{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:50:30Z","timestamp":1787010630557,"version":"build-2736575974"},"posted":{"date-parts":[[2025,10,22]]},"group-title":"Neuroscience","reference-count":118,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["Chair in Emerging technologies"],"award-info":[{"award-number":["Chair in Emerging technologies"]}],"id":[{"id":"https:\/\/ror.org\/0526snb40","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MC_UU_00003\/3"],"award-info":[{"award-number":["MC_UU_00003\/3"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MC_UU_00003\/6"],"award-info":[{"award-number":["MC_UU_00003\/6"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"award":["iCase studentship"],"award-info":[{"award-number":["iCase studentship"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NIHR205474"],"award-info":[{"award-number":["NIHR205474"]}],"id":[{"id":"https:\/\/ror.org\/0187kwz08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NIHR203316"],"award-info":[{"award-number":["NIHR203316"]}],"id":[{"id":"https:\/\/ror.org\/0187kwz08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Academic Clinical Fellowship"],"award-info":[{"award-number":["Academic Clinical Fellowship"]}],"id":[{"id":"https:\/\/ror.org\/0187kwz08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UKDRI-7206"],"award-info":[{"award-number":["UKDRI-7206"]}],"id":[{"id":"https:\/\/ror.org\/02wedp412","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["NS111019"],"award-info":[{"award-number":["NS111019"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Bioelectronic implants for neurostimulation aim to steer disordered neurophysiological processes back towards a healthy state. However, physiology is subject to biological rhythms, including the circadian rhythm and the sleep-wake cycle. These predictable rhythms affect disease symptomatology, biomarkers used in closed-loop therapies, and a physiological system\u2019s expected response to stimulation. Therefore, therapeutic devices should incorporate feedforward elements to align algorithm parameters with predictable changes in physiological state, as a parallel of physiological rheostatic control. Here we introduce the DyNeuMo-2c, the first clinical-grade implant capable of delivering closed-loop neurostimulation while flexibly changing its functional configuration according to time of day. The device can chronically measure brain activity and motion state to track potential biomarker patterns in natural, out-of-clinic settings, allowing identification and targeting of patient-specific chronotypes. The system implements a hierarchical control flow, with baseline therapy set by a circadian scheduler, and adaptive policies layered to take effect based on specific biomarkers indicating patient and disease state. Using a benchtop validation setup, we demonstrate that the system has the required capabilities for delivering time-contingent closed-loop therapy in two established clinical use cases: Parkinson\u2019s disease and epilepsy. Next, we deploy the system\n                  <jats:italic>in vivo<\/jats:italic>\n                  to deliver closed-loop deep brain stimulation in a healthy non-human primate model of vigilance, highlighting the importance of synchronisation between device operation and physiological state in various conditions (task performance, unconstrained behaviour, and sleep). Time-of-day-dependent adaptation of closed-loop stimulation enabled modulation of both vigilance and behaviour. Overall, the novel device architecture provides a proof-of-concept for delivering time-contingent therapy in chronic therapeutic settings where biological rhythms are of key importance.\n                <\/jats:p>","DOI":"10.1101\/2025.10.21.683630","type":"posted-content","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T19:00:14Z","timestamp":1761159614000},"source":"Crossref","is-referenced-by-count":2,"title":["A clinical grade neurostimulation implant for hierarchical control of physiological activity"],"prefix":"10.64898","author":[{"given":"Moaad","family":"Benjaber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayela","family":"Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Toth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E","family":"Fleming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Landin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4417-4240","authenticated-orcid":false,"given":"Victoria S","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A","family":"Crockett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Wook","family":"Ryou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alceste","family":"Deli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander L","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory J","family":"Piper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin M","family":"Tisdall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derk-Jan","family":"Dijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D","family":"Schiff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Sharott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith P","family":"Purpura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8164-8594","authenticated-orcid":false,"given":"Joram J","family":"van Rheede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J","family":"Denison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102503350616000_2025.10.21.683630v1.1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.brs.2019.11.008","article-title":"Clinical trials for deep brain stimulation: Current state of affairs","volume":"13","year":"2020","journal-title":"Brain Stimul"},{"key":"2025102503350616000_2025.10.21.683630v1.2","doi-asserted-by":"publisher","DOI":"10.3171\/2019.4.JNS181761"},{"key":"2025102503350616000_2025.10.21.683630v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0128-2"},{"key":"2025102503350616000_2025.10.21.683630v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0244-6"},{"key":"2025102503350616000_2025.10.21.683630v1.5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/mds.26703","article-title":"Innovations in deep brain stimulation methodology","volume":"32","year":"2017","journal-title":"Movement Disord"},{"key":"2025102503350616000_2025.10.21.683630v1.6","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41582-020-00426-z","article-title":"Technology of deep brain stimulation: current status and future directions","volume":"17","year":"2021","journal-title":"Nat Rev Neurol"},{"key":"2025102503350616000_2025.10.21.683630v1.7","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3389\/fnhum.2020.00353","article-title":"Perspective: Evolution of Control Variables and Policies for Closed-Loop Deep Brain Stimulation for Parkinson\u2019s Disease Using Bidirectional Deep-Brain-Computer Interfaces","volume":"14","year":"2020","journal-title":"Front. 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