Tailoring Human Sleep: selective alteration through Brainstem Arousal Circuit Stimulation

Brainstem nuclei, such as the pedunculopontine nucleus, send activating projections to cortex, modulating states of sleep, wakefulness and arousal levels. Surgical modulation of subcortical activity using deep brain stimulation (DBS) is utilised in the management of pain and movement disorders. DBS of brainstem arousal circuits in a state-dependent manner could offer an attractive alternative in severe pharmacoresistant cases of hypersomnia and in disorders of consciousness, where behavioural activation is desired. We wanted to investigate if we can selectively induce wakefulness and/or alter sleep state through DBS of the PPN region (PPNR). To this end, we used the opportunity of implanted PPNR electrodes in stimulation-naïve patients with multiple systems atrophy. PPNR activity was recorded during both slow wave sleep (SWS) and quiet wakefulness with simultaneous cortical EEG, in order to identify differences in brainstem oscillatory patterns during different states of excitability. PPNR DBS in two gamma frequency protocols (40Hz and 100Hz) was delivered during SWS of the same sleep stage and with comparable pre-trial levels of slow wave activity. Additionally, SHAM trials were used as a control where no stimulation was applied. We examined changes in cortical oscillatory power, changes in functional connectivity (coherence and causality) from pre- to post-stimulation and phase-locking of cortical oscillations with DBS frequencies and their sub-harmonics during stimulation. We also evaluated connectivity changes induced by DBS and corresponding differences in circuit dynamics between SWS and wakefulness. Beta and gamma PPNR oscillatory power increased when wake was compared to sleep. We saw clear PPNR power modulation by the phase of EEG slow wave, with significant increase in gamma compared to beta power during the ‘excitable’ part of the slow-wave cycle. Gamma PPNR DBS induced transitions to wakefulness and REM, while it truncated sleep time compared to baseline. The 40Hz stimulation protocol was more efficient in reducing slow wave activity and increasing cortical beta power, compared to PPNR DBS at 100Hz. Furthermore, intrinsic cortical rhythms phase-locked with 40 Hz PPNR DBS to a significantly higher degree compared to the 100Hz protocol, with regional differences in phase-locking, suggesting a complex biological phenomenon. Finally, functional connectivity changes induced by PPNR DBS were consistent with differences in circuit dynamics between SWS and wakefulness. Overall, these results highlight the possibility of using DBS of brainstem arousal circuits to promote arousal and wakefulness, which opens new perspectives for using closed-loop approaches to modulate vigilance states in humans for therapeutic benefit. ### Competing Interest Statement TD has business relationships with Bioinduction Ltd for research tool design and deployment, with stock ownership (< 1%). ### Clinical Trial NCT03593512 ### Funding Statement We would like to thank the NIHR Oxford Biomedical Research Center and the Oxford Medical and Life Sciences Translational Fund for supporting this research. We are also grateful to the Royal Academy of Engineering for funding for device development. Additional support for this specific project was provided by the Onassis Foundation (AD). We would also like to thank the Medical research Council, for support provided to investigators during the time of this project: VV (MR/S01134X/1), AG (MC\_PC\_16056), HT (MC\_UU\_00003/2) and BD (MC\_UU\_00003/1). HT and AD would also like to acknowledge the support of the Rosetrees Trust. TD has business relationships with Bioinduction Ltd for research tool design and deployment, with stock ownership (< 1%). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is a substudy of a clinical trial that was conducted in accordance with the Declaration of Helsinki, approved by a research ethics committee (Preston REC 18/NW/0403) and given Health Research Authority approval. All patients provided informed written consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The authors will consider requests to access the data that support the findings of this study in a trusted research environment. Contact: Alceste Deli, allie.deli{at}ouh.nhs.uk