Sleep is essential for life and good health. Sleep is divided into REM (Rapid eye movement) and Non-REM (NREM: N1/N2, N3) sleep. A primary function of sleep is cleaning day-time accumulated waste and toxic products, probably including misfolded proteins. REM sleep behavior disorder (RBD) is a parasomnia characterized by loss of REM sleep atonia (muscle paralysis) and dream-enactment behavior. The prevalence of RBD is approximately 2% in older (>55 years old) adults, and the vast majority of RBD patients will develop Parkinson’s disease (PD or other α-synuclein disorders) within 10 years. Our previous studies revealed that the basal ganglia have a critical role in developing PD sleep disorders. Following systemic treatment of non-human primates (NHPs, African green monkeys) with high doses (5*0.35mg/Kg IM injections over 4 days) of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and depletion of striatal dopamine, the NHPs developed severe PD symptoms including fragmentation of sleep, insomnia and significant changes of their REM sleep duration and intensity. The sleep disorders were correlated, and even preceded, by abnormal beta oscillations in the neural network of the basal ganglia-thalamus-cortex.
We hypothesize that restoration of normal sleep architecture by circadian, frequency, and phase-specific closed-loop Deep Brain stimulation (DBS) would slow (or hopefully stop) the progression of sleep disorders and Parkinson’s disease. In our next projects, we aim to use our understanding of the physiology of abnormal PD oscillations, deep brain stimulation (DBS), and sleep for the development of circadian, frequency, and phase-triggered closed-loop DBS (cfp-clDBS) to slow/stop the progression of sleep disorders and PD symptoms in the NHP chronic low-dose MPTP and/or SSRI (Prozac) model of prodromal PD. The NHPs will be housed in a 20m2 open yard. We will use polysomnography (PSG, i.e., EEG, EOG, EMG), ECG, body/brain thermistors, 3D accelerometer, and dense video surveillance to continuously (24/7) record the awake/sleep behavior of all NHPs over the whole research period. Subcutaneous ports will enable weekly samples of blood and CSF. NHPs will be implanted with bilateral DBS scaled-down leads targeting the subthalamic nucleus (STN). The STN leads will be connected to a skull-mount internal pulse generator that will enable 24/7 high-frequency (7000 Hz) sampling of the STN spiking and LFP activity. After a period of PSG and STN recording in the naïve state, we will use chronic low-dose MPTP or SSRI injections to Induce sleep disorders in the NHPs. After establishing sleep deficits and other PD prodromal symptoms, we will activate open-loop continuous high-frequency stimulation and circadian, frequency, and phase-triggered closed-loop DBS (cfp-clDBS) in the implanted NHPs. The cfp-clDBS would aim at augmenting delta oscillations during NREM sleep, augmenting gamma oscillations during REM sleep, and suppressing long episodes of beta oscillations during both sleep phases. At the end of the experiments, all surgical attachments will be removed, and after rehabilitation, the NHPs will be transferred to the Israeli Primate Sanctuary (https://www.ipsf.org.il/en/). We hope this study will provide evidence for the role of the basal ganglia in the development of sleep deficits and PD symptoms. It would suggest circadian, frequency, and phase closed-loop DBS (cfp-clDBS) therapy to slow/stop their progress at early stages of these disorders.
