Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: Evidence from event-related fMRI

www.elsevier.com/locate/ynimg NeuroImage 35 (2007) 1551 – 1561

Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: Evidence from event-related fMRI Henrik Walter, a,⁎ Nenad Vasic, b Annett Höse, b Manfred Spitzer, b and Robert Christian Wolf b a

Department of Psychiatry, Friedrich Wilhelms University, Bonn, Germany Department of Psychiatry, University of Ulm, Germany

b

Received 14 September 2006; revised 19 November 2006; accepted 5 January 2007 Available online 12 February 2007

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including the lateral prefrontal cortex, superior temporal areas and the striatum. However, less is known about the relationship of WM-dysfunction, cerebral activation, task-accuracy and diagnostic specificity. Using a novel WMtask and event-related functional magnetic resonance imaging (fMRI), we studied healthy control subjects (n = 17) and partially remitted, medicated inpatients meeting DSM-IV criteria for schizophrenia (n = 19) and major depressive disorder (n = 12). Due to the eventrelated technique, we excluded incorrectly performed trials, thus controlling for accuracy-related activation confounds. Compared with controls, patients with schizophrenia showed less activation in frontoparietal and subcortical regions at high cognitive load levels. Compared with patients with depression, schizophrenic patients showed less prefrontal activation in left inferior frontal cortex and right cerebellum. In patients with schizophrenia, a lack of deactivation of the superior temporal cortex was found compared to both healthy controls and patients with depression. Thus, we could not confirm previous findings of impaired lateral prefrontal activation during WM performance in schizophrenic patients after the exclusion of incorrectly performed or omitted trials in our functional analysis. However, superior temporal cortex dysfunction in patients with schizophrenia may be regarded as schizophrenia-specific finding in terms of psychiatric diagnosis specificity. © 2007 Elsevier Inc. All rights reserved. Keywords: Working memory; Schizophrenia; Depression; fMRI; Prefrontal cortex

⁎ Corresponding author. Department of Psychiatry, Divison of Medical Psychology, University of Bonn, Sigmund-Freud-Straße 25, D-53105 Bonn, Germany. Fax: +49 228 287 6097. Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.01.041

Introduction There is convincing evidence that working memory (WM) deficits in schizophrenia are associated with dysfunction of the lateral prefrontal cortex. However, recent data challenged the notion that prefrontal dysfunction can be reduced to the phenomenon of decreased prefrontal activation (Callicott et al., 2000; Manoach, 2003) since several WM studies using functional magnetic resonance imaging (fMRI) also reported increased activation of the prefrontal cortex (Callicott et al., 2000; Manoach et al., 1999, 2000), absent activation differences (Honey et al., 2002; Kindermann et al., 2004; Walter et al., 2003), or even a mixed pattern of regionally increasing and decreasing prefrontal activation (Callicott et al., 2003; Quintana et al., 2003). Several hypotheses have been put forward to reconcile these findings. For instance, the issue of accuracy differences between patients and healthy controls has led to the hypothesis that there might be a left-sided shift in an inverted U-shaped relationship between task demands and prefrontal activation (Callicott et al., 2003; Manoach, 2003). Thus, decreased activation of lateral prefrontal cortex in schizophrenic patients should only be apparent under high task demands associated with reduced performance, whereas normal or even increased prefrontal activation should occur under conditions of moderate or low task demands (Jansma et al., 2004). Furthermore, it has been proposed that prefrontal hyperactivation may be a sign of neural inefficiency, i.e., an attempt to compensate for regional dysfunction by increasing cerebral activation (Callicott et al., 2003; Quintana et al., 2003). An alternative explanation of negative prefrontal findings in patients with schizophrenia would be that the inverted-U seen in some studies, and supported by a recent meta-analysis on WM-related dysfunction in schizophrenia (Van Snellenberg et al., 2006), may occur as a result of the inclusion of incorrect trials. This explanation appears plausible given the fact that a subsequentmemory effect in DLPFC has been shown in healthy subjects performing WM tasks (Rypma and D’Esposito, 2003). Thus, it might be conceivable that if incorrect trials are included in a

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functional analysis, activation of DLPFC should decrease in conditions that are performed more poorly, such as conditions with high cognitive demand in WM or other tasks tapping executive functions. However, the interpretation of previous functional imaging results is further complicated by the fact that WM-tasks commonly employed in schizophrenia research may not be adequately parameterized and that comparisons between patients and controls are confounded by performance differences. Although a few fMRI studies have used extended parametric designs, i.e. more than two load levels (Jansma et al., 2004; Perlstein et al., 2003) an analysis of correct trials was not performed due to the block design paradigms used in previous studies. On the other hand, recent studies controlling performance by analyzing correct trials only (MacDonald et al., 2005) did not include a parametric modulation. Furthermore, only a few functional imaging studies in schizophrenia have addressed the problem of diagnosis-related specificity of WM-dysfunction in distinct psychiatric populations so far (Barch et al., 2003a,b; Hugdahl et al., 2004; MacDonald et al., 2005). Prefrontal dysfunction has also been reported for e.g. patients with major depression (Barch et al., 2003a,b; Hugdahl et al., 2004; Kimbrell et al., 2002). In order to evaluate if prefrontal dysfunction in a given task is common to both disorders (Dolan et al., 1994) or a specific finding in patients with schizophrenia (Barch et al., 2003a,b; MacDonald et al., 2005), the inclusion of a clinical comparison group is a scientific desideratum. In this study, we used the advantages of event-related fMRI to control for the confound of impaired task accuracy within a previously validated parametric verbal WM task (Wolf et al., 2006; Wolf and Walter, 2005) to investigate WM function in patients with schizophrenia compared to healthy controls and to patients with major depressive disorder. We were particularly interested in lateral prefrontal areas and the circuitry involving the lateral prefrontal cortex. Hypothesizing that accuracy differences would emerge at highest cognitive demand, we predicted the following functional findings in patients with schizophrenia compared with healthy controls: (i) no prefrontal activation differences at low load WM demand, (ii) increased prefrontal hyperactivation at moderate load levels associated with comparable or slightly reduced task-accuracy and (iii) clearly impaired task accuracy associated with decreased activation of lateral prefrontal cortex at highest WM-load. Furthermore, we raised the question if dysfunction of the prefrontal cortex would prove to be diagnosis-specific in schizophrenic patients.

Methods Subjects We studied 19 right-handed subjects with schizophrenia (6 females) and a clinical control group of 12 patients with recurrent non-psychotic major depression (4 females) recruited from among the inpatients treated at the Department of Psychiatry at the University of Ulm. Patients were diagnosed according to DSM-IV criteria, excluding subjects with concurrent axis I disorders. To minimize cerebral activation effects associated with poor performance, we included only subjects with an accuracy clearly above chance during performance of the fMRI activation task, which eventually led to the exclusion of four patients (3 males, 1 female). All patients were diagnosed according to DSM-IV-TR criteria, excluding subjects with concurrent DSM-IV axis I disorders. In addition to a detailed interview, conducted by an experienced clinical psychiatrist (A.H.), case notes were reviewed to corroborate the diagnosis of DSM-IV-schizophrenia or major depressive disorder. From the patients with schizophrenia included in the functional analysis (n = 15), 14 were treated with atypical neuroleptics (including clozapine, olanzapine, risperidone, quetiapine and amisulpiride), one patient was drug-naïve and one patient additionally received benperidole. Patients with major depression were taking various types of antidepressive agents including SSRIs, venlafaxine, mirtazapine and tranylcypromine, but not tricyclics. Symptoms were rated by means of the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the 21-item Hamilton Depression Scale (HAMD) and the Montgomery– Asberg Depression Rating Scale (MADRS) (Table 1). The healthy control group consisted of 17 right-handed subjects (8 females) matched for age, education and handedness, excluding subjects with neurological or psychiatric disorder, substance abuse or dependence within the past 6 months. The project was approved by the university’s ethics committee. After complete description of the study to the subjects, written informed consent was obtained. Cognitive activation task The cognitive activation task has been described elsewhere in full detail (Wolf et al., 2006; Wolf and Walter, 2005). In brief, three capital grey letters appeared on a black screen during the stimulus period. One, two or three of these letters would then become highlighted at the end of the stimulus period (Fig. 1). Subjects were

Table 1 Demographics and psychopathology Controls (n = 17)

Age (years) Laterality score a Education (years) Duration of illness (years) Brief psychiatric rating scale score Hamilton depression rating scale score b Positive and negative syndrome scale score Montgomery–Asberg depression rating scale score a b

Schizophrenia (n = 15)

Depression (n = 12)

Mean

SD

Mean

SD

Mean

SD

30.9 83.4 11.8

8.8 21.9 1.5

33.1 92.6 11.2 6.1 47.6 10.5 64.4

6.5 13.5 1.5 5.3 11.4 6.6 16.4

37.2 90.5 12.3 3.1 40.6 18.2

9.0 19.0 3.3 2.9 5.4 3.7

23.6

3.8

As rated by the Edinburgh handedness questionnaire. Significant difference between patient groups (p < 0.05, t-test).

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Fig. 1. Activation paradigm, shown for a trial of load level 2: In the stimulus period, three capital grey letters appeared on a black screen. One, two or three of these letters would then be highlighted at the end of the stimulus period. Subjects were instructed that during the subsequent delay period, they were to focus only on those letters which were highlighted and to memorize the letters which followed them in the alphabet (manipulated set). In the probe period a lower case letter was presented, and subjects had to indicate whether this letter was or was not part of the manipulated set. The control condition displayed three grey X's and required a stereotype button press in response to the presentation of a small x during the probe period.

instructed that during the subsequent 6000-ms delay period they were to focus only on those letters which were highlighted and to memorize the letters which followed them in the alphabet (manipulated set). In the probe period a lower case letter was presented, and subjects had to indicate whether this letter was or was not part of the manipulated set. The control condition displayed three grey X’s and required a stereotype button press in response to the presentation of a small x during the probe period, thus forming a motor task without mnemonic requirements. Data acquisition Data were acquired using a 1.5 T Magnetom VISION (Siemens, Erlangen, Germany) whole-body MRI system equipped with a standard head volume coil. T2*-weighted images were obtained using echo-planar imaging in an axial orientation (TR = 2400 ms, TE = 40 ms, FoV 192 mm, 64 × 64 matrix, 24 slices, slice thickness 4 mm, gap 2 mm). Stimuli were presented via LCD video goggles (Resonance Technologies, Northridge, CA) and both reaction times and accuracy indices were recorded. Head movement was minimized using padded ear phones. The fMRI-protocol was a rapid event-related design with a pseudorandomized time-jitter of 1.5 ± 0.5 TR inter-trial interval. Trial duration was 10 s + 2.4–4.8 s. Stimuli were pseudorandomized and counterbalanced for the relative appearance frequency of each letter per load, highlighted position or target. The task design avoided the appearance of probes from recent negative trials in order to prevent proactive interference during retrieval. All participating subjects were extensively trained prior to scanning by means of a parallel version of the task to ensure optimal adherence to the task’s requirements. Within the scanner, all subjects performed three sessions, each including 28 trials (7 trials per condition), comprising 164 volumes (492 volumes in total). The first 8 volumes of each session were discarded to allow for equilibration effects. Analysis of behavioral data Performance was recorded as percentage of correct responses (accuracy) during target and non-target trials. Reaction times of correct trials were recorded within ms resolution. Repeated measures between-group MANOVAs were performed with the

factor group and load for reaction times and accuracy. Both patient groups were compared to controls and with each other yielding three analyses. Newman–Keuls tests were calculated to explore interaction effects of group × load post hoc. Additionally, we performed hypothesis-driven planned t-tests for accuracy for all working memory conditions, yielding three group comparisons. fMRI data analysis A main functional data analysis excluding incorrectly performed trials was performed with SPM2 (www.fil.ion.ucl.ac. uk/spm/) implemented in MATLAB V6.1 (MathWorks, Natick, MA). Functional images were slice-timed, motion-corrected by realignment to the first volume of each session, spatially normalized to the EPI standard template of 3 × 3 × 3 mm voxels and then spatially smoothed with a 9-mm full-width at half-maximum (FWHM) isotropic Gaussian kernel. Data were analyzed within the framework of the General Linear Model (Friston et al., 1995a,b) using the canonical-hrf-function as a predictor. We modelled the stimulus and probe periods of all loads each as a single regressor. In contrast, delays were modelled for each load (and control) condition separately, as an event of 6 s spanning the whole delay period. Thus, the single-subject design matrix consisted of four delay regressors, one stimulus and one probe regressor. With this model we minimized the degree of event-autocorrelation between the three trial phases (stimulus, delay, and probe). Analyses were performed on two levels: On the 1st level subject specific delay effects of conditions were compared using linear contrasts, resulting in a t-statistic for each voxel (high-pass filter with a cutoff of 137 s, low-pass filter 4 s). 1st level analyses included correct trials only. Omitted and false trials were pooled and used as individual regressor of no interest for each subject. Main effects of load were calculated for the delay period of all four conditions (control and loads 1, 2 and 3). To account for interindividual variance and in order to generalize inferences, we performed analyses of variance (ANOVA) on the 2nd level by using subject-specific delay contrasts for all conditions. For withingroup comparisons we contrasted each load with the control condition. For group-by-condition interactions, we calculated the following contrasts: ([Load − Control condition]controls > [Load − Control condition]patients), ([Loadn+1 − Loadn]controls > [Loadn+1 − Loadn]patients) and vice versa. Group comparisons were made

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separately between patients with schizophrenia and control subjects as well as between patients with schizophrenia and those with depression. In order to reduce data complexity, the functional imaging results of the comparisons between patients with depression and healthy controls were reported and discussed elsewhere (Walter et al., 2006). For further characterization of the relative fMRI-signal increases with increasing load, we extracted mean effect parameters (corresponding to the percent signal change differences) per subject and load at the most significantly activated voxels in the dorsolateral prefrontal cortex (DLPFC) as well as in those temporal cortical regions emerging from the between-group comparisons (Tables 3 and 4). We report all functional imaging results at an a priori significance threshold of p < 0.001 at the voxel level (uncorrected) correcting for extent (p < 0.05 at the cluster level; Forman et al., 1995). Anatomical regions and denominations are reported according to the atlases of Talairach and Tournoux (1988) and Duvernoy (1999). Coordinates are maxima in a given cluster according to the standard MNItemplate. In order to assure that our functional imaging results were not only an effect of the exclusion of incorrectly performed and omitted trials, we performed a supplementary functional data analysis including all trials regardless of the level of task performance. Both 1st and 2nd level analyses were performed in exactly the same way as the main analysis after the inclusion of incorrectly and omitted trials. Results Behavioral results In all three groups, we found increasing reaction times (RT) with increasing load (p < 0.0001). Patients with schizophrenia were slower than healthy controls (F(1,34) = 33.447, p = 0.00001), but did not significantly differ from patients with depression (Table 2). A group × load interaction was not found. For accuracy, we observed a significant linear decline with increasing load in all three groups (p < 0.0001). Patients with schizophrenia performed worse compared with healthy controls (F(1,34) = 8.0683, p = 0.0076) but did not significantly differ from patients with depression. There was no group × load interaction between healthy controls and patients with schizophrenia. T-tests for accuracy revealed the following results: In Load 1, there were no group differences. At load level 2 (L2) patients with depression showed significantly less accurate performance compared to controls (p = 0.03). At load level 3 (L3) patients with schizophrenia (p = 0.0002) as well as patients with depression (p = 0.007) showed significantly less accurate performance com-

pared to controls. There were no significant differences in accuracy at any load level between the two patient groups (p < 0.05). Functional imaging results Main functional data analysis, excluding incorrectly performed trials Load effects within groups. All three groups showed a main effect of WM load-sensitive responses in a widely distributed network including the bilateral DLPFC and ventrolateral prefrontal cortex (VLPFC), premotor cortex, the supplementary motor area, bilateral striatum, cerebellum, and parietal cortex, similar to the findings described by Wolf and Walter (2005) (detailed figures and coordinates available on request). The robust activation found in the DLPFC and the VLPFC of the schizophrenic patient group is further illustrated by Z-scores for the main effects of load (T-values and Z-scores of the control group are given in brackets): right DLPFC: 8.41; 7.36 (7.11; 6.42), left DLPFC: 6.62; 6.05 (7.61; 6.79); right VLPFC: 6.79; 6.18 (6.06; 5.61); left VLPFC 11.40; inf (12.44; inf)—further within-group coordinates and main effects are available on request. Load effects between groups Schizophrenic patients versus healthy controls. There were no differences between groups at load level 1. At load level 2, several regions with relatively more activation were found in patients with schizophrenia, namely in the superior temporal gyrus (STG) and parahippocampal gyrus bilaterally as well as in the right middle and left superior frontal gyrus. At load level 3, controls showed relatively increased activation of the right superior frontal gyrus, bilateral parietal cortex, bilateral striatum and cerebellum. At load level 3, patients with schizophrenia showed relatively increased activation compared to healthy controls in the left STG (Table 3; Fig. 2). As shown by the mean activation size, both groups exhibited a linear activation relationship in the left and right DLPFC with increasing load demand. Task-related relative deactivation of the temporal cortices (relative to the control condition) was present in the healthy control group only (Fig. 3). An interaction effect between group and load [interaction contrast (L3 > L2)controls > (L3 > L2)schizophrenic patients] was found in the right caudate nucleus (x = 21, y = 18, z = −6; Z = 4.58) and regions of the left ventral striatum (x = −21, y = 21, z = −9, Z = 4.46), see also Fig. 4. Schizophrenic patients versus patients with major depression. At load level 1, patients with depression showed relatively increased activation of left inferior frontal gyrus. At load level 2, differences were found only for the comparison schizophrenic patients > patients

Table 2 Task performance Condition

Controls (n = 17) RT

Control Load 1 Load 2 Load 3

Schizophrenia (n = 15) Accuracy

RT

Depression (n = 12) Accuracy

RT

Accuracy

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

612 760 874 1021

174 114 94 153

98.6 93.2 90.9 87.1

4.1 12.6 11.9 13.2

797 960 1084 1187

155 146 127 149

90.2 84.2 83.0 69.4

20.7 16.8 16.9 18.2

693 875 1023 1189

117 133 181 195

98.4 93.2 74.5 70.5

4.2 10.8 26.7 17.6

Reaction time is given in ms, task accuracy in percent of correct responses.

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Table 3 Regions demonstrating load dependent brain activation differences between healthy control subjects and patients with schizophrenia Controls > Schizophrenia Anatomical region

Schizophrenia > Controls x

y

z

Z

Load 2

Load 3

Left putamen Right caudate Right superior frontal gyrus (BA 6) Left superior parietal lobule (BA 7) Right superior parietal lobule (BA 7) Right inferior parietal lobule (BA 40) Left cerebellum Right cerebellum

−15 21 30 −39 24 39 −39 33

12 18 −9 − 78 − 66 − 69 − 75 − 60

−3 3 69 30 60 45 − 24 − 48

4.29 4.37 5.55 4.44 4.21 4.24 4.60 4.11

Anatomical region

x

y

z

Z

Left superior temporal gyrus (BA 38) Right superior temporal gyrus (BA 38) Left parahippocampal gyrus Right parahippocampal gyrus Right middle frontal gyrus (BA 6) Left superior frontal gyrus (BA 8) Left superior temporal gyrus (BA 38)

−42 36 −9 15 48 −15 −39

9 18 − 36 − 36 0 30 9

− 27 − 30 −9 − 12 53 54 − 27

5.0 4.21 5.41 4.54 3.99 4.6 5.12

Results of the between-group ANOVA, p < 0.001 at the voxel, p < 0.05 corrected for spatial extent. x, y and z are Talairach coordinates of the most significant center of activation within a cluster; Z = Z-value; BA = Brodmann Area.

with major depression, namely in the bilateral temporal cortex. At load level 3, the same comparison again yielded relative more activation in the right STG. At load level 3, depressive patients showed increased activation in bilateral inferior frontal gyrus and right cerebellum (Table 4; Fig. 2). An interaction between group and load was not found. As shown by the mean activation size, both patient groups exhibited a linear activation relationship in the left and right DLPFC with increasing load demand. In the temporal cortices taskrelated deactivation was present in the group of depressed patients only (Fig. 3), whereas patients with schizophrenia again failed to show a deactivation pattern. Patients with major depression compared to healthy controls. The result of this comparison are presented and discussed in detail elsewhere (Walter et al., 2006) and therefore not presented in the figures and tables here. Basically, patients with depression showed increased activation of the left DLPFC (BA 46) at high WM load levels. Supplementary functional data analysis, including incorrectly performed trials Load effects within groups. As in our main analysis, all three groups showed a main effect of WM load-sensitive responses in a widely distributed network including the bilateral DLPFC and ventrolateral prefrontal cortex (VLPFC), premotor cortex, the supplementary motor area, bilateral striatum, cerebellum, superior and inferior parietal cortex. Load effects between groups Schizophrenic patients versus healthy controls. There were no differences in brain activation between groups at load level 1. At load level 2, we found relatively more activation in patients with schizophrenia in the superior temporal and parahippocampal as well as in the right middle temporal gyri. At load level 3, we found increased activation of the left superior frontal gyrus, bilateral striatum and bilateral parietal cortex in healthy controls. At this load level, several regions in which patients with schizophrenia showed increased activation compared to healthy controls, namely

in the bilateral STG and in the left MTG. As in our main analysis, which excluded incorrectly performed and omitted trials, all three groups exhibited a linear activation relationship in the left and right DLPFC with increasing load demand. Again, task-related relative deactivation of the temporal cortices was only found in the group of healthy volunteers and in patients with major depression. In contrast, patients with schizophrenia exhibited a pattern of sustained temporal cortical activity throughout load 1 to load 3. An interaction effect between group and load was found in the right caudate nucleus and regions of the left ventral striatum in patients with schizophrenia (Talairach coordinates not shown, available on request). Schizophrenic patients versus patients with major depression. At load level 1, there were no group differences. At load level 2, differences were found only for the comparison schizophrenia > depression, namely in the bilateral temporal cortex, left parietal cortex and right DLPFC. At load level 3, the same comparison yielded again relative more activation in the left STG and right MTG as well as in the right inferior frontal gyrus. At load level 3, depressive patients showed relatively more activation in the left inferior frontal gyrus and right cerebellum. An interaction between group and load was not found (Talairach coordinates not shown, available on request). Discussion In this study, we used a new parametric event-related fMRI task with three load levels to study delay-related WM activity in schizophrenia compared to healthy controls and patients with major depression. Both patient groups showed reduced accuracy and reaction times compared to healthy controls. In patients with schizophrenia, decreased cerebral activation was found in left superior prefrontal cortex, parietal cortex bilaterally and the striatum compared with healthy controls. Compared to patients with depression, schizophrenic patients showed less prefrontal activation in the left inferior frontal cortex and the right cerebellum. In patients with schizophrenia, increased activation of temporal cortex during high cognitive load was found in comparison to both healthy controls and patients with major depression, being the most specific

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Fig. 2. Results of the 2nd-level between group ANOVA for Load 2 and Load 3 (p < 0.001 at the voxel level, p < 0.05 corrected for spatial extent).

finding in or study in terms of diagnosis specificity and consistency over two demanding load levels. Prefrontal findings In our study, patients with schizophrenia did not exhibit significantly reduced activation in DLPFC or VLPFC compared to healthy controls even at the highest load level with significantly reduced accuracy. Thus, at least in this sample, we could not confirm previous findings of impaired lateral prefrontal activation during working memory performance in schizophrenia (Barch et al., 2001, 2003a,b; MacDonald and Carter, 2003; Menon et al., 2001; Perlstein

et al., 2003). However, patients show significantly less activation in left superior frontal cortex (BA 6). Although this can be interpreted as one sign of task related hypofrontality, the main focus of activation was not identified in the typical region of BA 46 which has been hypothesized to be impaired in schizophrenia. In our study, we failed to demonstrate an inverted U-shaped function of lateral prefrontal cortex activation in patients with schizophrenia within the context of both comparable (load level 2) and significantly impaired performance (load level 3) compared with healthy controls. Thus, our results can be interpreted as related to the disease and cannot be simply explained as a correlate of reduced accuracy, adding to and extending earlier findings of equal

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Fig. 3. Mean activation effects (estimated beta parameters) in the dorsolateral prefrontal (BA 9/46) and superior temporal cortex (BA 22/38). Green: healthy control subjects (left frontal: x = − 42, y = 24, z = 24; right frontal: x = 42, y = 39, z = 21; left temporal: x = −42, y = 9, z = − 27; right temporal: x = 36, y = 18, z = −30). Red: patients with schizophrenia (left frontal: x = − 42, y = 27, z = 27; right frontal: x = 39, y = 42, z = 27; left temporal: x = − 42, y = 9, z = − 27; right temporal: x = 36, y = 18, z = − 30). Blue: patients with depression (left frontal: x = − 42, y = 27, z = 21; right frontal: x = 42, y = 39, z = 21; left temporal: x = −45, y = 18, z = − 21; right temporal: x = 33, y = 18, z = − 24). Beta parameters were extracted from the within-group analyses (most significant voxel in DLPFC) and the between-groups analysis (most significant voxel derived from the activation differences between-group), respectively (p < 0.001 at the voxel level, p < 0.05 corrected for spatial extent).

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Fig. 4. Mean activation effects (estimated beta parameters) in the left ventral striatum (x = − 21, y = 21, z = − 9) and right caudate nucleus (x = 21, y = 18, z = −6). Green: healthy control subjects; red: patients with schizophrenia. Beta parameters were extracted from the most significant voxels of the between-groups analysis (p < 0.001 at the voxel, p < 0.05 corrected for spatial extent).

stable after performing a supplementary analysis including both correctly and incorrectly performed trials. Moreover, we additionally performed correlation analyses for both accuracy and RT using a simple regression model (p < 0.005). In healthy controls, we found a positive correlation with task accuracy and frontostriatal regions (as discussed in Wolf and Walter, 2005), while RT was positively correlated with left superior parietal areas. However, we could not demonstrate any significant correlation between accuracy and RT in both patient groups, one explanation being the heterogeneity in brain activation, which has been previously shown in patients with schizophrenia (Manoach et al., 2001). Thus, a methodological effect originating from different functional data analyses cannot sufficiently explain the absence of an inverted U-shaped relationship between cognitive demand and prefrontal activation in patients with schizophrenia. Given the fact that the pathophysiology of schizophrenia cannot be reduced to a pure lesion model, other factors might have contributed to our negative lateral prefrontal findings, e.g. medication status (Honey et al., 1999), duration of illness (Hill et al.,

DLPFC activation even within the context of reduced performance (Honey et al., 1999, 2002; Walter et al., 2003). Furthermore, being a particular methodological strength of this study, our event-related analysis excluded incorrectly performed and omitted trials, thus controlling for potential activation confounds arising from these trials. However, we concede that the absence of an inverted Ushaped relationship of task performance and prefrontal activation in our schizophrenic patients may only reflect that these subjects have not reached their point of an “activation brake-down”. However, accuracy was already worse at load level 3, being only slightly above chance in some subjects, indicating a severe decline in accuracy with highest WM load. A possible explanation of our negative prefrontal findings would be that the inverted U-shaped activation pattern supported by a recent meta-analysis on WM-related dysfunction in schizophrenia (Van Snellenberg et al., 2006), may occur as a result of the inclusion of incorrect trials in the functional analysis. However, our data does not provide evidence for this hypothesis – at least in our studied patient group – given the fact that our main results remained

Table 4 Regions demonstrating load dependent brain activation differences between patients with schizophrenia and those with major depression Schizophrenia > Depression Anatomical region Load 1 Load 2

Load 3

Left superior temporal gyrus (BA 38) Right superior temporal gyrus (BA 38) Left middle temporal gyrus (BA 21) Right superior temporal gyrus (BA 38)

Depression > Schizophrenia x − 45 33 −6 42

y 18 18 −45 15

z − 21 − 24 −6 − 18

Z 3.72 4.58 3.62 3.61

Anatomical region

x

Left inferior frontal gyrus (BA 46)

−45

y 27

z 21

3.41

Z

Left inferior frontal gyrus (BA 46) Right inferior frontal gyrus (BA 47) Right cerebellum

−39 27 36

27 39 − 63

18 − 18 − 42

4.48 3.82 4.71

Results of the between-group ANOVA, p < 0.001 at the voxel, p < 0.05 corrected for spatial extent. x, y and z are Talairach coordinates of the most significant center of activation within a cluster; Z = Z-value; BA = Brodmann Area.

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2004) or genetic influences (Bilder et al., 2004; Egan et al., 2001). However, the particular influence of these factors cannot be sufficiently disentangled from our data. Eventually, it might be speculated if an inverted U-effect may occur during an analysis of incorrectly performed trials only, i.e. under circumstances where capacity constraints become more evident as an effect of increasing cognitive demand. However, this type of analysis may yield less statistical power because it would include less trials with a negative impact of the signal-to-noise ratio of the fMRI signal. With regard to statistical power, it could be argued that the fact that we did not find the expected activation differences of the lateral prefrontal cortex in patients with schizophrenia might be explained by a lack of power due to our sample size, as a few studies demonstrating relatively decreased activation of DLPFC included larger samples (Barch et al., 2003a,b). However, most fMRI studies reporting hypofrontality had comparable (Perlstein et al., 2003) or even smaller sample sizes (Jansma et al., 2004; Menon et al., 2001) than our study. Moreover, the very robust activation in DLPFC and VLPFC is illustrated by Z-scores for the main effects of load within the schizophrenic patient group (see main functional data analysis). Compared to patients with major depression, schizophrenic patients showed reduced left prefrontal activation in the region of BA 46 at load levels 1 and 3 in the presence of comparable task performance (see Table 3). This may be related to the increased prefrontal activation of patients with depression compared to controls. In terms of diagnosis specificity however, we could not confirm recent findings of DLPFC hypoactivation as being specific for patients with schizophrenia but not other psychiatric disorders (Barch et al., 2003a,b; MacDonald et al., 2005), since schizophrenic patients did not show any frontal abnormalities compared with healthy controls, but behaviorally less relevant prefrontal activation changes when contrasted with a different diagnostic group. Temporal findings The between-group comparisons showed relative temporal hyperactivation in patients with schizophrenia for load level 2 and load 3 compared to healthy controls as well as compared to patients with major depression. When analyzing temporal activation in relation to prefrontal activation, healthy controls as well as patients with major depression showed a clear pattern of load-dependent increasing prefrontal activation and decreasing activation of the superior temporal cortex (STC). In contrast, there was no decrease of temporal activation with increasing cognitive load in patients with schizophrenia (Figs. 3 and 4). Influential theoretical concepts have emphasized the role of other brain regions connected to the prefrontal cortex which may account for apparent WM-deficits in schizophrenia. For example, it has been shown that information processing that is subserved by frontotemporal interactions may be impaired (Fletcher et al., 1996; Friston et al., 1995a,b; Frith et al., 1995). Specifically, a frontotemporal imbalance has been described in PET studies: temporal deactivation which was found to accompany frontal activation in healthy controls seems to be absent in patients with schizophrenia (but see Spence et al., 2000) and can be restored via dopaminergic manipulation (Fletcher et al., 1996). Although one fMRI study using a blocked design found evidence for impaired frontotemporal connectivity, fMRI studies on WM using blocked designs usually do not report

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such findings. This may be due to methodological limitations, such as a lack of an adequate non-mnemonic control condition. In our study, activation of temporal cortex in patients with schizophrenia was present in comparison to both healthy controls and patients with major depression. Moreover, these activation differences were found at medium as well as at high load levels in the presence of both comparable and significantly impaired task accuracy compared with healthy controls. We therefore conclude that differences of temporal cortex activation, as seen in our schizophrenic patients, is not only due to task requirements, but may be strongly associated to the disordered condition per se. Being in-line with previous findings on STC-dysfunction (Fletcher et al., 1996; Friston et al., 1995a,b; Frith et al., 1995), we could show that patients with schizophrenia indeed fail to deactivate this region (Fig. 3). One potential explanation for temporal cortex dysfunction in schizophrenia involves attentional processes (O’Leary et al., 1997) associated with function of the temporal lobe. Schizophrenic patients might compensate an inherent WM-dysfunction via STCactivation, possibly through compensatory adaptation to task-related requirements. A failure of STC-deactivation might thus be attributed to impaired attentional processing or to the fact that patients with schizophrenia may use different cognitive strategies to compensate for poor WM performance. The finding that patients exhibit greater activation of medial temporal lobe regions and decreased activation of parietal areas indeed suggests that these patients, at least to some extent, rely on episodic or long-term memory processes (Achim and Lepage, 2005). Adaptation of particular brain regions which are not necessary for WM may occur when task-related capacity is exceeded, or when subjects rely on different cognitive strategies (Honey and Fletcher, 2006; Manoach, 2003). The latter assumption is supported by the fact that differences of temporal lobe activation in our schizophrenic patient group were present at different behaviorally relevant stages of the task, i.e. both under comparable and reduced task accuracy. It is likely however – although not demonstrated in this cross-sectional study – that a failure of STCdeactivation may be related to symptomatic patients and to the diagnosis of schizophrenia, and not to stable traits of this disorder (Spence et al., 2000). Alternatively, a frontotemporal decoupling, as put forward by dysconnectivity-hypotheses (Friston et al., 1995a,b) might be another explanation for STC-activation in our study, although this hypothesis has not been directly tested in this study due to methodological constraints (e.g. due to the temporally closely spaced events). Parietal findings Compared to healthy controls, patients with schizophrenia showed less activation of left precuneus and bilateral parietal cortex. Since activation of BA 40 was present at high load levels only, it is conceivable that this activation differences may reflect task and accuracy relevant processes, probably related to storage and retrieval of verbally encoded information (Jonides et al., 1998). Thus, differences in this region in patients with schizophrenia compared with healthy controls may be associated with strategic differences in order to face the task’s cognitive requirements, since abnormal activation of the parietal cortex has been previously demonstrated (Walter et al., 2003). However, a few studies have also demonstrated increased parietal hyperactivation, which has been interpreted as a com-

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pensatory activation in the presence of decreased prefrontal activation (Hugdahl et al., 2004; Quintana et al., 2003). Since the interpretation and comparison of previous studies is complicated by the fact of different task-designs, differences in parietal activation remain a less clear issue being necessarily object of further investigation. It is important to emphasize though, that in our study decreased parietal activation was found only in patients with schizophrenia when compared to healthy controls and not when comparing both patient groups. Thus, parietal dysfunction in schizophrenic patients should be cautiously interpreted, at least in terms of diagnostic specificity. Striatal findings The role of frontostriatal loops in cognitive functions is well established (Houk, 1997). It has been argued that in analogy to motor tasks activation at high load levels and successful performance is closely related to additional striatal input (Wolf and Walter, 2005). One possible role of striatal input in WM could be the mediation of sustained activity in the DLPFC during the delay period via thalamic disinhibition (Houk, 1997). Consistent with this hypothesis, several studies have shown that the striatum is specifically activated in WM tasks when manipulation of information is necessary (Monchi et al., 2001; Wolf and Walter, 2005). There is increasing evidence for a disrupted frontostriatal circuit in schizophrenia as shown in metabolic, neuropsychological and functional activation studies (Buchsbaum et al., 1992; Manoach, 2003; Pantelis et al., 1997). Since striatal activation can be decisive at highest cognitive load levels (Wolf and Walter, 2005), we argue that patients with schizophrenia may fail to maintain optimal performance with higher task demands that rely on intact activation of the striatum. In this case, increased striatal activation may be present for task demands which patients still can cope with, whereas decreased activation can be found when processing capacities are clearly exceeded. This phenomenon may well reflect a core pathological feature as put forward by the ‘deficient automation’ hypothesis (Manoach, 2003). As a confound however, it could be argued that our striatal results might be explained by medication effects, since typical neuroleptics may alter metabolic rates during cognitive activation (Cohen et al., 1997) and striatal morphology (Benes et al., 1985). However, except for two patients, all of our schizophrenic patients were treated with atypical antipsychotics. Furthermore, there is also evidence of frontostriatal dysfunction in never-medicated patients with schizophrenia and other disorders of the schizophrenia spectrum (Buchsbaum et al., 1992). Moreover, the clear load-dependency found in our study demonstrates that the striatum is differentially responding to the increasing cognitive demand in an inverted U-shape manner (Fig. 4) – an activation pattern hitherto described for the prefrontal cortex (e.g. Callicott et al., 2000; Jansma et al., 2004). Conclusion In our study we found evidence for multiple dysfunctional WM network nodes in patients with schizophrenia. Our results could not confirm widespread prefrontal hypoactivation in patients with schizophrenia in the presence of reduced accuracy. The striatum, as part of the frontostriatal circuit subserving WM functions, was the only part of the brain showing an interaction effect of group × load, when patients with schizophrenia showed a higher activation level

in medium and lower activation in the highest load condition compared to healthy controls. Depending on cognitive load decreased activation was found in left ventrolateral prefrontal cortex compared with patients with major depression. This may be partly regarded as an effect of different strategies within the context of a manipulation task. The pattern of a lack of decreasing temporal activation with increasing cognitive load was independent of accuracy effects and the only finding specific to schizophrenia, being present compared to a healthy control group as well as to a group of patients with major depression. We conclude that it is not solely the dysfunction of a specific area like the lateral PFC but rather a disturbed coordination of a distributed network including the prefrontal cortex which underlies WM dysfunction in schizophrenia. Moreover, temporal dysfunction may be a core feature of the disorder in terms of diagnosis specificity. Acknowledgments This study was financially supported by Sanofi-Synthelabo. The authors would like to thank Katrin Brändle for technical assistance and Susanne Erk and Andreas Meyer-Lindenberg for critical discussions on previous versions of the manuscript. References Achim, A.M., Lepage, M., 2005. Episodic memory-related activation in schizophrenia: meta-analysis. Br. J. Psychiatry 187, 500–509. Barch, D.M., Carter, C.S., Braver, T.S., Sabb, F.W., MacDonald III, A., Noll, D.C., Cohen, J.D., 2001. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch. Gen. Psychiatry 58, 280–288. Barch, D.M., Braver, T.S., Carter, C.S., MacDonald III, A.W., Cohen, J.D., 2003a. Context-processing deficits in schizophrenia: diagnostic specifity, 4-week-course, and relationship to clinical symptoms. J. Abnorm. Psychol. 112, 132–143. Barch, D.M., Sheline, Y.I., Csernansky, J.G., Snyder, A.Z., 2003b. Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol. Psychiatry 53, 376–384. Benes, F.M., Paskevich, P.A., Davidson, J., Domesick, V.B., 1985. The effects of haloperidol on synaptic patterns in the rat striatum. Brain Res. 329, 265–273. Bilder, R., Volavka, J., Lachman, H.M., Grace, A.A., 2004. The catecholo-methyltransferase polymorphism: relations to the tonic–phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 29, 1943–1961. Buchsbaum, M.S., Haier, R.J., Potkin, S.G., Nuechterlein, K., Bracha, H.S., Katz, M., Lohr, J., Wu, J., Lottenberg, S., Jerabek, P.A., et al., 1992. Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch. Gen. Psychiatry 49, 935–942. Callicott, J.H., Bertolino, A., Mattay, V.S., Langheim, F.J., Duyn, J., Coppola, R., Goldberg, T.E., Weinberger, D.R., 2000. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb. Cortex 10, 1078–1092. Callicott, J.H., Mattay, V.S., Verchinski, B.A., Marenco, S., Egan, M.F., Weinberger, D.R., 2003. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am. J. Psychiatry 160, 2209–2215. Cohen, R.M., Nordahl, T.E., Semple, W.E., Andreason, P., Litman, R.E., Pickar, D., 1997. The brain metabolic patterns of clozapine- and fluphenazine-treated patients with schizophrenia during a continuous performance task. Arch. Gen. Psychiatry 54, 481–486. Dolan, R.J., Bench, C.J.B., Brown, R., Scott, L.C., Frackowiak, R.S.J., 1994. Neuropsychological dysfunction in depression: its relationship to regional cerebral blood flood. Psychol. Med. 24, 849–857.

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