Embedding digital chronotherapy into medical devices - A canine case study in controlling status epilepticus through multi-scale rhythmic brain stimulation

Circadian and other physiological rhythms play a key role in both normal homeostasis and disease processes. Such is the case of circadian and infradian seizure patterns observed in epilepsy. However, these rhythms are not fully exploited in the design of active implantable medical devices. In this paper we explore a new implantable stimulator that implements chronotherapy as a feedforward input to supplement both open-loop and closed-loop methods. This integrated algorithm allows for stimulation to be adjusted to the ultradian, circadian, and infradian patterns observed in patients through slowly-varying temporal adjustments of stimulation and algorithm sub-components, while also enabling adaption of stimulation based on immediate physiological needs such as a breakthrough seizure or change of posture. Embedded physiological sensors in the stimulator can be used to refine the baseline stimulation circadian pattern as a “digital zeitgeber”. A zeitgeber is any external stimulus that entrains or synchronises the subject’s natural rhythms. This algorithmic approach is tested on a canine with severe drug-resistant idiopathic generalized epilepsy exhibiting a characteristic diurnal pattern correlated with sleepwake cycles. Prior to implantation, the canine’s cluster seizures evolved to status epilepticus and required emergency pharmacological intervention. The cranially-mounted system was fullyimplanted bilaterally into the centromedian nucleus of the thalamus. Using combinations of time-based modulation, thalamocortical rhythm-specific tuning of frequency parameters, and fast-adaptive modes based on activity, the canine has experienced no further status epileptic events post-implant at the time of writing (seven months), and no significant clusters are observed any longer, allowing the elimination of rescue medication. The use of digitally-enabled chronotherapy as a feedforward signal to augment adaptive neurostimulators could prove a useful algorithmic method where sensitivity to temporal patterns are characteristics of the disease state, and is another mechanism to tailor a more patient-specific therapy approach. Deep Brain Stimulation | Centromedian Thalamus | Circadian | Entrainment | Epilepsy | Chronotherapy | Status Epilepticus | Arnold Tongues †M.Z. and S.M. have contributed equally to this work and share first authorship. ‡H.A.V. and T.D. share senior authorship. Correspondence: mayela.zamora@eng.ox.ac.uk sebastian.meller@tiho-hannover.de