UCLA

Neurodevelopmental disorders (NDDs) show considerable heterogeneity, both in terms of genetic underpinnings and clinical presentation. Certain NDDs arise due to rare genetic etiologies, providing a valuable opportunity to explore possible mechanisms of cognitive and behavioral dysfunction. For instance, duplications of 15q11.2-13.1 cause Dup15q syndrome, an NDD characterized by intellectual disability, autism spectrum disorder (ASD), epilepsy, motor delays, sleep impairment and abnormal brain activity. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased oscillatory activity within the beta range (12-30 Hz) that likely reflects aberrant GABAergic neurotransmission. By rigorously investigating the properties of this EEG biomarker, this dissertation expands our understanding of Dup15q syndrome pathophysiology and uses an innovative methodological pipeline to gather and process remote clinical EEG recordings from patients across the country, thus facilitating large scale studies across NDDs. Chapter 1 introduces NDDs, Dup15q syndrome and EEG biomarkers. Chapter 2 investigates the properties of beta oscillations in Dup15q syndrome, including their relationship to clinical symptomatology, stability over time, and reproducibility, both across analytic pipelines and across research and clinical EEG. Chapter 3 evaluates the presence of beta oscillations across brain states such as wakefulness and sleep and describes novel quantitative biomarkers of sleep disruption in children with Dup15q syndrome, including elevated beta oscillations in sleep and abnormal NREM sleep physiology. Chapter 4 explores the relationship between abnormal sleep physiology and the neurobehavioral phenotype in Dup15q syndrome. Chapter 5 discusses key next steps in further understanding the implications of genetic and brain circuit level changes that occur in Dup15q syndrome and considers whether pharmacological manipulation of the neural dysfunction can change outcomes. Both beta oscillations and healthy sleep rhythms necessary for healthy cognitive development rely on GABAergic modulation. As such, elevated beta oscillations and the sleep disruptions reported in this dissertation both point towards GABAergic dysfunction in Dup15q syndrome. Therapeutic advances in Dup15q syndrome can include disease-modifying therapies that target GABA signaling. The EEG biomarkers described in this dissertation have the potential to serve as measures of drug target engagement or as a proximal outcome measures that precede behavioral responses to treatment. Ultimately, these biomarkers will help monitor treatment progress and change in clinical outcomes in individuals with NDDs.