Jeffrey A. Gray’s research while affiliated with King's College London and other places

The present study investigated the effect of haloperidol-induced mood in normal healthy male volunteers on the retrieval of memories of real-life personal experiences using a between-subjects double-blind design. Forty subjects were required to retrieve past real life experiences associated with a series of stimulus words following administration of a single oral dose of 5mg haloperidol or placebo. The experiences were subsequently rated by subjects for their happiness felt at the time of the original experience. A significant decline in self-reported hedonic tone was observed in subjects given haloperidol. In addition, subjects on placebo recalled a significantly greater percentage of happy memories than subjects who were on haloperidol; a trend for a reverse pattern was observed for unhappy memories. The effects of the drug on the retrieval of memories were only in part mediated by the decline in hedonic tone scores. The effects of haloperidol are interpreted in terms of drug-induced dysphoria.

Abrupt discontinuities in recognizing categories of emotion are found for the labelling of consciously perceived facial expressions. This has been taken to imply that, at a conscious level, we perceive facial expressions categorically. We investigated whether the abrupt discontinuities found in categorization for conscious recognition would be replaced by a graded transition for subthreshold stimuli. Fifteen volunteers participated in two experiments, in which participants viewed faces morphed from 100% fear to 100% disgust along seven increments. In Experiment A, target faces were presented for 30 ms, in Experiment B for 170 ms. Participants made two-alternative forced-choice decisions between fear and disgust. Results for the 30 ms presentation time indicated a significant linear trend between degree of morphing and classification of the images. Results for 170 ms presentation time followed the higher order function found in studies of categorical perception. These results provide preliminary evidence for separate processes underlying conscious and nonconscious perception of facial expressions of emotion.

Schizophrenia patients display an excessive rate of smoking compared to the general population. Nicotine increases acoustic prepulse inhibition (PPI) in animals as well as healthy humans, suggesting that smoking may provide a way of restoring deficient sensorimotor gating in schizophrenia. No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans. To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI. In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 microg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1. Nicotine enhanced PPI in both groups. A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum in both groups after nicotine administration. Subsequent correlational analyses demonstrated that the PPI-enhancing effect of nicotine was related to increased hippocampal activity in both groups. Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity.

Coloured hearing synaesthetes experience colours to heard words, as confirmed by reliability of self-report, psychophysical testing and functional neuroimaging data. Some also describe the 'alien colour effect' (ACE): in response to colour names, they experience colours different from those named. We have previously reported that the ACE slows colour naming in a Stroop task, reflecting cognitive interference from synaesthetically induced colours, which depends upon their being consciously experienced. It has been proposed that the hippocampus mediates such consciously experienced conflict. Consistent with this hypothesis, we now report that, in functional magnetic resonance imaging of the Stroop task, hippocampal activation differentiates synaesthetes with the ACE from those without it and from non-synaesthete controls. These findings confirm the reality of coloured hearing synaesthesia and the ACE, phenomena which pose major challenges to the dominant contemporary account of mental states, functionalism. Reductive functionalism identifies types of mental states with causal roles: relations to inputs, outputs and other states. However, conscious mental states, such as experiences of colour, are distinguished by their qualitative properties or qualia. If functionalism is applied to conscious mental states, it identifies the qualitative type of an experience with its causal role or function. This entails both that experiences with disparate qualitative properties cannot have the same functional properties, and that experiences with disparate functional properties cannot have the same qualitative properties. Challenges to functionalism have often denied the first entailment. Here, we challenge the second entailment on empirical grounds. In coloured hearing synaesthesia, colour qualia are associated with both hearing words and seeing surfaces; and, in the ACE, these two functions act in opposition to one another. Whatever its merits as an account of other mental states, reductive functionalism cannot be the correct account of conscious experiences.

Learned irrelevance (LIrr) is closely related to latent inhibition (LI). In LI a to-be-conditioned stimulus (CS) is prexposed alone prior to the opportunity to learn an association between the CS and an unconditioned stimulus (UCS). In LIrr preexposure consists of intermixed presentations of both CS and UCS in a random relationship to each other. In both paradigms preexposure leads in normal subjects to reduced or retarded learning of the CS-UCS association. Acute schizophrenics fail to show LI. LI is usually demonstrated as a one-off, between-groups difference in trials to learning, so posing problems for neuroimaging. We have developed a novel, continuous, within-subject paradigm in which normal subjects show robust and repeated LIrr. We show that this paradigm is suitable for functional magnetic resonance imaging (fMRI) and gives rise, in normal subjects, to activation in the hippocampal formation, consistent with data from animal experiments on LI. We also report, consistent with previous studies of LI, loss (indeed, significant reversal) of LIrr in acute (first 2 weeks of current psychotic episode) schizophrenics. Chronic schizophrenics failed to demonstrate learning, precluding measurement in this group of LIrr. These findings establish the likely value of the new paradigm for neuroimaging studies of attentional dysfunction in acute schizophrenia.

Eysenck (1981) proposed that the personality dimension of introversion- extraversion (E) reflects individual differences in a cortical arousal system modulated by reticulothalamic- cortical pathways: it is chronically more active in introverts relative to extraverts and influences cognitive performance in interaction with task parameters. A circuit with connections to this system, including the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate (AC) cortex, has been identified in studies applying functional magnetic resonance imaging (fMRI) to a broad range of cognitive tasks. We examined the influence of E, assessed with the Eysenck Personality Questionnaire-Revised (Eysenck and Eysenck, 1991), in fMRI activity during an "n-back" task involving four memory loads (0-, 1-, 2-, and 3-back) and a rest condition in healthy men. To confirm the specificity of E effects, we also examined the effects of neuroticism and psychoticism (P) scores. We observed that, as predicted by Eysenck's model, the higher the E score, the greater the change in fMRI signal from rest to the 3-back condition in the DLPFC and AC. In addition, E scores were negatively associated with resting fMRI signals in the thalamus and Broca's area extending to Wernicke's area, supporting the hypothesized (negative) relationship between E and resting arousal. P scores negatively correlated with resting fMRI signal in the globus pallidus-putamen, extending previous findings of a negative relationship of schizotypy to striatal activity seen with older neuroimaging modalities to fMRI. These observations suggest that individual differences affect brain responses during cognitive activity and at rest and provide evidence for the hypothesized neurobiological basis of personality.

There is considerable evidence to suggest that the genetic vulnerabilities to depression and anxiety substantially overlap and quantitatively act to alter risk to both disorders. Continuous scales can be used to index this shared liability and are a complementary approach to the use of clinical phenotypes in the genetic analysis of depression and anxiety. The aim of this study (Genetic and Environmental Nature of Emotional States in Siblings) was to identify genetic variants for the liability to depression and anxiety after the application of quantitative genetic methodology to a large community-based sample (n = 34,371), using four well-validated questionnaires of depression and anxiety. Genetic model fitting was performed on 2658 unselected sibships, which provided evidence for a single common familial factor that accounted for a substantial proportion of the genetic variances and covariances of the four scales. Using the parameter estimates from this model, a composite index of liability (G) was constructed. This index was then used to select a smaller--but statistically powerful--sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. After the data were checked and cleaned, linkage analysis was performed on G and the personality scale of neuroticism using the regression-based linkage program MERLIN-REGRESS. The results indicated two potential quantitative trait loci (QTL): one on chromosome 1p (LOD 2.2) around 64 cM (43-70 cM) near marker D1S2892 and another on chromosome 6p (LOD 2.7) around 47 cM (34-63 cM) near marker D6S1610. Further exploratory sex-specific analyses suggested that these QTLs might have sex-limited effects.

Preliminary results have demonstrated the clinical efficacy of computerised cognitive-behavioural therapy (CBT) in the treatment of anxiety and depression in primary care. To determine, in an expanded sample, the dependence of the efficacy of this therapy upon clinical and demographic variables. A sample of 274 patients with anxiety and/or depression were randomly allocated to receive, with or without medication, computerised CBT or treatment as usual, with follow-up assessment at 6 months. The computerised therapy improved depression, negative attributional style, work and social adjustment, without interaction with drug treatment, duration of preexisting illness or severity of existing illness. For anxiety and positive attributional style, treatment interacted with severity such that computerised therapy did better than usual treatment for more disturbed patients. Computerised therapy also led to greater satisfaction with treatment. Computer-delivered CBT is a widely applicable treatment for anxiety and/or depression in general practice.

Cognitive-behavioural therapy (CBT) is effective for treating anxiety and depression in primary care, but there is a shortage of therapists. Computer-delivered treatment may be a viable alternative. To assess the cost-effectiveness of computer-delivered CBT. A sample of people with depression or anxiety were randomised to usual care (n=128) or computer-delivered CBT (n=146). Costs were available for 123 and 138 participants, respectively. Costs and depression scores were combined using the net benefit approach. Service costs were 40 British pounds (90% CI - 28 British pounds to 148 British pounds) higher over 8 months for computer-delivered CBT. Lost-employment costs were 407 British pounds (90% CI 196 British pounds to 586 British pounds) less for this group. Valuing a 1-unit improvement on the Beck Depression Inventory at 40 British pounds, there is an 81% chance that computer-delivered CBT is cost-effective, and it revealed a highly competitive cost per quality-adjusted life year. Computer-delivered CBT has a high probability of being cost-effective, even if a modest value is placed on unit improvements in depression.

Hippocampal activation was investigated, comparing allocentric and egocentric spatial memory. Healthy participants were immersed in a virtual reality circular arena, with pattern-rendered walls. In a viewpoint-independent task, they moved toward a pole, which was then removed. They were relocated to another position and had to move to the prior location of the pole. For viewpoint-dependent memory, the participants were not moved to a new starting point, but the patterns were rotated to prevent them from indicating the final position. Hippocampal and parahippocampal activation were found in the viewpoint-independent memory encoding phase. Viewpoint-dependent memory did not result in such activation. These results suggest differential activation of the hippocampal formation during allocentric encoding, in partial support of the spatial mapping hypothesis as applied to humans.