Download Excessive recruitment of neural systems subserving logical

Brain (2002), 125, 1793±1807
Excessive recruitment of neural systems subserving
logical reasoning in schizophrenia
N. F. Ramsey,1 H. A. M. Koning,1 P. Welles,1 W. Cahn,2 J. A. van der Linden2 and R. S. Kahn2
1Functional Imaging Section, Department of Psychiatry
and 2Department of Psychiatry, University Medical Center
of Utrecht, Utrecht, The Netherlands
Summary
Schizophrenic patients generally perform poorly on
tasks that address executive functions. According to several imaging studies, the dorsolateral prefrontal cortex
is hypoactive in schizophrenic patients during these
tasks. It is not, however, clear whether this ®nding is
associated more with impaired performance than
with the illness itself, as performance has not been
taken into account. We examined brain activity associated with executive function in schizophrenia using an
experimental fMRI design that reveals performance
effects, enabling correction for performance differences
between groups. As this approach has not been reported
before, and because brain function can be affected by
medication, the effect of antipsychotic medication was
also investigated. A task was used that requires logical
reasoning, alongside a closely matched control task.
Performance was accounted for by including individual
responses in fMRI image analyses, as well as in groupwise analysis. Effects of medication were addressed by
comparing medication-naõÈve patients and patients on
atypical antipsychotic medication with healthy controls
in two separate experiments. Imaging data were ana-
Correspondence to: Nick F. Ramsey, PhD,
Functional Imaging Section, Department of Psychiatry,
Room A.01.126, University Medical Center of Utrecht,
Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
E-mail: [email protected]
lysed with a novel, performance-driven method, but
also with a method that is similar to that used in earlier
studies, which reported hypofrontality. A modest reduction in performance was found in both patient groups.
Brain activity associated with logical reasoning was correlated positively with performance in all groups. In
patients on medication, activity did not differ from that
in controls after correcting for difference in performance. In contrast, performance-corrected activity was
signi®cantly elevated in medication-naõÈve patients. This
study indicates that schizophrenia may be associated
with excessive recruitment of brain systems during logical reasoning. Considering the fact that performance
was reduced in the patients, we argue that the ef®ciency
of neural communication may be affected by the illness.
It appears that in patients on atypical antipsychotic
medication, this neural inef®ciency is normalized. The
study shows that performance is an important factor in
the interpretation of differences between schizophrenic
patients and controls. The reported association between
performance and brain activity is relevant to clinical
imaging studies in general.
Keywords: brain function; executive function; fMRI; performance; schizophrenia
Abbreviations: DR = deductive reasoning; DSM = Diagnostic and Statistical Manual; GA = general activity; GLM =
general linear model; WCST = Wisconsin Card Sorting Task; WM = working memory
Introduction
The notion that schizophrenia is characterized by de®cient
executive functions, particularly working memory (WM),
seems well established (Goldberg et al., 1987; Park and
Holzman, 1992; Goldman-Rakic, 1994a; Cohen et al., 1996;
Morice and Delahunty, 1996; Heinrichs and Zakzanis, 1998;
Riley et al., 2000; Weickert et al., 2000). Neuropsychological
and functional neuroimaging studies indicate that executive
functions are mediated primarily by frontal brain structures,
as was shown in patients with frontal lobe lesions and in
ã Guarantors of Brain 2002
healthy subjects (Weinberger, 1993; Goldman-Rakic, 1994b).
Following a study by Ingvar and Franszen (1974) who
reported hypometabolism in the frontal cortex of schizophrenic patients, many neuroimaging studies have examined
frontal lobe function in schizophrenia (for reviews see
Spitzer, 1993; Goldman-Rakic, 1994a; Zakzanis and
Heinrichs, 1999). Frontal hypofunction has frequently been
reported in patients when they were engaged in cognitive
tasks at which they perform poorly, particularly in tasks that
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N. F. Ramsey et al.
Table 1 Characteristics of subjects
Experiment 1
n
Age (years)
Gender (male/female)
Handedness (EHI)
Experiment 2
HC
PT
HC
PT
10
24.1 (5.0)
7/3
0.90 (0.13)
10
28.9 (8.8)
9/1
0.94 (0.08)
10
28.4 (6.2)
7/3
0.91 (0.08)
11
27.7 (9.3)
8/3
0.72 (0.35)
HC = healthy controls; PT = patients; n = number of subjects; EHI = Edinburgh Handedness Inventory.
Numbers in parentheses represent standard deviations.
address WM (Weinberger et al., 1994; Weinberger and
Berman, 1996; Yurgelun-Todd et al., 1996; Curtis et al.,
1998; Fletcher et al., 1998; Stevens et al., 1998), such as the
Wisconsin Card Sorting Task (WCST) (Milner, 1964;
Berman et al., 1986; Weinberger et al., 1986) or other tasks
that were designed to address WM function more explicitly
(Cohen et al., 1994; d'Esposito et al., 1995; Callicott et al.,
1998; Barch et al., 2001; Perlstein et al., 2001). However,
with recent advances in task design for the study of WM,
some studies suggest that the concept of hypofrontality in
schizophrenia is too simple, and that both the characteristics
of the cognitive task used during functional imaging, and also
performance are essential for the interpretation of functional
brain imaging experiments. Since these studies report that
under carefully controlled conditions frontal activity is either
normal (Frith et al., 1995) or even enhanced (Manoach et al.,
1999; Callicott et al., 2000) in schizophrenic patients during
engagement in WM tasks, the hypothesis of (selective)
prefrontal cortex hypofunction may require revision. Authors
noted that the results were associated with performance, in
that equal (or enhanced) activity was observed when patients
were capable of achieving a near-normal level of performance (Frith et al., 1995; Manoach et al., 1999). Callicott and
colleagues (2000) also observed enhanced WM activity in
schizophrenic patients, and provided evidence that it may be
the result of physiological inef®ciency due to prefrontal
neuropathology, as measured with magnetic resonance
spectroscopy. The design and complexity of a WM task is
critical for the interpretation of functional brain imaging
results in schizophrenic patients, as it determines to a large
extent whether the patients are actually cognitively engaged
in the task or not. If they are not, for instance because the task
is too fast or complex, then brain activity is not necessarily
associated with the function of interest, as the function was
not invoked by the task. Performance data can be used to
determine engagement in the task, and as such can provide
essential information for the interpretation of neuroimaging
results (Fletcher et al., 1998; Callicott et al., 2000).
Several groups have now presented methods of accounting
for performance differences, which generally utilize the
concept of a load-response function (Manoach et al., 1997;
Callicott et al., 1998; Jansma et al., 2000; Perlstein et al.,
2001), which in turn involves multiple levels of task dif®culty
in order to capture brain activity during both normal and
de®cient functioning. These tasks are, however, quite different from the executive function tasks, such as the WCST,
which were used in the earlier studies that reported frontal
hypofunction in schizophrenia, in that they target the WM
component speci®cally. The current task targets the complex
of functions that contribute to the process of solving problems
by means of logical, deductive reasoning.
The present study was conducted to examine brain activity
associated with executive function in schizophrenic patients
from a new perspective. Recognizing that performance is a
key issue in functional neuroimaging, and therefore in the
interpretation of results obtained with schizophrenic patients,
the contribution of performance played a critical role in
experimental design and analysis of this study. We present
data from a functional MRI experiment with a WCST-like
task, but with a novel experimental design that incorporates
performance variables. The performance issue is taken into
account in several ways to clarify the association between
executive functions and brain activity in schizophrenic
patients (see Methods for a detailed description). Two
questions are addressed with regard to cognitive brain
function in schizophrenia: (i) is the relationship between
performance and brain activity different for patients and
controls?; and (ii) how is this relationship affected by
medication? To address these questions an experimental
design was chosen that accounted for performance differences at several levels (i.e. task, experiment and analysis).
The task resembles the WCST in that it requires manipulation
of internal and external information, and keeping information
available (`online') in the process. It involves application of
deductive reasoning to ®nd a solution to a simple problem. As
this experimental design differs from the design used in the
previous schizophrenia studies with the WCST task, we also
investigated the effect of medication. In separate experiments, patients on atypical antipsychotic medication and
medication-naõÈve patients are compared with healthy
controls.
Methods
Subjects
Subject characteristics are shown in Tables 1 and 2. All
subjects were right-handed as assessed with the Edinburgh
Schizophrenia, reasoning and the brain
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Table 2 Characteristics of patients
Experiment 1
Diagnosis (DSM-IV)
295.1
295.2
295.3
295.7
295.9
Time since ®rst psychosis (median in months)
Antipsychotic medication at time of fMRI
Olanzapine, median 10 mg/day
Clozapine, median 300 mg/day
Total time on antipsychotic medication (months)
Severity of positive symptoms (PANSS)
Severity of negative symptoms (PANSS)
1 patient
Experiment 2
6 patients
3 patients
±
63
1 patient
9 patients
±
±
1 patient
25
5 patients
5 patients
18
14.2 (4.3)
16.8 (4.1)
None
None
0
17.6 (2.7)
17.3 (4.0)
±
PANSS = positive and negative syndrome scale. Numbers in parentheses represent standard deviations.
Handedness Inventory (Old®eld, 1971). Subjects were
screened by a psychiatrist using the Comprehensive
Assessment of Symptoms and History, and History
Schedule for Affective Disorder and Schizophrenia
Lifetime version (Andreasen et al., 1992a). The severity of
symptoms was assessed with the Positive and Negative
Syndrome Scale (PANSS) (Kay et al., 1987). Patients with a
diagnosis of drug dependence (lifetime) or drug abuse (in the
3 months prior to entry into the study) were excluded. Healthy
controls did not have any Diagnostic and Statistical Manual
(DSM)-IV axis I diagnosis, and had no ®rst-degree relatives
with a psychiatric disorder.
In Experiment 1, 10 normal healthy controls participated,
and 10 patients that had been treated with atypical
antipsychotics for at least 4 weeks. All patients met DSMIV criteria for schizophrenia or schizoaffective disorder. Ten
healthy controls and 13 medication-naõÈve patients with
schizophrenia participated in Experiment 2. Four of the
patients were diagnosed as schizophreniform at the time of
the experiment (DSM-IV code 295.4). At a follow-up
diagnosis 6±12 months after the fMRI session, two patients
did not meet the criteria for schizophrenia (new DSM-IV
code 296.24, major depressive syndrome), and were therefore
excluded. In the other two patients a diagnosis of schizophrenia (DSM-IV code 295.3) was con®rmed.
All the subjects in this study gave their informed consent.
The study was approved by the Ethical Committee of the
University Medical Center of Utrecht in accordance with the
Declaration of Helsinki.
Task
The cognitive task was a version of the XT-task conceived by
Cicerone et al. (1983), modi®ed for use in the MRI scanner,
and addresses functions involved in logical, or more specifically deductive, reasoning. The task involves selection of
one of two stimuli presented together. Stimulus pairs, one
Fig. 1 Two stimuli are shown for the XT task. Every 3.6 s a set of
two characters is projected onto the display. The subjects choose
one by pressing one of two buttons. The correctness of the
response is displayed at the bottom.
item at the left and one at the right side of the screen, are
presented once every 3.6 s, and the response is fed back
immediately as a circle around the selected stimulus (Fig. 1).
At the end of each trial a message appears below the stimulus
pair stating whether the response was correct or incorrect, for
600 ms. Failure to respond within 3.0 s after stimulus
presentation is counted as incorrect. The stimuli consist of
different coloured (blue or red) letters (X or T) that can be
either large or small. Therefore, eight features (i.e. two
different items in each of four categories/dimensions) are
represented on each trial, i.e. large or small, red or blue, X or
T, and left or right. Thus, the two stimuli of a pair always
differ in all four dimensions. One of these dimensions is
relevant to the task at any moment in the sense that the
computer program dictates which feature is correct. The
relevant feature changes after 10, 12 or 14 trials (mean 12
trials), without notice. During the experiment the relevant
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rule changed 30 times. Each set of 10, 12 or 14 stimuli is
referred to as an `epoch'.
The period during which the subject is searching for the
rule is de®ned as the experimental condition (`search'
condition). Performance is measured by the number of
stimuli that is used before the rule is found. The control
condition starts when the correct rule has been found. At this
point, the rule simply has to be applied during the remainder
of presented stimuli (until the task switches to a new rule that
has to be found), effectively changing the task to a simple
choice task which contains the same information input and
response requirement. As the control condition only involves
maintaining and applying the found rule, it is referred to as
the `maintain' condition. A similar approach has also been
presented by Konishi et al. (1999) and Barcelo et al. (1997) as
a method of separating executive functions from other
cognitive functions. Performance was expressed as the
number of items that were used during `search' (i.e. the
time it took to ®nd the correct rule), averaged across all 30
epochs. With this task and system of coding, the best possible
performance score averaged across epochs was calculated to
be 4. The score that would be obtained with completely
random responding was calculated to average 10.5.
matrix 128, FOV 256, ¯ip angle 30°, slice thickness 1.2 mm,
130 slices). The anatomical scan was used to spatially
localize the detected activity.
The task was presented by means of a video projector, a
through-projection screen and a mirror ®xed to the headcoil.
Responses were recorded by means of an air-pressure
buttonbox system. The head was kept in place with a strap
and foam padding. Six runs of 60 stimuli each were presented.
Scans were time-locked to the stimuli. Each run started and
ended with a rest period of 8 (24) scans, adding up to 46 (138)
volumes per run, lasting 5 min 34 s. The task presentation
started 7.25 s before the scan run to compensate for the delay
in the haemodynamic response.
fMRI image registration
All registration procedures were applied to the dataset of each
subject separately. Image resolution was preserved by means
of tricubic spline interpolation (Thevenaz et al., 1998). The
30° ¯ip angle functional scan (FA30 scan) was used for
registration of the anatomical scan to the functional
scans. The functional scans were each registered to the
FA30 scan automatically as described previously (Ramsey
et al., 1998).
fMRI scans
The study consisted of two experiments: one with medicated
patients and healthy controls, and the other with medicationnaõÈve patients and their healthy controls. The scan technique
used for both was navigated BOLD (blood oxygenation level
dependent)-sensitive 3D PRESTO (van Gelderen et al., 1995;
Ramsey et al., 1998). Due to an upgrade of the MRI machine
after the ®rst experiment, the functional scan time was
reduced by a factor of three, while the number of slices in the
volume increased from 22 to 26. The upgrade resulted in
better signal-to-noise ratio (better detection of BOLD signal
change) and a larger volume covering more tissue of inferior
visual, temporal and frontal cortices. Given this difference,
the two experiments are analysed separately, comparing
patients only with their corresponding controls. The details of
scan procedures for Experiment 1 are shown below, with the
values for Experiment 2 given in parentheses when they
differed.
Scans were acquired in runs of 46 (138) with 3D PRESTO,
on a Philips ACS-NT 1.5 Tesla Gyroscan with a PT1000
(PT6000) (Philips Medical Systems, Best, The Netherlands)
gradient set (Ramsey et al., 1998). Scan parameters were: TE
(echo time) = 36 ms, TR (repetition time) = 24 ms, ¯ip angle
= 10.5°, ®ve (17) read-out echoes per TR, ®eld of view (FOV)
183 3 225 3 77 mm (91), matrix 52 3 64 3 22 mm (26),
voxel size 3.51 mm isotropic, scan time 7.25 s (2.42 s). Six
runs were acquired during the task. This was followed by a
functional scan with a 30° ¯ip angle, which was used as the
`anchor' volume for co-registration of functional and anatomical volumes. The session was completed ®nally with an
anatomical scan (3D-FFE, Fast®eld Echo, TE = 4.6, TR = 30,
Analyses of individual fMRI datasets
For each subject, the functional dataset was analysed with
multiple regression in two ways: one where all scans acquired
during task execution were contrasted with the scans acquired
during rest [general activity (GA)], and one where the
`search' condition was contrasted with the `maintain' condition [deductive reasoning (DR)]. In the GA analysis, no
distinction was made between `search' and `maintain'. This
analysis corresponds to the classical block-wise analysis of
WCST PET data, and was included to assess whether results
obtained in this fashion would be replicated. In the DR
analysis only the scans acquired during the task were
analysed, therefore rest-scans were excluded. The experimental factor for the DR regression analysis was based on
individual performance. For this, each scan was assigned to
either `search' or `maintain', based on the correctness of the
response given to the stimulus that was time-locked to that
scan. Thus, an incorrect response resulted in coding of that
scan as `search'. Additional factors were entered into the
regression analysis to correct for signal trends. t-values were
generated for the experimental factor for each voxel (Worsley
and Friston, 1995), resulting in one GA and one DR t-map for
each subject. Maps were thresholded at t = 4.5, which
corresponds to a P-value of 0.05, Bonferroni-corrected for
total number of scanned voxels in the brain (Ramsey et al.,
1998). For each subject, the number of voxels exceeding the
signi®cance threshold was determined in 22 manually
segmented volumes of interest (VOIs). These numbers were
entered in the group analyses, which are described below.
Schizophrenia, reasoning and the brain
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Table 3 Summary of performance, volume of imaged brain and total volume of activated brain
in all VOIs for the GA and the DR analyses
Experiment 1
Task performance
Analysed brain volume (cc)
Total GA activity (nvx)
Total GA activity (cc)
Total DR activity (nvx)
Total DR activity (cc)
Experiment 2
HC
PT
HC
PT
5.7 (0.5)
742 (10)
318.5 (55.1)
13.8 (2.4)
60.5 (10.6)
2.6 (0.5)
6.1 (0.3)
764 (22)
181.5 (37.6)
7.8 (1.6)
34.3 (10.7)
1.5 (0.5)
6.2 (0.2)
858 (25)
576.5 (156.2)
24.9 (6.8)
91.9 (20.5)
4.0 (0.9)
7.2 (0.5)
814 (15)
596.2 (114.8)
25.8 (5.0)
131.3 (30.3)
5.7 (1.3)
HC = healthy controls; PT = patients; GA = general activity analysis; DR = deductive reasoning analysis;
cc = cubic centimetres; nvx = number of activated voxels. Numbers in parentheses represent standard
deviations.
Segmentation of anatomical scans
For each subject, the anatomical volume was manually
segmented into 22 VOIs, 11 for each hemisphere. For
outlining the VOIs an anatomical atlas was used (Duvernoy,
1991) to follow the division of Brodmann areas (Brodmann,
1909). Frontal cortex VOIs corresponded to cingulate gyrus
(Brodmann area, BA 24/33), frontal pole (BA 10), ventrolateral inferior (BA 44/45), dorsolateral inferior (BA 9/46),
middle (BA 8/9) and superior (BA 6) frontal cortex. Parietal
VOIs corresponded to superior lobule (BA 7), supramarginal
(BA 39) and angular gyrus (BA 40). Finally, the posterior
cingulate (BA 23/29) and visual cortex (BA 17/18/19) were
segmented.
To ascertain that segmentation did not bias group comparisons of activity, VOIs were tested by means of a general
linear model (GLM) analysis with repeated measures
(volumes of the set of 22 VOIs, divided by hemisphere),
including data from both experiments. P-values are shown for
the e-corrected F-tests. Signi®cant effects of VOI [F(10,370)
= 261.6, P < 0.001], hemisphere [F(1,37) = 68.8, P < 0.001]
and experiment [F(1,37) = 16.7, P < 0.001] were found, but
there were no signi®cant main or interaction effects involving
group (all P > 0.13 in the e-corrected F-tests), indicating that
there were no differences in segmentation between patients
and controls.
Group-wise statistical comparisons of fMRI data
For comparisons between patients and controls, a GLM
analysis (analysis of variance with repeated measurements)
for repeated measures was performed, with the following
parameter settings: within-subject factors area (11 VOIs per
hemisphere) and hemisphere; between-subject factor illness
and covariate performance (number of `search' items). This
design was applied separately to the GA and to the DR image
data. Effects were assessed for signi®cance with multivariate
analysis, and are presented as e-corrected average F-tests.
Voxel counts were ®rst tested for normal distribution by
means of a Kolmogorov±Smirnov test in each VOI. As the
vast majority of VOIs showed normal distribution of voxel
counts, further analyses were performed with parametric
statistical procedures. As very low levels of activity in VOI
would preclude detection of group-wise differences in brain
activity levels (the `¯oor effect'), voxel counts in each VOI
were tested (one-sample t-tests against zero) for each group,
experiment and comparison (GA and DR) separately.
Signi®cant activity was present in almost all VOIs (except
for BA 23/29), allowing for a meaningful comparison of
volumes of activity between groups.
Results
The main variable for which groups were not matched was
performance. To assess how performance affected reasoningrelated brain activity, correlations were calculated between
performance and total DR brain activity. Correlations were
signi®cant (patients and controls combined: Experiment 1,
r = ±0.55, P = 0.012; Experiment 2, r = ±0.46, P = 0.036). In
the separate groups, this correlation was also present, albeit
weakly (r ranged from ±0.64 to ±0.54, each P < 0.10). Based
on the effect of performance on brain activity, performance
was included in all the GLM analyses as a covariate.
Experiment 1: patients on medication compared
with healthy controls
Performance
Patients used slightly more items to ®nd the rule than the
controls, but this was not signi®cant [t(18) = 0.75, P = 0.46]
(Table 3). We noticed that one healthy control had performed
near chance level and therefore quali®ed as an outlier
(Shif¯er, 1988). When testing performance without this
subject, a signi®cant reduction in performance emerged for
patients [t(17) = 2.44, P = 0.026]. Individual performance
determined coding of the fMRI scans of each subject,
resulting in assigning, on average, 47% of the fMRI scans
to the `search' condition in controls and 51% in patients. The
remaining scans were assigned to the `maintain' condition.
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N. F. Ramsey et al.
Fig. 2 Patterns of general brain activity (`GA' analysis, task versus rest) for patients on medication and
for healthy controls (Experiment 1). For each VOI the mean number of sign®cant voxels (t > 4.5) is
shown. Bars represent standard error of the mean (SEM). Each VOI is labelled with Brodmann area codes
on the x-axis. F, P and O represent frontal, parietal and occipital cortex, respectively.
Brain activity
In the GA analyses, activity was found bilaterally in frontal,
parietal and occipital VOIs in both patients and controls
(Fig. 2). No main effect of illness was found with GLM
analysis comparing patients with controls. The analysis did
reveal a signi®cant interaction between area, hemisphere and
illness [multivariate F(10,8) = 3.44, P < 0.05], but no other
effects involving illness. Furthermore, performance was not
signi®cant as a main effect and did not interact with illness.
Following up on the three-way interaction effect, univariate
analyses were performed on each area, without performance
as covariate (as it did not interact with illness effects). This
revealed that brain activity was signi®cantly reduced in
patients in the following areas: left and right anterior
cingulate [BA 24/33, F(1,18) = 5.32, P = 0.033 and F(1,18)
= 4.99, P = 0.038, respectively], left posterior cingulate [BA
23/29/30, F(1,18) = 7.11, P = 0.016], left dorsolateral
prefrontal cortex [BA 9/46, F(1,18) = 5.59, P = 0.030], right
inferior frontal gyrus [BA 44/45, F(1,18) = 14.5, P = 0.001]
and left superior parietal cortex [BA 7, F(1,18) = 10.81, P =
0.004]. Thus, when analysing the fMRI data in a conventional
way, i.e. disregarding the difference between `search' and
`maintain', reduced activity was observed in frontal and
parietal regions in the patients.
In the DR analysis, activity during `search' was compared
with activity during `maintain' (Fig. 3). The main effect of
area was signi®cant [F(10,170) = 3.68, P = 0.007], indicating
that activity was different across the VOIs. No effects were
found for the hemisphere factor, and none of the interactions
was signi®cant (P > 0.20). The effect of the covariate
performance was signi®cant [F (1,17) = 6.74, P = 0.019]. The
main effect of illness, i.e. an apparent overall reduction, was
not signi®cant (P = 0.15) (Fig. 4), nor were interactions
involving illness (P > 0.31). The effect of performance
indicated a linear relationship between performance and
summed brain activity, and in the absence of any effect of
illness this relationship appears to be the same for both groups
(Fig. 5). To check whether the one healthy control with
exceptionally low performance affected the image data, the
GLM analysis was conducted again without this subject. This
did not alter the ®ndings with regard to illness [main effect
F(1,16) = 1.6, P = 0.23, interactions involving illness P >
0.24].
To control for performance in an alternative way, the
groups were matched for performance by excluding low
performing patients and high performing controls. The GLM
analysis was conducted again, without performance as
covariate, but with seven subjects in each group matched
for performance. The results con®rmed the whole-group
analyses in that there were no signi®cant effects of illness
(neither main nor interaction effects).
Experiment 2: medication-naõÈve patients
compared with healthy controls
Performance
Mean performance for both groups is shown in Table 3.
Medication-naõÈve patients used more items to ®nd the rule
than the controls [t(19) = 2.0, P = 0.06]. Individual
performance determined coding of the fMRI scans of each
subject, resulting in assigning, on average, 52% of the fMRI
scans to the `search' condition in controls and 60% in
patients. The remaining scans were assigned to the `maintain'
condition.
Schizophrenia, reasoning and the brain
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Fig. 3 Patterns of brain activity associated with reasoning (`DR' analysis, `search' versus `maintain') for
patients on medication and for healthy controls (Experiment 1). For each VOI the mean number of
signi®cant voxels (t > 4.5) is shown. Bars represent SEM. Each VOI is labelled with Brodmann area
codes on the x-axis. F, P and O represent frontal, parietal and occipital cortex, respectively.
Brain activity
GA analysis did not reveal any differences between patients
and controls in pattern or extent of activity (Fig. 6).
Performance did not affect overall brain activity (no signi®cant effect as covariate and no correlation with overall
activity). Due to the more sensitive scan technique, activity
levels were higher than those in Experiment 1 (see Table 3).
As in Experiment 1, activity was equally present in both
hemispheres (Table 3).
Analysis of the DR data revealed a main effect of illness
[F(1,18) = 6.5, P = 0.02]. As can be seen in Figs 7 and 8,
patients exhibited increased activity during `search' compared with controls. Overall, volume of activity was
increased by 43% in patients relative to controls (Table 3).
The main effect of the performance covariate (Fig. 9) was
prominent [F(1,18) = 11.4, P = 0.003]. In addition, a main
effect of area emerged [F(10,180) = 3.0, P = 0.008], and of
hemisphere [F(1,18) = 7.7, P = 0.012], indicating a differential pattern of activity. Several interactions were signi®cant: hemisphere by performance [F(1,18) = 7.0, P = 0.017]
and hemisphere by illness [F(1,18) = 5.6, P = 0.03]. There
was no interaction involving area and illness together. This
indicates that illness did not affect any speci®c brain region,
but it did affect the hemispheres differently. Following up on
the hemisphere by illness interaction, the VOI voxel counts
were combined within each hemisphere. Subsequent univariate analysis on each hemisphere showed that the strongest
effect of illness occurred in the right hemisphere [main illness
effect in right hemisphere F(1,18) = 8.7, P = 0.009, and in left
hemisphere F(1,18) = 2.7, P = 0.12]. The effect of performance remained signi®cant in both cases [F(1,18) = 13.8, P =
0.002 and F(1,18) = 5.6, P = 0.03], respectively. Although the
Fig. 4 Plot of total brain activity as unstandardized residual
activity (associated with reasoning, `DR' analysis) for patients on
medication and for healthy controls (Experiment 1), after
partialling out the effect of performance on the XT task by means
of regression analysis.
GLM analysis did not indicate differential effects of illness on
separate VOIs, we analysed the data from each VOI
separately by means of a univariate GLM to assess in
which regions the effect of illness was most pronounced. An
effect of illness was signi®cant in the right BA 24/33 [F(1,18)
= 6.3, P = 0.02], right BA 8/9 [F(1,18) = 8.4, P = 0.01] and
right BA 39 [F(1,18) = 4.9, P = 0.04].
To control for performance in an alternative way, the
groups were matched for performance by excluding low
performing patients and high performing controls. The GLM
analysis was conducted again, without performance as
covariate, but with seven subjects in each group matched
1800
N. F. Ramsey et al.
for performance. The results con®rmed the whole-group
analyses with performance as covariate, in that there was a
signi®cant main effect of illness [F(1,12) = 4.7, P = 0.05].
The interaction effects were also the same: area [F(10,120) =
9.3, P < 0.001], hemisphere [F(1,12) = 5.1, P = 0.04] and
illness by hemisphere [F(1,12) = 6.0, P = 0.03].
Fig. 5 Scatterplot showing the relationship between total brain
activity (associated with reasoning, `DR' analysis, `search' versus
`maintain' as number of voxels in all VOIs) and performance on
the XT task, for patients on medication and for healthy controls
(Experiment 1). Total activity is the number of signi®cant voxels
(t > 4.5) summed over all VOIs. The lines represent the best linear
®t obtained with regression analysis.
Discussion
This study examined brain activity patterns associated with
executive function involved in logical reasoning in schizophrenic patients with and without antipsychotic medication.
In two separate experiments these patients were compared
with healthy controls, using a novel task that allowed for
separation of the effect of performance and the effect of
illness. In patients as well as in controls, the level of taskspeci®c brain activity was linearly dependent on level of
performance. In both groups of patients, a modest reduction
in performance was found, indicating a reduced ef®ciency of
processing information relevant to the task as it took longer to
®nd the rule, which may be related to perseverance (Sullivan
et al., 1993) or to a WM de®cit (Gold et al., 1997). In the ®rst
experiment, with patients treated with antipsychotic medication, the difference in performance explained the difference
in level of brain activity associated with logical reasoning,
indicating that if patients and controls were matched on
performance, the brain activity patterns would be equal. In the
medication-naõÈve patients, however, a signi®cant elevation of
brain activity associated with reasoning remained after
partialling out the effect of performance. This ®nding
indicates that although performance predicted brain activity,
there was an increase in the level of activity that was
independent of performance. As the current study examined
volumes of active brain tissue, this performance-independent
effect re¯ects an excessive utilization of neurones to accomplish the task. The enhanced activity was not speci®c for any
of the regions associated with reasoning, but it was greatest in
the right hemisphere. The fact that performance was not
severely affected (16% reduction) con®rms that the medication-naõÈve patients were effectively engaged in the task, and
Fig. 6 Patterns of general brain activity (`GA' analysis, task versus rest) for medication-naõÈve patients and
for healthy controls (Experiment 2). For each VOI the mean number of signi®cant voxels (t > 4.5) is
shown. Bars represent SEM. Each VOI is labelled with Brodmann area codes on the x-axis. F, P and O
represent frontal, parietal and occipital cortex, respectively.
Schizophrenia, reasoning and the brain
1801
Fig. 7 Patterns of brain activity associated with reasoning (`DR' analysis, `search' versus `maintain') for
medication-naõÈve patients and for healthy controls (Experiment 2). For each VOI the mean number of
signi®cant voxels (t > 4.5) is shown. Bars represent SEM. Each VOI is labelled with Brodmann area
codes on the x-axis. F, P and O represent frontal, parietal and occipital cortex, respectively.
that the neural systems subserving logical reasoning were
operating productively. It appears from this study that
atypical antipsychotics normalize this neural inef®ciency,
potentially by improving ef®ciency of communication within
the network(s) that subserve executive functions.
Furthermore, the schizophrenic patients (regardless of medication status) did not exhibit selective dysfunction of frontal
brain structures as the patterns of brain activity, i.e. the
distribution of activity across the brain, were not signi®cantly
different from those obtained from the healthy controls.
Brain activity in medication-naõÈve patients
The design of the present cognitive paradigm, in which task
and control task are closely matched, has not been reported
before and therefore the results cannot be related directly to
other studies. In order to relate the current study to previous
studies, particularly those in which the WCST was used, we
compared the scans acquired during task execution to those
acquired during a rest state, and tested for differences
between patients and controls (GA analysis). In the medication-naõÈve patients no reduced activity was observed when
comparing task activity to rest, in contrast with other reports
with both medication-free and medication-naõÈve schizophrenic patients (Berman et al., 1986; Weinberger et al.,
1986; Rubin et al., 1991, 1994; Andreasen et al., 1992b;
Catafau et al., 1994; Parellada et al., 1994, 1998). In some of
the WCST studies a cognitive control task was employed to
control for brain activity not related to WM, and these
generally report reduced activity in frontal structures
(Berman et al., 1986; Weinberger et al., 1986), but activity
was reduced in temporal and parietal regions also, although
Fig. 8 Plot of total brain activity as unstandardized residual
activity (associated with reasoning, `DR' analysis) for medicationnaõÈve patients and for healthy controls (Experiment 2), after
partialling out the effect of performance on the XT task by means
of regression analysis.
not signi®cantly. The absence of an effect in the current study
may be due to the fact that we did not perform a groupaveraged map analysis. As has been argued by others
(Weinberger and Berman, 1996; Manoach et al., 2000),
activity may be more distributed within cortical regions in
schizophrenic patients, leading to a failure to ®nd overlapping
regions of activity when images are smoothed and overlaid
within groups, and consequently leading to a signi®cant
regional difference with controls. Alternatively, the patients
in the current study may have been less cognitively impaired
than those in the other studies.
1802
N. F. Ramsey et al.
the tasks address different sets of brain functions. Whereas
the XT task requires both manipulation of information and
holding it available (i.e. the sets of rules during `search'), the
task used by Barch and colleagues mainly involves coding
and maintaining information (Barch et al., 2001). Considering evidence of frontal pathology in various areas of
schizophrenia research (Weinberger and Berman, 1988) on
the one hand and the recent reports of enhanced activity of
frontal cortex in schizophrenic patients (Manoach et al.,
1999; Callicott et al., 2000) on the other, prefrontal cortex
may be better described as dysfunctional rather than
hypofunctional (Callicott et al., 2000).
Fig. 9 Scatterplot showing the relationship between total brain
activity (associated with reasoning, `DR' analysis, `search' versus
`maintain') and performance on the XT task, for medication-naõÈve
patients and for healthy controls (Experiment 1). Total activity is
the number of signi®cant voxels (t > 4.5) summed over all VOIs.
The lines represent the best linear ®t obtained with regression
analysis.
To measure brain activity associated with logical reasoning
selectively, the experimental task (the `search' condition) and
the control task (the `maintain' condition) were closely
matched, and scans acquired during both conditions were
compared. The most important aspect of this design is that the
analysis of fMRI scans was based on performance for each
individual subject. Medication-naõÈve patients exhibited
enhanced reasoning-selective brain activity despite reduced
performance. This ®nding is not in line with other studies
where WCST-related brain activity in medication-free
patients was reported to be reduced in frontal cortex in
comparison with activity during an indirect control task
(Berman et al., 1986; Weinberger et al., 1986). The
apparently opposite ®nding may be explained by several
differences between studies. First, in the current study brain
activity was measured relative to a closely matched control
task, and the analysis was corrected for actual performance.
Secondly, the imaging data were analysed individually as
opposed to in a group-wise manner, and it is probable that the
study was consequently less sensitive to a potential difference
in cortical distribution and focality of activity between
groups. Thirdly, the XT task may be easier for patients. When
a task exceeds processing capacity, subjects may disengage
from the task. Fourthly, as the previous studies involved
medication-free as opposed to medication-naõÈve patients,
residual effects of antipsychotic medication cannot be ruled
out. With a different type of task (a modi®ed `continuous
performance task'), Barch and colleagues recently showed
that dorsolateral prefrontal cortex, but no other region, was
hypoactive in medication-naõÈve schizophrenic patients when
WM was involved (Barch et al., 2001). The most likely
explanation for the difference with the current study is that
Brain activity in patients on antipsychotic
medication
When comparing the scans acquired during task execution
with those acquired during a rest state (the GA analysis), a
signi®cant reduction of brain activity was found in patients on
medication in prefrontal cortex, in accordance with other
WCST studies (Berman et al., 1986; Weinberger et al., 1986;
Andreasen et al., 1992b; Volz et al., 1997; Ragland, 1998). In
addition, activity was reduced in anterior cingulate and
parietal cortex. Anterior cingulate appears to be speci®cally
involved when errors are likely to occur (Carter et al., 1998),
which is the case during our `search' condition. Reduced
anterior cingulate activity in schizophrenia has been reported
with a selective attention task that addresses this region
speci®cally (Carter et al., 1997). Although parietal cortex
involvement is not reported in most of the WCST neuroimaging papers, it has been shown to activate in healthy
subjects, as measured by event-related potentials (Barcelo
et al., 1997).
When comparing scans acquired during `search' with those
acquired during `maintain' (the DR analysis), brain activity in
patients on atypical antipsychotic medication did not differ
from that in controls. Patients performed worse on the task
than controls (excluding one outlier), but when corrected for
the effect of performance on brain activity, brain activity
patterns did not differ signi®cantly between the groups. When
taking these results together with the ®nding that task activity
relative to rest (GA analysis) was reduced in patients on
medication, it appears that activity in WM-related areas in
these patients was reduced during both task conditions
(`search' and `maintain'), while the difference in activity
between the conditions was not affected.
Relevance of performance for functional
imaging of executive function
The main difference between this study and some of the
neuroimaging studies on executive function or on WM in
schizophrenia is the emphasis on correction for performance
effects. We argue that performance can be a confounding
factor in patient studies on several levels (design of the task,
Schizophrenia, reasoning and the brain
experimental design and analysis of fMRI data) and will
typically result in a bias towards reduced brain activation in
poorly performing patients (Frith et al., 1995; Price and
Friston, 1999; Callicott et al., 2000; Perlstein et al., 2001).
Poor performance can re¯ect two opposite types of functional
state of the brain: an engaged brain system that fails to
perform, and a brain system that is disengaged due to other
causes of bad performance or to task design (Bullmore et al.,
1999). Given that one state can not be differentiated from the
other in many tasks (in both cases responses will re¯ect
guessing), interpretation of reduced brain activity in poorly
performing subjects is not straightforward (Bullmore et al.,
1999) as it may well re¯ect failure to fully engage in the task.
Studies utilizing the WCST are also confounded by
performance in another way. Scans are typically acquired
during blocks labelled as the active condition, and are
compared either with a rest-state (Rubin et al., 1991;
Parellada et al., 1998) or with a separate control task
(Berman et al., 1986; Weinberger et al., 1986; Buchsbaum
et al., 1997). In doing so, however, activity during the two
stages of the task (`search' and `maintain') are combined,
although the sets of functions that are involved are quite
different. During `search', all the rules have to be kept in
memory, a strategy has to be applied to test each one of them,
and decisions have to be made for each rule. These operations
are regarded as complex executive functions, involving setswitching and re-routing of stimulus and response selection
processes (Shimamura, 2000). During `maintain', a simple
rule has to be applied to each stimulus and no higher-order
processing is required. In the typical block-design experiments, the executive functions that are engaged during
`search', and which are thought to be impaired in schizophrenia, are not then distinguished from functions involved in
`maintain'. However, schizophrenic patients generally have
no problem performing a simple task that can be performed
by verbally rehearsing one rule, such as `maintain' (Cohen
et al., 1999).
Distribution of brain activity
An important question in the assessment of brain dysfunction
in schizophrenia is whether it is regionally-speci®c or not
(e.g. Cohen et al., 1996; Weinberger and Berman, 1996;
Goldman-Rakic and Selemon, 1997; Andreasen et al., 1999).
Whereas various previous studies indicate that schizophrenic
patients exhibit a selective de®cit in frontal structures, the
present ®ndings suggest that a more extended network of
brain regions involved in logical reasoning, rather than a
speci®c region, is affected in medication-naõÈve patients. In all
groups, performance was correlated with total brain activity
in the DR analysis, indicating that better performance was
associated with higher levels of brain activity across the
network. Thus, two effects were observed: (i) in all subjects
performance bene®ted from higher levels of brain activity in
the network; and (ii) performance in medication-naõÈve
patients did not bene®t from the performance-independent
1803
additional elevation of brain activity that was observed in this
group. Whereas the ®rst effect indicates that good performance requires extensive participation of brain systems in the
task, the second indicates that in medication-naõÈve patients
the excess of activity fails to result in better performance. We
did not ®nd clear evidence that either of these effects is
regionally speci®c. We argue that the elevated activity in
medication-free patients re¯ects a reduction of the ef®ciency
with which the brain structures that constitute the network
communicate with each other. Reduced ef®ciency in schizophrenia has been alluded to before (Callicott et al., 2000), and
recent studies have examined the phenomenon of ef®ciency
in more detail in healthy subjects, showing that with practice
of a cognitive task, performance improves while brain
activity decreases (Buchel et al., 1999; Jansma et al.,
2001). This is reportedly associated with enhanced `effective
connectivity' (Buchel et al., 1999), in other words improved
ef®ciency of communication (Jansma et al., 2001), between
WM regions. In the light of this, excessive activity in
medication-naõÈve patients may re¯ect a failure to accomplish
ef®cient communication between the involved brain regions
in (repeatedly) solving the problem of ®nding the new rule
during the `search' condition. The fact that excessive activity
was predominantly lateralized to the right hemisphere is a
little surprising given earlier studies that have implicated the
left hemisphere in schizophrenia, but it does agree with one of
our earlier studies on language lateralization in schizophrenic
patients (Sommer et al., 2001). In that study we also noted the
relevance of performance, and argued that hypoactivity in
the left hemisphere, as reported in other papers, may be
associated with impaired performance that has not been
corrected for.
In order to investigate the whole network of brain regions
involved in reasoning, the analysis included all the regions
that have been indicated in WCST studies, i.e. prefrontal
(Berman et al., 1986, 1995; Weinberger et al., 1986;
Parellada et al., 1994; Rubin et al., 1994; Nagahama et al.,
1996; Catafau et al., 1998; Tien et al., 1998), medial frontal
(Catafau et al., 1998) and parietal (Berman et al., 1995;
Nagahama et al., 1996; Tien et al., 1998) cortices. The
consequence of this approach, as compared with separate
tests within individual structures or voxels, is that sensitivity
to small but consistent differences in activity across VOIs (i.e.
a main effect) is enhanced at the expense of identifying
differences in selective VOIs (i.e. interaction effects).
Therefore, the ®nding of overall enhanced activity in
medication-naõÈve patients does not disprove the notion that
speci®c brain regions are affected more than others
(Weinberger and Berman, 1988), even though no interaction
effects were found.
Medication effects
Reduced ef®ciency of the network subserving logical
reasoning was observed only in medication-naõÈve patients
and not in patients who were stable on antipsychotic
1804
N. F. Ramsey et al.
treatment. Various theories on the psychopharmacology of
schizophrenia stress the dopaminergic actions of antipsychotics, and state that a dysregulation of limbic and frontocortical
dopamine systems may underlie the various symptoms of
schizophrenia (Weinberger and Berman, 1988), including
executive functions (Goldman-Rakic, 1996). Indeed, PET
and single photon emission computed tomography studies
have con®rmed both abnormal basal, i.e. resting, levels of
dopamine receptor levels (for a review see Laruelle, 1998),
and abnormal responsivity to exogenous stimulation
(Laruelle et al., 1999). The present ®nding that the disproportionate utilization of brain systems subserving reasoning
was not observed in patients with atypical antipsychotic
treatment, agrees with reports that brain functions are
normalized with such treatment (Honey et al., 1999).
Indirect enhancement of prefrontal dopamine activity by
means of stress or a pharmacological challenge in monkeys
proved to reduce WM performance selectively, lending
further support to the role of dopamine in the organization
of processes subserving this function (Murphy et al., 1996;
Arnsten and Goldman-Rakic, 1998).
The results of the current study are affected by several
limitations that need to be mentioned. First, comparison of the
two experiments in the current study requires some caution,
because different scanning parameters were used. The
experimental design and the task were identical. The overall
difference between the two experiments was limited to an
overall increase in numbers of active voxels due to enhanced
sensitivity with the upgraded scanner hardware. There was no
indication, based on comparison of the two control groups,
that the patterns of activity were affected by the upgrade
(except for visual cortex where the upgrade enabled larger
coverage of the visual cortex). The upgrade did not affect
comparisons between patients and their controls. Secondly,
although the results suggest an effect of atypical antipsychotic medication, this was not tested directly. A more ®rm
conclusion would require a design where patients are tested
twice, i.e. once `on' and once `off' medication.
Our ®nding of enhanced activity across multiple areas of
the brain, including dorsolateral frontal cortex, in medicationnaõÈve patients supports the notion of reduced capacity of a
cognitive network, potentially due to excessive recruitment of
neural systems and/or inef®cient communication between
brain regions, rather than the notion of a selective brain
structure that fails to operate adequately. Furthermore, the
fact that excessive recruitment was not observed in the
patients on atypical antipsychotics suggests that such treatment may improve communication within the cognitive
network. The current ®ndings cannot be compared with
previous studies directly, because in our study performance
was taken into account, and the control condition (`maintain')
was closely matched to the experimental condition (`search').
The interpretation of our results, however, challenges the
hypothesis of prefrontal hypofunction that has been supported
by the previous WCST studies, both in medication-naõÈve
patients and in patients on antipsychotics. The present study
demonstrates that poor performance may be a confounding
factor in the interpretation of neuroimaging results and, as
such, deserves more attention. The hypothesis that some of
the executive function de®cits in schizophrenia result from
neural inef®ciency is supported by other studies (Manoach
et al., 1999; Callicott et al., 2000) but requires more research.
It is clear that the characteristics of the task used during
scanning greatly in¯uence the results. Considering that novel
task designs used in healthy controls focus more on the
dynamics of WM function (Buchel et al., 1999; Jansma et al.,
2001), use of these tasks in schizophrenic patients will
improve our understanding of the neural mechanisms underlying information processing de®cits in schizophrenia.
Acknowledgements
We wish to thank Dr W. P. Th.M. Mali for his support of the
fMRI studies, the staff of the schizophrenia ward of the
University Medical Centre for supporting the patients during
the study and Dr Daniel Weinberger for many elucidating
discussions and his comments and suggestions on the paper.
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Received October 5, 2001. Revised January 6, 2002.
Accepted February 25, 2002