Development of a bioelectronic system for applying chronobiology to improve the treatment of neurological disorders

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Brain stimulation therapies targeting the subthalamic nucleus (STN), ventrolateral thalamus (VL), and globus pallidus (GP) have been established as effective treatments of drug refractory symptoms of PD, ET and dystonia. DBS of the centromedian thalamic nucleus (CMN) is also emerging as a target for refractory epilepsy including severe childhood-onset epilepsy: Lennox-Gastaut syndrome (LGS). Although sleep dysfunction is a common co-morbidity of these neurological disorders and a key determinant of quality of life for patients and their families, DBS does not currently account for sleep in therapy optimization. The Picostim DyNeuMo Mk-2 introduces a combination of slow-adaptive circadian-based stimulation patterns with a fast-acting pathway for seizure management, paving the way for new neurotechnologies for applied chronobiology.The DyNeuMo research tool improves on current DBS systems (e.g. Medtronic Activa, St. Jude, and Boston Scientific DBS) providing adaptive DBS (aDBS), low power consumption, continuous stimulation, and improved symptom suppression. Recent studies have highlighted the impact of stimulation on sleep architecture - such as the interrelationship between sleep, circadian rhythms, and stimulation of the anterior nucleus (ANT) for epilepsy and PPN DBS for PD and MSA9. Emerging bioelectronic systems that can provide chronic and objective measurements of seizure activity in ambulatory epileptic patients, have amplified the growing interest in seizure forecasting and provided validation of circadian rhythms in humans. Moreover, recent studies have demonstrated that seizure timing may have a phase preference relative to multidien and circadian rhythms in interictal epileptiform activity in humans, and pharmacologically induced epileptic rats. Novel neurotechnologies and innovative platform design integrating chronobiology may provide insight into neural dynamics; circadian patterns, and brain rhythms fluctuation over time - contributing to a clinical framework for stimulation parameter optimization.The clinical hypothesis of this project is that aDBS - implementing applied chronobiology for circadian rhythm responsive and patient-specific therapies - is more effective than currently available DBS systems. The primary objective is to characterise the impact of neural stimulation on patients' sleep architecture and develop closed-loop therapies using the DyNeuMo. The secondary objective is to explore the extent of which feedback using varying biomarkers may be used to develop a DBS to afford a more comprehensive control of symptoms. In this project I will leverage a translational approach of applied neuroscience and biomimetic algorithms to:1. Refine and fully integrate the toolkit for the DyNeuMo research system using ultradian, circadian, and multidien rhythms as a feedforward control signal.2. Acquire and analyse data from the implant and characterise how physiological markers linked to sleep respond to stimulation.3. Develop and test circadian rhythm responsive stimulation protocols in investigational trials.