Noradrenaline and Acetylcholine shape Functional Connectivity organization of NREM substages: an empirical and simulation study

Abstract

Sleep onset is characterized by a departure from arousal, and can be separated into well-differentiated stages: NREM (which encompasses three substages: N1, N2 and N3) and REM (Rapid Eye Movement). Awake brain dynamics are maintained by various wake-promoting mechanisms, particularly the neuromodulators Acetylcholine (ACh) and Noradrenaline (NA), whose levels naturally decrease during the transition to sleep. The combined influence of these neurotransmitters on brain connectivity during sleep remains unclear, as previous models have examined them mostly in isolation or only in deep sleep. In this study, we employ a Whole Brain model to investigate how changes in brain neurochemistry during NREM sleep, specifically involving ACh and NA, affect the Functional Connectivity (FC) of the brain. Using a Wilson-Cowan whole brain model informed by an empirical connectome and a heterogeneous receptivity map of neuromodulators, we explore these dynamics. Initial FC analysis reveals distinct connectivity changes: a decrease in Locus Coeruleus (LC) connectivity with the cortex during N2 and N3, and a decrease in Basal Forebrain (BF) connectivity with the cortex during N3. Additionally, compared to Wakefulness (W), there is a transition to a more integrated state in N1 and a more segregated state in N3. We adjust the coupling and input-output slope of the Whole Brain model for ACh and NA, based on BF or LC priors, to show that region-specific neurotransmitter distribution is key to explaining their effects on FC. This work enhances our understanding of neurotransmitters roles in modulating sleep stages and their significant contribution to brain state transitions between different states of consciousness, both in health and disease.