Embedding Digital Chronotherapy into Bioelectronic Medicines

Abstract

Biological rhythms permeate all living organisms at a variety of timescales. These rhythms are fundamental to physiological homeostasis, and their disruption is thought to play a key role in the initiation, progression, and expression of disease. In the last two decades, neuromodulation has been established as an effective adjunct therapy for medically refractory neurological disorders. To date, however, due to the limited sensing and algorithm capabilities of neuromodulation devices, exploring the influence of biological rhythms on therapy efficacy has not been feasible. However, with the development of new bioelectronic devices capable of long-term data recording and adaptive stimulation parameter adjustments, clinical neuroscience researchers are now gaining unprecedented insight into patient physiology across a variety of neurological diseases, including longitudinal rhythmic behavior. In this perspective, we propose that future bioelectronic devices should integrate chronobiological considerations in their physiological control structure to maximize the benefits of therapy. We specifically highlight this need for deep brain stimulation (DBS) chronotherapy, where the DBS therapeutic dosage would be titrated based on the time-of-day and synchronized to each patient’s individual chronotype/sleep-wake cycle. This is motivated by preliminary longitudinal data recorded from both patients with Parkinson’s disease (PD) and epilepsy, which show periodic symptom biomarkers synchronized to sub-daily (ultradian), daily (circadian), and longer time scale (infradian) rhythms. In addition, considering side effects, tonic stimulation can undermine diurnal patterns and cause fragmentation of sleep-wake rhythms. Based on these observations, we suggest a control structure for future bioelectronic devices which incorporates anticipatory, time-based adaptation of stimulation control, locked to patient-specific biological rhythms, as an adjunct to classical feedforward and feedback control methods. Initial results from three case studies using chronotherapy-enabled prototypes will illustrate the concept. The proposed control architecture for a future bioelectronic implant mimics more closely the classical integration of adaptive, feedforward, and feedback control methods found in physiology, and could be useful as a general method for personalized therapy refinement.