Functional disconnectivity in subjects at high genetic risk of schizophrenia

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Abstract
Schizophrenia is a highly heritable psychotic disorder. It has been suggested that deficits of the established state arise from abnormal interactions between brain regions. We sought to examine whether such connectivity abnormalities would be present in subjects at high genetic risk for the disorder. Functional connectivity analysis was carried out on functional MRI images from 21 controls and 69 high risk subjects performing the Hayling sentence completion task; 27 high risk subjects reported isolated psychotic symptoms, the remaining high risk subjects and controls did not. There were no significant differences in task performance between the groups. Based on previous findings we hypothesized: (i) state-related differences in connectivity between dorsolateral prefrontal cortex and lateral temporal lobe; (ii) genetically mediated reductions in a medial prefrontal-thalamic-cerebellar network; and (iii) increased prefrontal-parietal connectivity in high risk subjects (to a greater extent in those with isolated psychotic symptoms). Connectivity analysis was performed in two ways: with and without variance associated with task effects modelled and removed from the data. We did not find evidence to support our first hypothesis with either analysis method. However, consistent with hypothesis (ii), decreased connectivity between right medial prefrontal regions and contralateral cerebellum was found. This was only statistically significant in the analysis with task effects modelled and removed from the data. Finally, consistent with hypothesis (iii), increased connectivity between the left parietal and left prefrontal regions in high risk subjects was found in both analyses. These results, all in a situation uncontaminated by the effects of anti-psychotic medication, performance differences and prolonged illness, suggest there are abnormalities in functional connectivity over and above those attributable to task effects in high risk subjects. These connectivity abnormalities may underlie the diverse deficits seen in the established condition and the more subtle deficits seen in close relatives of those with the disorder.