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 state transitions may underlie the neural basis of WM deficit. We investigate whether shared and illness-specific alterations in controllability underlie WM deficits in MPDs. We examined functional magnetic resonance imaging data during an <i>n</i>-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). We calculated each brain region's capacity to steer transitions to connectomic states with less input (average controllability) and to difficult-to-reach states with high input (modal controllability). The effect of altered controllability on clinical and cognitive characteristics and their likely genetic and neurotransmitter basis were investigated. All MPDs demonstrated a common but graded pattern of reduced modal controllability within the frontoparietal network compared to HC, with SZ showing the most pronounced impairment. Relative to BD and MDD, SZ exhibited the broadest profile of reduced average and modal controllability across the cortex, particularly in sensory, default mode, and salience networks. The affected brain regions preferentially expressed genes that determine synaptic biology and chemoarchitecture involving glutamate/γ-aminobutyric acid (GABA) and monoamine [dopamine and 5-hydroxytryptamine (5-HT)] neurotransmitter systems. A graded, transdiagnostic reduction in the influence of the sensory networks and triple network system in implementing state transitions underlies WM deficits in MPDs. This deficit, especially pronounced in SZ, has its likely basis in synaptic biology and in glutamate/GABA and monoamine (dopamine and 5-HT) neurotransmitters.