Aperiodic neural activity is a biomarker for depression severity.

A reliable physiological biomarker for Major Depressive Disorder (MDD) is necessary to improve treatment success rates by shoring up variability in outcome measures. In this study, we establish a passive biomarker that tracks with changes in mood on the order of minutes to hours. We record from intracranial electrodes implanted deep in the brain - a surgical setting providing exquisite temporal and spatial sensitivity to detect this relationship in a difficult-to-measure brain area, the ventromedial prefrontal cortex (VMPFC). The aperiodic slope of the power spectral density captures the balance of activity across all frequency bands and is construed as a putative proxy for excitatory/inhibitory balance in the brain. This study demonstrates how shifts in aperiodic slope correlate with depression severity in a clinical trial of deep brain stimulation for treatment-resistant depression (TRD). The correlation between depression severity scores and aperiodic slope is significant in N=5 subjects, indicating that flatter (less negative) slopes correspond to reduced depression severity, especially in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient response to MDD treatment, facilitating individualized therapies in both intracranial and non-invasive monitoring scenarios. ### Competing Interest Statement CH, KB, and MM are inventors of a planned patent on the electrophysiology biomarker reported in the current manuscript. KB is inventor of an issued patent on an unrelated method of electrical stimulation to treat depression, anxiety, and pain. SAS has consulting agreements with Boston Scientific, Neuropace, Abbott, and Zimmer Biomet. WKG has received donated devices from Medtronic and has consulting agreements with Biohaven Pharmaceuticals. SJM is supported through the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas and receives support from The Menninger Clinic. SJM has received research support from Biohaven Pharmaceuticals, Janssen, Merck, NeuroRx, Sage Therapeutics, and VistaGen Therapeutics. SJM has served as a consultant to the following companies outside the scope of the submitted work: Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Eleusis, Engrail Therapeutics, , Levo Therapeutics, Neumora, Neurocrine, Perception Neurosciences, Praxis Precision Medicines, Relmada Therapeutics, Seelos Therapeutics, Signant Health, Sunovion, and XW Pharma. The remaining authors declare no competing interests. ### Clinical Trial NCT03437928 ### Clinical Protocols ### Funding Statement The project was supported by the United States National Institutes of Health (CH, MM, BP, EB, BAM, JC, DB, WKG, NP, SAS: NIH R01-MH127006 to KB; MM, BAM: NIH K01-MH116364 to KB; JA, JX, RC, DO, AA, VP, MA, KM, SM, JC, DB, WKG, NP, SAS, KB: NIH UH3-NS103549 to SAS, NP, WKG). ### 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 Baylor College of Medicine Institutional Review Board gave ethical approval for this work. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data, code, and materials used in the analysis are available to any interested researcher for the purpose of reproducing or extending the analysis. Primary data are also hosted on the National Institutes of Mental Health Data Archive (NDA), and analysis data frames are posted on the Data Archive of the BRAIN Initiative (DABI).