Institute of Psychiatry, London
Maudsley Hospital, South London and Maudsley Trust
Institute of Psychiatry, London
Correspondence: Professor Til Wykes, Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. Tel: 0171 919 3596; e-mail: t.wykes{at}iop.kcl.ac.uk
Declaration of interest This work was supported by the Wellcome Trust.
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ABSTRACT |
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Aims To determine whether there are concomitant brain activation changes as a result of engaging in cognitive remediation therapy (CRT).
Method Three groups (patients receiving control therapy or CRT and a healthy control group) were investigated in a repeated measures design using the two-back test. Functional magnetic resonance imaging (fMRI) data and a broad assessment of executive functioning were completed at baseline and post-treatment. Brain activation changes were identified after accounting for possible task-correlated motion artefact.
Results fMRI analyses indicate that the control group showed decreased activation but the two patient groups showed an increase in activation over time. The patient group that received successful CRT had significantly increased brain activation in regions associated with working memory, particularly the frontocortical areas.
Conclusions This is the first time that brain activation changes in a seriously disabled group of patients with schizophrenia can be associated clearly with psychological rather than pharmacological therapy.
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INTRODUCTION |
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METHOD |
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Participants
At the time of the study there were ethical restrictions on the use of fMRI
with women, therefore the study concentrated only on men. Twelve men were
drawn from consecutive recruits in an ongoing randomised control trial of CRT:
six from the CRT group and six from the control therapy group. All patients
were recruited from the community psychiatric services covering a large
geographical area in south London. They fulfilled DSM-IV
(American Psychiatric Association,
1994) criteria for schizophrenia and also:
In addition, six healthy men with no history of psychiatric disorder were recruited from the local community. All participants gave written consent to take part in the study after the procedures had been fully explained. The groups did not differ in mean age (CRT group: 35 years; patient control: 36 years; healthy control: 36 years) and there were no differences between groups in the mean number of years of formal education (13, 12 and 12 years, respectively). The patients were a chronic group with more than two-thirds having been in contact with the psychiatric services for more than 10 years.
Therapies
Both therapies consisted of 40 one-hour individual sessions over a 12-week
period. The control therapy sessions consisted of occupational therapy
activities such as role play, making a life diary and relaxation. In the CRT
group, the sessions consisted of paper and pencil tasks that were used to
practise information processing strategies in three executive functions:
cognitive flexibility, working memory and planning. For the memory sessions
the therapist included tasks on which information has to be manipulated in
memory. The therapist would encourage the use of efficient information
processing strategies, including the chunking of information and the use of
mnemonic strategies for successful completion of these tasks. Further details
are given in Wykes et al
(1999).
Medication
All patient participants were maintained on antipsychotic medication
throughout the course of the study and there was little change over the course
of treatment in the type or dosage of the medication prescribed. At baseline,
nine participants were prescribed typical antipsychotic medication (four on
CRT and five on control therapy) and the remainder were prescribed newer
antipsychotic medication. At post-treatment one person had changed the type of
drug (from typical to atypical in the CRT group) and one person had been
transferred from risperidone to clozapine (control therapy). The average dose
for the typical antipsychotic medication was 643 mg/day chlorpromazine
equivalents (Foster, 1989).
The percentage of maximum dose for the atypicals was 64%. At the end of
treatment four patients (two in each group) were taking an increased dose of
their typical antipsychotic medication. There were no significant differences
between groups in the levels of prescribed medication.
Neuropsychological tasks
Detailed descriptions of these tasks are given in Wykes et al
(1999).
Cognitive flexibility
Memory
Procedure
Each patient first consented to be in the CRT trial and, after baseline
assessment, each was randomised to either the CRT group or the control therapy
group. They were then asked to take part in the scanning project. If they
agreed, and were also able to complete the activation task (the two-back task)
with at least an 80% accuracy rate outside the scanner, they were included in
the current study. Following the 12-week therapy window the two patient groups
completed the second set of scans. The healthy control group also completed
the scans with a 3-month interval. All groups completed cognitive performance
tasks at the time of the scanning procedure.
Functional magnetic resonance imaging
Cognitive activation task
The task adopted in this study was the ubiquitous n-back task in
which the participant has to identify whether a visually presented letter had
appeared before. The load chosen for this study was two-back because it has
been shown to be a relatively easy task for our patients to perform with high
accuracy. Callicott et al
(1999) have suggested that
individuals may disengage from the task if it is too difficult, and so
reasonable accuracy on the task was thought to be important rather than
controlling for capacity constraints. The task involves continuously updating
a record of the previous two letters into a short-term store and then
comparing the current letter on the screen with the contents of that store.
These are the cognitive operations in working memory described by Baddeley
(1986). The activation during
this task was compared with the activation in a vigilance condition that
controlled for the perception of the letters as well as the motor response to
targets. The two tasks are matched for target frequency. The activation
paradigm used for this study is based on that described by Cohen et
al (1994), and further
developed by Mellers et al
(1995), and consists of three
conditions.
The beginning of each condition is indicated to the participant by a message on the screen (Look for X or Task) and participants are asked to say each letter to themselves (subvocally) as it appears on the screen in both the vigilance and working memory conditions. The rate of letter presentation (one every 1.2 s) and the frequency of target responses (two or three in each 15-letter epoch) are the same in the vigilance and working memory conditions. Both of these conditions therefore required participants to attend to the screen, to encode the letters and to deliver a specified motor response.
The working memory condition differed from the vigilance condition in that it required participants to keep a continuously updated record of the previous two letters and to compare the current letter on the screen with that occurring two before. The fMRI experiment described here involved a comparison of working memory and the vigilance conditions performed by each participant while they were in the scanner. The two conditions alternated ten times over a 5-min imaging period, giving five contrasting blocks. Each condition ran for 30-s epochs, during which image volumes, each consisting of ten axial slices, were acquired.
Image acquisition
Magnetic resonance images were acquired using a 1.5-Tesla General Electric
Sigma system (General Electric, Milwaukee, USA) fitted with ANMR hardware and
software (Advanced Nuclear Magnetic Resonance, Woburn, Massachusetts, USA). A
quadrature birdcage head coil was used for radiofrequency transmission and
reception. Foam padding within the head coil and a restraining forehead band
minimised head movement throughout the scanning procedure. Using a midsagittal
scout image, ten axial slice positions (5 mm thick, 0.5 mm interslice gap)
were orientated in the anterior commissureposterior commissure
(ACPC) plane and the fourth slice was positioned on the ACPC
plane. For each participant, 100 T2*-weighted
multi-slice data-sets depicting blood-oxygenation-level-dependent (BOLD)
contrast were acquired by use of a gradient echo echoplanar technique (echo
time=40 ms; repetition time=3000 ms).
Image analysis
Image preprocessing. Prior to brain activation mapping, the
effects of subject motion were minimised by a three-dimensional re-alignment
and regression procedure at the individual level and correlated at group level
by inclusion as a covariate in the analysis. This procedure has been described
previously in detail by Bullmore et al
(1999).
Brain activation mapping. Periodic change in
T2*-weighted signal intensity at the
experimentally determined frequency of alternation between OFF and ON
conditions were estimated by an iterated least-squares fit of a sinusoidal
regression model to the movement-corrected time series observed at each voxel.
This model included a pair of sine and cosine terms at the fundamental
frequency of the OFF/ON conditions, represented by the coefficients
and
. The sign of
indicates the timing of the periodic response
signal in relation to the OFF/ON conditions. If
>0, then the fitted
model response indicates that a maximum signal is observed during the ON
condition, whereas if
<0 the model indicates the maximum signal
during the OFF condition. The power of the ON/OFF response frequency was
estimated by
2+
2 and divided by its
standard error, giving a standardised test statistic entitled the fundamental
power quotient (FPQ). The FPQ was computed at each voxel. Significantly
activated voxels (with a probability of a false-positive activation
<10-3) were identified by spatiotemporal randomisation testing
(Brammer et al, 1997).
These were coloured and super-imposed on the mean grey-scale (echo-planar)
image to yield a brain activation map for each participant
(Bullmore et al,
1996). Generic brain activation maps were constructed following
the method set out in Brammer et al
(1997).
Overall statistical analysis
Because of the small sample size and the possibility of type II errors, the
analysis set out to identify only the largest differences. Small but
significant differences may have been present but these were not the focus of
the study. The statistical analysis of the brain imaging data was carried out
as follows. First, cortical areas were identified which were of relevance to
the memory component of the task, the perception of the target and the motor
response (i.e. the vigilance v. working memory condition). These
regions of interest were identified using analyses of covariance following the
method described in Curtis et al
(1999). The coordinates of
these brain areas were then checked against the generic brain activation map
for normal control data and were chosen for further analysis if they had a
maximum FPQ of at least 1.9 (voxel-wise type I error probability <0.00001).
The FPQ values for each of these previously identified regions were then used
in all subsequent analyses: a doubly multivariate repeated measures analysis
with group as the between-subject factor (healthy controls,
control therapy patients and CRT patients) and time and
brain region as the repeated measures within-subject factors for
testing all brain regions simultaneously; and if this analysis indicated
differences, then these were investigated by looking at the univariate test
measures separately to distinguish the differences.
In addition to these analyses, participants were rated as to whether they had made significant gains on the memory tests other than that used in the fMRI experiments. If significant gains were made (improvements across all tests), then they were labelled as a CRT-successful group and their data were compared with those of the remaining participants in a similar way to the analyses described above.
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RESULTS |
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On the activation paradigms adopted in the scanner there was no difference between the patient and control groups on the identification of a target (mean per cent correct: patients 97%, controls 95%). However, the patients were less able to identify the target sequences in the working memory paradigm, although they were still performing above chance (mean per cent correct: patients 70%, controls 99%; t=3.3, P<0.01) and there were no differences between the two patient groups.
Changes over treatment phase
After treatment there were no significant changes in the symptom and
disability scores in either therapy group. However, there was a significant
improvement in self-esteem (t=2.61, P<0.05) in the CRT
group.
There were no changes in the neuropsychological test scores of the healthy control participants (shown in Table 1) and there were no significant changes in the patient groups' detection rates for targets while in the scanner (t=-0.22, P=0.9). Table 1 also gives data on the percentage of individuals in the two patient groups who improved by more than one standard error of the baseline scores (Wykes et al, 1999). Few differences were apparent on the cognitive flexibility tests. However, there was a definite advantage to the CRT group in the memory domain, where for three of the four tests more than twice as many people improved in the CRT group compared with the control therapy group. Half of the CRT group (i.e. n=3) showed an improved score from baseline to post-treatment on the tests of memory (i.e. showed an improved score on at least half of the tests).
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Functional magnetic resonance imaging data
Following the statistical analysis set out above, the regions identified as
differing between the groups at baseline using the analyses of covariance are
shown in Table 2. The location
of the foci of these cerebral differences are referred to by their x,
y and z coordinates, as set out by the Talairach & Tournoux
(1988) atlas, and by their
Brodmann area positioning. All the differences were those in which there were
higher numbers of activated voxels in the healthy control participant group
than in either of the two patient participant groups. There were no
differences between the two patient groups of any significance. These results
indicate, as in most other studies of working memory, that patients with
schizophrenia show less activation, especially in frontal regions.
Changes over time: between and within groups
A doubly multivariate repeated measures analysis was carried out with
group as the between-subject factor and time as
the within-subject factor, where all ten brain regions identified in
Table 2 were tested
simultaneously (i.e. to test the consistency of the changes across all brain
regions using the GreenhouseGeisser adjustment). The results of this
analysis showed that there was no overall effect of group (Pillai's trace
F=2.59, d.f. 11,6, P=0.127) or time (F=1.525, d.f.
11,6, P=0.34) but the overall group x time interaction was
significant (F=2.41, d.f. 11,6, P=0.046). Nine out of ten
univariate tests had statistically significant interactions. Tukey post
hoc tests were carried out on the change scores in the individual
univariate tests and these significant contrasts are shown in
Table 3.
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The post hoc differences were investigated further using paired t-statistics. These showed that there were consistent changes for the CRT group in the right inferior frontal gyrus and left and right occipital cortex (lingual gyrus) (all showing increases in FPQ values from baseline to post-therapy). For the control therapy group there was a significant increase in the left frontal (orbito-frontal) and right frontal cortex. For the normal controls there were significant changes in the left inferior/middle frontal gyrus, right frontal cortex, right inferior frontal and right insula/inferior frontal, which were all in the direction of decreased activation post-therapy (see Table 2 for details of coordinates and Brodmann areas).
In order to illustrate these differences, Fig. 1 shows the activation change in the right inferior frontal gyrus, where the CRT group increased their activations, the control therapy group remained almost the same and the healthy controls decreased activation. Similar findings were found for the two occipital cortex measures, although here there were also some changes in the control therapy group (see Fig. 2).
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The overall results of the FPQ analyses above show that there is a consistent increase in the power of the activation in the CRT group, whereas the normal control group reduced activation. In addition to the increase in activation in the frontal areas, there were also increases in the visual cortex for the patient groups. There were no differences in activation change between those who changed their medication and those who were on stable doses, nor between those on typical and those on atypical medication. On the whole, the changes in activation were for the healthy control group to decrease activation and for the patient groups to increase activation, with the CRT group increasing activation more consistently in key regions.
Exploratory analyses of cognitive changes following CRT
From the neuropsychological data collected outside the scanner it was clear
that only three of the six participants had received any substantial benefit
from the CRT (i.e. improved across the domain of memory tests). There were no
initial differences between these three patients and the remaining three who
received therapy. In particular, there were no differences in medication (one
person in each of the two subgroups received the newer antipsychotic
medications). A one-way analysis of covariance (ANCOVA) showed a significant
change in activation in frontal and visual areas for these three successful
patients. Red-coloured voxels indicated greater activation in the three CRT
participants at post-treatment. The error threshold was set at 0.01 with a
total of 51 voxels found to be significantly activated (two error voxels were
expected). The details of the major changes over time are described in
Table 4.
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The activation maps shown in Fig. 3 show that there is an increase in the size and number of activations. The number of generically activated voxels had risen from 43 to 133 (shown in red). The most prominent were identified around the frontal and visual cortical areas.
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When further doubly multivariate repeated measures analyses were carried out on the FPQ values there were no significant effects of time, group or group x time interaction in the areas identified in Table 2 and no significant differential changes in the univariate tests. The only trend noted in the data was for the CRT improved group to decrease activation in Brodmann area 11 (right frontal cortex; F=4.16, P<0.08), which is similar to that noted in the normal control group.
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DISCUSSION |
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At baseline the results from the working memory activation scans replicated the results of many other studies, that is, there was significantly less activation in both patient groups compared with the healthy control group, particularly in the frontal and visual cortex (cf. Carter et al, 1998; Curtis et al, 1999; Honey et al, 1999; Wexler et al, 2000). This marked hypofrontality in patients with schizophrenia has been noted particularly in tasks with a marked working memory component (Callicott et al, 1999), despite the patients having similar characteristics to the healthy controls and despite making sure that the patients were carrying out the task to a similar level.
At post-treatment there were improvements in performance on the neuropsychological tasks, but improvements in memory were specifically related to receiving CRT, as was found in the larger study reported elsewhere (Wykes et al, 1999, 2002). At post-treatment there were also increases in activation in the areas that were significantly less activated in the healthy control group at baseline. Three patients in particular made generalised improvements (increased performance on all memory tests) and they had the largest activations.
The healthy control group changed little in performance on the memory tasks both in and outside the scanner. However, their brain activation generally decreased on the memory task at the time of the post-treatment scans. This change in activation with practice on the task has been noted by others (e.g. Goldman-Rakic, 1994). It is therefore even more surprising that the change in the patient groups was to increase their activation in key brain regions; this is particularly so in the CRT group. There were no other differences in clinical variables (e.g. medication or symptoms) that could account for the changes, so the most parsimonious explanation is that the CRT was responsible. Further evidence for this hypothesis comes from the association of marked increases in brain activity in those people who received the most benefit from the CRT.
What do these data indicate about the hypofrontality in schizophrenia
noted in previous studies?
Previous studies that identified hypofrontality in patients with
schizophrenia have generally been cross-sectional and, because of the multiple
replications observed, hypofrontality has been assumed to be not only
pervasive but also a trait phenomenon. However, this study has shown that it
is neither a pervasive functional deficit nor a trait phenomenon. This has
been pointed out by Curtis et al
(1999), who found that
hypofrontality was related to the type of task being carried out, with verbal
fluency tasks showing more of this phenomenon than semantic decision tasks.
But in that study it was not possible to identify the cause of these
differences as there was little control over the behavioural response to the
verbal fluency task, because it was covert, and the semantic decision task was
easier. Either factor might have affected their results, in addition to any
putative cognitive processing differences. In this longitudinal study the
patients were presented with the same task so that the difficulty level was
the same, the behavioural response was overt so that performance could be
monitored and we must assume that the cognitive processing requirements were
the same on each occasion. Therefore, the changes in activation patterns must
be related to state rather than trait differences in cognition and brain
activation.
What is the likely mechanism for the changes in activation?
There are two main issues here: to explain why healthy participants
decrease activation on the second presentation of the working memory paradigm,
which was 3 months later; and to explain why there were differential changes
in the patient groups, particularly the CRT group. Activity in the frontal
cortex could be related to a search for relevant information strategies that
make the task simpler (or less effortful) to complete. One metaphor for this
process would be the compiler setting up the schema for the contention
scheduler in the model proposed by Shallice & Burgess
(1996), which may or may not
be available to conscious examination. If this is the case, then practice will
make access to a particular set of efficient schema more likely and the search
can be terminated, producing smaller activations in particular brain regions.
This might explain the decrease in the controls.
The increase for the patients could then be due to activating their search for a suitable contention schedule and associated schema on the second occasion. Both patient groups have been provided with one-to-one therapy and it might be expected that the effects of either therapy would be to increase attention during the task, but there were differential changes between the groups, particularly in prefrontal regions, that might be related to the specific therapy received. In neither type of therapy was the specific task practised. Cognitive remediation therapy concentrated on encouraging participants to adopt an organised approach to all tasks and particularly to increasing the use of specific information processing strategies. There is also an emphasis on rehearsal and other mnemonic strategies, which are useful in tasks requiring the storage and retrieval of material over both short and long (up to 10 min) periods. It is possible that the changes in visual cortex are part of an improvement in using visual processing strategies in addition to verbal rehearsal. This might explain the lack of an advantage to the CRT group in the improvement on the visual span task.
Alternatively (or additively), both groups of patients receiving psychological therapy may have increases in their general attention, although other brain regions may then have been implicated that were not identified in the analyses presented here. It is also possible that increases in self-esteem lead to changes in self-efficacy, which lead to improvements in the pathways that are known to be used in this task. What is clear is that the improvements in neuropsychological task performance were produced by practice on information processing strategy choice and use, which is under conscious control.
The specific changes in activation patterns that were identified in this study were towards increases in regions that were identified as contributing to performance in the healthy control group and in other studies of working memory (Cohen et al, 1997). This is significant because there have been speculations that patients with schizophrenia may activate different brain regions in order to compensate for functional deficits. This was not apparent in the present study, although of course there may have been subtle activation that would not be found in such a small study. Smith & Jonides (1998) suggest from their review that the left parietal cortex subserves the storage component of working memory and that left hemisphere speech areas subserve rehearsal. If this is the case (and there are many other regions implicated by other research groups), then neither of these areas are stimulated more than others in this study. This implies that the storage component is static or decreased in patients with schizophrenia, so that they must use more maintenance functions to increase their performance. This maintenance function has been suggested as being subserved by the prefrontal cortex (Cohen et al, 1997), which was one of the areas of increased activation at post-treatment. However, C. Frith (personal communication, 2002) considers activation in right prefrontal regions to be the result of monitoring for the appropriateness of the response. If this is the case, then participants with schizophrenia were not carrying out this self-monitoring before treatment but began monitoring afterwards.
Honey et al (1999) found similar results with another type of therapy, risperidone, which was associated with improvements in frontal cortex functioning over a shorter period of time. Although there are methodological difficulties with their study, particularly the lack of randomisation or blind assessment, the effects were to increase the frontal activation in those patients who were treated with atypical antipsychotic medication compared with controls. The effects of CRT cannot be explained as an effect of medication because three-quarters of the participants were prescribed typical antipsychotic medication and the type of medication was not correlated with the level of activation change. The differences achieved post-therapy in the Honey et al study were therefore achieved in the group that was least likely to improve. It may be that providing both psychological and atypical pharmacological therapy may produce an additive effect, but it is clear that psychological therapy with typical medication can produce such an effect.
Was there a normalisation of activation following intervention?
The activation patterns were significantly different from those of the
healthy control participants before therapy but did not differ significantly
after therapy. To this extent the patterns could be said to have normalised.
However, they did not achieve the same levels of activation as the healthy
participants at entry to the trial, but perhaps this is too stringent a
criterion because the healthy participants decreased activation probably
because of practice effects as well as reduced novelty. Both of these factors
would also have affected the patient groups. Wexler et al
(2000) suggest that it is
possible to produce normalisation of performance following extended practice
at a memory task, although their data are for only one patient.
In conclusion, this study has shown that cognitive performance changes following CRT are correlated with changes in brain activation, particularly increases in frontal regions. Recent studies have concentrated on the changes related to medication (Honey et al, 1999). However, there was no evidence that the changes measured either outside or inside the scanner were related to medication, although clearly there may be additive (or multiplicative) effects that can be identified only in a larger study. Our study demonstrates that hypofrontality may be ameliorated by psychological treatment. It remains to be seen whether such improvements in brain functions are sustained without further intervention or whether top-up or maintenance therapy is required. The research community has now amassed enough evidence that psychological therapy changes cognition in schizophrenia, and with the new evidence of accompanying brain changes we now have further hope of alleviating some of the misery associated with this disorder.
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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 March 13, 2001. Revision received March 28, 2002. Accepted for publication April 16, 2002.
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