Rhythms of Brain Impedance

Brain impedance is a fundamental electrical property that depends on tissue extracellular volume. We tracked impedance, behavioral state, and epileptiform activity in humans using an investigational device and identified behavioral state dependent impedance oscillations spanning hours to weeks in amygdala, hippocampus, and thalamus. Impedance reaches a minimum in slow wave sleep, is intermediate in rapid-eye-movement sleep and maximal during wakefulness consistent with previously observed extracellular volume changes in rodent glymphatic system. ### Competing Interest Statement GW, BB, JVG, and BL are named inventor for intellectual property developed at Mayo Clinic and licensed to Cadence Neuroscience Inc. BNL royalties are waived to his Mayo Clinic research account. GW, VK, FV, VS and BB have filed intellectual property for impedance modulation and tracking. GW has licensed intellectual property developed at Mayo Clinic to NeuroOne, Inc. BL, GW, and NG are investigators for the Medtronic Deep Brain Stimulation Therapy for Epilepsy Post-Approval Study (EPAS). VK consults for Certicon a.s. IB has received compensation from an internship with Cadence Neuroscience Inc., for work unrelated to the current publication. Mayo Clinic has received research support and consulting fees on behalf of GW, BNL and BB from UNEEG, NeuroOne Inc., Epiminder, Medtronic Plc., and Philips Neuro. PEC has received research grant support from Neuronetics, NeoSync and Pfizer, Inc. He has received grant-in-kind (equipment support for research studies) from Assurex; MagVenture, Inc; and Neuronetics, Inc. He has served as a consultant for Engrail Therapeutics, Myriad Neuroscience, Procter & Gamble, and Sunovion. TD is a consultant for Synchron, on the advisory board of Cortec Neuro, shareholder-collaborator of Bioinduction Ltd, and shareholder-director of Amber Therapeutics Ltd. TD also has patents in the field of impedance measurement instrumentation, and their application for epilepsy seizure prediction. The other authors have no disclosures. ### Clinical Trial NCT03946618 ### Funding Statement We deeply appreciate the efforts of our patients who made this research possible. We thank 1) Mayo Clinic research team and in particular the efforts of Karla Crockett, Cindy Nelson, and Starr Guzman. 2) The Medtronic Inc. team for providing the investigational Medtronic Summit RC+STM devices and engineering support from Abbey Becker, PhD and Dave Linde, PhD. The research was primarily funded by NIH Brain Initiative UH2&3 NS095495, R01 NS112144, and R01 NS092882. Additional funding for analysis of impedance was provided by DARPA HR0011-20-2-0028), Mayo Clinic philanthropy, and community expertise and resources made available by the NIH Open Mind Consortium NIH U24-NS113637 (). V.K. was partially supported by the Czech Technical University, Prague, Czech Republic. ### 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: The study was conducted under FDA IDE: G180224 and Mayo Clinic IRB: 18-005483 Human Safety and Feasibility Study of Neurophysiologically Based Brain State Tracking and Modulation in Focal Epilepsy. The patients provided written consent in accordance with IRB and FDA requirements. Study registration . 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 data and code for analysis that support the findings of this study are available from the corresponding author upon reasonable request. * (AMG) : Amygdala (ANT) : Anterior Nucleus of Thalamus (EBS) : Electrical brain stimulation (ECS) : Extracellular space (HPC) : Hippocampus (INSS) : Implantable Neural Sensing and Stimulation device ( Z ) : Brain impedance () : Z-score of impedance (LFP) : Local field potentials (REM) : Rapid-eye-movement (NREM) : Non-rapid eye movement sleep