Evidence implicates subtle neuronal pathology of the prefrontal cortex (PFC) in schizophrenia, but how this pathology is reflected in physiological neuroimaging experiments remains controversial. We investigated PFC function in schizophrenia using functional magnetic resonance imaging (fMRI) and a parametric version of the n-back working memory (WM) task. In a group of patients who performed relatively well on this task, there were three fundamental deviations from the 'healthy' pattern of PFC fMRI activation to varying WM difficulty. The first characteristic was a greater magnitude of PFC fMRI activation in the context of slightly impaired WM performance (i.e. physiological inefficiency). The second was that the significant correlations between behavioral WM performance and dorsal PFC fMRI activation were in opposite directions in the two groups. Third, the magnitude of the abnormal dorsal PFC fMRI response was predicted by an assay of N-acetylaspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9, 46) to varying WM difficulty - supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. These data suggest that under certain conditions the physiological ramifications of dorsal PFC neuronal pathology in schizophrenia includes exaggerated and inefficient cortical activity, especially of dorsal PFC.

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.aggression ͉ antisocial ͉ functional MRI ͉ monoamine oxidase A ͉ serotonin

These results suggest that a genetically determined variation in prefrontal dopamine catabolism impacts the therapeutic profile of olanzapine.

Key Points Question Is there any genetic variant associated with adolescent brain development that can inform psychopathology of schizophrenia? Findings In this imaging genetics study of brain structure, a significant association between a missense mutation in SLC39A8 (a gene previously associated with schizophrenia) and gray matter volume in putamen was discovered and replicated using 10 411 healthy participants from 5 independent studies. Compared with healthy control individuals, such association was significantly weakened in both patients with schizophrenia and unaffected siblings. Meaning Common genetic variant indicates an involvement of neuronal ion transport in both pathophysiology of schizophrenia and structural development of putamen.