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Background In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms. Methods A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9–12 years and assessed at age 11–14 years (T1) and 17–21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire. Results Diurnal cortisol (β = 0.915, 95% confidence interval: 0.062–1.769) and daily stressors (β = 0.379, 95% confidence interval: 0.034–0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (β = 0.743, 95% confidence interval: 0.081–1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased. Conclusions Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods.

In the domain of machine learning, Neural Memory Networks (NMNs) have recently achieved impressive results in a variety of application areas including visual question answering, trajectory prediction, object tracking, and language modelling. However, we observe that the attention based knowledge retrieval mechanisms used in current NMNs restrict them from achieving their full potential as the attention process retrieves information based on a set of static connection weights. This is suboptimal in a setting where there are vast differences among samples in the data domain; such as anomaly detection where there is no consistent criteria for what constitutes an anomaly. In this paper, we propose a plastic neural memory access mechanism which exploits both static and dynamic connection weights in the memory read, write and output generation procedures. We demonstrate the effectiveness and flexibility of the proposed memory model in three challenging anomaly detection tasks in the medical domain: abnormal EEG identification, MRI tumour type classification and schizophrenia risk detection in children. In all settings, the proposed approach outperforms the current state-of-the-art. Furthermore, we perform an in-depth analysis demonstrating the utility of neural plasticity for the knowledge retrieval process and provide evidence on how the proposed memory model generates sparse yet informative memory outputs. Funding acknowledgement: QUT Project ID 2018001348 (ARC Future Fellowship FT170100294)

Out-of-school suspension is associated with adverse educational, justice, health, and welfare outcomes. Little research has focussed on suspensions from primary (elementary) school, despite early exclusions representing high-risk events for poor outcomes. This study aimed to identify early life predictors of primary school suspensions in a sample of 34,855 Australian children using linked education, health, child protection, and justice records for children and their parents. Associations between 26 sociodemographic, pregnancy/birth, child, and parent factors (measured prior to 3rd grade) and subsequent suspensions, issued during the 3rd through 6th grades (ages ~8–11 years), were examined in bivariate and multivariable logistic regressions. In the fully adjusted model, 18 factors were associated with suspension, with the largest effects for male gender, child protection services contacts, and aggressive behaviour. Identification of students at risk of early suspension using multi-sector information available at school entry may assist educators and policymakers to deliver preventative interventions.

Highlights • We determined the extent of gender-specific intergenerational antisocial behavior. • Gender-specific associations were not larger than associations across-gender. • The largest associations were between mothers' and daughters' antisocial behavior.

Background Longitudinal data on health costs associated with physical and mental conditions are not available for children reported to child protection services. Objective To estimate the costs of hospitalization for physical and mental health conditions by child protection status, including out-of-home-care (OOHC) placement, from birth until 13-years, and to assess the excess costs associated with child protection contact over this period. Participants and setting Australian population cohort of 79,285 children in a multi-agency linkage study. Methods Costs of hospitalization were estimated from birth (if available) using Round 17, National Hospital Cost Data Collection (2012-13; deflated to 2015-16 AUD). Records of the state child protection authority determined contact status. Data were reported separately for children in OOHC. Hospital separations were classified as mental disorder-related if the primary diagnosis was recorded in ICD-10 Chapter V (F00-F99). Results Hospital separations were more common in children with child protection contact. Physical health care costs per child decreased with age for all children, but were significantly higher for children with contact. Mental health costs per child were always significantly higher for children with contact, with marked increases at 3 ≤ 4 years and 8 ≤ 9 years. Point estimates of annual costs per child were always highest for children with an OOHC placement. The net present value of the excess costs was $3,224 per child until 13- years, discounted at 5 %. Conclusions Children in contact with child protection services show higher rates and costs for physical and mental health hospitalizations in each of their first 13 years of life.

Social withdrawal is a robust childhood risk factor for later schizophrenia. The aims of this paper were to assess the evidence for childhood social withdrawal among adults with schizophrenia and, comparatively, in children aged 9-14 years who are putatively at-risk of developing schizophrenia. We conducted a meta-analysis, including cohort and case-control studies reporting social withdrawal measured by the Child Behavior Checklist (CBCL) in adults with schizophrenia vs. controls. Further, an experimental study compared CBCL withdrawal scores from typically-developing children with scores from two groups of putatively at-risk children: (i) children displaying a triad of replicated antecedents for schizophrenia, and (ii) children with at least one first- or second-degree relative with schizophrenia or schizoaffective disorder. Six studies met inclusion criteria for the meta-analysis (N = 3828), which demonstrated a large effect of increased childhood social withdrawal in adults with schizophrenia (standardized mean difference [SMD] score = 1.035, 95% CI = 0.304-1.766, p = 0.006), with no indication of publication bias, but considerable heterogeneity (I(2) = 91%). Results from the experimental study also indicated a large effect of increased social withdrawal in children displaying the antecedent triad (SMD = 0.743, p = 0.001), and a weaker effect in children with a family history of schizophrenia (SMD = 0.442, p = 0.051). Childhood social withdrawal may constitute a vulnerability marker for schizophrenia in the presence of other antecedents and/or genetic risk factors for schizophrenia.

Background Intervention aimed at preventing schizophrenia may be most effective if targeted at specific, but modifiable, functional impairments that present during childhood. We have developed a novel method of screening community samples aged 9 to 12 years to identify children who present a triad of putative antecedents of schizophrenia (ASz), defined as 1) speech and/or motor development lags/problems; 2) internalizing, externalizing, and/or peer-relationship problems in the clinical range; and 3) psychotic-like experiences. This study examined whether ASz children display brain function abnormalities during error processing that are similar to those exhibited by adults with schizophrenia. Methods Twenty-two ASz children and 26 typically developing (TD) children with no antecedents of schizophrenia completed an error-inducing Go/NoGo task during event-related potential recording. Group differences were examined in the amplitude and latency of four event-related potential components: the initial error-related negativity (ERN) and later error-positivity (Pe) elicited on false-alarm responses to NoGo trials, and the corresponding initial correct response negativity (CRN) and later correct response positivity (Pc) elicited during processing of correct responses to Go trials. Results Relative to TD children, ASz children were characterized by reduced ERN amplitude but unaffected CRN, Pe, and Pc amplitudes. No group differences were observed in the latency of any component. Conclusions Children presenting a triad of putative antecedents of schizophrenia show error-processing dysfunction mimicking that observed in adults with schizophrenia using the same Go/NoGo paradigm. The ASz children displayed specific early error-processing deficits rather than a generalized deficit in self-monitoring.

Numerous studies have described attenuated event-related potential (ERP) component amplitudes in schizophrenia (e.g., P300, Mismatch Negativity (MMN), Error Negativity/Error-Related Negativity (Ne/ERN)). Functional magnetic resonance imaging (fMRI) studies have typically shown decreased recruitment of diverse brain areas during performance of tasks that elicit the above ERP components. Recent research suggests that phase-resetting of slow-oscillations (e.g., in the delta and theta bands) underlies the potentials observed in ERP averages. Several studies have reported that slow-oscillations are increased in amplitude in people with schizophrenia at rest. Few studies have examined event-related low-frequency oscillations in schizophrenia. We examined event-related evoked and induced delta and theta activity in 17 people with schizophrenia and 17 healthy controls in two go/no-go task variants. We analyzed stimulus-related and response-related oscillations associated with correct-hits, correct-rejects and false-alarms. Our results reveal a pattern of reduced delta and theta activity for task-relevant events in schizophrenia. The findings indicate that while low-frequency oscillations are increased in amplitude at rest, they are not coordinated effectively in schizophrenia during various information processing tasks including target-detection, response-inhibition and error-detection. This slow-oscillation coordination abnormality may help explain the decreased recruitment of brain areas seen in fMRI studies.

Prospective longitudinal investigations are needed to identify causal processes leading to schizophrenia. However, there is presently no cost-effective way to identify children who are at risk of developing schizophrenia spectrum disorders: Although having a family history of schizophrenia is associated with elevated risk for developing spectrum disorders, the majority of individuals with schizophrenia do not have an afflicted relative. The present study aimed to test the feasibility of screening a community sample of children, aged 9 to 12 years, to identify children who experienced a triad of putative antecedents of schizophrenia that had been identified from previous research, including: (1) speech and/or motor development lags or problems; (2) social, emotional, or behavioural problems; and (3) psychotic-like-experiences (PLEs). 548 children and 264 caregivers completed questionnaires. 9.2% of boys and 4.1% of girls displayed the triad of antecedents. 58.9% of the children reported "certain experience" of one or more PLEs. The results suggest that questionnaire screening of community samples of children for the putative antecedents of schizophrenia spectrum disorders is feasible. Accuracy of identification will only be established by follow-up studies.

Accumulating evidence suggests that psychopathy is associated with behavioral and event-related potential (ERP) abnormalities during semantic language tasks. Psychopaths' ERP abnormalities are most prominent in the 300-500 ms post-stimulus time window. It is unclear whether these ERP differences are related to neurocognitive processes associated with the P300 (i.e., poor attention/orienting/working memory) or N400 (i.e., aberrant semantic processes). To address this issue, the present study employed a canonical semantic sentence processing paradigm known to selectively elicit the N400. Fifty incarcerated participants were divided into psychopathic (n = 25) or nonpsychopathic (n = 25) groups based on scores from the Hare Psychopathy Checklist-Revised. The N400 and P600 components elicited by terminal words of sentences either congruent or incongruent with the previous sentence context were examined. No differences were observed between groups in the behavioral or ERP data. These data do not support the hypothesis that the semantic processes, and underlying neural systems, associated with the generation of the N400 during sentence processing tasks are abnormal in psychopathy.

We report a random-effects analysis of an event-related fMRI study (n = 28) of cerebral activity during the reading of sentences that ended with a word that was either congruent or incongruent with the previous sentence context. Event-related potential studies have shown that this task elicits a late negativity peaking around 400 ms poststimulus (N400) that is larger for incongruent than for congruent sentence endings. A direct comparison of the activation for incongruent words versus that for congruent words revealed significantly greater activation for incongruent words than congruent words in bilateral inferior frontal and inferio-medial temporal cortex, left lateral frontal cortex, left posterior fusiform gyrus, bilateral motor cortex, and supplementary motor area. These results are consistent with data from intracranial electrical recording studies of the N400 electrical potential. The results are discussed as they relate to the localization of the cerebral sites underlying semantic processing in general and the localization of the scalp recorded N400 event-related potential in particular.

Background: Persisting psychotic-like experiences (PLEs) are associated with an increased risk of internalising symptoms in adolescence. Whether this association holds similarly for externalising symptoms, and from mid-childhood, is unclear. This prospective study investigated the extent to which PLE persistence was associated with internalising and externalising psychopathology in a community sample of children aged 9-11 years at study commencement. Methods: 8099 children (mean age 10.4 years) completed questionnaires assessing PLEs, externalising and internalising symptoms. A subsample of 547 children completed reassessment, on average, two years later. Results: Two-thirds (66%) of children reported PLEs at baseline. Approximately two years later, PLEs persisted in 39% of those children. After adjustment for previous psychopathology and other potential confounds, children with persisting PLEs were at higher risk for internalising (odds ratio [OR]=1.94; 95% confidence interval [CI] 1.13-3.34) and externalising (OR=1.97; 95% CI 1.19-3.26) psychopathology than children whose PLEs remitted; and, than children who never presented PLEs. Conclusions: Persistent PLEs from mid-childhood are associated with later internalising and externalising psychopathology in the general population, whereas transitory PLEs may be part of a spectrum of normative childhood development. Interventions that target persistent PLEs may contribute to a reduction in common childhood psychopathology.

Background & aim: Understanding the emotional state of others is fundamental to effective social interaction and the development of empathy. Critical information is conveyed via the eyes, and reduced attention to the eyes is associated with poorer emotion recognition and empathic deficits in individuals with disorders affecting social cognition such as autism or some types of conduct problems. Deliberately redirecting attention to the eyes may be a way of improving behaviour. However, the effects of directing attention on brain activity during emotional processing has not been studied previously. Our aim was to determine whether manipulation of visual attention in youths affects their eye gaze patterns and brain responses to expression of emotions in others. Method: Eighteen typically developing male youths aged 8-16 performed an implicit facial emotion processing task while viewing different facial expressions (fearful, neutral, happy), presented in three separate blocks under three different instructions: undirected, eye-gaze and mouth-gaze. Eye tracking (dwell time) and functional-MRI data were acquired concurrently as measures of visual attention and brain response, respectively. Results: Eye tracking indicated that the youths attended more to the eyes than the mouth in the undirected condition. Redirecting attention to the eyes and mouth significantly increased attention to these areas. Compared to undirected, directing attention to the fearful eyes also produced a greater increase in attention than neutral eyes. Attention directed to eyes elicited greater brain activity in frontal regions than undirected attention. Discussion & conclusions: The undirected eye gaze patterns indicate natural orienting to eyes in healthy youths, which can be effectively altered with instruction. Directing attention to fearful eyes engaged attention relatively longer than neutral, consistent with the threat value of fearful faces. These data also demonstrate that manipulation of visual attention modulates activity in frontal regions, perhaps reflecting greater engagement of executive function due to attentional demands. Understanding attentional manipulation effects in a healthy sample will inform ongoing work addressing potentially perturbed response patterns in a conduct problem cohort.

Background Volume reduction in insular cortex may constitute an important neuropathology in schizophrenia. We provide the first meta-analysis of studies that conducted region-of-interest analyses of the magnitude of effect and pattern of insula volume reduction in schizophrenia compared with healthy control subjects. Methods Included studies examined insula volume in schizophrenia relative to healthy control subjects. Studies were located via electronic database searches and hand searching. Study selection, data extraction, and quality assessment were completed by two independent reviewers. Hedge's g effect sizes were calculated using Comprehensive Meta-Analysis (v.2) to quantify volumetric differences between people with and without schizophrenia, accounting for moderating influences of age, sex, illness duration, medication, whole brain volume, and potential differences in hemispheric and anatomical subregions. Results Random-effects analysis showed reductions of bilateral insula (n = 945, g = −.446, 95% confidence interval −.639 to −.252, p = .00001), with moderate heterogeneity apparent (I2 = 76%). This effect was consistent across left and right insula and not influenced by illness stage or sex. Additional analyses revealed larger reductions of anterior (n = 605, g = −.643, p < 0.001; I2 = 52%) than of posterior insula (n = 453, g = −.321, p = .028; I2 = 55%). Meta-regression analyses did not identify any significant predictors of reduced insula volume. Conclusions This meta-analysis indicates medium-sized reduction of insula volume in schizophrenia, of greatest magnitude in the anterior subregion. Cellular distinctions across anterior and posterior insula may contribute to understanding the neuropathology and functional significance of the observed volumetric differences.

Introduction Identifying the relative strength of evidence associated with non-genetic risk factors and putative antecedents of schizophrenia will guide research and may inform the design of early detection and intervention strategies. Aims To present and quality assess current evidence for non-genetic risk factors and putative antecedents derived from well-conducted systematic reviews that report pooled data. Method Medline, Embase, CINAHL, Current Contents, and PsycINFO databases were searched systematically, and supplemented by hand searching. Review reporting quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, review methodology was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist, and evidence quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Twenty-four reviews met inclusion criteria. The risk factors with the highest quality evidence, reporting medium effect sizes, were advanced paternal age, obstetric complications, and cannabis use. The strongest evidence among the putative antecedents was identified for motor dysfunction and low IQ. Conclusions More research is required that applies sound methodological practices, taking into consideration specificity for schizophrenia and possible confounding factors, to robustly identify the non-genetic risk factors and putative antecedents of schizophrenia.

Background Persisting psychotic-like experiences (PLEs) are associated with an increased risk of internalising symptoms in adolescence. Whether this association holds similarly for externalising symptoms, and from mid-childhood, is unclear. This prospective study investigated the extent to which PLE persistence was associated with internalising and externalising psychopathology in a community sample of children aged 9–11 years at study commencement. Methods 8099 children (mean age 10.4 years) completed questionnaires assessing PLEs, externalising and internalising symptoms. A subsample of 547 children completed reassessment, on average, two years later. Results Two-thirds (66%) of children reported PLEs at baseline. Approximately two years later, PLEs persisted in 39% of those children. After adjustment for previous psychopathology and other potential confounds, children with persisting PLEs were at higher risk for internalising (odds ratio [OR] = 1.94; 95% confidence interval [CI] 1.13–3.34) and externalising (OR = 1.97; 95% CI 1.19–3.26) psychopathology than children whose PLEs remitted; and, than children who never presented PLEs. Conclusions Persistent PLEs from mid-childhood are associated with later internalising and externalising psychopathology in the general population, whereas transitory PLEs may be part of a spectrum of normative childhood development. Interventions that target persistent PLEs may contribute to a reduction in common childhood psychopathology.

Background: Subclinical psychotic-like experiences (PLEs) are common among the general population, particularly in children. Nevertheless, they confer elevated risk for later psychotic illness. This risk might be increased only in the context of additional psychosis risk markers, with recent research highlighting associations between depression/anxiety and the persistence of PLEs during adolescence. Yet, schizophrenia and related disorders are predicted by childhood externalising (EXT) as well as internalising (INT) psychopathology. Thus, the present study examined the latent structure underlying PLEs, EXT, and INT symptoms in a community sample of children aged 9-11 years. The study further examined whether longitudinal PLE trajectories over two years, particularly PLE persistence, predicted the presence of later INT and EXT problems. Methods: A community sample of 7,966 children (95% of eligible children; 51% male; mean age 10.4 years) completed questionnaires in class that assessed nine PLEs, EXT symptoms (conduct problems, hyperactivity and INT symptoms (emotional problems and peer relationship problems). A subsample of 547 children (46% male, mean age 12.2 years) completed reassessment after an average of two years, with their caregivers additionally reporting on children’s INT and EXT symptoms at both times (T0 and T1). Data in the longitudinal analysis were weighted to reflect the baseline population sample. Factor analysis of child-reported data in the large community sample (T0) was conducted to determine the latent structure underlying PLEs and other psychopathology in the general child population. In the longitudinal analysis, four PLE trajectories were defined using child-reported PLEs: persistent (PLEs at T0 and T1); remitting (PLEs at T0, but not at T1); incident (no PLEs at T0, but PLEs at T1); and none (no PLEs at T0 or T1). These trajectories were used to predict the presence of child-/parent-reportedINT and EXT problemsat T1. Analyses were repeated after correcting for age, sex, duration of follow-up, and T0 INT and EXT problems. Results: Two thirds (66%) of children aged 9-11 years reported at least one PLE at T0, with individual prevalence on the nine items ranging between 9-35%. All nine PLE items loaded on a single psychotic-like construct, which was discriminable from, though correlated with, latent dimensions representing INT and EXT problems. PLE trajectory prevalence rates over two years were: persistent 25%, remitting 39%, incident 5%, none 31%; with a majority of the children who reported a PLE at T0 no longer doing so at T1 (61%). Children whose PLEs remitted presented comparable rates of T0 and T1 INT or EXT problems to their peers who never presented PLEs. Children whose PLEs persisted were more likely to present T1 INT and EXT problems than their peers who never presented PLEs (INT odds ratio [OR]=3.1; EXT OR=2.4), as well as children whose PLEs remitted (INT OR=1.8; EXT OR=1.8). These associations remained after correcting for potential confounders and prior (T0) INT and EXT psychopathology. Discussion: Among the general childhood population aged 9-11 years, PLEs are common, though transient in the majority. Assessing PLEs at this age is viable, and permits delineation of a subset of children whose PLEs persist two years later, during transition to adolescence. PLE persistence relates to later externalising and internalising problems. Thus, interventions to reduce emotional and behavioural problems might target children presenting persistent PLEs, with some requiring additional strategies to ameliorate anxiety and depression symptoms, and others, behavioural and attentional problems.

The idea that the content of delusions and hallucinations may have meaning or be symbolically significant is not new. From a psychodynamic perspective, the experience of psychosis has long been conceptualised as a defence against unbearable or unmanageable emotions (Martindaleetal2013)andthecontentofpsychoticexperiencesistherefore considered to have meaning and relevance for clinical practice (Martindale 2007). In adult samples, the content of delusions and hallucinations has been found to be associated with the experience of trauma and abuse (Raune et al. 2006, Reiff et al. 2012). To the best of our knowledge, no study to date has examined the content of sub-clinical psychotic-like experiences (PLEs) using non-clinical child or adolescent samples. This study aims to identify the presence of themes in the content of PLEs among children and adolescents from the general population and to examine associations between the content of the psychotic experience and adverse or abusive life events.

Background: A robust marker of brain dysfunction in schizophrenia (Cohen’s d=0.89) is reduction in amplitude of the P3 (or P300) event-related potential (ERP) that indexes attention and working memory processes. It is elicited typically using a two-tone auditory oddball paradigm that presents infrequent task-relevant target stimuli (which require a behavioural response) within a train of frequent task-irrelevant non-target (or standard) stimuli. The P3 amplitude reduction to target stimuli is present at the chronic and first-episode phases of schizophrenia, and may predict transition to psychosis among at-risk adolescents/young adults. We sought to characterise potential premorbid brain function abnormalities among at-risk children aged 9-12 years in detail, using an auditory novelty oddball task variant that dissociates an earlier, automatic frontocentral P3a subcomponent elicited by infrequent task-irrelevant salient novel stimuli from a later parietal P3b sub-component elicited by the infrequent task-relevant target stimuli. Methods: We examined brain function in two at-risk groups, including a group with family history of schizophrenia (FHx; n=20) and a group of children presenting a triad of replicated antecedents of schizophrenia (ASz; n=20), namely (i) psychotic-like experiences; (ii) a social, emotional, or behavioural problem; and (iii) a speech-and/or-motor developmental delay or abnormality. At-risk groups were compared with a group of typicallydeveloping (TD; n=28) peers who had no family history or antecedents of schizophrenia. Groups did not differ significantly on age, sex, ethnicity, socio-economic status, or handedness. Three group (FHx, ASz, TD) x three stimulus (targets, novels, non-targets) x five site (Fz, FCz, Cz, CPz, Pz) repeated-measures ANOVAs on peak P3 amplitude and latency data were conducted, and were repeated as ANCOVAs to control for poorer intellectual function (IQ) among the at-risk groups relative to TD children. Results: A significant group-by-condition interaction indicated reduced novelty P3a amplitude, but not target P3b or non-target P3 amplitudes, in both at-risk groups relative to TD children. This result remained after correcting for IQ differences between groups. No latency differences were observed. Discussion: At-risk children aged 9-12 years, both those with family history and those presenting multiple childhood antecedents, display disturbances in frontal mechanisms supporting involuntary attention orienting to salient stimuli, while more conscious parietal mechanisms supporting stimulus evaluation and context updating are, as yet, unaffected in these children. The latter may emerge more proximally to transition to psychosis; 48month follow-up assessments are underway to ascertain the evolution of these components as participants mature through adolescence.

Schizophrenia is a diffuse brain disease that affects many facets of cognitive function. One of the most replicated findings in the neurobiology of schizophrenia is that the event-related potentials to auditory oddball stimuli are abnormal, suggesting abnormalities in attention and memory processes. Recently, we have used event-related fMRI to elucidate the abnormal neural architecture underlying target detection in chronic patients with schizophrenia. Compared with control participants, selective deficits were observed in the lateral frontal cortex, thalamus, superior temporal gyms, cingulate, and parietal lobes. Here we present the results of a similar study from a group of first-episode psychotic patients. Consistent with the results observed with chronic medicated patients, diffuse hemodynamic abnormalities were observed in the first episode patients in multiple cortical and subcortical sites. The first episode patients were also tested six weeks after treatment with atypical neuroleptics. Improvements in neural function, manifest as significantly larger hemodynamic responses to target stimuli, were observed in bilateral amygdala, hippocampus, dorsolateral prefrontal cortex, and supramarginal gyms and in the posterior cingulate. These data are consistent with the hypothesis that schizophrenia is characterized by a widespread pathological process affecting many cerebral areas. The data also suggest atypical neuroleptics improve neural function at diverse cerebral sites.

Introduction Psychopathy is a personality disorder characterised by disturbance in affective, interpersonal, and behavioural domains. Typically, it is the behavioural disturbances, including impulsivity, poor behavioural controls, and persistent contravention of societal norms, that brings the psychopath to the attention of society. The psychopaths’ behavioural disturbance has been conceptualized as arising from impaired response inhibition. Event-related potential research (Kiehl et al., 2000, Biological Psychiatry, 48) suggests that psychopathy is associated with abnormal neural activity during suppression of inappropriate responses. We used event-related fMRI to elucidate the neurobiological correlates of response inhibition during performance of a Go/NoGo task. Using this task in healthy controls Liddle et al. (2001, Human Brain Mapping, 12) demonstrated the importance of lateral frontal cortex in response inhibition. We hypothesised that psychopaths would show less activation in lateral frontal cortex during processing of NoGo stimuli than would healthy controls. Methods Fourteen psychopaths were recruited from a maximum-security prison and compared with fourteen healthy control participants selected from the general population. Psychopathy was assessed using the Hare Psychopathy Checklist-Revised (PCL-R) (Hare, 1991). Groups were matched for age, parental socioeconomic status, and IQ. All participants were right-handed, native English speakers, without history of head injury or psychotic illness. Task procedures are as described in Liddle et al. (2001). The visual stimuli for the Go and NoGo trials were the letters ‘X’ and ‘A’ respectively, presented for a period of 250 msecs each. Each trial commenced with a descending count of asterisks in order to increase motor response preparation. Twenty-four Go and 24 NoGo trials were randomly presented in a single scanning session. Imaging was performed using a General Electric 1.5 T whole body system fitted with a Horizon echo-speed upgrade. Functional image volumes were collected with a gradient-echo sequence (TR/IE 2500/50 ms, flip angle 90”, FOV 24x24 cm, 64x64 matrix, 62.5 kHz bandwidth, 3.75x3.75 mm in plane resolution, 4 mm slice thickness, 29 slices). Functional images were realigned, normalised, and smoothed using Statistical Parametric Mapping (SPM99). Event-related responses to the Go and NoGo stimuli were modeled with a synthetic haemodynamic response function composed of two gamma functions and their temporal derivatives. To test the hypothesis of reduced activation in lateral frontal cortex in psychopaths, we tested for significant group differences in activation during NoGo trials within I0mm diameter spherical regions centred on the loci of activation in lateral frontal cortex reported by Liddle et al. (2001). Results No significant differences between groups in accuracy of performance were observed. In accordance with the hypothesis, psychopaths exhibited significantly less activation in lateral frontal cortex, bilaterally, than healthy controls during NoGo trials: xyz = -48 -4 52, Z=3.78; xyz = 36 0 36, Z=3.66. Discussion We have demonstrated that inhibiting a behavioural response is associated with less lateral frontal activation in psychopaths compared to healthy control subjects. This is consistent with previous electrophysiological findings. Kiehl et al. (2000) reported that psychopaths exhibited a reduced amplitude of the frontal negative potential (N275) during NoGo trials. Taken together, these findings indicate that the cerebral mechanism for response inhibition is impaired in psychopathy.