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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.

A recent theoretical account delineated the role of the anterior cingulate cortex (ACC) in cognitive control as the detection of conflict between competing information streams. Using functional magnetic resonance imaging, we examined the activity of this brain structure during different forms and degrees of conflict between the word and the color dimensions of Stroop stimuli. Overall, our results showed a dissociation between the degree of conflict and ACC activation. More specifically, although ACC activation was very extensive when print color interfered with word reading performance, the level of conflict, as measured by reaction time costs, was only moderate compared to other conditions. These results suggest that either the ACC is differentially sensitive to various types of conflict or its function should be extended to include other cognitive constructs, such as resolution of prior inhibition.

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.

Identification of markers of abnormal brain function in children at-risk of schizophrenia may inform early intervention and prevention programs. Individuals with schizophrenia are characterised by attenuation of MMN amplitude, which indexes automatic auditory sensory processing. The current aim was to examine whether children who may be at increased risk of schizophrenia due to their presenting multiple putative antecedents of schizophrenia (ASz) are similarly characterised by MMN amplitude reductions, relative to typically developing (TD) children. EEG was recorded from 22 ASz and 24 TD children aged 9 to 12 years (matched on age, sex, and IQ) during a passive auditory oddball task (15% duration deviant). ASz children were those presenting: (1) speech and/or motor development lags/problems; (2) social, emotional, or behavioural problems in the clinical range; and (3) psychotic-like experiences. TD children presented no antecedents, and had no family history of a schizophrenia spectrum disorder. MMN amplitude, but not latency, was significantly greater at frontal sites in the ASz group than in the TD group. Although the MMN exhibited by the children at risk of schizophrenia was unlike that of their typically developing peers, it also differed from the reduced MMN amplitude observed in adults with schizophrenia. This may reflect developmental and disease effects in a pre-prodromal phase of psychosis onset. Longitudinal follow-up is necessary to establish the developmental trajectory of MMN in at-risk children., Highlights • Examined MMN (duration deviant) in children purportedly at risk of schizophrenia • Greater frontal MMN amplitude for children at risk than typically developing peers • Increased MMN contrasts with MMN amplitude reduction in adults with schizophrenia • Possible basis in maturational and disease processes in frontal and temporal lobes • May index pre-prodromal phase of psychosis onset in children at risk