Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia.

Schizophrenia has been thought of as a disorder of reduced functional and structural connectivity. Recent advances in neuroimaging techniques such as functional magnetic resonance imaging, structural magnetic resonance imaging, diffusion tensor imaging, and small animal imaging have advanced our ability to investigate this hypothesis. Moreover, the power of longitudinal designs possible with these noninvasive techniques enable the study of not just how connectivity is disrupted in schizophrenia, but when this disruption emerges during development. This article reviews genetic and neurodevelopmental influences on structural and functional connectivity in human populations with or at risk for schizophrenia and in animal models of the disorder. We conclude that the weight of evidence across these diverse lines of inquiry points to a developmental disruption of neural connectivity in schizophrenia and that this disrupted connectivity likely involves susceptibility genes that affect processes involved in establishing intra- and interregional connectivity.

Gender-moderated dorsolateral prefrontal reductions in 22q11.2 Deletion Syndrome: implications for risk for schizophrenia.

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.

Obstetric complications and risk for conversion to psychosis among individuals at high clinical risk.

AIM: Examining risk factors among high-risk populations stands to inform treatment and to elucidate our understanding of the pathophysiology of schizophrenia. Despite substantial evidence implicating the incidence of obstetric complications (OCs) as a risk factor for schizophrenia, little is known about the relationship between OCs and risk for conversion among high-risk individuals. METHODS: We prospectively followed individuals at high risk for developing psychotic disorders for a two-year period to determine if a history of OCs is associated with conversion. RESULTS: Individuals who converted to psychosis had significantly more OCs when compared to non-converting participants; a history of OCs was associated with increased odds of conversion (odds ratio = 4.90, confidence interval :1.04/22.20). OCs were positively associated with prodromal symptomatology. CONCLUSIONS: To date, this report represents the first empirical evidence suggesting that OCs confer increased risk of conversion to psychosis. It is possible that OCs interact with brain maturational processes in the pathophysiology of schizophrenia and can serve as a risk marker.

Gender differences in symptoms, functioning and social support in patients at ultra-high risk for developing a psychotic disorder.

Gender differences have been widely observed in the clinical presentation, psychosocial functioning and course of illness in first-episode and chronic patients suffering from schizophrenia. However, little is known about gender differences in the psychosis prodrome. This study investigated gender differences in symptoms, functioning and social support in individuals at ultra-high-risk for developing a psychotic disorder. Sixty-eight ultra-high-risk patients were assessed at baseline, and twenty-seven returned for follow-up assessments approximately 6 and 12 months later. Clinical symptoms and functioning were assessed by clinical interview; social support was measured using a self-report questionnaire. There were no gender differences in demographic variables, symptoms or functioning at baseline. Males were found to have significantly higher levels of negative symptoms and marginally lower levels of functioning when baseline and follow-up time points were considered collectively. Additionally, females reported higher levels of social support at baseline. Differences in negative symptoms were found to mediate differences in functioning between male and female patients. This study suggests that gender based differences in symptom presentation and functional outcome may predate conversion to psychosis. Follow-up studies should examine the relationship between symptoms, functioning and social support in this population.