Task-related Controllability of Functional Connectome During a Working Memory Task in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Working memory (WM) deficit is a prominent and common cognitive impairment in major psychiatric disorders (MPDs). Altered control of brain states transitions may underlie the neural basis of WM deficit. Brain controllability derived from Network Control Theory provides a mathematical framework to study how external signals may affect neural network dynamics and influence the transition to desired states. We investigate if shared and illness-specific alterations in controllability underlie WM deficits in MPDs. We examined fMRI data during a n-back WM task from 105 patients with schizophrenia (SZ), 67 with bipolar disorder (BD), 51 with major depressive disorder (MDD), and 80 healthy controls (HCs). A region’s capacity to steer transitions to connectomic states with less input (average controllability) and difficult-to-reach states with high input (modal controllability) were compared across groups. The effect of altered controllability on clinical and cognitive characteristics, and their likely genetic and neurotransmitter basis were investigated. Compared to HCs, all MPDs had lower modal controllability of frontoparietal network. SZ and MDD shared modal controllability in default mode network and salience network nodes compared to BD and HCs. Only SZ had lower modal controllability of sensorimotor, auditory, and visual network nodes than HCs, indicating the need for higher sensory inputs to facilitate a state transition in SZ. Expression of genes that determine synaptic biology and chemoarchitecture involving glutamate/GABA and monoamine (dopamine and 5HT) receptor systems were more likely in the affected brain regions. A graded, transdiagnostic reduction in the influence of the triple network system and sensory networks in implementing state transitions underlies working memory deficits in MPDs. This deficit, especially pronounced in SZ, has its likely basis in synaptic biology and in glutamate/GABA and monoamine (dopamine and 5HT) systems.