Sleep is vital for maintaining cognitive, emotional, and physical health. One of its essential functions is the clearance of neurotoxic waste products such as misfolded proteins (e.g., via glymphatic processes) during deep sleep stages. Disruptions in sleep architecture, particularly REM Sleep Behavior Disorder (RBD), have emerged as early and predictive markers for neurodegenerative diseases, especially Parkinson’s disease (PD). RBD is characterized by loss of muscle atonia during Rapid Eye Movement (REM) sleep, leading to dream-enactment behaviors. This disorder affects ~1-2% of the population and precedes PD in most idiopathic cases. Pharmacologically induced RBD, especially due to Selective Serotonin Reuptake Inhibitors (SSRIs) administration, is commonly observed in younger populations treated for depression and anxiety. While considered secondary, SSRI-induced RBD is increasingly recognized as a potential prodromal stage of synucleinopathies, complicated by the overlapping neural substrates of serotonin and dopamine systems. Yet, the underlying mechanisms linking serotonin modulation, sleep disorders, and neurodegeneration remain poorly understood. We propose to use a non-human primate (NHP) model of SSRI-induced RBD to investigate the causal relationships among SSRI treatment, RBD, and synucleinopathies. Furthermore, we aim to test whether adaptive, circadian-, frequency-, and phase-specific closed-loop deep brain stimulation (cfp-clDBS) of the subthalamic nucleus (STN) can restore physiological sleep patterns. We hypothesize that restoring normal sleep will reduce abnormal basal ganglia oscillations and slow or prevent the accumulation of pathological α-synuclein proteins.

Supervisor: Prof. Hagai Bergman