Imperial College Faculty of Medicine, London
University of Cambridge
Imperial College Faculty of Medicine, London
Correspondence: Dr Eileen Joyce, Imperial College Faculty of Medicine, Charing Cross Site, St Dunstan's Road, London W6 8RP. e-mail: e.joyce{at}ic.ac.uk
Funding from The Wellcome Trust.
* Presented in part at the European First Episode Schizophrenia Network
Meeting, Whistler BC, Canada, 27 April 2001.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To examine executive function in first-episode schizophrenia, characterise the nature of the impairment and specify any relationships with symptoms and duration of untreated psychosis (DUP).
Method Patients (n=136) and normal controls (n=81) were assessed with the Cambridge Automated Neuropsychological Test Battery, National Adult Reading Test IQ, and Scales for the Assessment of Positive and Negative Symptoms.
Results Memory and executive impairments in patients were independent of IQ level. Spatial working memory was impaired because of inadequate strategy use. On a planning task, patients showed reduced planning times and suboptimal problem-solving. On an attentional set-shifting task, 75% of patients were able to perform an extra-dimensional shift thought to be a core attribute of prefrontal cortex function. Those who failed had significantly longer DUP.
Conclusions Prefrontal cortex function deteriorates at the onset of psychosis and continues to worsen over time.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Clinical assessments
Patients were assessed on recruitment with the Scales for the Assessment of
Positive Symptoms (SAPS; Andreasen,
1981) and Negative Symptoms (SANS;
Andreasen, 1983). Scores for
positive, disorganisation and negative syndromes of schizophrenia
(Liddle & Barnes, 1990) were calculated for each patient by summing the SAPS and SANS global sub-scale
scores pertaining to each factor. Duration of untreated psychosis (DUP) was
established for each patient by reviewing relevant information in the case
notes, and questioning the patient and relatives and/or carers. A modified
questionnaire (Loebel et al,
1993) was used, relating to the onset of positive psychotic
symptoms (Lieberman et al,
1993).
Cognitive function
In order to test as wide a range of patients as possible and to reduce
state effects, neuropsychological assessments were undertaken when the patient
was able to cooperate with the requirements of the testing procedure, usually
once they had been medicated. To examine the specificity of frontal executive
impairments, IQ and memory were also assessed. The National Adult Reading Test
(NART) was used to estimate IQ (Nelson
& Willison, 1991). Several subjects in both groups declined to
take this test because of dyslexia or other reading problems. IQ was obtained
for 110 patients and 73 controls. CANTAB tests of memory and executive
function were administered on an IBM-compatible PC with a touch-sensitive
screen (Sahakian & Owen,
1992).
Spatial span (Owen et al,
1990)
This measured the ability to remember the order of sequences of squares
presented on the screen in increasing number. This task was completed by 135
patients.
Pattern and spatial recognition memory
(Sahakian et al, 1988)
In the pattern recognition test, 12 abstract visual stimuli were presented
sequentially on the screen. Each stimulus was then presented along with a
novel stimulus and the subjects were asked to touch the familiar stimulus.
This was repeated with 12 different stimuli, giving a maximum possible score
of 24. In the spatial task, five identical squares were presented in series,
each in a different location. One square was then presented at each target
location along with a square at a novel location. Subjects were asked to touch
the square at the location they recognised from the learning phase. Four such
trials using different locations were administered, giving a maximum possible
score of 20. These tasks were completed by 132 patients.
Spatial working memory (Owen et
al, 1990)
Subjects were required to open sets of boxes, varying between
three and eight in number, to find tokens. Errors were recorded when boxes in
which tokens had been found were reopened. A common strategy employed in the
performance of this task is to follow a predetermined sequence, beginning with
one box and returning to start each new search with that box after a token has
been found. A measure of this strategy was derived by counting the number of
search sequences starting with the same box at the six- and eight-box stages.
All patients completed this task.
Planning (Owen et al,
1990)
In this modification of the Tower of London task
(Shallice, 1982), subjects
moved coloured balls in an arrangement displayed on the screen
to match a goal arrangement. Subjects were asked to attempt the solution in
the minimum number of moves, which could be 2, 3, 4 and 5. For each problem, a
yoked control condition provided measures of motor initiation and execution
times. As a stringent measure of accuracy, the proportion of problems solved
in the minimum number of moves, i.e. perfect solutions, was used. Latency
measures were: (a) initial thinking time (planning time), derived by
subtracting the time taken to complete the first move of each problem during
the control phase from that of the planning phase; and (b) subsequent thinking
time per move, derived by subtracting the time to complete the task after the
first move during the control phase from that of the planning phase, divided
by the number of moves taken for each problem. A total of 135 patients
completed this task.
Attentional set-shifting (Owen et
al, 1991)
Subjects were required to learn a series of visual discriminations in which
one of two stimulus dimensions (shape or line) was relevant. Once correct
responding was established, they were introduced to different exemplars of the
same dimensions. Subjects needed to maintain attention to the same dimension
for correct responding, thus testing their ability to generalise the rule they
had just learned (intra-dimensional shift, IDS). At the later,
extra-dimensional shift stage (EDS), the rule was reversed so that the
previously irrelevant dimension now became relevant. This tested the ability
to inhibit the previously correct response set and adopt a new response set by
shifting attention from one dimension to the other. Thus, the EDS stage is
analogous to the attentional shift involved in Wisconsin Card Sorting Test
performance. A total of 133 patients completed this task.
Statistical analysis
Results were analysed using SPSS 10. Latency and DUP data were
log10 transformed to reduce skew; t-tests were used for
two-group single variable measures, with degrees of freedom adjusted according
to Levene's test for equality of variance. For repeated measures data, the
analysis of variance (ANOVA) was used. To explore whether general IQ explained
performance on the more specific tests, Pearson's correlation coefficients
between NART IQ and memory and executive variables were calculated and, where
significant, the analyses were repeated with an analysis of covariance
(ANCOVA) entering IQ as a covariate. For the attentional set-shifting task,
the numbers of subjects and controls passing or failing each stage were cast
into contingency tables and analysed using the likelihood ratio method
(Kullback, 1959;
Robbins, 1977). The resultant
information statistic (2i) is distributed as chi-squared.
Because of multiple comparisons, was set at 0.01.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and controls were matched for age but not gender ratio (Table 1). Preliminary analyses were performed on control data and no gender differences in neuropsychological performance were found, in line with previous work with these tests (Robbins et al, 1994). The mean IQ of the patient group was significantly lower than that of the control group. The relationship between IQ and memory and executive function was examined statistically as described above.
|
Spatial span, pattern and spatial recognition memory
As shown in Table 2,
patients were significantly impaired on all three memory tasks. Pattern and
spatial recognition memory correlated significantly with IQ (r=0.26
and 0.24, respectively; P<0.001). ANCOVAs showed that, although IQ
contributed to performance (F1,177=7.17 and 6.38,
respectively; P<0.01) the group differences remained significant
(F1,177=16.19 and 9.65, respectively; P<0.01).
Thus, specific impairments in short-term spatial memory capacity and long-term
episodic memory were evident in the patient group.
|
Spatial working memory
Figure 1(a) shows that
patients made more errors than controls at the more difficult six- and
eight-box stages (group effect: F1,214=39.90,
P<0.001; group x difficulty interaction:
F3,642=28.28, P<0.001). IQ correlated with
total errors (r= -0.36, P<0.001). An ANCOVA showed that,
although IQ contributed to performance (F1,79=19.32,
P<0.001), the group difference for errors remained highly
significant (F1,179=16.98, P<0.001).
|
Performance of this task can be influenced by both short-term memory capacity and the degree to which an efficient strategy is adopted (Owen et al, 1990). In our previous study (Hutton et al, 1998), spatial span and working memory strategy score correlated with spatial working memory errors in the patient group. Therefore, in the present study, we entered these measures as covariates in separate ANCOVAs. After covarying for strategy, there was no group difference in spatial working memory error score (group effect: F1,213=2.05, n.s.), the effect of strategy being highly significant (F1,213=138.87, P=0.001). After covarying for spatial span, the group difference for spatial working memory errors remained significant (group effect: F1,212=20.17, P<0.001) despite a significant effect of spatial span (F1,212=35.82, P=0.001).
Thus, there was a specific impairment in spatial working memory in the patient group. The group difference in errors was largely accounted for by the less efficient use of a search strategy in the patient group rather than differences in short-term spatial memory capacity.
Planning
Figure 1 shows that patients
solved fewer problems perfectly at the 3-, 4- and 5-move levels of difficulty
(group effect: F1,213=43.01, P<0.001; group
x difficulty interaction: F1,639=12.51,
P<0.001). IQ correlated with perfect solutions (r=0.29,
P=0.001). An ANCOVA showed that, although IQ contributed to
performance (F1,179=6.89, P=0.01), the group
difference in perfect solutions remained highly significant
(F1,179=21.66, P=0.001).
Figure 2 shows that the time spent thinking about the problem prior to the first move increased linearly with increasing problem difficulty in the control group. This effect was not seen in the patients who were significantly faster (group difference: F1,214=15.42, P=0.001; group x difficulty interaction: F3,642=2.95, P=0.03). An ANCOVA showed that IQ did not contribute to initial thinking time (F1,180=1.87, n.s.). Patients and controls did not differ in the time taken for each subsequent move (F1,214=2.83, n.s.).
|
Correlations were performed for each group between log10 initial thinking time and proportion of perfect solutions obtained for each stage of difficulty. A highly significant positive relationship was found between time taken to think about the 5-move problem and performance in the control group (r=0.53, P=0.001) and a weaker, non-significant relationship for the same measures in the patient group (r=0.16, P=0.07).
Thus, patients were impaired in planning in that they solved fewer moves perfectly. In addition, patients spent significantly less time planning the solutions. Performance was highly related to planning time for the hardest problems in controls but not in patients.
Attentional set-shifting
Figure 3 shows that more
patients than controls failed the test. This was significant when measured
either by stage reached (t(177)=-4.11, P<0.001) or by
number passing and failing (2i=12.26,
P<0.001). When the number of subjects passing and failing each
stage was examined, this was significant at the extra-dimensional shift stage
only (2i=7.65, P=0.006). IQ did not correlate
with stage reached (r=-0.09, n.s.).
|
As the majority of patients passed the test, we looked for other evidence of impairment in these by examining the number of errors at the intra-dimensional and extra-dimensional shift stages (IDS: patients 1.81 (s.d. 4.94), controls 0.81 (s.d. 0.92); EDS: patients 9.54 (s.d. 9.14), controls 6.13 (s.d. 6.69)). Although there was tendency for patients to make more errors than controls overall (group effect: F1,174=3.60, P=0.06) they did not make proportionately more errors at the EDS stage (group x stage interaction: F1,174=0.08, n.s.). When those passing and failing this task were compared for IQ, spatial span, pattern and spatial recognition memory, spatial working memory errors and perfect solutions on the planning task, there were no significant differences (range of t: 0.26-0.87).
Relationships between neuropsychological function, symptoms and
duration of untreated psychosis
Correlations were performed in the patient group between IQ, spatial
working memory errors, number of perfect solutions on the planning task, stage
reached on the attentional set-shifting task, pattern and spatial recognition
memory scores, log10 DUP and scores for positive, negative and
disorganisation syndromes (Table
3). The data showed that the neuropsychological scores tended to
intercorrelate except for the attentional set-shifting task score, which
failed to correlate with any other task. Conversely, only performance on the
attentional set-shifting task correlated with log10 DUP
(r= -0.23, P=0.01), indicating that the shorter the duration
of untreated psychosis the higher the stage reached. When patients passing and
failing this task were compared, log10 DUP was significantly longer
in the group that failed (47.5 (s.d. 72.54) weeks v. 93.6 (s.d.
118.05) weeks; t(113)= -2.59, P=0.01).
|
There were no significant correlations between syndrome scores and neuro-psychological scores or log10 DUP (range of r=0.00-0.16).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
NART IQ correlated with many measures of memory and executive function, questioning the specificity of our findings. However, in all cases, significant differences remained between the groups when IQ was taken into account in the statistical analysis. In the patient group, measures of planning, working memory strategy and recognition memory intercorrelated. Neuropsychological performance in the patient group was not related to symptoms or medication type. Taken together, these data suggest that specific impairments in memory and executive function are present at the onset of chizophrenia and that deficits in the two cognitive domains coexist. These conclusions are in agreement with previously published studies (Hoff et al, 1992; Saykin et al, 1994; Bilder et al, 2000).
Nature of executive impairment at the onset of schizophrenia
The analysis of an enlarged cohort of patients and controls and the
inclusion of additional neuropsychological and clinical measures allows
further interpretation of our results.
The pattern of reduced number of perfect solutions on the planning task and increased spatial working memory errors, because of the inadequate use of a search strategy, is also found in patients with chronic schizophrenia (Elliott et al, 1998; Pantelis et al, 1999). Patients with frontal lobe resections are similarly impaired but not those with temporal lobe resections or cortical and subcortical dementia such as Alzheimer's disease and Parkinson's disease (Owen et al, 1990, 1992, 1995, 1996c; Sahgal et al, 1992). Functional imaging studies of the planning and spatial working memory tasks in normal volunteers have shown that the critical area of activation is the dorsolateral prefrontal cortex (Baker et al, 1996; Owen et al, 1996a, b). Taken together, our results suggest that dorsolateral prefrontal cortex function is impaired at the onset of schizophrenia.
However, the performance of our patients differs from that of patients with chronic schizophrenia and frontal lobe resection in several important respects. In the planning task, our patients were faster to initiate responses than controls but no different in the time taken to complete each subsequent move. Patients with frontal resections and chronic schizophrenia, by contrast, have normal initial thinking times but are slower in thinking about subsequent moves than controls (Owen et al, 1990; Pantelis et al, 1999).
Another difference between the performance of our patients and that of patients with frontal lobe resection and chronic schizophrenia is with respect to attentional set-shifting task performance. Far fewer first-episode patients failed this task compared with groups of patients with frontal resection (Owen et al, 1991) and chronic schizophrenia (Elliott et al, 1995; Pantelis et al, 1999). Approximately 75% of our patients performed this task normally. They completed the task and made no more errors on the most stringent EDS stage than controls. This contrasts markedly with patients with chronic schizophrenia, who are most impaired on the attentional set-shifting task out of all CANTAB executive tasks (Elliott et al, 1998).
The minority of patients who did fail the attentional set-shifting task were specifically impaired on the EDS stage, which requires inhibition of a previously acquired response set and a shift of attention away from one stimulus dimension to another. The ability to inhibit a pre-potent response and execute an alternate response is considered a core attribute of prefrontal cortex function and fundamental to performance of other so-called frontal tasks such as the Wisconsin Card Sorting Task. This specific pattern of impairment on the attentional set-shifting task was also found in patients with frontal resections (Owen et al, 1991) and performance of the EDS stage critically activated dorsolateral prefrontal cortex in a functional imaging study of normal volunteers (Rogers et al, 2000). In patients with chronic schizophrenia, however, failure occurred on EDS and other stages, indicating additional cognitive difficulties in this group such as discrimination learning and rule abstraction (Elliott et al, 1995; Pantelis et al, 1999).
Relationship between neuropsychological function and duration of
untreated psychosis
Our findings indicate that at illness onset, the nature of the executive
impairment is different from that of chronic patients. The finding that
first-episode patients initially respond quicker than controls and the lack of
relationship between planning time and correct performance apparent in
controls requires further investigation, as this may reflect the involvement
of different cognitive processes in the two groups. Further, although there
were no relationships between performance and syndrome scores, it would be
important to know whether the profile of deficits in first-episode
schizophrenia reflects the acute stage of the illness and whether this changes
to that of chronic patients over time.
A relationship between chronicity and neuropsychological function is indicated by the finding that the only differentiating factor between those passing and failing the attentional set-shifting task was duration of untreated psychosis. Patients who passed the test had a mean DUP of 47.5 weeks whereas those who failed had been ill for almost twice as long (93.6 weeks). One possible explanation is that prefrontal function begins to deteriorate at the onset of psychosis and thus is more evident in those who had had a longer DUP. In support of this, we found that attentional set-shifting performance had deteriorated at 1-year follow-up assessments in a smaller group of patients (Joyce et al, 1999). This would also explain why many more patients with chronic schizophrenia are impaired on this task compared with first-episode patients (Elliott et al, 1995; Pantelis et al, 1999).
The contribution of duration of untreated psychosis to the severity and out-come of psychosis is controversial (see Verdoux et al, 2001). In a previous study we found no association between DUP and symptoms at presentation (Barnes et al, 2000). The finding of a robust association between DUP and attentional set-shifting ability in the current study suggests that this task may be more sensitive to the effect of untreated psychosis than symptom measures. However, until longitudinal measures are available, we are unable to distinguish between the effects of illness chronicity per se and treatment delay on the pathophysiological processes underlying schizophrenia.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA.
Andreasen, N. (1981) Scale for Assessment of Negative Symptoms (SANS). Iowa, IA: University of Iowa.
Andreasen, N. (1983) Scale for the Assessment of Positive Symptoms (SAPS). Iowa, IA: University of Iowa.
Baker, S. C., Rogers, R. D., Owen, A. M., et al (1996) Neural systems engaged by planning: a PET study of the Tower of London Task. Neuropsychologia, 34, 515-526.[CrossRef][Medline]
Barnes, T. R. E., Hutton, S. B., Chapman, M.J., et al
(2000) West London first-episode study of schizophrenia:
Clinical correlates of duration of untreated psychosis. British
Journal of Psychiatry, 177,
207-211.
Bilder, R., Lipschutz, L., Reiter, G., et al (1992) Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophrenia Bulletin, 18, 437-448.[Medline]
Bilder, R., Goldman, R., Robinson, D., et al
(2000) Neuropsychology of first-episode schizophrenia:
initial characterisation and clinical correlates. American Journal
of Psychiatry, 157,
549-559.
Elliott, R., McKenna, P., Robbins, T., et al (1995) Neuropsychological evidence for frontostriatal dysfunction in schizophrenia. Psychological Medicine, 25, 619-630.[Medline]
Elliott, R., McKenna, P., Robbins, T., et al (1998) Specific neuropsychological deficits in schizophrenic patients with preserved intellectual function. Cognitive Neuropsychiatry, 3, 45-70.[CrossRef]
Hoff, A., Riordan, H., O'Donnell, M., et al (1992) Neuropsychological functioning of first-episode schizophreniform patients. American Journal of Psychiatry, 149, 898-903.[Abstract]
Hutton, S., Puri, B., Duncan, L.-J., et al (1998) Executive function in first-episode schizophrenia. Psychological Medicine, 28, 463-473.[CrossRef][Medline]
Joyce, E., Hutton, S., Ambery, F., et al (1999) Improvement or deterioration in different executive cognitive processes early in the course of schizophrenia (abstract). Schizophrenia Research, 36, 264.
Kullback, S. (1959) Information Theory and Statistics. New York: John Wiley & Sons.
Liddle, P. F. & Barnes, T. R. (1990) Syndromes of chronic schizophrenia. British Journal of Psychiatry, 157, 558-561.[Medline]
Lieberman, J., Jodt, D., Alvir, J., et al (1993) Brain morphology, dopamine and eye tracking abnormalities in 1st-episode schizophrenia prevalence and clinical correlates. Archives of General Psychiatry, 50, 357-368.[Abstract]
Loebel, A., Liberman, J., Alvir, J., et al (1993) Duration of psychosis and outcome in first episode schizophrenia. Archives of General Psychiatry, 149, 1183-1188.
Mohamed, S., Paulsen, J., O'Leary, D., et al
(1999) Generalised cognitive deficits in schizophrenia: A
study of first episode patients. Archives of General
Psychiatry, 56,
749-754.
Nelson, H. & Willison, J. (1991) The Revised National Adult Reading Test (NART) Test Manual (2nd edn). Windsor: NFERNelson.
Owen, A., Downes, J., Sahakian, B., et al (1990) Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia, 28, 1021-1034.[Medline]
Owen, A., Roberts, A., Polkey, C., et al (1991) Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia, 29, 991-1006.
Owen, A., James, M., Leigh, P., et al (1992) Fronto-striatal cognitive deficits at different stages of Parkinson's disease. Brain, 115, 1727-1751.[Abstract]
Owen, A., Sahakian, B. J., Semple, J., et al (1995) Visuospatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia, 33, 1-24.[CrossRef][Medline]
Owen, A., Doyon, J., Petrides, M., et al (1996a) Planning and spatial working memory examined with a positron emission tomography study in humans. European Journal of Neuroscience, 8, 353-364.[Medline]
Owen, A., Evans, A. C. & Petrides, M. (1996b) Evidence for a two stage model of spatial working memory processing within the lateral frontal cortex: a positron emission tomography study. Cerebral Cortex, 6, 31-38.[Abstract]
Owen, A., Morris, R. G., Sahakian, B. J., et al (1996c) Double dissociation of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Brain, 119, 102-119.
Pantelis, C., Barnes, T., Nelson, H., et al (1997) Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain, 120, 1823-1843.[Abstract]
Pantelis, Barber, F., Barnes, T., et al (1999) A comparison of set-shifting ability in patients with schizophrenia and frontal lobe damage. Schizophrenia Research, 37, 251-270.[CrossRef][Medline]
Robbins, T.W. (1977) A critique of the methods available for the measurement of spontaneous motor activity. In Handbook of Psychopharmacology (eds L. L. Iversen, S. D. Iversen & S. H. Snyder), vol. 7, pp. 37-82. New York: Plenum Press.
Robbins, T.W., James, M., Owen, A. M., et al (1994) Cambridge Automated Neuropsychological Test Battery (CANTAB). A factor analytic study in a large sample of normal volunteers. Dementia, 5, 266-281.[Medline]
Rogers, R., Andrews, T., Grasby, P., et al
(2000) Contrasting cortical and sub-cortical activations
produced by attentional set-shifting and reversal learning in humans.
Journal of Cognitive Neuroscience,
12,
142-162.
Sahakian, B. & Owen, A. (1992) Computerised assessment in neuropsychiatry using CANTAB. Journal of the Royal Society Medicine, 85, 399-402.[Medline]
Sahakian, B., Morris, R., Evenden, J., et al (1988) A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson's disease. Brain, 111, 695-718.[Abstract]
Sahgal, A., Lloyd, S., Wray, C. J. et al (1992) Does visuospatial memory in Alzheimer's disease depend on the severity of the disorder? International Journal of Geriatric Psychiatry, 7, 427-436.
Saykin, A. J., Shtasel, D. J., Gur, R. E., et al (1994) Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Archives of General Psychiatry, 51, 124-131.[Abstract]
Shallice, T. (1982) Specific impairments in planning. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 298, 199-209.[Medline]
Verdoux, H., Liraud, F., Bergery, C., et al (2001) Is the association between duration of untreated psychosis and outcome confounded? A two year follow-up study of first-admitted patients. Schizophrenia Research, 49, 231-214.[CrossRef][Medline]