Sheffield Cognition and Neuroimaging Laboratory (SCANLab), Academic Clinical Psychiatry, Division of Genomic Medicine, University of Sheffield
Academic Unit of Radiology, University of Sheffield
SCANLab, Academic Clinical Psychiatry, Division of Genomic Medicine, University of Sheffield, Sheffield, UK
Correspondence: Dr Sean A. Spence, Sheffield Cognition and Neuroimaging (SCANLab), Academic Clinical Psychiatry, Division of Genomic Medicine, University of Sheffield, The Longley Centre, Norwood Grange Drive, Sheffield S5 7JT, UK. Tel: +44 (0) 114 22 61519; Fax: +44 (0) 114 22 61522; E-mail: s.a.spence{at}sheffield.ac.uk
Declaration of interest This study was supported by an investigator-led award (to S.A.S.) from Cephalon (UK). M.D.H. is supported by the Wellcome Trust (UK).
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ABSTRACT |
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Aims To study the acute effects of modafinil administration upon brain activity and cognitive performance in people with chronic schizophrenia.
Method In a randomised double-blind placebo-controlled crossover design, 19 patients received either modafinil (100 mg) or placebo prior to undertaking a working memory task with functional magnetic resonance imaging.
Results Seventeen patients completed the study and another underwent acute relapse 4 days post-drug. Modafinil administration was associated with significantly greater activation in the anterior cingulate cortex during the working memory task. The anterior cingulate cortex signal correlated with cognitive performance, although only a subset of patients exhibited `enhancement'.
Conclusions Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation.
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INTRODUCTION |
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METHOD |
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Participants
Right-handed males aged 18-60 years, with premorbid IQ >70 on the
National Adult Reading Test (NART; Nelson
& O'Connell, 1978) and a DSM-IV
(American Psychiatric Association,
1994) diagnosis of schizophrenia and prominent negative
symptomatology (rating 3 on at least one item of the Scale for the Assessment
of Negative Symptoms (SANS); Andreasen,
1983) were included. Exclusion criteria were: prominent `positive'
symptomatology (marked delusions and/or hallucinations); recent history of
mental state instability; changes to psychotropic medication or admission to
hospital within 3 months of assessment; significant history of neurological,
endocrine or cardiovascular disorder; hypersensitivity to modafinil;
concurrent prescription of other stimulant medication; concurrent substance
misuse; and contraindications to magnetic resonance imaging scanning (metallic
implants, foreign bodies and claustrophobia).
Thirty-two patients were approached and 21 agreed to participate following a full explanation of the study. Nineteen of these satisfied detailed assessment of the inclusion and exclusion criteria. Participants underwent psychiatric (Brief Psychiatric Rating Scale; Overall & Gorham, 1962; SANS; Scale for the Assessment of Positive Symptoms; Andreasen, 1984; Beck Depression Inventory; Beck et al, 1961; Mini-Mental State Examination; Folstein et al, 1975), physical (including an electrocardiogram) and neuropsychological assessment (Simpson-Angus Scale; Simpson & Angus, 1970; Abnormal Involuntary Movements Scale; Guy, 1976; Barnes Akathisia Scale; Barnes, 1989).
Written informed consent was obtained from each patient. The study was approved by the North and South Sheffield Research Ethics Committees, and also the Rotherham and the Doncaster and South Humber Research Ethics Committees. Because the study was funded by an `investigator-led award' and was not a `company-sponsored trial', research indemnity was provided by the Sheffield Care Trust (and reciprocally participating National Health Service trusts) and clinical trial insurance was provided by the University of Sheffield.
Procedures
We utilised a randomised, double-blind placebo-controlled crossover design.
Patients were studied on 2 days, 1 week apart. On each day, patients received
oral modafinil (100 mg) or placebo 2 h prior to functional magnetic resonance
imaging (fMRI) scanning. Administration and scanning times were predicated on
the drug's pharmacokinetics in humans; peak plasma levels occur 2-4 h
post-acute oral dosing (Cephalon,
1999; Robertson &
Hellriegel, 2003). Randomisation, performed by a pharmacist (not a
member of the research team), was achieved by drawing labelled counters; this
ensured that approximately equivalent numbers of patients received modafinil
and placebo on day 1, and vice versa on day 2. Patients were required
not to smoke or consume caffeine prior to scanning. They were admitted for
24-h observation after the scanning procedure. The outcome measures were: a
difference in fMRI signal, during a working memory task, between the modafinil
and placebo conditions; a difference in behavioural performance (accuracy),
during the same intra-scanner task, between modafinil and placebo conditions;
and a patient-wise bivariate correlation between the first two measures.
Psychological paradigm
Inside the scanner, patients performed a standard working memory task (the
`2-back'; Callicott et al,
1998). This difficult task required subjects to monitor, update
and temporally `tag' the contents of their working memory
(Manoach, 2003). A series of
numbers (between 1 and 4) was presented visually, in a pseudo-random order,
one every 2 s. Colour coding of these stimuli cued patients to indicate (by
pressing a button) either which number was currently presented on the screen
(the `0-back'; baseline condition) or which number had been presented two
trials earlier (i.e. the `2-back'; active condition). Stimuli were delivered
using Presentation (Neurobehavioral Systems Inc, California, USA) software
running on a personal computer via a video projector and mirror located inside
the scanner bore. Patients responded by pressing one of four buttons on an
intra-scanner box optically connected to the computer system via an interface
(New Micros Inc, Texas, USA). In an alternating, blocked 0-back/2-back design,
15 consecutive `0-back' stimuli (lasting 30 s) were followed by 15 consecutive
`2-back' stimuli (also lasting 30 s). This sequence was repeated six times;
hence the functional scans lasted 6 min in total.
Patients practised the task prior to entering the scanner but did so only three times in order to minimise any automation of the procedure. Different performance levels have been permitted in previous studies. Some have incorporated a wide range of accuracy among patients with schizophrenia (Callicott et al, 1998, where performance was relatively poor; Meyer-Lindenberg et al, 2001; Bertolino et al, 2003) whereas others have set more stringent thresholds (Callicott et al, 2000, 2003). Comparison with a healthy control group necessarily requires comparable levels of performance across the groups, but in our study we wished to compare patients' performances against themselves (on and off modafinil). Hence, we allowed for a range of performance accuracy. This was partly pragmatic, given that we were deliberately studying people with chronic schizophrenia and prominent negative symptomatology (the likely recipients of putative cognitive enhancers), but also design-led because we required a range of performance across the group to detect changes in performance within subjects exposed to modafinil (hence avoiding `ceiling effects') and to allow for post hoc correlations with performance per se (Manoach et al, 1999; Callicott et al, 2000, 2003).
Functional image acquisition and analysis
At each of 120 functional imaging time points, 3264 mm contiguous
T2*-weighted slices were acquired using echo-planar
imaging on a 1.5 T system (Eclipse, Philips, Ohio) at Sheffield University
(repetition time=3 s; echo time=40 ms; field of view= 240 mm; in-plane
matrix=128 x 128).
Images were analysed using SPM99 (http://www.fil.ion.ucl.ac.uk/). The blood oxygenation level-dependent (BOLD) response that is measured by fMRI is thought to represent a vascular marker of neuronal activation (Logothetis et al, 2001). Following timing and movement correction, spatial normalisation and smoothing with a Gaussian kernel of 6 mm full width at half-maximum (Friston et al, 1995), we used a `boxcar' wave convolved with a synthetic haemodynamic response function to model the BOLD response. Each patient had two fMRI data-sets (modafinil and placebo); for each individual data-set, a first-level voxel-wise contrast of activation during the working memory v. baseline was undertaken. This generated contrast images, which were then used in a second-order (random-effects) group analysis.
Random-effects analyses allow quantitative inferences to be drawn regarding the average behaviour of the population from which patients are selected, across different scanning sessions. Such an analysis is mandatory in psychopharmacological designs where the main effect of interest exists only between distinct scanning sessions (i.e., modafinil v. placebo; Friston et al, 1999). Individual contrast images were entered as data points in a whole-group analysis of covariance (ANCOVA) that compared brain activation during working memory v. baseline conditions on modafinil with activation during working memory v. baseline on placebo. Order of scanning (whether modafinil was received on day 1 or day 2) comprised the `nuisance' covariate. This produced a group parametric brain map of t-statistics, in the stereotactic space of the Montreal Neurological Institute (MNI; Evans et al, 1993), showing brain areas more activated during working memory than baseline conditions on modafinil compared with placebo. We emphasise that intra-session effects (working memory v. baseline) were modelled at the first level but that the main inter-session effect (modafinil v. placebo) was modelled in the second-level (random effects) analysis.
We also produced two subsidiary brain maps, demonstrating brain areas more activated during working memory than baseline on placebo only and modafinil only, using two single group ANCOVAs (as before, with scanning order as `nuisance' covariate). Hence, we were able to ensure that the expected pattern of cortical activation was obtained during the `2-back' irrespective of drug/placebo condition.
Because our study was hypothesis driven, we set our significance threshold at P<0.01, uncorrected for height and extent of activation. We also designated a small volume (sphere of diameter= 10 mm) that could be used to correct for multiple comparisons (family-wise error method) should activation in the a priori region of interest (anterior cingulate cortex) be observed at the uncorrected threshold. For the purposes of reporting and neuroanatomical labelling, the stereotactic coordinates of activated areas were transformed from MNI space into the system of Talairach & Tournoux (1988).
Brain activation/behavioural performance correlations
For each patient we calculated a measure of performance (percentage
accuracy) during the working memory task on both study days, and hence a
`difference' score between the modafinil and placebo conditions. Taking the
anterior cingulate cortex as a region of interest, we also estimated the
magnitude of fMRI signal change (derived from the `beta' parameters in SPM99)
during the working memory task (v. baseline) on both study days. For
each patient, this allowed us to calculate the difference in the anterior
cingulate cortex signal change, during the working memory task, between
modafinil and placebo conditions. We then ran patient-wise bivariate
correlations between the difference in behavioural performance on modafinil
v. placebo and the difference in anterior cingulate cortex signal
change on modafinil v. placebo.
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RESULTS |
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Demographic data
Patients were predominantly middle-aged males who had been ill for
approximately 15 years (Table
1). Sixteen were single; none was in paid employment but five
performed voluntary work; 16 received maximum disability living allowance;
eight lived in their `own' accommodation; three with parents, two in supported
group projects and four in rehabilitation units. Most patients were receiving
oral antipsychotics (n=13), which were `atypical' in all but one
case. Four patients received intramuscular (`typical') depot medication. Of
these 17 patients, none changed medication during the study period. Nine
patients received modafinil on day 1 and placebo on day 2; eight received the
reverse.
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Behavioural measures
Statistical comparisons were prespecified, except where indicated. We used
non-parametric tests to analyse the group behavioural (accuracy) data during
the working memory task under placebo and modafinil conditions (these were not
normally distributed). Under placebo conditions, response accuracy for the
control `0-back' condition was 19-88% (median 71%) and did not differ
significantly from that on modafinil: range 11-99%, median 71% (Wilcoxon
signed rank test; Z=0.12; P=0.91). Under placebo conditions,
response accuracy for the `2-back' task was 5-85% (median 26%) and did not
differ significantly from that on modafinil: range 4-79%, median 22% (Wilcoxon
signed rank test; Z=0.97; P=0.33).
Brain activations
Functional image analysis showed that on both the modafinil and placebo
days the patients exhibited activations during the 2-back condition (relative
to the 0-back) in predicted brain regions (Tables
2 and
3), specifically the
prefrontal, anterior cingulate and parietal cortices (Callicott et
al, 2000,
2003;
Meyer-Lindenberg et al,
2001).
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Patient-wise differences in anterior cingulate cortex activation
(Fig. 1) and behavioural
performance (between modafinil and placebo conditions) were positively and
significantly correlated (Fig.
2; Spearman's =0.42; one-tailed P<0.05). However,
this correlation did not reflect a straightforward relationship between
improved activation and improved performance. Rather, it reflected an
increased fMRI signal in the majority of patients during the modafinil
session, with concomitant improvement of memory performance in half and a
decreased signal in a minority of patients (in response to modafinil), most of
whom exhibited reduced performance on the drug
(Fig. 2). Hence, for the
patient group as a whole there was a relationship between the degree to which
anterior cingulate cortex activation, during the memory task, was modulated
(increased/decreased) by the drug and their level of cognitive performance.
Although a subgroup of patients exhibited enhanced cognition (in association
with increased anterior cingulate cortex activation), no patient exhibiting
reduced anterior cingulate cortex activity improved cognitively.
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We further investigated this post hoc `deficit/benefit' hypothesis and found that those exhibiting improved working memory performance on modafinil had demonstrated significantly worse performance on a verbal fluency task at initial assessment compared with other patients. Responders generated 7-18 words in 1 min (median 10); non-responders generated 4-25 words, median 11.5 (Mann-Whitney U-test; Z=2.19; P=0.03). There were no correlations between intra-scanner working memory task performance and specific symptom ratings.
Finally, by way of validating our sample against those described in successive reports, which have repeatedly described positive correlations between 2-back accuracy and right dorsolateral prefrontal cortex activity in people with schizophrenia compared with `normals' (Callicott et al, 1999, 2000), we examined the correlates of performance per se on the 2-back task. We found the right dorsolateral prefrontal cortex implicated under both conditions (placebo; x=44 mm, y=41 mm, z=9 mm, 21 voxels, Z=2.75, P<0.01, uncorrected, for height of activation; modafinil: x=44 mm, y=49 mm, z=18 mm, 62 voxels, Z=3.15, P<0.01, uncorrected, for height of activation).
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DISCUSSION |
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Cognitive response
Despite enhanced anterior cingulate cortex activation at the group level
(during working memory performance), most of our patients did not exhibit
enhanced cognition. For the group as a whole there was no effect of modafinil
upon working memory (on this protocol). Therefore it might be posited that
increased anterior cingulate cortex activation is either unrelated to
cognition or indicative of reduced efficiency of cognitive processing
(Callicott et al,
2000; Manoach,
2003). If greater anterior cingulate cortex activation occurs
without an increase in cognitive performance then brain function might be said
to be less efficient in the presence of modafinil. However, it is important to
note that cognitive function did improve in a minority of patients, and that
although it might be posited that this is to be expected statistically (as
merely a manifestation of variation around the mean), there is a feature of
the data that runs counter to this interpretation. This is the
positive correlation between anterior cingulate cortex activation and
cognitive improvement (Fig. 2).
If modafinil simply made anterior cingulate cortex function less efficient,
then we should expect such a correlation to be negative. The positive
correlation implies that the magnitude of anterior cingulate cortex activation
and cognitive performance are indeed related in the context of modafinil
exposure; those exhibiting the greater anterior cingulate cortex response also
exhibit the greater cognitive enhancement (of working memory).
Accounting for `responders'
It is of interest that those exhibiting greater physiological and cognitive
response to modafinil tended to be those who were receiving `typical'
neuroleptic medications (depots and sulpiride). The numbers are small but
there may be a rationale for this finding. The neurotransmitter systems
implicated in the promotion of wakefulness by modafinil include the
dopaminergic and serotonergic systems. Although antipsychotics share
antagonism of the dopaminergic system (especially at the D2 receptor), the
typicals and atypicals differ in their affinities for other receptors,
particularly 5HT2A (Keefe
et al, 1999). In animal models modafinil's effect of
increasing alertness is attenuated by 5HT2A antagonism
(Shelton et al,
1995), hence, it is possible that atypical antipsychotic treatment
(if antagonising 5HT2A) might constrain the cognotropic effects of
modafinil (a hypothesis deserving further study). Alternatively, the ability
of atypicals themselves to enhance cognition (albeit to a limited extent;
Keefe et al, 1999)
might curtail further improvement (on modafinil).
Safety
There are a number of caveats to our study and its findings. First, for the
reasons described, we deliberately utilised a relatively low dose of
modafinil. This may have been sub-optimal. Nevertheless, one of our
participants underwent psychotic relapse 4 days post-drug. We cannot determine
whether modafinil was responsible. Although covert non-adherence to concurrent
medication cannot be excluded (he was receiving an oral antipsychotic), we
must be wary of seeking to exculpate the test medication. However, a psychotic
reaction to a single dose of modafinil is unprecedented (to our
knowledge), although there are cases of psychosis emerging de novo in
those receiving multiple doses. The manufacturer's prescribing information
reports that: `one healthy male volunteer developed ideas of reference,
paranoid delusions, and auditory hallucinations in association with multiple
daily 600 mg doses of [modafinil] and sleep deprivation. There was no evidence
of psychosis 36 hours after drug discontinuation.'
(Cephalon, 1999). The
British National Formulary does not mention psychosis as either a
contraindication to or a consequence of modafinil exposure.
In a recent study of 20 patients with schizophrenia exposed to a single dose of 200 mg of modafinil, the drug elicited no exacerbation of psychosis (Turner et al, 2004). However, there are anecdotal accounts of schizophrenic relapse following repeated dosing (Narendran et al, 2002; Rosenthal & Bryant, 2003). Further multi-dosing studies in other centres may help to clarify the magnitude of such a putative risk.
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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 May 18, 2004. Revision received October 19, 2004. Accepted for publication October 21, 2004.
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