EEG-Based Biomarkers of Neural Circuit Function in Rett Syndrome

Abstract

Atypical sensory processing is a key feature of many neurodevelopmental disorders, likely contributing to higher-order deficits in cognition, communication, and behavior. However, the neural mechanisms underlying these abnormalities remain incompletely understood. Rett syndrome (RTT) is one neurodevelopmental disorder, related to autism spectrum disorder and predominantly caused by de novo mutations in the X-linked MECP2 gene. RTT is characterized by an initial period of typical early development followed by rapid regression leading to profound motor, communication, autonomic, and other impairments; disruptions to cognitive function and sensory processing have more recently emerged as core features. Electroencephalography (EEG) at rest, as well as time-locked to sensory stimuli (event-related potentials, or ERPs), offers powerful tools to study the neural dynamics underlying these disruptions, with the potential to bridge neural circuit dysfunction with clinically relevant neurophysiological markers and behavioral outcomes. This dissertation integrates findings from three EEG-based studies in Rett syndrome. First, we aimed to investigate variability in neural responses to sensory stimuli by measuring inter-trial phase coherence (ITPC). We found increased trial-by-trial variability in individuals with RTT in response to both visual and auditory stimuli, correlating with dampened ERPs and atypical sensory processing phenotype. In the second study, we utilized resting-state EEG to investigate thalamocortical contributions to sensory processing dysfunction by measuring transient beta events (short bursts of beta-frequency activity linked to thalamocortical drive and implicated in tactile processing). We observed elevated transient beta event rates in RTT as well as other related neurodevelopmental disorders, pointing to disruptions within thalamocortical sensory pathways. Finally, we investigated interactions between oscillatory frequencies at rest in RTT by analyzing phase-amplitude coupling, a mechanism of neural coordination that supports a range of cognitive and sensory processes. Results demonstrated significantly increased theta-gamma and alpha-gamma coupling in RTT, and computational modeling further identified dysfunction in VIP+ interneurons as a candidate cellular mechanism underlying this enhanced coupling. Collectively, these findings advance the field’s understanding of the neural dynamics underlying altered sensory and cognitive processing in RTT, paving the way for use as functional biomarkers and providing insights that can inform future work.