Multivariate deep phenotyping reveals behavioral correlates of non-restorative sleep in 22q11.2 Deletion Syndrome

Converging evidence suggests that sleep disturbances can directly contribute to a transdiagnostic combination of behavior and neurocognitive difficulties characterizing most forms of psychopathology. However, it remains unclear how the growing comprehension of sleep neurophysiology should best inform sleep quality assessment in mental health patients. To address this fundamental question, we performed deep multimodal sleep and behavioral phenotyping in 37 individuals at high genetic risk for psychopathology due to 22q11.2 Deletion Syndrome (Mean age:19±8.17, M/F=22/15) and 34 Healthy Controls (Mean age:17.06±6.87, M/F=12/22). We implemented a multivariate analysis pipeline informed by the current neurobiological understanding of the behavioral consequences of sleep disruption. We detected multivariate patterns of disrupted sleep architecture consistently influenced by age and diagnosis across recordings and experimental settings. With high-density EEG polysomnography we detected atypical trajectories of Slow-Wave-Activity (SWA) reduction, influenced by age and sleep duration which, according to the Synaptic-Homeostasis-Hypothesis, could reflect combined alterations in neurodevelopmental and synaptic homeostasis mechanisms in 22q11DS. Blunted SWA reduction was linked with EEG markers of residual sleep pressure in morning-vs-evening EEG and with questionnaires estimating subjective somnolence in everyday life, potentially representing a clinically relevant signature of non-restorative sleep. Moreover, blunted SWA decline was linked to a transdiagnostic combination of behavioral difficulties, including negative psychotic symptoms, ADHD symptoms, and neurocognitive impairments in processing speed and inhibitory-control. These findings suggest that systematic screening and management of sleep disturbances could directly improve behavioral outcomes in 22q11DS. They highlight the potential of precision/multivariate phenotyping approaches for characterizing the role of sleep disturbances in developmental psychopathology.