Reduced P300 amplitude during retrieval on a spatial working memory task in a community sample of adolescents who report psychotic symptoms.

BACKGROUND: Deficits in working memory are widely reported in schizophrenia and are considered a trait marker for the disorder. Event-related potentials (ERPs) and imaging data suggest that these differences in working memory performance may be due to aberrant functioning in the prefrontal and parietal cortices. Research suggests that many of the same risk factors for schizophrenia are shared with individuals from the general population who report psychotic symptoms. METHODS: Forty-two participants (age range 11-13 years) were divided into those who reported psychotic symptoms (N = 17) and those who reported no psychotic symptoms, i.e. the control group (N = 25). Behavioural differences in accuracy and reaction time were explored between the groups as well as electrophysiological correlates of working memory using a Spatial Working Memory Task, which was a variant of the Sternberg paradigm. Specifically, differences in the P300 component were explored across load level (low load and high load), location (positive probe i.e. in the same location as shown in the study stimulus and negative probe i.e. in a different location to the study stimulus) and between groups for the overall P300 timeframe. The effect of load was also explored at early and late timeframes of the P300 component (250-430 ms and 430-750 ms respectively). RESULTS: No between-group differences in the behavioural data were observed. Reduced amplitude of the P300 component was observed in the psychotic symptoms group relative to the control group at posterior electrode sites. Amplitude of the P300 component was reduced at high load for the late P300 timeframe at electrode sites Pz and POz. CONCLUSIONS: These results identify neural correlates of neurocognitive dysfunction associated with population level psychotic symptoms and provide insights into ERP abnormalities associated with the extended psychosis phenotype.

Language processing abnormalities in adolescents with psychotic-like experiences: an event related potential study.

Language impairments are a well established finding in patients with schizophrenia and in individuals at-risk for psychosis. A growing body of research has revealed shared risk factors between individuals with psychotic-like experiences (PLEs) from the general population and patients with schizophrenia. In particular, adolescents with PLEs have been shown to be at an increased risk for later psychosis. However, to date there has been little information published on electrophysiological correlates of language comprehension in this at-risk group. A 64 channel EEG recorded electrical activity while 37 (16 At-Risk; 21 Controls) participants completed the British Picture Vocabulary Scale (BPVS-II) receptive vocabulary task. The P300 component was examined as a function of language comprehension. The at-risk group were impaired behaviourally on receptive language and were characterised by a reduction in P300 amplitude relative to the control group. The results of this study reveal electrophysiological evidence for receptive language deficits in adolescents with PLEs, suggesting that the earliest neurobiological changes underlying psychosis may be apparent in the adolescent period.

Neurophysiological functioning of occasional and heavy cannabis users during THC intoxication.

RATIONALE: Experienced cannabis users demonstrate tolerance to some of the impairing acute effects of cannabis. OBJECTIVES: The present study investigates whether event-related potentials (ERPs) differ between occasional and heavy cannabis users after acute Δ9-tetrahydrocannabinol (THC) administration, as a result of tolerance. METHODS: Twelve occasional and 12 heavy cannabis users participated in a double-blind, placebo-controlled, crossover study. On two separate days, they smoked a joint containing 0 or 500 µg/kg body weight THC. ERPs were measured while subjects performed a divided attention task (DAT) and stop signal task (SST). RESULTS: In the DAT, THC significantly decreased P100 amplitude in occasional but not in heavy cannabis users. P300 amplitude in the DAT was significantly decreased by THC in both groups. The N200 peak in the SST was not affected by treatment in neither of the groups. Performance in the SST was impaired in both groups after THC treatment, whereas performance in the DAT was impaired by THC only in the occasional users group. CONCLUSIONS: The present study confirms that heavy cannabis users develop tolerance to some of the impairing behavioral effects of cannabis. This tolerance was also evident in the underlying ERPs, suggesting that tolerance demonstrated on performance level is not (completely) due to behavioral compensation.

Language, motor and speed of processing deficits in adolescents with subclinical psychotic symptoms.

OBJECTIVES: Neuropsychological impairment is a core feature of schizophrenia. Adolescents reporting subclinical psychotic symptoms are considered to be at greater risk of developing a psychotic illness later in life than adolescents who do not report such symptoms and, thus, may represent an at-risk group for further study. We wished to investigate neuropsychological functioning in early adolescence in relation to reports of psychotic symptoms. METHODS: Participants were recruited from local primary schools after a two-stage screening and parental consent process. In brief, 277 adolescents were screened and 37 attended for testing. Seventeen adolescents who were deemed to report 'definite' psychotic symptoms after clinical interview and 20 control adolescents underwent a clinical interview and a one-hour neuropsychological battery. RESULTS: Adolescents who report psychotic symptoms exhibited significant impairments in receptive language (as measured by the British Picture Vocabulary Scale), motor function (as measured by the Pegboard test) and executive function/speed of processing (as measured by the Trail-Making test). There were no significant differences between the groups on measures of attention, memory or expressive language, abstract reasoning or overall scholastic ability. CONCLUSIONS: Taken together with the results from birth cohort, genetic high risk and prodromal studies, these findings are consistent with a neural inefficiency/disconnectivity hypothesis in those at risk for psychosis. These results highlight the need to investigate developmental brain circuits subserving language and motor function and processing speed and how these change over time in at-risk adolescents.

The HR/LR model: Further evidence as an animal model of sensation seeking.

Sensation seeking is a personality trait characterized by risk-taking and the desire to experience novel stimuli. Evidence suggests that sensation seeking may increase an individual's psychological and neurobiological vulnerabilities to drug abuse. One potential animal model of human sensation seeking is high response to novelty in rats. High responders (HRs) prefer a novel environment to a familiar one and show an increase in locomotor activity in the new environment. These rats also show lower levels of anxiety-like behaviour on several tests. Furthermore, HRs display a much higher propensity to self-administer psychostimulants compared to low responders (LRs). HR rats and sensation seeking humans share a number of similarities, for instance both exhibit elevated mesolimbic dopamine activity, which has been implicated in central reward signaling and drug addiction. Evidence of common behavioural tendencies, physiological responses and gene expression patterns suggest that the HR model could be used as an animal model to investigate substance abuse in sensation seeking humans.

Increased X-linked inhibitor of apoptosis protein (XIAP) expression exacerbates experimental autoimmune encephalomyelitis (EAE).

Dysregulated apoptotic signaling has been implicated in most forms of cancer and many autoimmune diseases, such as multiple sclerosis (MS). We have previously shown that the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP) is elevated in T cells from mice with experimental autoimmune encephalomyelitis (EAE). In MS and EAE, the failure of autoimmune cells to undergo apoptosis is thought to exacerbate clinical symptoms and contribute to disease progression and CNS tissue damage. Antisense-mediated knockdown of XIAP, in vivo, increases the susceptibility of effector T cells to apoptosis, thus attenuating CNS inflammation and thereby alleviating the clinical signs of EAE. We report for the first time, generation of transgenic mice whereby the ubiquitin promoter drives expression of XIAP (ubXIAP), resulting in increased XIAP expression in a variety of tissues, including cells comprising the immune system. Transgenic ubXIAP mice and wild-type (WT) littermates were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and monitored daily for clinical symptoms of EAE over a 21-day period. The severity of EAE was increased in ubXIAP mice relative to WT-littermates, suggesting that XIAP overexpression enhanced the resistance of T cells to apoptosis. Consistent with this finding, T cells derived from MOG35-55-immunized ubXIAP mice and cultured in the presence of antigen were more resistant to etoposide-mediated apoptosis compared to WT-littermates. This work identifies XIAP is an important apoptotic regulator in EAE and a potential pharmacological target for treating autoimmune diseases such as MS.