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Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We combined finite-element modeling, cadaver measurements (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20092 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long\u2013Evans rats (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200911 animals, &gt;500 induced seizures analyzed across conditions).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s43856-026-01595-6","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T21:18:23Z","timestamp":1776806303000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Non-vectorial integration of intersectional short-pulse stimulation enables enhanced deep brain modulation and effective seizure control"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-508X","authenticated-orcid":false,"given":"Tam\u00e1s","family":"F\u00f6ldi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5736-2967","authenticated-orcid":false,"given":"Miklos","family":"Szoboszlay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Chadaide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bence","family":"Radics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6913-6667","authenticated-orcid":false,"given":"B\u00e1lint","family":"Horv\u00e1th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Endre","family":"Vecserny\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istv\u00e1n","family":"Lang\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"R\u00e1fi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Pejin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5646-8265","authenticated-orcid":false,"given":"L\u00edvia","family":"Barcsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3473-9351","authenticated-orcid":false,"given":"G\u00e1bor","family":"Koz\u00e1k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00f3ra","family":"Forg\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krist\u00f3f","family":"Furugly\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6599-6799","authenticated-orcid":false,"given":"Oliv\u00e9r","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anett J.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Laszlovszky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Somogyv\u00e1ri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5240-1904","authenticated-orcid":false,"given":"Magor L.","family":"L\u0151rincz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0044-4632","authenticated-orcid":false,"given":"Orrin","family":"Devinsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0084-8530","authenticated-orcid":false,"given":"Antal","family":"Ber\u00e9nyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"1595_CR1","first-page":"735","volume":"337","author":"A Ber\u00e9nyi","year":"2012","unstructured":"Ber\u00e9nyi, A., Belluscio, M., Mao, D. & Buzs\u00e1ki, G. 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Szeged, Hungary a manufacturer of signal-multiplexed neuronal amplifiers. A.B. is the CEO of Neunos ZRt, Szeged, Hungary, a company developing neurostimulator devices, and has equity in Blackrock Neurotech. He is listed as an inventor on patents and patent applications related to ISP stimulation and various aspects of closed-loop neurostimulation. O.D. receives grant support from NINDS, NIMH, MURI, CDC, and NSF. He has equity and\/or compensation from the following companies: Blackrock Neurotech, Tilray, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, Ajna Biosciences, and California Cannabis Enterprises (CCE). He has received consulting fees or equity options from Emotiv, Ultragenyx, and Praxis Precision Therapeutics. He holds patents for the use of cannabidiol in treating neurological disorders, but these are owned by GW Pharmaceutical,s and he has waived any financial interests. He holds other patents in molecular biology. 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