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Schizophrenia and neurodevelopment – Where do we stand today?

Schizophrenia and neurodevelopment – Where do we stand today?

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood or adolescent periods. The objective is to place schizophrenia neuropathology in a neurodevelopmental context.

This requires solid, scrutinized evidence of changes occurring during normal development of the cerebral cortex. We review literature on the development of the prefrontal cortex and chart major molecular and cellular events on a similar time line. Whilst neurogenesis, neuronal migration and myelination undergo most dramatic changes prenatally, these processes also extend into adolescence.

Expressions of inhibitory interneuron markers and GABA receptor subunits are dynamic, including during adolescence. While there are reports of synaptic regression throughout the first decade of life this has been balanced by evidence of dendritic growth and increase in expression of molecular markers of proteins required for excitatory synapse function until early adulthood. The NMDA receptor subunits reveal decreases, increases and constant level of mRNA expression in postnatal life.  We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in the first decade of life and into adolescence.

Conference: MAPrc
Areas of Interest / Categories: MAPrc 2014

MAPrc 2014

The effect of symptomatic improvement on gamma synchrony in psychosis: a pilot study.

Impaired functional connectivity, as measured by synchronous gamma activity, has been observed in both the early and chronic stages of schizophrenia, as well as in unaffected first-degree relatives. This suggests gamma synchrony may be a trait-like marker of psychosis susceptibility, and not just a state-dependant characteristic. To conduct a pilot study into the short-term temporal stability of gamma synchrony and its relationship to symptomatic improvement in young patients who have been treated for recent onset psychosis. 20 medicated subjects underwent both clinical (PANSS) and electrophysiological (auditory oddball task during EEG) evaluation at both baseline and 8 weeks follow-up.

The effect of symptomatic improvement on gamma synchrony in psychosis: a pilot study.

Impaired functional connectivity, as measured by synchronous gamma activity, has been observed in both the early and chronic stages of schizophrenia, as well as in unaffected first-degree relatives. This suggests gamma synchrony may be a trait-like marker of psychosis susceptibility, and not just a state-dependant characteristic. To conduct a pilot study into the short-term temporal stability of gamma synchrony and its relationship to symptomatic improvement in young patients who have been treated for recent onset psychosis. 20 medicated subjects underwent both clinical (PANSS) and electrophysiological (auditory oddball task during EEG) evaluation at both baseline and 8 weeks follow-up.

Cerebral cortical grey matter deficits in schizophrenia and their associations with ageing, psychopathology, cognition and treatment response.

The diagnosis of schizophrenia lacks a broadly accepted biological basis and its heterogeneity may well represent a group of disorders with different aetiologies. Even so, brain imaging can map and quantify structural brain abnormalities in vivo as an intermediate (or endo-) phenotype of the disorder. To identify the degree of regional grey matter deficits in relation to age, the severity of psychopathology and cognitive/ neurological impairment, and treatment response in schizophrenia. Eighteen schizophrenia patients (32.2 years [SD 14.3], meeting DSM-IV criteria were examined. Eighteen pair-wise age (±2 years) and gender-matched healthy volunteers (31.9 years [SD 14.3]) served as control group.

Keeping the Body in Mind: Exercise Physiology Services within a Community-based Early Psychosis Treatment Program

People with first episode psychosis (FEP) are prone to significant weight gain and metabolic abnormalities in the early stages of treatment putting them at significant risk of developing physical co-morbidities, including type-2 diabetes and metabolic syndrome. These co-morbidities reduce quality of life and life expectancy within this population. Despite known benefits of regular exercise including anxiolytic and anti-depressive effects, very low treatment adherence within FEP programs limits the effectiveness of exercise as a potential intervention. Determining the characteristics of FEP patients who frequently participate in a facilitated exercise program may assist in the development of strategies aimed at improving adherence. To determine the characteristics of frequent users of a facilitated exercise program.

Cardiometabolic risk indicators at 18-64 years in Australians with psychosis

Individuals with psychosis have an elevated risk for heart disease and are more likely to die prematurely from heart disease than the general population. The age at which cardiovascular risk indicators are first elevated relative to the general population is unknown. Mean waist circumference, BMI, blood pressure, fasting blood glucose, triglycerides, LDL, HDL and total cholesterol were plotted by age and sex in a representative sample of 1,642 individuals with psychosis (aged 18+) who were in contact with mental health services and 11,247 controls (aged 25+) from the general population. Correlations between risk indicators were compared between samples.

Role of intracellular mediators in clozapine induced ErbB1-ERK signalling in prefrontal cortical neurons: relevance to therapeutic efficacy.

Dysregulation of the epidermal growth factor (EGF) system, implicated in synaptic plasticity, long-term potentiation and dendritic spine connectivity has been linked to schizophrenia. For instance, in patient brain and blood low EGF levels resulting in compensatory up-regulation of the EGF receptor (ErbB1) is postulated to represent a hypofunctioning signalling state. Consistent with this hypothesis our preclinical in vitro and in vivo data demonstrate that the antipsychotic drug clozapine increases ErbB1 signalling via G-protein coupled receptor (GPCR) transactivation in prefrontal cortex and striatum1,2,3. The clozapine induced increase in ErbB1 signalling results in delayed activation of the extracellular signal regulated kinase (ERK) pathway with downstream activation of the transcription factors, p90RSK and c-Fos.

The effect of Ketamine on striatal functional connectivity as a model for risk for psychosis.

Ketamine is a potent antagonist of the N-methyld-aspartate receptor that induces positive psychotic symptoms in healthy individuals reminiscent of those seen in people with schizophrenia. Ketamine is believed to act by imposing a broad modulatory effect on brain networks, particularly cortico-striatothalamic circuitry. To investigate the effect of a sub-anaesthetic dose of ketamine on the resting-state functional connectivity of dorsal and ventral corticostriatal circuits, structures that have strongly been implicated in the emergence of psychotic symptoms, and to characterize the symptom correlates of putative changes in cortico-striato-thalamic functional connectivity induced by ketamine infusion.