A circuit-level biomarker of Rett syndrome based on ectopic phase-amplitude coupling during slow-wave-sleep

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of purposeful hand use and spoken language following an initial period of normal development. Although much is known about the genetic and molecular underpinnings of RTT, less is known about the circuit-level etiopathology. Coupling of oscillations during slow-wave-sleep (SWS) underlies important neurocognitive processes in adulthood, yet its emergence has yet to be described in early typical development (TD) or in RTT. We therefore addressed these unknowns by describing SWS cross-frequency coupling in both RTT and early TD using a retrospective study design. We found that in TD, phase-amplitude coupling (PAC) during SWS was dominated by coupling of slow-wave (0.5-2 Hz) phase to theta amplitude (5-8 Hz, "SW:T") as well as slow-wave to spindle-range (12-15 Hz, "SW:S"). Coupling exhibited characteristic vertex-prominent spatial topography, which emerged during an early developmental window. This topography failed to develop in patients with RTT due to persistent ectopic coupling. Furthermore, we found that subtypes of RTT exhibit distinct PAC topographic profiles, and that ectopic PAC correlates with clinical severity. These findings suggest that altered PAC dynamics and spatial organization during SWS may underlie the circuit-level pathophysiology of RTT and suggest that ectopic coupling may contribute to RTT pathogenesis.