{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:56:20Z","timestamp":1772153780364,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Seizures are manifestations of hyperexcitability in the brain. Non\u2010invasive weak current stimulation, delivered through cathodal transcranial direct current stimulation (ctDCS), has emerged to treat refractory epilepsy and seizures, although the cellular\u2010to\u2010populational electrophysiological mechanisms remain unclear. Using the ctDCS <jats:italic>in vivo<\/jats:italic> model, we investigate how neural excitability is modulated through weak direct currents by analysing the local field potential (LFP) and extracellular unit spike recordings before, during and after ctDCS versus sham stimulation. In rats with kainic acid (KA)\u2010induced acute hippocampal seizures, ctDCS reduced seizure excitability by decreasing the number and amplitude of epileptic spikes in LFP and enhancing delta (\u03b4) power. We identified unit spikes of putative excitatory neurons in CA1\u00a0stratum pyramidale based on waveform sorting and validated via optogenetic inhibitions which increased aberrantly in seizure animals. Notably, cathodal stimulation significantly reduced these unit spikes, whereas anodal stimulation exhibited the opposite effect, showing polarity\u2010specific and current strength\u2010dependent responses. The reduced unit spikes after ctDCS coupled to \u03b4 oscillations with an increased coupling strength. These effects occurred during stimulation and lasted 90\u00a0min post\u2010stimulation, accompanied by inhibitory short\u2010term synaptic plasticity changes shown in paired\u2010pulse stimulation after ctDCS. Consistently, neuronal activations measured by c\u2010Fos significantly decreased after ctDCS, particularly in CaMKII<jats:sup>+<\/jats:sup>\u2010excitatory neurons while increased in GAD<jats:sup>+<\/jats:sup>\u2010inhibitory neurons. In conclusion, epileptic excitability was alleviated with cathodal weak direct current stimulation by diminishing excitatory neuronal activity and enhancing endogenous \u03b4 oscillations through strengthened coupling between unit spikes and \u03b4 waves, along with inhibitory plasticity changes, highlighting the potential implications to treat brain disorders characterized by hyperexcitability.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16657-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Electric fields generated by transcranial weak electric current stimulation were measured at CA1, showing polarity\u2010specific and current strength\u2010dependent modulation of unit spike activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Polyspike epileptiform discharges were observed in rats with kainic acid (KA)\u2010induced hippocampal seizures. Cathodal transcranial direct current stimulation (ctDCS) reduced the number and amplitude of the epileptic spikes in local field potentials (LFPs) while increased \u03b4 oscillations.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Neuronal unit spikes aberrantly increased in seizures and coupled with epileptiform discharges. ctDCS reduced excitatory neuronal firings at CA1 and strengthened the coupling between unit spikes and \u03b4 waves.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Neuronal activations, measured by c\u2010Fos, decreased in CaMKII<jats:sup>+<\/jats:sup>\u2010excitatory neurons while increased in GAD<jats:sup>+<\/jats:sup>\u2010inhibitory neurons after ctDCS.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These effects on LFP and unit spikes lasted up to 90\u00a0min post\u2010stimulation. Inhibitory short\u2010term plasticity changes detected through paired\u2010pulse stimulation underpin the enduring effects of ctDCS on seizures.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp287969","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T22:47:32Z","timestamp":1744066052000},"page":"2763-2782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cathodal weak direct current decreases epileptic excitability with reduced neuronal activity and enhanced delta oscillations"],"prefix":"10.1113","volume":"603","author":[{"given":"Chia\u2010Chu","family":"Chiang","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering, Neural Engineering Center Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao\u2010Er","family":"Chien","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Chieh","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyun\u2010Ting","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Information Engineering National Cheng Kung University  Tainan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng\u2010Fu","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Information Engineering National Cheng Kung University  Tainan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-5157","authenticated-orcid":false,"given":"Kuei\u2010Sen","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine National Cheng Kung University  Tainan Taiwan"},{"name":"Institute of Basic Medical Sciences, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8355-6324","authenticated-orcid":false,"given":"Dominique M.","family":"Durand","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Case Western Reserve University  Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering, Neural Engineering Center Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4369-1791","authenticated-orcid":false,"given":"Yi\u2010Jen","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine National Cheng Kung University  Tainan Taiwan"},{"name":"Department of Neurology, National Cheng Kung University Hospital, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncom.2013.00140"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00042-3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.11.052"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3241"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2016.133"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.02.002"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80525-5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1990.sp018080"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2802-y"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.09.033"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2024.04.007"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17514"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-19-07255.2003"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.01.014"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0971-11.2011"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNP.0000000000000806"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23021-2"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2016.08.016"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.07.023"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.037629"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2023.03.040"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2013.10.011"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2021.11.001"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50823"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2023.107200"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0417-20.2020"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv208"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41711-x"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15840-6"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx179"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.092429"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3950"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.247171"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2014157118"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2016.08.013"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0559-0"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.909421"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2022.114109"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2021.01.020"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4786-14.2015"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.06.016"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02928-3"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.003"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2020.07.006"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2021.04.025"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113264"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2017.08.007"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bandc.2014.09.002"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2016.00479"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2019.09.006"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12984-022-01094-4"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-017-0399-8"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP287969","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:35:29Z","timestamp":1748324129000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP287969"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,7]]},"references-count":52,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1113\/JP287969"],"URL":"https:\/\/doi.org\/10.1113\/jp287969","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,7]]},"assertion":[{"value":"2024-10-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}