and functional response in the patient group in both frontal and parietal regions. Statistical comparison of the observed correlation coef®cient r, between reaction time and functional response in parietal cortex, using Fisher's ztransformed r values, indicated that the correlation was signi®cantly different between patients and controls in both left and right parietal cortex using a one-tailed comparison at P ˆ 0.05 (z ˆ 1.75 and 1.6, respectively). 4. Discussion In this study patients with schizophrenia demonstrated a de-coupling of the relationship between response latency and posterior parietal activation evident in controls during the performance of a verbal working memory task. The absence of this relationship in schizophrenic patients is intriguing, as the patients exhibited normal task accuracy and robust parietal activation; also increased mean response latency to the working memory task was observed in the patients, with a similar dispersion of reaction times compared to controls, thus increased parietal activation might have been predicted from the control data. Increased response latency was observed in the patient group for both the working memory and control conditions. The increased reaction time was therefore not speci®c to working memory, consistent

with previous studies which indicate that increased reaction time in schizophrenic patients is generalised across a wide range of cognitive tasks (Nuechterlein, 1977; Nuechterlein and Dawson, 1984). Response latency has been shown to be related to severity of psychotic symptoms (Vinogradov et al., 1998) and to be predictive of acute (Zahn and Carpenter, 1978) and chronic (Cancro et al., 1971) clinical outcome. All patients in the study were receiving typical neuroleptics, however, this is unlikely to have in¯uenced response latency: increased reaction times have been reported in schizophrenic patients long before the introduction of antipsychotics to clinical practice in the 1950s (Shakow and Huston, 1936; Huston et al., 1937), and have been demonstrated in unmedicated patients (Braff and Saccuzzo, 1982) and asymptomatic ®rst-degree relatives (Maier et al., 1994; Conklin et al., 2000). Delayed reaction time is therefore considered to be of fundamental importance in schizophrenia, and suggested to re¯ect generalised reduced processing speed (Brebion et al., 1998), distinct from that evident in normal ageing (Schatz, 1998). The present study included patients pre-selected on the basis of intact working memory performance in a task requiring storage of two items in the memoranda. The ®nding of no signi®cance between group differences in these data thus concurs with Fletcher et al. (1998) and Manoach et al. (1999) in observing robust functional response in response to a task within the performance capacity of the patients, and thus supports the implication from these studies that hypofrontality under certain conditions may relate to performance capacity being exceeded in patients. This study also extends these ®ndings, demonstrating that even at a cognitive load which is within the performance capacity of the patients, and at which robust fronto-parietal activation is observed to be comparable to that of healthy volunteers, the functional reserve in the parietal cortex associated with increased response latency evident in controls, is absent in schizophrenic patients. The implications of this ®nding are necessarily speculative at this stage, however this may indicate a primary dysfunction of phonological storage in working memory dysfunction in schizophrenia. It is also possible that this may be related to, or even predictive of, performance failure apparent at higher cognitive loads, and the associated attenuation of prefrontal response. Granholm et al.

G.D. Honey et al. / Schizophrenia Research 53 (2002) 45±56 Fig. 3. Scatterplots of regional mean power of activation against working memory reaction time in bilateral posterior parietal cortex, dorsolateral prefrontal cortex and SMA in the patient group. No correlation observed between reaction time and the power of functional response in any of the regions examined in the controls.

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(1997) have used measurements of task-evoked pupillary responses as a psychophysiological index of processing overload. They found that during presentation of digits for subsequent delayed recall, schizophrenic patients showed reduced increases in pupil size at high, but not low cognitive loads, in comparison to healthy volunteers. They interpret this ®nding as evidence of reduced storage capacity in the phonological loop slave system, as during presentation of the digits, it is unlikely that suf®cient time is available to engage in signi®cant active manipulation, requiring activation of executive control mechanisms. In support of this qualitative distinction, reduced increases in pupillary size were evident in response to all cognitive loads during the delay phase. Irrespective of the interpretation of the failure of the reaction time/parietal response relationship in patients observed in this study, these ®ndings also have implications generally for functional imaging studies in schizophrenia. Regional activations observed in schizophrenic patients, even in the context of intact performance capacity, may represent different cognitive/physiological processes than might be inferred from functional responses in healthy controls. This may conceivably re¯ect compensatory changes in cognitive strategy, pharmacological effects of anti-psychotic medication, or pathological effects of symptomatology; it is not possible from this study to distinguish between these potential explanations. Clearly, a direct comparison of functional imaging data between patient and control groups may not be straightforward. In conclusion, the present study has extended the ®ndings of functional imaging studies characterising the neurobiological basis of working memory performance in patients with schizophrenia. These ®ndings may provide some indication as to the mechanism of working memory dysfunction in schizophrenia, and further suggests that simple between-group comparisons involving patients with schizophrenia and healthy volunteers may potentially be complicated by changes in the relationship between behavioural performance and functional activation in schizophrenia.

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