{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T12:06:18Z","timestamp":1784376378816,"version":"3.55.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The age-related impairment of glial-lymph (glymphatic) mechanisms for brain waste clearance has been suspected as a causal factor in the accumulation of toxic metabolites, including amyloid beta and tau proteins in Alzheimer\u2019s Disease and alpha synuclein in Parkinson\u2019s Disease and Lewy Body Dementia. Because electrical current at low frequencies flows preferentially through extracellular space (ECS), measures of brain electrical impedance may track changes over time in ECS as a function of cerebrospinal fluid (CSF) dynamics that are important to brain waste clearance in sleep. We applied a single-frequency measure of electrical impedance in a study of transcranial electrical stimulation (tES) to enhance deep N3 sleep in healthy adults, using a novel method for estimating the intracranial impedance compartment through separately estimating and subtracting the electrode-skin impedance. The results suggest that, regardless of tES, brain impedance slowly decreases over the course of the night\u2019s sleep versus waking, with a marked decrease in rapid eye movement (REM). Furthermore, the therapeutic tES protocol (applied to synchronize and enhance slow oscillations of N3) resulted in significant brain impedance decreases in the transition from N2 to N3 (as well as in REM), consistent with the fast magnetic resonance imaging (MRI )evidence of respiration-linked CSF inflow at these intervals.<\/jats:p>\n                  <jats:p>Statement of Significance Sleep appears to be a critical period for the brain\u2019s removal of metabolic waste products through its lymph system, which involves both perivascular cerebrospinal fluid (CSF) flow, transport of CSF through the extracellular space of the parenchyma, and glial (aquaporin 4 end feet) transfer across the blood\u2013brain barrier. The decline of waste removal with the decline of stage N3 sleep in aging may be relevant to the neurodegeneration leading to dementia. The present results suggest that transcranial electrical stimulation strategically applied at key sleep stages, such as the N2-N3 transition, may not only enhance the duration of N3 and rapid eye movement sleep, but may facilitate the transient extracellular space expansion driven by cardiac pulses and respiration that supports brain waste clearance in healthy sleep.<\/jats:p>","DOI":"10.1093\/sleep\/zsag079","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:34:14Z","timestamp":1776944054000},"source":"Crossref","is-referenced-by-count":0,"title":["tES synchronization of slow oscillations in N3 sleep decreases brain electrical impedance: implications for improved brain waste clearance"],"prefix":"10.1093","volume":"49","author":[{"given":"Steven","family":"Shofner","sequence":"first","affiliation":[{"name":"Brain Electrophysiology Laboratory Company and Neurosom, Inc. , Eugene, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle K","family":"Morgan","sequence":"additional","affiliation":[{"name":"Brain Electrophysiology Laboratory Company and Neurosom, Inc. , Eugene, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6437-5464","authenticated-orcid":false,"given":"Phan","family":"Luu","sequence":"additional","affiliation":[{"name":"Brain Electrophysiology Laboratory Company and Neurosom, Inc. , Eugene, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Shusterman","sequence":"additional","affiliation":[{"name":"Brain Electrophysiology Laboratory Company and Neurosom, Inc. , Eugene, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexie","family":"Doncov","sequence":"additional","affiliation":[{"name":"Brain Electrophysiology Laboratory Company and Neurosom, Inc. , Eugene, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Heys","sequence":"additional","affiliation":[{"name":"Montana State University , Bozeman, Montana,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Ray","sequence":"additional","affiliation":[{"name":"Montana State University , Bozeman, Montana,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda M","family":"Lim","sequence":"additional","affiliation":[{"name":"Veterans Administration Portland Health Care System and Oregon Health and Sciences University Alzheimer\u2019s Disease Research Center , Portland, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don M","family":"Tucker","sequence":"additional","affiliation":[{"name":"Brain Electrophysiology Laboratory Company and Neurosom, Inc. , Eugene, Oregon,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"issue":"147","key":"2026071807464045500_ref1","doi-asserted-by":"publisher","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci Transl Med"},{"issue":"6156","key":"2026071807464045500_ref2","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1126\/science.1241224","article-title":"Sleep drives metabolite clearance from the adult brain","volume":"342","author":"Xie","year":"2013","journal-title":"Science."},{"issue":"6465","key":"2026071807464045500_ref3","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1126\/science.aax5440","article-title":"Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep","volume":"366","author":"Fultz","year":"2019","journal-title":"Science."},{"key":"2026071807464045500_ref4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2025.121290","article-title":"Ultrafast complex-valued 4D fMRI reveals sleep-induced brain respiratory pulsation changes in both magnitude and phase signals","volume":"317","author":"Syv\u00e4oja","year":"2025","journal-title":"NeuroImage."},{"issue":"8","key":"2026071807464045500_ref5","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/j.tins.2016.05.002","article-title":"Sleep: a novel mechanistic pathway, biomarker, and treatment target in the pathology of Alzheimer's disease?","volume":"39","author":"Mander","year":"2016","journal-title":"Trends Neurosci"},{"key":"2026071807464045500_ref6","volume-title":"Military Health System Research Symposium","author":"Morgan","year":"2024"},{"issue":"10","key":"2026071807464045500_ref7","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1038\/s41551-025-01394-9","article-title":"A wireless device for continuous measurement of brain parenchymal resistance tracks glymphatic function in humans. Nat","volume":"9","author":"Dagum","year":"2025","journal-title":"Biomed Eng"},{"issue":"7","key":"2026071807464045500_ref8","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1016\/j.bpj.2017.05.054","article-title":"Analysis of claims that the brain extracellular impedance is high and non-resistive","volume":"113","author":"Barbour","year":"2017","journal-title":"Biophys J"},{"key":"2026071807464045500_ref9","volume-title":"Wearable EEG\/EIT System for Monitoring and Enhancing Glymphatic Clearance (GC) During Sleep Using Skin-Path-Corrected Single-Frequency Impedance to Compute a GC Index with GC-Window-Gated Stimulation","author":"Tucker","year":"2025"},{"key":"2026071807464045500_ref10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1109\/JTEHM.2019.2898193","article-title":"Transcranial impedance changes during sleep: a rheoencephalography study","volume":"7","author":"Meghdadi","year":"2019","journal-title":"IEEE J Transl Eng Health Med"},{"key":"2026071807464045500_ref11","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-68374-8","article-title":"The glymphatic system clears amyloid beta and tau from brain to plasma in humans","author":"Dagum P","journal-title":"Nat Commun"},{"key":"2026071807464045500_ref12","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.sleep.2021.03.001","article-title":"Transcranial electrical stimulation targeting limbic cortex increases the duration of human deep sleep","volume":"81","author":"Hathaway","year":"2021","journal-title":"Sleep Med"},{"issue":"7063","key":"2026071807464045500_ref13","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1038\/nature04284","article-title":"Hypothalamic regulation of sleep and circadian rhythms","volume":"437","author":"Saper","year":"2005","journal-title":"Nature."},{"issue":"4","key":"2026071807464045500_ref14","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/0013-4694(72)90122-8","article-title":"Cephalic skin potentials in electroencephalography","volume":"33","author":"Picton","year":"1972","journal-title":"Electroencephalogr Clin Neurophysiol"},{"key":"2026071807464045500_ref15","doi-asserted-by":"crossref","first-page":"3854","DOI":"10.1007\/978-3-540-36841-0_975","volume-title":"World Congress on Medical Physics and Biomedical Engineering 2006","author":"Turovets","year":"2007"},{"issue":"8","key":"2026071807464045500_ref16","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1109\/TBME.2017.2777143","article-title":"Skull modeling effects in conductivity estimates using parametric electrical impedance tomography","volume":"65","author":"Fern\u00e1ndez-Corazza","year":"2017","journal-title":"IEEE Trans Biomed Eng"},{"key":"2026071807464045500_ref17","volume-title":"Electrochemical Methods for Neuroscience","author":"Hrab\u011btov\u00e1","year":"2007"},{"issue":"1","key":"2026071807464045500_ref18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-75460-4","article-title":"Modulation of solute diffusivity in brain tissue as a novel mechanism of transcranial direct current stimulation (tDCS)","volume":"10","author":"Xia","year":"2020","journal-title":"Sci Rep"},{"key":"2026071807464045500_ref19","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.731028","article-title":"Direct current stimulation disrupts endothelial glycocalyx and tight junctions of the blood-brain barrier in vitro","author":"Xia","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"1","key":"2026071807464045500_ref20","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-019-0126-9","article-title":"Analysis of convective and diffusive transport in the brain interstitium","volume":"16","author":"Ray","year":"2019","journal-title":"Fluids Barriers CNS"},{"key":"2026071807464045500_ref21","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fpsyt.2016.00087","article-title":"Transcranial electrical neuromodulation based on the reciprocity principle","volume":"7","author":"Fernandez-Corazza","year":"2016","journal-title":"Front Psychiatry"},{"key":"2026071807464045500_ref22","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.brs.2017.01.189","article-title":"Strategies for targeting deep brain structures using the TES reciprocity based methods","volume":"10","author":"Fernandez-Corazza","year":"2017","journal-title":"Brain Stimul"}],"container-title":["SLEEP"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/sleep\/advance-article-pdf\/doi\/10.1093\/sleep\/zsag079\/68142664\/zsag079.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/49\/7\/zsag079\/68142664\/zsag079.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/49\/7\/zsag079\/68142664\/zsag079.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:46:47Z","timestamp":1784375207000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/sleep\/article\/doi\/10.1093\/sleep\/zsag079\/8661336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":22,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4,23]]},"published-print":{"date-parts":[[2026,7,13]]}},"URL":"https:\/\/doi.org\/10.1093\/sleep\/zsag079","relation":{},"ISSN":["0161-8105","1550-9109"],"issn-type":[{"value":"0161-8105","type":"print"},{"value":"1550-9109","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,4,23]]},"article-number":"zsag079"}}