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Contemporary theories propose that dysregulation of emotional perception is involved in the aetiology of psychosis. 298 healthy adolescents were assessed at age 14- and 19-years using fMRI while performing a facial emotion task. Psychotic-like experiences (PLEs) were assessed with the CAPE-42 questionnaire at age 19. The high PLEs group at age 19 years exhibited an enhanced response in right insular cortex and decreased response in right prefrontal, right parahippocampal and left striatal regions; also, a gradient of decreasing response to emotional faces with age, from 14 to 19 years, in the right parahippocampal region and left insular cortical area. The right insula demonstrated an increasing response to emotional faces with increasing age in the low PLEs group, and a decreasing response over time in the high PLEs group. The change in parahippocampal/amygdala and insula responses during the perception of emotional faces in adolescents with high PLEs between the ages of 14 and 19 suggests a potential ‘aberrant’ neurodevelopmental trajectory for critical limbic areas. Our findings emphasize the role of the frontal and limbic areas in the aetiology of psychotic symptoms, in subjects without the illness phenotype and the confounds introduced by antipsychotic medication.

Cognitive control has traditionally been associated with pFC based on observations of deficits in patients with frontal lesions. However, evidence from patients with Parkinson disease indicates that subcortical regions also contribute to control under certain conditions. We scanned 17 healthy volunteers while they performed a task-switching paradigm that previously dissociated performance deficits arising from frontal lesions in comparison with Parkinson disease, as a function of the abstraction of the rules that are switched. From a multivoxel pattern analysis by Gaussian Process Classification, we then estimated the forward (generative) model to infer regional patterns of activity that predict Switch/Repeat behavior between rule conditions. At 1000 permutations, Switch/Repeat classification accuracy for concrete rules was significant in the BG, but at chance in the frontal lobe. The inverse pattern was obtained for abstract rules, whereby the conditions were successfully discriminated in the frontal lobe but not in the BG. This double dissociation highlights the difference between cortical and subcortical contributions to cognitive control and demonstrates the utility of multivariate approaches in investigations of functions that rely on distributed and overlapping neural substrates.

Background Schizophrenia is characterized by prominent cognitive deficits, impacting on memory and learning; these are strongly associated with the prefrontal cortex. Objective/hypothesis To combine two interventions, transcranial direct current stimulation (tDCS) over the prefrontal cortex and cognitive training, to examine change in cognitive performance in patients with schizophrenia. Methods A double blind, sham-controlled pilot study of 49 patients with schizophrenia, randomized into real or sham tDCS stimulation groups. Subjects participated in 4 days of cognitive training (days 1, 2, 14, 56) with tDCS applied at day-1 and day-14. The primary outcome measure was change in accuracy on working memory and implicit learning tasks from baseline. The secondary outcome measure was the generalization of learning to non-trained task, indexed by the CogState neuropsychological battery. Data analysis was conducted using multilevel modelling and multiple regressions. Results 24 participants were randomized to real tDCS and 25 to sham. The working memory task demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 (b = 0.68, CI 0.14–1.21; p = 0.044) and at day-56 (b = 0.71, 0.16–1.26; p = 0.044). There were no significant effects of tDCS on implicit learning. Trend evidence of generalization onto untrained tasks of attention and vigilance task (b = 0.40, 0.43–0.77; p = 0.058) was found. Conclusions This is the first study to show a significant longer-term effect of tDCS on working memory in schizophrenia. Given the current lack of effective therapies for cognitive deficits, tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia.

Background It is widely accepted that neurocognitive performance is linked to functional outcomes in schizophrenia (Green, Kern, Braff, & Mintz, 2000). Research, however, shows that this relationship is likely to be mediated by other factors such as social competence (Brekke, Kay, Lee, & Green, 2005). Indeed, performance on cognitive tasks only explain 20% of the variance in work related skills (Bowie et al., 2008). Furthermore, the composite score generated by the gold standard neurocognitive measure, the MATRICS Consensus Cognitive Battery (MCCB), fails to predict work or education related functioning and independent living (August, Kiwanuka, McMahon, & Gold, 2012). To address these limitations, we developed a novel and ecologically valid virtual reality (VR) task with the aim to simultaneously measure cognition and functional capacity in schizophrenia. The assessment is set in a minimarket environment where participants are required to buy selected items from a shopping list. In this study, our objective was to establish the construct validity of the VR task in relation to the MCCB, and test whether it can predict functional outcomes. In addition, we tested whether app-based cognitive training can improve cognition and/or functional outcomes at follow-up as an exploratory objective. Methods Thirty patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited from South London. At baseline, participants completed the VR task and MCCB, the Positive and Negative Syndrome Scale (PANSS), and various functional capacity/outcome measures including the Global Assessment of Functioning (GAF), Social and Occupational Functioning Assessment Scale (SOFAS), UCSD Performance-Based Skills Assessment-Brief (UPSA-B), and World Health Organization Disability Assessment Schedule II (WHODAS-II). A subset of participants was randomly allocated to receive a 4-week long, app-based training; either playing with an immersive or a 2D spatial memory training game. Those who completed the training were invited back for a follow-up visit. Construct validity of the VR task will be assessed through a series of bivariate correlations. The predictive ability of the VR task for functional outcomes will be tested through linear regression models. Finally, the efficacy of spatial memory training will be assessed using repeated measures ANOVA. Results Data analysis is currently ongoing, and results will be presented at the conference. Discussion This study will provide the first indication whether VR can be employed to test cognition and functional capacity simultaneously in patients with schizophrenia. Given the current lack of reliable and ecologically valid functional outcome measures, new assessments that are sensitive to clinically meaningful cognitive improvements are desperately needed.

Importance Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses. Objective To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task. Design, Setting, and Participants A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017. Main Outcomes and Measures Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori–defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined. Results Of the 1434 adolescents, 2 groups (n = 149 each) (high PLEs, n = 149, 50 [33.6%] male; low PLEs, n = 149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation ( F 1, 93 = 5.559; P = .02; F 1, 93 = 5.009; P = .03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant time × group interaction ( F 1, 93 = 7.448; P = .01). Conclusion and Relevance The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them.

Clinical trials in psychiatry inherit methods for design and statistical analysis from evidence-based medicine. However, trials in other clinical disciplines benefit from a more specific relationship between instruments that measure disease state (e.g. biomarkers, clinical signs), the underlying pathology and diagnosis such that primary outcomes can be readily defined. Trials in psychiatry use diagnosis (i.e. a categorical label for a syndrome) as a proxy for the underlying disorder, and outcomes are defined, for example, as a percentage change in a univariatetotal scoreon some clinical instrument. We label this approach to defining outcomesweak aggregationof disease state. Univariate measures are necessary, because statistical methodology is both tractable and well-developed for scalar outcomes, but we show that weak aggregate approaches do not capture disease state sufficiently, potentially leading to loss of information about response to intervention. We demonstrate how multivariate disease state can be captured using geometric concepts of spaces defined over routine clinical instruments, and show how clinically meaningful disease states (e.g. representing different profiles of symptoms, recovery or remission) can be defined as prototypes (geometric locations) in these spaces. Then, we show how to derive univariate (scalar) measures, which capture patient's relationships to these prototypes and argue these representstrong aggregatesof disease state that may be a better basis for outcome measures. We demonstrate our proposal using a large publically available dataset. We conclude by discussing the impact of strong aggregates for analyses in traditional and novel trial designs.

Introduction Traditionally, studies investigating the functional implications of age-related structural brain alterations have focused on higher cognitive processes; by increasing stimulus load, these studies assess behavioral and neurophysiological performance. In order to understand age-related changes in these higher cognitive processes, it is crucial to examine changes in visual and auditory processes that are the gateways to higher cognitive functions. This study provides evidence for age-related functional decline in visual and auditory processing, and regional alterations in functional brain processing, using non-invasive neuroimaging. Methods Using functional magnetic resonance imaging (fMRI), younger (n = 11; mean age = 31) and older (n = 10; mean age = 68) adults were imaged while observing flashing checkerboard images (passive visual stimuli) and hearing word lists (passive auditory stimuli) across varying stimuli presentation rates. Results Younger adults showed greater overall levels of temporal and occipital cortical activation than older adults for both auditory and visual stimuli. The relative change in activity as a function of stimulus presentation rate showed differences between young and older participants. In visual cortex, the older group showed a decrease in fMRI blood oxygen level dependent (BOLD) signal magnitude as stimulus frequency increased, whereas the younger group showed a linear increase. In auditory cortex, the younger group showed a relative increase as a function of word presentation rate, while older participants showed a relatively stable magnitude of fMRI BOLD response across all rates. When analyzing participants across all ages, only the auditory cortical activation showed a continuous, monotonically decreasing BOLD signal magnitude as a function of age. Conclusions Our preliminary findings show an age-related decline in demand-related, passive early sensory processing. As stimulus demand increases, visual and auditory cortex do not show increases in activity in older compared to younger people. This may negatively impact on the fidelity of information available to higher cognitive processing. Such evidence may inform future studies focused on cognitive decline in aging.

Psychosis is characterized by an elementary lack of trust in others. Trust is an inherently rewarding aspect of successful social interactions and can be examined using neuroeconomic paradigms. This study was aimed at investigating the underlying neural basis of diminished trust in psychosis. Functional magnetic resonance imaging data were acquired from 20 patients with psychosis and 20 healthy control subjects during two multiple-round trust games; one with a cooperative and the other with a deceptive counterpart. An a priori region of interest analysis of the right caudate nucleus, right temporo-parietal junction and medial prefrontal cortex was performed focusing on the repayment phase of the games. For regions with group differences, correlations were calculated between the haemodynamic signal change, behavioural outcomes and patients' symptoms. Patients demonstrated reduced levels of baseline trust, indicated by smaller initial investments. For the caudate nucleus, there was a significant game × group interaction, with controls showing stronger activation for the cooperative game than patients, and no differences for the deceptive game. The temporo-parietal junction was significantly more activated in control subjects than in patients during cooperative and deceptive repayments. There were no significant group differences for the medial prefrontal cortex. Patients' reduced activation within the caudate nucleus correlated negatively with paranoia scores. The temporo-parietal junction signal was positively correlated with positive symptom scores during deceptive repayments. Reduced sensitivity to social reward may explain the basic loss of trust in psychosis, mediated by aberrant activation of the caudate nucleus and the temporo-parietal junction. © 2013 The Author.

The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of ‘low schizotypes’ was significantly different from ‘high schizotypes’ with ‘average schizotypes’ having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.

Spatial language descriptions, such as The bottle is over the glass, direct the attention of the hearer to particular aspects of the visual world. This paper asks how they do so, and what brain mechanisms underlie this process. In two experiments employing behavioural and eye tracking methodologies we examined the effects of spatial language on people's judgements and parsing of a visual scene. The results underscore previous claims regarding the importance of object function in spatial language, but also show how spatial language differentially directs attention during examination of a visual scene. We discuss implications for existing models of spatial language, with associated brain mechanisms.

Background Auditory verbal hallucinations (AVH) are the most prevalent symptom in schizophrenia. They are associated with increased activation within the temporoparietal cortices and are refractory to pharmacological and psychological treatment in approximately 25% of patients. Low frequency repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex has been demonstrated to be effective in reducing AVH in some patients, although results have varied. The cortical mechanism by which rTMS exerts its effects remain unknown, although data from the motor system is suggestive of a local cortical inhibitory effect. We explored neuroimaging differences in healthy volunteers between application of a clinically utilized rTMS protocol and a sham rTMS equivalent when undertaking a prosodic auditory task. Method Single-blind placebo controlled fMRI study of 24 healthy volunteers undertaking an auditory temporoparietal activation task, who received either right temporoparietal rTMS or sham RTMS. Results The main effect of group was bilateral inferior parietal deactivation following real rTMS. An interaction of group and task type showed deactivation during real rTMS in the right superior temporal gyrus (STG), left thalamus, left postcentral gyrus and cerebellum. However, the left parietal lobe showed an increase in activation following right sided real rTMS, but this increase was specific to a non-linguistic, tone-sequence task. Conclusion rTMS does cause local inhibitory effects, not only in the underlying region of application, but also in functionally connected cortical regions. However, there is also a related, task dependent, increase in activation within selected cortical areas in the contralateral hemisphere; these are likely to reflect compensatory mechanisms, and such cortical activation may in some cases contribute to, or retard, some of the therapeutic effects seen with rTMS.

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria.

Background: Clozapine is the treatment of choice for medication refractory psychosis, but it does not benefit half of those put on it. There are numerous studies of potential post-clozapine strategies, but little data to guide the order of such treatment in this common clinical challenge. We describe a naturalistic observational study in 153 patients treated by a specialist psychosis service to identify optimal pharmacotherapy practice, based on outcomes. Methods: Medication and clinical data, based on the OPCRIT tool, were examined on admission and discharge from the national psychosis service. The primary outcome measure was the percentage change in mental state examination symptoms between admission and discharge and the association with medication on discharge. Exploratory analyses evaluated the specificity of individual medication effects on symptom clusters. Results: There were fewer drugs prescribed at discharge relative to admission, suggesting an optimisation of medication, and a doubling of the number of patients treated with clozapine. Treatment with clozapine on discharge was associated with maximal decrease in symptoms from admission. In the group of patients that did not respond to clozapine monotherapy, the most effective drug combinations were clozapine augmentation with 1) sodium valproate, 2) lithium, 3) amisulpride, and 4) quetiapine. There was no support for a dose-response relationship for any drug combination. Conclusions: Clozapine monotherapy is clearly the optimal medication in medication refractory schizophrenia and it is possible to maximise its use. In patients unresponsive to clozapine monotherapy, augmentation with sodium valproate, lithium, amisulpride and quetiapine, in that order, is a reasonable treatment algorithm. Reducing the number of ineffective drugs is possible without a detrimental effect on symptoms. Exploratory data indicated that clozapine was beneficial across a range of symptoms domains, whereas olanzapine was beneficial specifically for hallucinations and lamotrigine for comorbid affective symptoms.

Amphetamine sensitisation (AS) is an established animal model of the hypersensitivity to psychostimulants seen in patients with schizophrenia. AS also models the dysregulation of mesolimbic dopamine signalling which has been implicated in the development of psychotic symptoms. Recent data suggest that the enhanced excitability of mesolimbic dopamine neurons in AS is driven by a hyperactivity of hippocampal (subiculum) neurons, consistent with a strong association between hippocampal dysfunction and schizophrenia. While AS can be modelled in human volunteers, its functional consequences on dopaminoceptive brain regions (i.e. striatum and hippocampus) remains unclear. Here we describe the effects of a sensitising dosage pattern of dextroamphetamine on the neural correlates of motor sequence learning in healthy volunteers, within a randomised, double-blind, parallel-groups design. Behaviourally, sensitisation was characterised by enhanced subjective responses to amphetamine but did not change performance (i.e. learning rate) during an explicit sequence learning task. In contrast, functional magnetic resonance imaging (fMRI) measurements showed that repeated intermittent amphetamine exposure was associated with increased blood-oxygen-level dependent (BOLD) signal within the medial temporal lobe (MTL) (subiculum/entorhinal cortex) and midbrain, in the vicinity of the substantia nigra/ventral tegmental area (SN/VTA) during sequence encoding. Importantly, MTL hyperactivity correlated with the sensitisation of amphetamine-induced attentiveness. The MTL-midbrain hyperactivity reported here mirrors observations in sensitised rodents and is consistent with contemporary models of schizophrenia and behavioural sensitisation. These findings of meso-hippocampal hyperactivity during AS thus link pathophysiological concepts of dopamine dysregulation to cognitive models of psychosis.

Importance Forward models predict the sensory consequences of planned actions and permit discrimination of self- and non–self-elicited sensation; their impairment in schizophrenia is implied by an abnormality in behavioral force-matching and the flawed agency judgments characteristic of positive symptoms, including auditory hallucinations and delusions of control. Objective To assess attenuation of sensory processing by self-action in individuals with schizophrenia and its relation to current symptom severity. Design, Setting, and Participants Functional magnetic resonance imaging data were acquired while medicated individuals with schizophrenia (n = 19) and matched controls (n = 19) performed a factorially designed sensorimotor task in which the occurrence and relative timing of action and sensation were manipulated. The study took place at the neuroimaging research unit at the Institute of Cognitive Neuroscience, University College London, and the Maudsley Hospital. Results In controls, a region of secondary somatosensory cortex exhibited attenuated activation when sensation and action were synchronous compared with when the former occurred after an unexpected delay or alone. By contrast, reduced attenuation was observed in the schizophrenia group, suggesting that these individuals were unable to predict the sensory consequences of their own actions. Furthermore, failure to attenuate secondary somatosensory cortex processing was predicted by current hallucinatory severity. Conclusions and Relevance Although comparably reduced attenuation has been reported in the verbal domain, this work implies that a more general physiologic deficit underlies positive symptoms of schizophrenia.

BackgroundPeople with psychoses often report fixed, delusional beliefs that are sustained even in the presence of unequivocal contrary evidence. Such delusional beliefs are the result of integrating new and old evidence inappropriately in forming a cognitive model. We propose and test a cognitive model of belief formation using experimental data from an interactive ‘Rock Paper Scissors’ (RPS) game.MethodParticipants (33 controls and 27 people with schizophrenia) played a competitive, time-pressured interactive two-player game (RPS). Participants' behavior was modeled by a generative computational model using leaky integrator and temporal difference methods. This model describes how new and old evidence is integrated to form a playing strategy to beat the opponent and to provide a mechanism for reporting confidence in one's playing strategy to win against the opponent.ResultsPeople with schizophrenia fail to appropriately model their opponent's play despite consistent (rather than random) patterns that can be exploited in the simulated opponent's play. This is manifest as a failure to weigh existing evidence appropriately against new evidence. Furthermore, participants with schizophrenia show a ‘jumping to conclusions’ (JTC) bias, reporting successful discovery of a winning strategy with insufficient evidence.ConclusionsThe model presented suggests two tentative mechanisms in delusional belief formation: (i) one for modeling patterns in other's behavior, where people with schizophrenia fail to use old evidence appropriately, and (ii) a metacognitive mechanism for ‘confidence’ in such beliefs, where people with schizophrenia overweight recent reward history in deciding on the value of beliefs about the opponent.

Psychotic illness is a disorder of social interaction unique to humans. However, up to now research has failed to pin down the exact determinants of the complex and interactive processes associated with the development of trust and reciprocity in psychosis. Utilizing a novel multi-round version of an interactive trust game experiment, we show that patients with psychosis and healthy relatives with a heightened risk for the illness exhibit lower baseline levels of trust compared with healthy controls. This effect partly overlapped with a reduced general intelligence. Furthermore, patients were unable to modify their trusting behaviour neither in response to information about the general trustworthiness of their interaction partner, nor in response to their partners' specific direct behavioural feedback. Relatives, in contrast, modified their trusting behaviour towards similar levels as healthy subjects in response to both. The results show that behavioural flexibility in response to socially relevant information is a critical determinant of success in the instantiation and maintenance of social relationships. A lack thereof may drive social dysfunction and the progression from subclinical symptoms to a full-blown psychosis. This offers a testable mechanistic hypothesis for progression from prodrome to psychotic illness, and may provide a therapeutic avenue to grapple the psychotic symptoms of social dysfunction. © The Author (2012).

There is surprisingly little literature on age-related effectsin passive visual and auditory processing in humans. Inthis study, we use parameterised visual and auditory stim-uli to investigate the relationship between a) visual fre-quency and graded visual cortical activations b) auditoryword presentation frequency and graded auditory corticalactivations in both young and elderly groups. Weattempted to model the relationship between visual /auditory stimuli frequency and differential effects on cor-tical activation in both groups.

Recent work suggests that the amphetamine sensitization model of schizophrenia can safely be induced in healthy volunteers and is associated both with behavioral and dopaminergic hypersensitivity to amphetamine. However, the effects of a sensitization on brain function remain unclear.To assess the impact of a sensitizing dosage regimen of dextroamphetamine on human cortical functioning and cognition.Randomized, double-blind, parallel-groups design using pharmacological functional magnetic resonance imaging.The neuroimaging research unit at the Institute of Psychiatry, King's College London, London, England.Healthy male volunteers (n = 22).Dextroamphetamine (20 mg) or placebo administration at 4 testing sessions, using a dosage regimen shown to induce sensitization (ie, 3 doses administered with a 48-hour interdose interval and a final dose after a 2-week washout period).Sensitization was characterized by enhanced subjective response to the drug, changes in behavioral performance (reaction time and accuracy), and functional magnetic resonance imaging measurements of brain activity during an N-back working memory task.Sensitization was associated with more rapid responding during the performance of an intermediate-load working memory challenge. During a high-load cognitive challenge, sensitization did not produce performance deficits, but functional magnetic resonance imaging showed hyperactivity of the dorsolateral prefrontal cortex and aberrant recruitment of the superior temporal gyrus, caudate nucleus, and thalamus. Furthermore, the change in striatal activity was negatively correlated with the enhanced subjective effects of the drug, whereas prefrontal hyperactivity was positively correlated with sensitized measures of alertness.These transient load-dependent abnormalities of frontal and temporal activity induced by amphetamine sensitization support neuroimaging findings in schizophrenic patients, implying that amphetamine sensitization may help to bridge pathophysiological theories of schizophrenia that focus on pharmacological (dopaminergic) and cognitive mechanisms, respectively.

Psychophysical evidence suggests that sensations arising from our own movements are diminished when predicted by motor forward models and that these models may also encode the timing and intensity of movement. Here we report a functional magnetic resonance imaging study in which the effects on sensation of varying the occurrence, timing and force of movements were measured. We observed that tactile-related activity in a region of secondary somatosensory cortex is reduced when sensation is associated with movement and further that this reduction is maximal when movement and sensation occur synchronously. Motor force is not represented in the degree of attenuation but rather in the magnitude of this region's response. These findings provide neurophysiological correlates of previously-observed behavioural forward-model phenomena, and advocate the adopted approach for the study of clinical conditions in which forward-model deficits have been posited to play a crucial role.