Department of Psychiatry, University of British Columbia, Vancouver, Canada
Correspondence: Dr Adrianna Mendrek, Department of Psychiatry, University of Montreal, Centre de recherche Fernand-Seguin, 7331 Hochelaga, Montreal, Québec H1N 3V2, Canada. Tel: +1 514 251 4015 ext. 3528; fax: +1 514 251 2617; e-mail: amendrek{at}crfs.umontreal.ca
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To delineate regional brain dysfunctions that remain stable and those that fluctuate during the course of schizophrenia.
Method A cohort of patients with first-episode schizophrenia and a matched group of control participants underwent functional magnetic resonance imaging on two occasions 68 weeks apart during performance of a working memory task. The patients disease was in partial remission at the second scan.
Results Relative to control participants, the function of the left dorsolateral prefrontal cortex, left thalamus and right cerebellum remained disturbed in the people with schizophrenia, whereas the dysfunction of the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and cingulate gyrus normalised, with significant reduction in symptoms.
Conclusions These results suggest that dysfunction of the left fronto-thalamo-cerebellar circuitry is a relatively stable characteristic of schizophrenia, whereas disturbance of the right circuitry and cingulate gyrusis predominantly a state-related phenomenon.
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INTRODUCTION |
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METHOD |
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In addition to an interview and a review of case notes to corroborate the diagnosis of schizophrenia and assess changes in symptoms over time, all patients were assessed with the Signs and Symptoms of Psychotic Illness scale (SSPI; Liddle et al, 2002), which measures the severity of 20 signs and symptoms of acute and chronic psychotic illness; a score of 18 (s.d.=7) is typical of an acute psychotic state (Liddle et al, 2002). The group of patients in our study obtained a mean score of 19.85 (s.d.=10.72) during the first assessment with the SSPI (within the first week of treatment) and a mean score of 13.0 (s.d.=10.78) during the second assessment (after 68 weeks of treatment).
The group of eight healthy control participants, with no current or past psychotic illness and no psychotic illness in a first-degree relative, did not differ from the group of patients in terms of age, gender, parental socio-economic status or IQ (Table 1). Parental socio-economic status was assessed using the Hollingshead criteria for parental social position (Hollingshead & Redlich, 1958) and IQ was measured using the Quick test (Ammons & Ammons, 1962). All participants were right-handed according to the Annett Handedness scale (Annett, 1970). The study was approved by the ethics review committee of the University of British Columbia. All participants gave written consent after the experimental details were explained to them.
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Behavioural test and data analysis
The behavioural task used in our study was one used previously in
neuroimaging investigations of working memory
(Awh et al, 1996;
Cohen et al, 1997;
Jonides et al, 1997).
This version of the n-back task consisted of a screen display of a
succession of letters; the person tested was required to press a button
whenever the designated letter appeared. In our study, participants either had
to press the button whenever the letter X appeared (the 0-back
task) or press it any time they saw a letter identical to one presented two
screens earlier (the 2-back task). Each letter was displayed for
a duration of 250 ms with an inter-stimulus interval of 2 s. Participants were
required to complete two runs of alternating 30 s periods of 0-back and 2-back
testing, separated by 20 s rest periods; each run lasted about 7 min. Both
tasks involved similar sensory processing of information and a similar amount
of motor activity. Before scanning, participants were given full instructions
and a 3 min practice session, in which they had to reach a 70% accuracy level.
Despite successful practice, two patients failed to reach the required 60%
level of accuracy during performance of the task in the scanner and their data
were discarded from the analysis. All participants performed the task on two
separate occasions, 68 weeks apart.
The behavioural data were analysed using betweenwithin repeated measures, condition (0-back, 2-back) by group (patients, controls) by scanning session (first, second), factorial analyses of variance (ANOVAs). Separate ANOVAs were used to evaluate performance accuracy and reaction time data. Errors of omission were defined as a failure to respond to the target stimulus within 1500 ms of stimulus onset; errors of commission were defined as a response to a non-target stimulus within the same time frame.
Imaging procedure and analysis
Imaging was performed using a standard clinical GE 1.5 tesla whole-body MRI
scanner (General Electric, Milwaukee, Wisconsin, USA) fitted with a Horizon
echo-speed upgrade. Whole-brain echo-planar fMRI was performed using a
gradient echo pulse sequence (repetition time 3000 ms, echo time 40 ms, flip
angle 90°, field of view 24 cm x 24 cm, 64 x 64 matrix, band
width 62.5 kHz, 3.75 x 3.75 mm inplane resolution, 5 mm slice thickness,
29 slices). The functional images acquired in each run were reconstructed
offline and subsequently realigned, motion corrected and normalised into the
MRI template and stereotactic space
(Talairach & Tournoux,
1988) using Statistical Parametric Mapping software (SPM99;
Wellcome Department of Cognitive Neurology, Institute of Neurology, London).
The motion estimates for individual participants did not exceed 3 mm or
3°, and there was no significant difference between the groups. The
realigned and normalised images were smoothed with an 8 mm full-width at
half-maximum Gaussian filter.
The statistical analyses were performed using a random effects model as
implemented in SPM99 for UNIX. In the computation of this analysis, first the
observed time courses of image intensities were temporarily filtered to remove
noise associated with low-frequency confounds such as respiration. In
addition, each type of epoch (i.e. 2-back, 0-back and rest) was modelled by a
boxcar waveform with a temporal delay of 6 s to account for the relatively
slow onset of the haemodynamic response. Then, single images for each
participant in each session were created based on the 2-back v.
0-back and 0-back v. rest contrasts. These contrast images were
subsequently entered into a second-level random-effects analysis, which
employed t-tests to assess the significance of the planned
comparisons between conditions and between groups. The mean difference in
cerebral activation between the 2-back and 0-back conditions and the
difference between the 0-back and rest condition within each group and within
each scanning session were assessed using one-sample t-tests. These
analyses were performed for the entire brain volume at the cluster level
(P0.05 corrected for multiple comparisons, thresholded at
P
0.001) as implemented in SPM99
(Friston et al,
1994). The differences between groups in the contrast between
2-back and 0-back and between 0-back and rest in each session were assessed
using two-sample t-tests. In addition to the search in the entire
brain volume for the within-group analysis, in order to increase statistical
sensitivity and to reduce the probability of type 2 error in assessing our
hypothesis regarding the fronto-thalamo-cerebellar and corticolimbic systems,
the between-group as well as the within-group between-session comparisons were
restricted to voxels contained within predefined regions of interest. These
regions of interest were eight spheres 12 mm in radius centred on the loci of
peak activation in the brain regions relevant to our hypothesis (previously
identified in a pilot study of a separate group of 11 healthy volunteers),
sited in the bilateral dorsolateral prefrontal cortex, bilateral thalamus,
bilateral cerebellum and the anterior and posterior cingulate gyrus
(Table 2). In testing for the
significance of changes in these regions, we applied the criterion of
P
0.005. In order to avoid global normalisation artefacts
(Andersson, 1997; Aguirre et al, 1998;
Desjardins et al,
2001), this procedure was not performed.
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RESULTS |
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Imaging data
The analyses of the pattern of cerebral activity during the 2-back
v. 0-back condition in healthy participants demonstrated significant
activations in bilateral prefrontal, premotor and parietal cortex, as well as
in bilateral cerebellum and thalamus (Table
3, Fig. 2a). The
0-back v. rest comparison revealed significant findings in the
supplementary motor area, but not in any of the above-mentioned regions
implicated in a working memory function
(Table 3,
Fig. 2b). The same pattern of
activity was apparent in these participants, during the second scanning
session 68 weeks later (Table
3, Fig. 2c, d).
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In contrast, the comparison between the 2-back and 0-back tasks in the acutely ill patients revealed activation only in a few isolated clusters of the prefrontal and parietal cortex (Table 4, Fig. 3a). Analysis of 0-back v. rest demonstrated significant and widespread pattern of activations in the bilateral prefrontal and parietal cortex, thalamus and cerebellum (Table 4, Fig. 3b). This shifted pattern of activity, with extensive activation during the 0-back task relative to rest and minimal increase in activation from 0-back to 2-back, normalised over time with treatment, although not completely. Thus, after 68 weeks of treatment, accompanied by a significant improvement in symptoms, the activation during the 0-back v. rest condition diminished (Table 4, Fig. 3c) and the activation of 2-back v. 0-back had increased (Table 4, Fig. 3d).
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The above phenomenon is illustrated by the magnitude of activation of the left dorsolateral prefrontal cortex in the different conditions in the two groups of participants (Fig. 4). Thus, healthy participants showed no activation of this brain area during the 0-back task but significant activation during the 2-back task, resulting in a highly significant difference between the two conditions. In comparison, patients with acute psychosis activated dorsolateral prefrontal cortex to a comparable level during both tasks, resulting in a non-significant difference between the two. In effect, the patients exhibited relative hyperfrontality during the 0-back task compared with controls. Importantly, at this session they did not achieve the magnitude of activation present in healthy participants during the 2-back task. In patients in remission the difference in dorsolateral prefrontal cortex activation was detectable between the two test conditions, but again this brain area did not attain the levels of activity apparent in controls during the 2-back task.
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The between-group analysis of data obtained during the first scanning session revealed that in comparison with control participants, patients exhibited less activity in the specified regions of interest in the bilateral dorsolateral prefrontal cortex, thalamus, cerebellum and posterior cingulate cortex during the 2-back v. 0-back condition. In contrast, the comparison between 0-back and rest revealed greater activity in patients relative to controls in all of the above structures except the left thalamus and right cerebellum (Table 5). The between-group analysis of data obtained at the second scanning session revealed that patients exhibited less activity in specified regions of interest in the left dorsolateral prefrontal cortex, left thalamus and right cerebellum during the 2-back v. 0-back condition and relatively more activity in the left dorsolateral prefrontal cortex during 0-back v. rest (Table 5).
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Finally, the comparison of regions of interest between the first and second scanning sessions in healthy participants did not reveal any significant differences, whereas the same comparison in patients revealed significant changes in the activation pattern over time in the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and posterior cingulate (Table 6).
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DISCUSSION |
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The pattern of neural activation during performance of the n-back task normalised to some extent over time with antipsychotic treatment and improvement in the clinical state of the patients. Thus, in the second scanning session, patients did not exhibit any anomalous overactivation during the 0-back v. rest condition, but the level of cerebral activation observed during the 2-back v. 0-back condition was still diminished relative to control participants.
Principal between-group findings
The between-group region of interest analyses confirmed and extended the
within-group results. Compared with control participants, patients with acute
psychosis exhibited significant underactivation bilaterally in the
dorsolateral prefrontal cortex, cerebellum, thalamus and posterior cingulate
in the 2-back v. 0-back condition, while showing overactivation in
all of these regions (with the exception of right cerebellum and left
thalamus) during 0-back v. rest. The relative underactivation during
the 2-back task coupled with the lack of overactivation during the 0-back task
implies true underutilisation of the right cerebellum and left thalamus in
acute psychosis (as opposed to maximal activation during 0-back and no
additional increase during the 2-back task). Moreover, both right cerebellum
and left thalamus remained underused in the second scanning session in
patients with partially remitted disease relative to control participants,
pointing to the stable nature of this disturbance. This interpretation is
supported by the observation of a similar pattern of decreased activation in
clinically stable, medicated patients
(Mendrek et al,
2004). Nevertheless, it must be emphasised that our findings
cannot exclude significant effects on regions outside the set of preselected
regions of interest.
Like the right cerebellum and left thalamus, the left dorsolateral prefrontal cortex also remained functionally suppressed, although to a lesser degree (see below and Fig. 4 for explanation of this anomaly). In contrast, activation of the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and posterior cingulate normalised over time with antipsychotic treatment and attenuation of symptoms, to a level that was not significantly different from that in the healthy group, suggesting that disturbance of these sites represents a state marker for acute exacerbation of schizophrenia.
The question of changes in the pattern of cerebral activity accompanying the resolution of psychosis was also addressed with the between-session analysis of the patients with schizophrenia, which revealed significant change in activation over time in the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and posterior cingulate. It is important to point out that in these patients the disease was in partial rather than full remission during the second scanning session, and further normalisation of function of these structures could be anticipated with the complete resolution of symptoms.
Lateralisation effect
Overall, the results revealed that the more persistent abnormalities of the
acute psychotic state were localised in the left cerebral hemisphere and right
cerebellum, whereas more transient features were localised in the right
cerebral hemisphere and left cerebellum. However, again it is essential to
point out that this conclusion is restricted to areas that were included in
the region of interest analysis. The observed relationship between cerebral
and cerebellar abnormalities is consistent with existence of contralateral
connections between the dorsolateral prefrontal cortex and cerebellum relayed
by thalamic nuclei (Middleton &
Strick, 2001). Accordingly, the concurrent dysfunction of the
dorsolateral prefrontal cortex, cerebellum and thalamus in our schizophrenia
group may represent underlying disturbance in the connectivity between these
structures. This finding, together with other reports (e.g.
Andreasen et al, 1996;
Wiser et al, 1998; Crespo-Facorro et al,
1999), provides support for the cognitive dysmetria
theory of schizophrenia (Andreasen,
1999), while the presence of lateralisation effect adds a new
layer of complexity to the model. Moreover, the observation of more persistent
abnormalities in the left hemisphere is in line with evidence from structural
abnormality studies in schizophrenia, in which most of the studies that found
significant asymmetry reported greater abnormality in the left hemisphere
(Hopkins & Lewis, 2000).
The persistence of the left hemisphere abnormalities and the transience of the
right hemisphere abnormalities during performance of the n-back task
are also broadly consistent with the hemispheric imbalance model proposed by
Gruzelier (1984). On the basis
of evidence from electrophysiological studies, Gruzelier proposed that in
schizophrenia symptoms reflecting excitation (which tend to be transient) are
associated with right hemisphere dysfunction, whereas symptoms reflecting
withdrawal (which tend to be more persistent) are associated with relative
underactivity of the left hemisphere.
Prefrontal cortex findings
Our results shed new light on the debate regarding prefrontal function in
schizophrenia (Weinberger & Berman,
1996; Manoach,
2003) and may help to reconcile the inconsistent findings of a
number of fMRI studies, some of which demonstrated diminished prefrontal
activation during working memory tasks in people with schizophrenia relative
to control participants (Callicott et
al, 1998; Carter et
al, 1998; Stevens et
al, 1998; Perlstein
et al, 2001), whereas others found enhanced activation
(Manoach et al, 1999,
2000;
Callicott et al,
2000) or no difference between the groups
(Honey et al, 2002).
We observed both overactivation of the prefrontal cortex during the 0-back
task and underactivation during the 2-back task in patients relative to
controls. This finding fits well with empirical evidence of a nonlinear,
inverted U-shaped response in dorsolateral prefrontal cortex function to
parametrically increasing working memory difficulty. Thus, in healthy
volunteers dorsolateral prefrontal cortex activation increases together with
the working memory load; but although the initial reduction in working memory
capacity may be associated with relative overactivation of this brain region
(Rypma & DEsposito,
1999), further decline in the capacity to process information is
accompanied by its relative underactivation
(Callicott et al,
1999). Manoach
(2003) has proposed that this
inverted U-shaped function is shifted to the left in people with
schizophrenia, such that the increase, plateau and eventual decrease in
activation can be observed with lower working memory loads than in healthy
individuals. Our data suggest that in addition to this leftwards shift there
might be also a downwards shift in dorsolateral prefrontal cortex function in
schizophrenia. Specifically, although prefrontal dysfunction in the patient
group was modulated to a certain degree by clinical status and the type of
presented challenge, there appears also to exist a persistent abnormal
limitation of left dorsolateral prefrontal cortex activation in schizophrenia.
This limitation might be related to structural anomaly of this region in
schizophrenia reported by Selemon et al
(1995) and Rajkowska et
al (1998).
Present results in the light of previous longitudinal studies
This study is one of the first longitudinal investigations of a cohort of
patients at two different stages of their illness, a study design that has
become more feasible with the widespread availability of non-invasive fMRI
technology. Partly because of the challenging nature of these studies, only a
few such reports in schizophrenia have been published
(Honey et al, 1999;
Manoach et al, 2001;
Stephan et al, 2001).
Honey et al (1999)
demonstrated that after switching from typical to atypical antipsychotic
medication, patients exhibited increased prefrontal and parietal activation
during a working memory task. Stephan et al
(2001) tested two groups of
people with schizophrenia, one drug-free and one treated with olanzapine and
found that the pharmacological treatment normalised cerebellar functional
connectivity during a simple motor task. Manoach et al
(2001) studied
testretest reliability of working memory performance in clinically
stable patients with schizophrenia and in healthy volunteers and found that
even given reliable task performance and a stable clinical status, individual
participants showed variability in cerebral activation, although the
group-averaged activation pattern did not differ between the first and second
scanning sessions.
Study limitations
Our results are subject to some limitations. For example, the fact that
patients were treated throughout the course of the study with antipsychotic
medication does not allow us to distinguish changes in brain function
attributable to long-term primary pharmacological effects from changes
attributable to alteration in clinical state. Specifically, some of our
results might be interpreted as evidence that medication ameliorates
abnormality in one network (right fronto-thalamo-cerebellar) but not in
another (left fronto-thalamo-cerebellar). However, we consider it unlikely
that all of the effects we observed reflect the effects of medication. In
particular, the differences between patients and controls in the first
scanning session are unlikely to be due to medication, as these differences
were in the opposite direction to the changes that occurred during sustained
medication. Moreover, the differences between the groups in cerebral
activation could have arisen partly through the significantly inferior
performance on the n-back task of patients relative to control
participants. However, although the behavioural differences could have
partially contributed to the differential pattern of cerebral activations,
overall this explanation is too simplistic, because the performance of
patients was inferior on both the 0-back and the 2-back tasks, whereas
cerebral activation was increased in the first task and decreased in the
second. Furthermore, although the patients working memory did improve
between the first and second scanning sessions, there was no significant
correlation between change in the task performance and cerebral activity.
Finally, since we specifically investigated working memory we cannot draw any
conclusion about the functional substrates of other cognitive processes.
To summarise, the overall findings of our study suggest that underutilisation of the left dorsolateral prefrontal cortex, left thalamus and right cerebellum represents a stable, potential trait marker of schizophrenia, whereas disturbances in the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and cingulate gyrus are a state-related phenomenon.
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Clinical Implications and Limitations |
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Limitations
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ACKNOWLEDGMENTS |
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Received for publication October 8, 2003. Revision received March 24, 2004. Accepted for publication April 22, 2004.
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