PMID- 32542794 OWN - NLM STAT- MEDLINE DCOM- 20210104 LR - 20231127 IS - 1531-8249 (Electronic) IS - 0364-5134 (Print) IS - 0364-5134 (Linking) VI - 88 IP - 3 DP - 2020 Sep TI - Drug-Responsive Inhomogeneous Cortical Modulation by Direct Current Stimulation. PG - 489-502 LID - 10.1002/ana.25822 [doi] AB - OBJECTIVE: Cathodal direct current stimulation (cDCS) induces long-term depression (LTD)-like reduction of cortical excitability (DCS-LTD), which has been tested in the treatment of epilepsy with modest effects. In part, this may be due to variable cortical neuron orientation relative to the electric field. We tested, in vivo and in vitro, whether DCS-LTD occurs throughout the cortical thickness, and if not, then whether drug-DCS pairing can enhance the uniformity of the cortical response and the cDCS antiepileptic effect. METHODS: cDCS-mediated changes in cortical excitability were measured in vitro in mouse motor cortex (M1) and in human postoperative neocortex, in vivo in mouse somatosensory cortex (S1), and in a mouse kainic acid (KA)-seizure model. Contributions of N-methyl-D-aspartate-type glutamate receptors (NMDARs) to cDCS-mediated plasticity were tested with application of NMDAR blockers (memantine/D-AP5). RESULTS: cDCS reliably induced DCS-LTD in superficial cortical layers, and a long-term potentiation (LTP)-like enhancement (DCS-LTP) was recorded in deep cortical layers. Immunostaining confirmed layer-specific increase of phospho-S6 ribosomal protein in mouse M1. Similar nonuniform cDCS aftereffects on cortical excitability were also found in human neocortex in vitro and in S1 of alert mice in vivo. Application of memantine/D-AP5 either produced a more uniform DCS-LTD throughout the cortical thickness or at least abolished DCS-LTP. Moreover, a combination of memantine and cDCS suppressed KA-induced seizures. INTERPRETATION: cDCS aftereffects are not uniform throughout cortical layers, which may explain the incomplete cDCS clinical efficacy. NMDAR antagonists may augment cDCS efficacy in epilepsy and other disorders where regional depression of cortical excitability is desirable. ANN NEUROL 2020;88:489-502. CI - (c) 2020 American Neurological Association. FAU - Sun, Yan AU - Sun Y AD - Department of Neurology and the F. M. Kirby Neurobiology Center, Boston, Massachusetts, USA. AD - Neuromodulation Program and Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. FAU - Dhamne, Sameer C AU - Dhamne SC AD - Department of Neurology and the F. M. Kirby Neurobiology Center, Boston, Massachusetts, USA. AD - Neuromodulation Program and Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. FAU - Carretero-Guillen, Alejandro AU - Carretero-Guillen A AUID- ORCID: 0000-0003-2370-2534 AD - Department of Physiology, Anatomy and Cellular Biology, Pablo de Olavide University, Seville, Spain. FAU - Salvador, Ricardo AU - Salvador R AD - Neuroelectrics Corporation, Cambridge, Massachusetts, USA. FAU - Goldenberg, Marti C AU - Goldenberg MC AD - Department of Neurology and the F. M. Kirby Neurobiology Center, Boston, Massachusetts, USA. AD - Repository Core, Boston Children's Hospital, Boston, Massachusetts, USA. FAU - Godlewski, Brianna R AU - Godlewski BR AD - Repository Core, Boston Children's Hospital, Boston, Massachusetts, USA. FAU - Pascual-Leone, Alvaro AU - Pascual-Leone A AD - Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. AD - Guttmann Institute, Autonomous University of Barcelona, Barcelona, Spain. FAU - Madsen, Joseph R AU - Madsen JR AD - Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA. FAU - Stone, Scellig S D AU - Stone SSD AD - Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA. FAU - Ruffini, Giulio AU - Ruffini G AD - Neuroelectrics Corporation, Cambridge, Massachusetts, USA. FAU - Marquez-Ruiz, Javier AU - Marquez-Ruiz J AD - Department of Physiology, Anatomy and Cellular Biology, Pablo de Olavide University, Seville, Spain. FAU - Rotenberg, Alexander AU - Rotenberg A AUID- ORCID: 0000-0002-6495-5928 AD - Department of Neurology and the F. M. Kirby Neurobiology Center, Boston, Massachusetts, USA. AD - Neuromodulation Program and Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. AD - Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. AD - Guttmann Institute, Autonomous University of Barcelona, Barcelona, Spain. LA - eng GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - R01 MH100186/MH/NIMH NIH HHS/United States GR - R01 NS088583/NS/NINDS NIH HHS/United States GR - UL1 RR025758/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200725 PL - United States TA - Ann Neurol JT - Annals of neurology JID - 7707449 RN - 0 (Excitatory Amino Acid Antagonists) SB - IM MH - Animals MH - Cerebral Cortex/*drug effects/*physiopathology MH - Epilepsy/physiopathology MH - Excitatory Amino Acid Antagonists/*pharmacology MH - Humans MH - Long-Term Synaptic Depression/drug effects/*physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Transcranial Direct Current Stimulation/*methods PMC - PMC10675838 MID - NIHMS1723138 COIS- Potential Conflicts of Interest Nothing to report. EDAT- 2020/06/17 06:00 MHDA- 2021/01/05 06:00 PMCR- 2023/11/25 CRDT- 2020/06/17 06:00 PHST- 2019/10/11 00:00 [received] PHST- 2020/06/11 00:00 [revised] PHST- 2020/06/12 00:00 [accepted] PHST- 2020/06/17 06:00 [pubmed] PHST- 2021/01/05 06:00 [medline] PHST- 2020/06/17 06:00 [entrez] PHST- 2023/11/25 00:00 [pmc-release] AID - 10.1002/ana.25822 [doi] PST - ppublish SO - Ann Neurol. 2020 Sep;88(3):489-502. doi: 10.1002/ana.25822. Epub 2020 Jul 25.