Aberrant controllability of functional connectome during working memory tasks in patients with schizophrenia and unaffected siblings

Background: Working memory deficit, a key feature of schizophrenia, is a heritable trait shared with unaffected siblings. It can be attributed to dysregulation in transitions from one brain state to another.

Aims: Using network control theory, we evaluate if defective brain state transitions underlie working memory deficits in schizophrenia.

Method: We examined average and modal controllability of the brain's functional connectome in 161 patients with schizophrenia, 37 unaffected siblings and 96 healthy controls during a two-back task. We use one-way analysis of variance to detect the regions with group differences, and correlated aberrant controllability to task performance and clinical characteristics. Regions affected in both unaffected siblings and patients were selected for gene and functional annotation analysis.

Results: Both average and modal controllability during the two-back task are reduced in patients compared to healthy controls and siblings, indicating a disruption in both proximal and distal state transitions. Among patients, reduced average controllability was prominent in auditory, visual and sensorimotor networks. Reduced modal controllability was prominent in default mode, frontoparietal and salience networks. Lower modal controllability in the affected networks correlated with worse task performance and higher antipsychotic dose in schizophrenia (uncorrected). Both siblings and patients had reduced average controllability in the paracentral lobule and Rolandic operculum. Subsequent out-of-sample gene analysis revealed that these two regions had preferential expression of genes relevant to bioenergetic pathways (calmodulin binding and insulin secretion).

Conclusions: Aberrant control of brain state transitions during task execution marks working memory deficits in patients and their siblings.