Network Action of Subcallosal Cingulate White Matter Deep Brain Stimulation

Deep brain stimulation (DBS) within the subcallosal cingulate cortex (SCC) alleviates symptoms of depression through an unclear therapeutic mechanism. Precise stimulation of SCC white matter (SCCwm) is thought to be necessary to achieve therapeutic response, and clinical recordings can now be used to test this hypothesis. In this paper we characterized the where, what, and how of SCCwm-DBS immediate effects, its network action , at therapeutic stimulation frequencies. First, using simultaneous LFP and EEG, we determined whether the effects of SCCwm-DBS are local at the SCC and/or remote at downstream cortical regions. We then charactized the spatial pattern effected by DBS across high-density EEG, finding multi-oscillatory response modes. Finally, we demonstrated that these modes are spatially consistent with white matter tracts targeted during surgical implantation. These results clarify the immediate actions of SCCwm-DBS as broad low-frequency power increases in brain regions downstream to stimulated white matter. This quantitative characterization of SCCwm-DBS network action has implications for future clinical trials, and may accelerate adaptive therapy optimization. ### Competing Interest Statement CCM is a paid consultant for Boston Scientific Neuromodulation, receives royalties from Hologram Consultants, Neuros Medical, Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, CereGate, Autonomic Technologies, Cardionomic, Enspire DBS. HM has a consulting agreement with Abbott Labs (previously St Jude Medical, Neuromodulation), which has licensed her intellectual property to develop SCC DBS for the treatment of severe depression (US 2005/0033379A1). RG serves as a consultant to and receives research support from Medtronic, and serves as a consultant to Abbott Labs. The terms of these arrangements have been approved by Emory University, Icahn School of Medicine, and Case Western Reserve in accordance with policies to manage conflict of interest. All other authors have no COI to declare. ### Funding Statement This study was funded by The Whitaker Foundation, National Institutes of Health (UH3NS103550 R01MH106173), Hope for Depression Research Foundation and European Unions Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3). Implanted devices used in the work were donated by Medtronic, Inc. (Minneapolis, MN). ### 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: Six consecutive patients were implanted between June 1, 2013 and January 1, 2017 as a part of an IRB approved research protocol at Emory University studying the SCCwm-DBS for TRD ([ClinicalTrials.gov][1] Identifier [NCT01984710][2]) using inclusion and exclusion criteria described in [1]. Written informed consent was provided by each patient to participate in the study protocol (FDA IDE G130107) and the study was continuously monitored by the Emory University Department of Psychiatry and Behavioral Sciences Data and Safety Monitoring Board. 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 Intermediate data can be made available upon request to corresponding author. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01984710&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F29%2F2022.07.27.22278130.atom