Age of Onset, Brain Controllability, and Working Memory Performance in First-Episode Schizophrenia

Background and Hypothesis The onset-age of schizophrenia introduces considerable heterogeneity in cognitive functions such as working memory (WM) among patients. One of the key properties of the brain that varies with age-related development is the network-level controllability of brain state transitions. We tested the effect of onset-age on brain controllability to evaluate its impact on WM deficits in schizophrenia. Study Design We examined the average and modal controllability of the brain connectome in 85 first-episode early-onset schizophrenia (EOS), 62 younger healthy controls (yHC), 71 first-episode adult-onset schizophrenia (AOS), and 85 older healthy controls (oHC) during N-back tasks. We first detected the regions with illness and onset-age interaction in a whole-brain search, and then conducted a correlation analysis with WM performance and clinical characteristics, followed by an out-of-sample gene annotation analysis. Study Results We detected the illness*onset-age interaction in the sensorimotor network, auditory network, and subcortical network for average controllability and the default mode network, visual network, and salience network for modal controllability (p-fdr < 0.05). The interaction effects in the visual and subcortical networks primarily resulted from the AOS vs. oHC differences; the effects in the default mode network resulted from EOS vs. yHC differences. We observed no significant correlation between controllability with cognitive performance or clinical characteristics. The affected regions had preferential expression of genes relevant to synaptic signaling and neurodegenerative processes (p-fdr < 0.05). Conclusion Onset-age introduces considerable heterogeneity in the controllability over brain state transition during WM tasks among patients with schizophrenia.