期刊
ANNALS OF NEUROLOGY
卷 88, 期 3, 页码 489-502出版社
WILEY
DOI: 10.1002/ana.25822
关键词
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资金
- Boston Children's Hospital Translational Research Program
- Spanish Ministry of Economy and Competitiveness (MINECO)
- European Fund for Regional Development (FEDER) [BFU2014-53820-P, BFU2017-89615-P]
- Repository Core for Neurological Disorders, Department of Neurology, Boston Children's Hospital
- Intellectual and Developmental Disabilities Research Center [NIH P30HD018655]
- NIH (National Institute of Neurological Disorders and Stroke) [R01NS088583]
- NIH (National Institute of Mental Health) [R01100186]
- Smith Family Foundation
- Assimon Family Foundation
- Sage Pharmaceuticals
- Eisai Pharmaceuticals
- Massachusetts Life Sciences
- Neuroelectrics
- Brainsway
- Sidney R. Baer Jr. Foundation
- Football Players Health Study at Harvard University
- Harvard Catalyst | Harvard Clinical and Translational Science Center (NIH National Center for Research Resources and National Center for Advancing Translational Sciences) [UL1 RR025758]
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
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