– RECAST

Sleep-wake disturbances (SWD) such as sleep fragmentation and excessive daytime sleepiness are early symptomatic manifestations of prodromal Parkinson’s disease (PD) and occur in up to 90% of patients over the course of the disease. They are a major source of PD-related disability, diminished quality of life, and an important disease-modifying factor leading to accelerated motor and cognitive decline, and psychiatric manifestations. Interventions that rebalance SWD may therefore have the potential to relevantly alleviate the burden of symptoms and even to decelerate the progression of PD. The effectivity of the pharmacological treatment strategies presently available is not only limited but is also associated with treatment-related complications. In this context, deep brain stimulation (DBS), as a well-established symptomatic treatment for motor symptoms in PD, might constitute a powerful tool for a mechanistic understanding of SWD by causally intervening and potentially rebalancing the impaired neural circuit switching between the inhibitory and excitatory neuronal populations that mediate SWD in PD. However, current DBS protocols in PD are applied independent of the sleep-wake cycle or sleep architecture. Furthermore, they target the subthalamic nucleus (STN) which is not directly involved in sleep-wake regulation, and therefore does not alleviate the impairment of sleep dynamics with regard to latency, fragmentation, and slow wave activity. We seek to understand the underlying mechanisms of SWD to tailor a more holistic personalized treatment approach in PD. To this end, we aim to translate basic research findings on the neuromodulation of sleep via substantia nigra (SN) stimulation into human application. Experimental work from within the consortium has shown that the activation or inactivation of specific GABAergic neurons in the rodent SN pars reticulata (SNr) biased the direction of natural behavioral transitions (e.g., from locomotion via non-locomotor movement and quiet wakefulness to sleep), and promoted or suppressed sleep, respectively. We therefore propose to perform spatially precise, temporally selective, and frequency-specific co-stimulation of the human SN on the basis of circadian rhythms and sleep cycles. Specifically, a new generation of DBS multichannel electrodes allows to reach the STN (motor symptoms) and SNr (sleep disturbances) via the same standard surgical trajectory and stimulate both targets simultaneously and/or separately. By applying segmented electrode contacts for directional steering of the electrical stimulation field, and multiple independent current circuits for the simultaneous application of different stimulation patterns and frequencies, this novel DBS technology allows for the individualization of the stimulation parameters and their adaptation to the neuroanatomical-functional requirements of the two distinct but spatially adjacent DBS target structures STN and SN.