Controlling Clinical States Governed by Different Temporal Dynamics With Closed-Loop Deep Brain Stimulation: A Principled Framework.

Closed-loop strategies for deep brain stimulation (DBS) are paving the way for improving the efficacy of existing neuromodulation therapies across neurological disorders. Unlike continuous DBS, closed-loop DBS approaches (cl-DBS) optimize the delivery of stimulation in the temporal domain. However, clinical and neurophysiological manifestations exhibit highly diverse temporal properties and evolve over multiple time-constants. Moreover, throughout the day, patients are engaged in different activities such as walking, talking, or sleeping that may require specific therapeutic adjustments. This broad range of temporal properties, along with inter-dependencies affecting parallel manifestations, need to be integrated in the development of therapies to achieve a sustained, optimized control of multiple symptoms over time. This requires an extended view on future cl-DBS design. Here we propose a conceptual framework to guide the development of multi-objective therapies embedding parallel control loops. Its modular organization allows to optimize the personalization of cl-DBS therapies to heterogeneous patient profiles. We provide an overview of clinical states and symptoms, as well as putative electrophysiological biomarkers that may be integrated within this structure. This integrative framework may guide future developments and become an integral part of next-generation precision medicine instruments.