{"title":"阴极弱直流电通过减少神经元活动和增强δ振荡来降低癫痫的兴奋性。","authors":"Chia-Chu Chiang, Miao-Er Chien, Yu-Chieh Huang, Jyun-Ting Lin, Sheng-Fu Liang, Kuei-Sen Hsu, Dominique M. Durand, Yi-Jen Wu","doi":"10.1113/JP287969","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n \n <div>Seizures are manifestations of hyperexcitability in the brain. Non-invasive weak current stimulation, delivered through cathodal transcranial direct current stimulation (ctDCS), has emerged to treat refractory epilepsy and seizures, although the cellular-to-populational electrophysiological mechanisms remain unclear. Using the ctDCS <i>in vivo</i> 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)-induced acute hippocampal seizures, ctDCS reduced seizure excitability by decreasing the number and amplitude of epileptic spikes in LFP and enhancing delta (δ) power. We identified unit spikes of putative excitatory neurons in CA1 stratum 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-specific and current strength-dependent responses. The reduced unit spikes after ctDCS coupled to δ oscillations with an increased coupling strength. These effects occurred during stimulation and lasted 90 min post-stimulation, accompanied by inhibitory short-term synaptic plasticity changes shown in paired-pulse stimulation after ctDCS. Consistently, neuronal activations measured by c-Fos significantly decreased after ctDCS, particularly in CaMKII<sup>+</sup>-excitatory neurons while increased in GAD<sup>+</sup>-inhibitory neurons. In conclusion, epileptic excitability was alleviated with cathodal weak direct current stimulation by diminishing excitatory neuronal activity and enhancing endogenous δ oscillations through strengthened coupling between unit spikes and δ waves, along with inhibitory plasticity changes, highlighting the potential implications to treat brain disorders characterized by hyperexcitability.\n\n <figure>\n <div><picture>\n <source></source></picture><p></p>\n </div>\n </figure>\n </div>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>Electric fields generated by transcranial weak electric current stimulation were measured at CA1, showing polarity-specific and current strength-dependent modulation of unit spike activity.</li>\n \n <li>Polyspike epileptiform discharges were observed in rats with kainic acid (KA)-induced hippocampal seizures. Cathodal transcranial direct current stimulation (ctDCS) reduced the number and amplitude of the epileptic spikes in local field potentials (LFPs) while increased δ oscillations.</li>\n \n <li>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 δ waves.</li>\n \n <li>Neuronal activations, measured by c-Fos, decreased in CaMKII<sup>+</sup>-excitatory neurons while increased in GAD<sup>+</sup>-inhibitory neurons after ctDCS.</li>\n \n <li>These effects on LFP and unit spikes lasted up to 90 min post-stimulation. Inhibitory short-term plasticity changes detected through paired-pulse stimulation underpin the enduring effects of ctDCS on seizures.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 9","pages":"2763-2782"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287969","citationCount":"0","resultStr":"{\"title\":\"Cathodal weak direct current decreases epileptic excitability with reduced neuronal activity and enhanced delta oscillations\",\"authors\":\"Chia-Chu Chiang, Miao-Er Chien, Yu-Chieh Huang, Jyun-Ting Lin, Sheng-Fu Liang, Kuei-Sen Hsu, Dominique M. Durand, Yi-Jen Wu\",\"doi\":\"10.1113/JP287969\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n \\n <div>Seizures are manifestations of hyperexcitability in the brain. Non-invasive weak current stimulation, delivered through cathodal transcranial direct current stimulation (ctDCS), has emerged to treat refractory epilepsy and seizures, although the cellular-to-populational electrophysiological mechanisms remain unclear. Using the ctDCS <i>in vivo</i> 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)-induced acute hippocampal seizures, ctDCS reduced seizure excitability by decreasing the number and amplitude of epileptic spikes in LFP and enhancing delta (δ) power. We identified unit spikes of putative excitatory neurons in CA1 stratum 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-specific and current strength-dependent responses. The reduced unit spikes after ctDCS coupled to δ oscillations with an increased coupling strength. These effects occurred during stimulation and lasted 90 min post-stimulation, accompanied by inhibitory short-term synaptic plasticity changes shown in paired-pulse stimulation after ctDCS. Consistently, neuronal activations measured by c-Fos significantly decreased after ctDCS, particularly in CaMKII<sup>+</sup>-excitatory neurons while increased in GAD<sup>+</sup>-inhibitory neurons. In conclusion, epileptic excitability was alleviated with cathodal weak direct current stimulation by diminishing excitatory neuronal activity and enhancing endogenous δ oscillations through strengthened coupling between unit spikes and δ waves, along with inhibitory plasticity changes, highlighting the potential implications to treat brain disorders characterized by hyperexcitability.\\n\\n <figure>\\n <div><picture>\\n <source></source></picture><p></p>\\n </div>\\n </figure>\\n </div>\\n </section>\\n \\n <section>\\n \\n <h3> Key points</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Electric fields generated by transcranial weak electric current stimulation were measured at CA1, showing polarity-specific and current strength-dependent modulation of unit spike activity.</li>\\n \\n <li>Polyspike epileptiform discharges were observed in rats with kainic acid (KA)-induced hippocampal seizures. Cathodal transcranial direct current stimulation (ctDCS) reduced the number and amplitude of the epileptic spikes in local field potentials (LFPs) while increased δ oscillations.</li>\\n \\n <li>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 δ waves.</li>\\n \\n <li>Neuronal activations, measured by c-Fos, decreased in CaMKII<sup>+</sup>-excitatory neurons while increased in GAD<sup>+</sup>-inhibitory neurons after ctDCS.</li>\\n \\n <li>These effects on LFP and unit spikes lasted up to 90 min post-stimulation. Inhibitory short-term plasticity changes detected through paired-pulse stimulation underpin the enduring effects of ctDCS on seizures.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":50088,\"journal\":{\"name\":\"Journal of Physiology-London\",\"volume\":\"603 9\",\"pages\":\"2763-2782\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-04-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287969\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Physiology-London\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1113/JP287969\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Physiology-London","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1113/JP287969","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Cathodal weak direct current decreases epileptic excitability with reduced neuronal activity and enhanced delta oscillations
Seizures are manifestations of hyperexcitability in the brain. Non-invasive weak current stimulation, delivered through cathodal transcranial direct current stimulation (ctDCS), has emerged to treat refractory epilepsy and seizures, although the cellular-to-populational electrophysiological mechanisms remain unclear. Using the ctDCS in vivo 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)-induced acute hippocampal seizures, ctDCS reduced seizure excitability by decreasing the number and amplitude of epileptic spikes in LFP and enhancing delta (δ) power. We identified unit spikes of putative excitatory neurons in CA1 stratum 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-specific and current strength-dependent responses. The reduced unit spikes after ctDCS coupled to δ oscillations with an increased coupling strength. These effects occurred during stimulation and lasted 90 min post-stimulation, accompanied by inhibitory short-term synaptic plasticity changes shown in paired-pulse stimulation after ctDCS. Consistently, neuronal activations measured by c-Fos significantly decreased after ctDCS, particularly in CaMKII+-excitatory neurons while increased in GAD+-inhibitory neurons. In conclusion, epileptic excitability was alleviated with cathodal weak direct current stimulation by diminishing excitatory neuronal activity and enhancing endogenous δ oscillations through strengthened coupling between unit spikes and δ waves, along with inhibitory plasticity changes, highlighting the potential implications to treat brain disorders characterized by hyperexcitability.
Key points
Electric fields generated by transcranial weak electric current stimulation were measured at CA1, showing polarity-specific and current strength-dependent modulation of unit spike activity.
Polyspike epileptiform discharges were observed in rats with kainic acid (KA)-induced hippocampal seizures. Cathodal transcranial direct current stimulation (ctDCS) reduced the number and amplitude of the epileptic spikes in local field potentials (LFPs) while increased δ oscillations.
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 δ waves.
Neuronal activations, measured by c-Fos, decreased in CaMKII+-excitatory neurons while increased in GAD+-inhibitory neurons after ctDCS.
These effects on LFP and unit spikes lasted up to 90 min post-stimulation. Inhibitory short-term plasticity changes detected through paired-pulse stimulation underpin the enduring effects of ctDCS on seizures.
期刊介绍：
The Journal of Physiology publishes full-length original Research Papers and Techniques for Physiology, which are short papers aimed at disseminating new techniques for physiological research. Articles solicited by the Editorial Board include Perspectives, Symposium Reports and Topical Reviews, which highlight areas of special physiological interest. CrossTalk articles are short editorial-style invited articles framing a debate between experts in the field on controversial topics. Letters to the Editor and Journal Club articles are also published. All categories of papers are subjected to peer reivew.
The Journal of Physiology welcomes submitted research papers in all areas of physiology. Authors should present original work that illustrates new physiological principles or mechanisms. Papers on work at the molecular level, at the level of the cell membrane, single cells, tissues or organs and on systems physiology are all acceptable. Theoretical papers and papers that use computational models to further our understanding of physiological processes will be considered if based on experimentally derived data and if the hypothesis advanced is directly amenable to experimental testing. While emphasis is on human and mammalian physiology, work on lower vertebrate or invertebrate preparations may be suitable if it furthers the understanding of the functioning of other organisms including mammals.
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