The impedance is a fundamental electrical property of brain tissue, playing a crucial role in shaping the characteristics of local field potentials, the extent of ephaptic coupling, and the volume of tissue activated by externally applied electrical brain stimulation. We tracked brain impedance, sleep-wake behavioral state, and epileptiform activity in five people with epilepsy living in their natural environment using an investigational device. The study identified impedance oscillations that span hours to weeks in the amygdala, hippocampus, and anterior nucleus thalamus. The impedance in these limbic brain regions exhibit multiscale cycles with ultradian (∼1.5-1.7 h), circadian (∼21.6-26.4 h), and infradian (∼20-33 d) periods. The ultradian and circadian period cycles are driven by sleep-wake state transitions between wakefulness, nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Limbic brain tissue impedance reaches a minimum value in NREM sleep, intermediate values in REM sleep, and rises through the day during wakefulness, reaching a maximum in the early evening before sleep onset. Infradian (∼20-33 d) impedance cycles were not associated with a distinct behavioral correlate. Brain tissue impedance is known to strongly depend on the extracellular space (ECS) volume, and the findings reported here are consistent with sleep-wake-dependent ECS volume changes recently observed in the rodent cortex related to the brain glymphatic system. We hypothesize that human limbic brain ECS changes during sleep-wake state transitions underlie the observed multiscale impedance cycles. Impedance is a simple electrophysiological biomarker that could prove useful for tracking ECS dynamics in human health, disease, and therapy.SIGNIFICANCE STATEMENT The electrical impedance in limbic brain structures (amygdala, hippocampus, anterior nucleus thalamus) is shown to exhibit oscillations over multiple timescales. We observe that impedance oscillations with ultradian and circadian periodicities are associated with transitions between wakefulness, NREM, and REM sleep states. There are also impedance oscillations spanning multiple weeks that do not have a clear behavioral correlate and whose origin remains unclear. These multiscale impedance oscillations will have an impact on extracellular ionic currents that give rise to local field potentials, ephaptic coupling, and the tissue activated by electrical brain stimulation. The approach for measuring tissue impedance using perturbational electrical currents is an established engineering technique that may be useful for tracking ECS volume.

Bioelectronics Neurophysiology and Engineering Laboratory Department of Neurology Mayo Clinic Rochester Minnesota 55905

Center for Sleep Medicine Departments of Neurology and Medicine Divisions of Sleep Neurology and Pulmonary and Critical Care Medicine Mayo Clinic Rochester Minnesota 55905

Czech Institute of Informatics Robotics and Cybernetics Czech Technical University 16000 Prague Czech Republic

Department of Biomedical Engineering Faculty of Electrical Engineering and Communication Brno University of Technology 61600 Brno Czech Republic

Department of Engineering Science Medical Research Council Brain Network Dynamics Unit University of Oxford Oxford OX3 7DQ United Kingdom

Department of Neurologic Surgery Mayo Clinic Rochester Minnesota 55905

Department of Physiology and Biomedical Engineering Mayo Clinic Rochester Minnesota 55905

Department of Radiology Mayo Clinic Rochester Minnesota 55905

Departments of Psychiatry and Psychology and

Faculty of Biomedical Engineering Czech Technical University 16000 Prague Czech Republic

International Clinical Research Center St Anne's University Hospital 60200 Brno Czech Republic

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Anastassiou CA, Perin R, Markram H, Koch C (2011) Ephaptic coupling of cortical neurons. Nat Neurosci 14:217–223. 10.1038/nn.2727 PubMed DOI

Bard AJ, Faulkner LR (2001) Electrochemical methods: fundamentals and applications. 2nd ed. New York: Wiley.

Baud MO, Kleen JK, Mirro EA, Andrechak JC, King-Stephens D, Chang EF, Rao VR (2018) Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun 9:88. 10.1038/s41467-017-02577-y PubMed DOI PMC

Baumann SB, Wozny DR, Kelly SK, Meno FM (1997) The electrical conductivity of human cerebrospinal fluid at body temperature. IEEE Trans Biomed Eng 44:220–223. 10.1109/10.554770 PubMed DOI

Bazil CW (2017) Sleep and epilepsy. Semin Neurol 37:407–412. 10.1055/s-0037-1604352 PubMed DOI

Bergman DJ, Stroud D (1992) Physical properties of macroscopically inhomogeneous media. In: Solid state physics (Ehrenreich H, Turnbull D, eds), pp 147–269. Amsterdam: Academic Press.

Berry RB, Brooks R, Gamaldo CE, Harding SM, Marcus CL, Vaughn BV (2012) The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.0. Darien, IL: American Academy of Sleep Medicine.

Binder DK, Papadopoulos MC, Haggie PM, Verkman AS (2004) In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J Neurosci 24:8049–8056. 10.1523/JNEUROSCI.2294-04.2004 PubMed DOI PMC

Butson CR, Cooper SE, Henderson JM, McIntyre CC (2007) Patient-specific analysis of the volume of tissue activated during deep brain stimulation. Neuroimage 34:661–670. 10.1016/j.neuroimage.2006.09.034 PubMed DOI PMC

Buzsáki G, Anastassiou CA, Koch C (2012) The origin of extracellular fields and currents—EEG, ECoG, LFP and spikes. Nat Rev Neurosci 13:407–420. 10.1038/nrn3241 PubMed DOI PMC

Destrieux C, Fischl B, Dale A, Halgren E (2010) Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. Neuroimage 53:1–15. 10.1016/j.neuroimage.2010.06.010 PubMed DOI PMC

Ding FF, O'Donnell J, Xu QW, Kang N, Goldman N, Nedergaard M (2016) Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science 352:550–555. 10.1126/science.aad4821 PubMed DOI PMC

Durazzo TS, Spencer SS, Duckrow RB, Novotny EJ, Spencer DD, Zaveri HP (2008) Temporal distributions of seizure occurrence from various epileptogenic regions. Neurology 70:1265–1271. 10.1212/01.wnl.0000308938.84918.3f PubMed DOI

Elazar Z, Kado RT, Adey WR (1966) Impedance changes during epileptic seizures. Epilepsia 7:291–307. 10.1111/j.1528-1157.1966.tb03809.x PubMed DOI

Fischl B, Kouwe A, Destrieux C, Halgren E, Ségonne F, Salat DH, Busa E, Seidman LJ, Goldstein J, Kennedy D, Caviness V, Makris N, Rosen B, Dale AM (2004) Automatically parcellating the human cerebral cortex. Cereb Cortex 14:11–22. 10.1093/cercor/bhg087 PubMed DOI

Fox JE, Bikson M, Jefferys JGR (2004) Tissue resistance changes and the profile of synchronized neuronal activity during ictal events in the low-calcium model of epilepsy. J Neurophysiol 92:181–188. 10.1152/jn.00123.2004 PubMed DOI

Gilron RÄ, Little S, Perrone R, Wilt R, de Hemptinne C, Yaroshinsky MS, Racine CA, Wang SS, Ostrem JL, Larson PS, Wang DD, Galifianakis NB, Bledsoe IO, San Luciano M, Dawes HE, Worrell GA, Kremen V, Borton DA, Denison T, Starr PA (2021) Long-term wireless streaming of neural recordings for circuit discovery and adaptive stimulation in individuals with Parkinson’s disease. Nat Biotechnol 39:1078–1085. PubMed PMC

Gregg NM, Nasseri M, Kremen V, Patterson EE, Sturges BK, Denison TJ, Brinkmann BH, Worrell GA (2020) Circadian and multiday seizure periodicities, and seizure clusters in canine epilepsy. Brain Commun 2:fcaa008. 10.1093/braincomms/fcaa008 PubMed DOI PMC

Gregg NM, Sladky V, Nejedly P, Mivalt F, Kim I, Balzekas I, Sturges BK, Crowe C, Patterson EE, Van Gompel JJ, Lundstrom BN, Leyde K, Denison TJ, Brinkmann BH, Kremen V, Worrell GA (2021) Thalamic deep brain stimulation modulates cycles of seizure risk in epilepsy. Sci Rep 11:24250. 10.1038/s41598-021-03555-7 PubMed DOI PMC

Hablitz LM, Nedergaard M (2021) The glymphatic system: a novel component of fundamental neurobiology. J Neurosci 41:7698–7711. 10.1523/JNEUROSCI.0619-21.2021 PubMed DOI PMC

Halperin BI, Bergman DJ (2010) Heterogeneity and disorder: contributions of Rolf Landauer. Physica B Condens Matter 405:2908–2914. 10.1016/j.physb.2010.01.002 DOI

Hermes D, Miller KJ, Noordmans HJ, Vansteensel MJ, Ramsey NF (2010) Automated electrocorticographic electrode localization on individually rendered brain surfaces. J Neurosci Methods 185:293–298. 10.1016/j.jneumeth.2009.10.005 PubMed DOI

Hofstra WA, de Weerd W (2009) The circadian rhythm and its interaction with human epilepsy: a review of literature. Sleep Med Rev 13:413–420. 10.1016/j.smrv.2009.01.002 PubMed DOI

Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM (2019) The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363:880–884. 10.1126/science.aav2546 PubMed DOI PMC

Horn A, Li N, Dembek TA, Kappel A, Boulay C, Ewert S, Tietze A, Husch A, Perera T, Neumann WJ, Reisert M, Si H, Oostenveld R, Rorden C, Yeh FC, Fang Q, Herrington TM, Vorwerk J, Kühn AA (2019) Lead-DBS v2: towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage 184:293–316. 10.1016/j.neuroimage.2018.08.068 PubMed DOI PMC

Janca R, et al.. (2014) Detection of Interictal Epileptiform Discharges Using Signal Envelope Distribution Modelling: Application to Epileptic and Non-Epileptic Intracranial Recordings. Brain Topography 28:172–183. PubMed

Jefferys JGR, Prida L, Wendling F, Bragin A, Avoli M, Timofeev I, Lopes da Silva FH (2012) Mechanisms of physiological and epileptic HFO generation. Prog Neurobiol 98:250–264. 10.1016/j.pneurobio.2012.02.005 PubMed DOI PMC

Johnson MD, Otto KJ, Kipke DR (2005) Repeated voltage biasing improves unit recordings by reducing resistive tissue impedances. IEEE Trans Neural Syst Rehabil Eng 13:160–165. 10.1109/TNSRE.2005.847373 PubMed DOI

Karoly PJ, Rao VR, Gregg NM, Worrell GA, Bernard C, Cook MJ, Baud MO (2021) Cycles in epilepsy. Nat Rev Neurol 17:267–284. 10.1038/s41582-021-00464-1 PubMed DOI

Koessler L, Colnat-Coulbois S, Cecchin T, Hofmanis J, Dmochowski JP, Norcia AM, Maillard LG (2017) In-vivo measurements of human brain tissue conductivity using focal electrical current injection through intracerebral multicontact electrodes. Hum Brain Mapp 38:974–986. 10.1002/hbm.23431 PubMed DOI PMC

Kremen V, et al.. (2018) Integrating brain implants with local and distributed computing devices: a next generation epilepsy management system. IEEE J Transl Eng Health Med 6:2500112. 10.1109/JTEHM.2018.2869398 PubMed DOI PMC

Kremen V, et al.. (2017) Behavioral State Classification in Epileptic Brain Using Intracranial Electrophysiology. J Neural Eng 14:026001. PubMed PMC

Kremen V, Brinkmann BH, Gompel JJV, Stead M, Louis EKS, Worrell GA (2019) Automated unsupervised behavioral state classification using intracranial electrophysiology. J Neural Eng 16:026004. 10.1088/1741-2552/aae5ab PubMed DOI

Kuiper NH (1960) Tests concerning random points on a circle. Indagationes Mathematicae (Proceedings) 63:38–47. 10.1016/S1385-7258(60)50006-0 DOI

Larson R, Odoni A (1981) Urban operations research. Englewood Cliffs, NJ: Prentice Hall.

Lempka SF, Miocinovic S, Johnson MD, Vitek JL, McIntyre CC (2009) In vivo impedance spectroscopy of deep brain stimulation electrodes. J Neural Eng 6:046001. 10.1088/1741-2560/6/4/046001 PubMed DOI PMC

Logothetis NK, Kayser C, Oeltermann A (2007) In vivo measurement of cortical impedance spectrum in monkeys: implications for signal propagation. Neuron 55:809–823. 10.1016/j.neuron.2007.07.027 PubMed DOI

Miceli S, Ness TV, Einevoll GT, Schubert D (2017) Impedance spectrum in cortical tissue: implications for propagation of LFP signals on the microscopic level. eNeuro 4:ENEURO.0291-16.2016. 10.1523/ENEURO.0291-16.2016 PubMed DOI PMC

Mivalt F, Kremen V, Sladky V, Balzekas I, Nejedly P, Gregg NM, Lundstrom BN, Lepkova K, Pridalova T, Brinkmann BH, Jurak P, Gompel JJV, Miller K, Denison T, Louis EKS, Worrell GA (2022) Electrical brain stimulation and continuous behavioral state tracking in ambulatory humans. J Neural Eng 19:016019. 10.1088/1741-2552/ac4bfd PubMed DOI PMC

Nicholson C (1993) Ion-selective microelectrodes and diffusion measurements as tools to explore the brain-cell microenvironment. J Neurosci Methods 48:199–213. 10.1016/0165-0270(93)90092-6 PubMed DOI

Nicholson C, Hrabětová S (2017) Brain extracellular space: the final frontier of neuroscience. Biophys J 113:2133–2142. 10.1016/j.bpj.2017.06.052 PubMed DOI PMC

Pal Attia T, Crepeau D, Kremen V, Nasseri M, Guragain H, Steele SW, Sladky V, Nejedly P, Mivalt F, Herron JA, Stead M, Denison T, Worrell GA, Brinkmann BH (2021) Epilepsy personal assistant device‚ a mobile platform for brain state, dense behavioral and physiology tracking and controlling adaptive stimulation. Front Neurol 12:704170. 10.3389/fneur.2021.704170 PubMed DOI PMC

Penny WD, Friston KJ, Ashburner JT, Kiebel SJ, Nichols TE (2011) Statistical parametric mapping: the analysis of functional brain images. Amsterdam: Elsevier.

Percival DB, Walden AT (1993) Spectral analysis for physical applications. Cambridge, UK: Cambridge UP.

Qiu C, Shivacharan RS, Zhang M, Durand DM (2015) Can neural activity propagate by endogenous electrical field? J Neurosci 35:15800–15811. 10.1523/JNEUROSCI.1045-15.2015 PubMed DOI PMC

Ranck JB (1966) Electrical impedance in the subicular area of rats during paradoxical sleep. Exp Neurol 16:416–437. 10.1016/0014-4886(66)90107-5 PubMed DOI

Ranck JB (1970) Electrical impedance changes in many sites of brain in paradoxical sleep, anesthesia, and activity. Exp Neurol 27:454–475. PubMed

Rasmussen MK, Mestre H, Nedergaard M (2022) Fluid transport in the brain. Physiol Rev 102:1025–1151. 10.1152/physrev.00031.2020 PubMed DOI PMC

Sauerheber R, Heinz B (2015) Temperature effects on conductivity of seawater and physiologic saline, mechanism and significance. Chem Sci 6:56087588.

Savtchenko LP, Poo MM, Rusakov DA (2017) Electrodiffusion phenomena in neuroscience: a neglected companion. Nat Rev Neurosci 18:598–612. 10.1038/nrn.2017.101 PubMed DOI

Savtchenko LP, Zheng K, Rusakov DA (2021) Conductance of porous media depends on external electric fields. Biophys J 120:1431–1442. 10.1016/j.bpj.2021.02.012 PubMed DOI PMC

Sillay KA, Rutecki P, Cicora K, Worrell G, Drazkowski J, Shih JJ, Sharan AD, Morrell MJ, Williams J, Wingeier B (2013) Long-term measurement of impedance in chronically implanted depth and subdural electrodes during responsive neurostimulation in humans. Brain Stimul 6:718–726. 10.1016/j.brs.2013.02.001 PubMed DOI

Sladky V, et al.. (2022) Distributed brain co-processor for tracking spikes, seizures and behaviour during electrical brain stimulation. Brain Commun 4:fcac115. 10.1093/braincomms/fcac115 PubMed DOI PMC

Stanslaski S, Herron J, Chouinard T, Bourget D, Isaacson B, Kremen V, Opri E, Drew W, Brinkmann BH, Gunduz A, Adamski T, Worrell GA, Denison T (2018) A chronically implantable neural coprocessor for investigating the treatment of neurological disorders. IEEE Trans Biomed Circuits Syst 12:1230–1245. 10.1109/TBCAS.2018.2880148 PubMed DOI PMC

Thomson DJ (1982) Spectrum estimation and harmonic analysis. Proc IEEE 70:1055–1096. 10.1109/PROC.1982.12433 DOI

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373–377. 10.1126/science.1241224 PubMed DOI PMC

Case report: Bridging limbic network epilepsy with psychiatric, memory, and sleep comorbidities: case illustrations of reversible psychosis symptoms during continuous, high-frequency ANT-DBS

Acute to long-term characteristics of impedance recordings during neurostimulation in humans

Acute to long-term characteristics of impedance recordings during neurostimulation in humans