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arXiv · 2107.02993

Embedding digital chronotherapy into medical devices -- A canine validation for controlling status epilepticus through multi-scale rhythmic brain stimulation

Mayela Zamora·Sebastian Meller·Filip Kajin·James J Sermon·Robert Toth·Moaad Benjaber·Derk-Jan Dijk·Rafal Bogacz·Gregory A Worrell·Antonio Valentin·Benoit Duchet·Holger A Volk·Timothy Denison
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Abstract

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. 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". This approach is tested on a canine with severe drug-resistant idiopathic generalized epilepsy exhibiting a diurnal pattern correlated with sleep-wake cycles. Prior to implantation, the canine's cluster seizures evolved to status epilepticus (SE) and required emergency pharmacological intervention. The cranially-mounted system was fully-implanted bilaterally into the centromedian nucleus of the thalamus. Using time-based modulation, thalamocortical rhythm-specific tuning of frequency parameters as well as fast-adaptive modes based on activity, the canine experienced no further SE events post-implant as of the time of writing (seven months). Importantly, no significant cluster seizures have been observed either, allowing the reduction of rescue medication. The use of chronotherapy as a feedforward signal to augment adaptive neurostimulators could prove a useful method in conditions where sensitivity to temporal patterns are characteristics of the disease state, providing a novel mechanism for tailoring a more patient-specific therapy approach.

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Mayela Zamora, Sebastian Meller, Filip Kajin, James J Sermon, Robert Toth, Moaad Benjaber, Derk-Jan Dijk, Rafal Bogacz, Gregory A Worrell, Antonio Valentin, Benoit Duchet, Holger A Volk, Timothy Denison. 2021-07-07. Embedding digital chronotherapy into medical devices -- A canine validation for controlling status epilepticus through multi-scale rhythmic brain stimulation. https://doi.org/10.3389/fnins.2021.734265

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