The Fault Lies on the Other Side: Altered Brain Functional Connectivity in Psychiatric Disorders is Mainly Caused by Counterpart Regions in the Opposite Hemisphere

Many psychiatric disorders are associated with abnormal resting-state functional connectivity between pairs of brain regions, although it remains unclear whether the fault resides within the pair of regions themselves or other regions connected to them. Identifying the source of dysfunction is crucial for understanding the etiology of different disorders. Using pathway- and network-based techniques to analyze resting-state functional magnetic imaging data from a large population of patients with attention deficit hyperactivity disorder (239 patients, 251 controls), major depression (39 patients, 37 controls), and schizophrenia (69 patients, 62 controls), we show for the first time that only network-based cross-correlation identifies significant functional connectivity changes in all 3 disorders which survive correction. This demonstrates that the primary source of dysfunction resides not in the regional pairs themselves but in their external connections. Combining pathway and network-based functional-connectivity analysis, we established that, in all 3 disorders, the counterparts of pairs of regions in the opposite hemisphere contribute 60-76% to altered functional connectivity, compared with only 17-21% from the regions themselves. Thus, a transdiagnostic feature is of abnormal functional connectivity between brain regions produced via their contralateral counterparts. Our results demonstrate an important role for contralateral counterpart regions in contributing to altered regional connectivity in psychiatric disorders.