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Project Topic
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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 diseasemodifying 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 wellestablished 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 costimulation 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. In this consortium, we wish to address the
original mechanistic questions of “where”, “when” and “how” to stimulate the human SN in an aim to modulate
circadian rhythms and sleep cycles to improve SWD in PD; more specifically: Can we identify the distinct spatial
distribution (“where”) and firing patterns (“how”) of the sleep-related neurons described in the rodent SN also in the
human SN with imaging techniques (e.g., neuromelanin-sensitive, susceptibility-weighted and connectivity-based
neuroimaging, structure-symptom analysis) and physiological recordings (e.g., multiunit activity and local field
potentials, LFP)? Can the timing of SN-DBS (“when”) with regard to the circadian cycle improve daytime arousal and
SWD? Do these physiologically informed stimulation paradigms induce plastic changes in sleep-related local circuits
and brain networks? Can the difficult sleep stage scoring in PD be performed in an automated and online manner by
machine learning approaches to trigger stimulation? Can the classical EEG-based arousal and sleep classification be
conducted on the basis of LFP recordings in the STN/SN region via the novel sensing capabilities of the new generation
of DBS devices that has recently become available? Can we determine the optimal pattern of SN-DBS (“how”) in
relation to the macro- and micro-sleep architecture? Does this physiologically-informed, state-dependent SN-DBS
improve sleep dynamics? Do these interventions improve the circadian rhythm and disease progression as captured
by clinical und subclinical measures (e.g., perturbations in cellular and molecular sub-networks), and multimodal
quantification of structural and functional brain network changes?
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