Abstracts

Rationale: Under the cathode, direct current stimulation (DCS) leads to long-term depression (DCS-LTD) in cortical excitability, which depends on distinct molecular pathway as compared to anodal DCS induced long-term potentiation (DCS-LTP) effects (Ann Neurol. 2016; 80(2):233-46). Transcranial cathodal DCS is undergoing active testing in epilepsy, but its clinical efficacy is modest, at best. We aim to test, through experiments in isolated human cortical slices derived from epilepsy surgery, a) whether cathodal DCS can also induce LTD in human cortex isolated from epileptogenic zone, as it does in healthy subjects and animals, b) whether DCS modulates cortical excitability uniformly throughout human cortical layers, and c) whether a novel drug-DCS pairing can enhance the uniformity of the cortical response and thus improve the suppressive capacity of cathodal DCS. Methods: Human cortical tissue was transferred into oxygenated ice-cold artificial cerebrospinal fluid after surgical removal of the epileptogenic zone of patients (ages 1 to 14 years) with focal cortical dysplasia. The tissue was either from temporal lobe, insular cortex, or occipital lobe. DCS was delivered through two Ag/AgCl electrodes to human cortical slices. Field excitatory postsynaptic potential (fEPSP) slopes evoked by test stimuli were recorded by a microelectrode array spanning across cortical layers in human cortical slices, and the fEPSP slope changes, one hour after in vitro DCS (400μA, 25min), were plotted as an interpolated two-dimensional map using Matlab software. Results: In 5 cortical slices where we successfully recorded in vitro signal, DCS-LTD was induced under cathode. In tissue from one patient, fEPSP slope was reduced to as much as 53.5% of baseline (p<0.001). However, in the entire group, patches of either unchanged or potentiated fEPSP were also elicited under cathodal stimulation. The fraction of the microelectrode array channels that expressed DCS-LTD under cathode was only 26.3 ± 3.0% per subject (n=5). Given that DCS-LTD and DCS-LTP depends on the activation of mGluR5- and NMDA-type glutamate receptors, respectively, we further tested the effect of an uncompetitive NMDAR antagonist, memantine, on the anatomy of DCS modulation of cortical excitability. We found more microelectrode array channels expressing DCS-LTD (52.9 ± 7.0%, n=4) in the presence of 100μM memantine as compared to the DCS-only group (p<0.01). Conclusions: Cathodal DCS induce LTD-like changes of cortical excitability in human cortical slices derived from epileptogenic zone of patients. However, the DCS plastic effects are not uniform throughout cortical layers, which may partly explain the incomplete efficacy of transcranial cathodal DCS in clinical trials. Since blocking NMDAR activity could facilitate DCS-LTD in human cortex in vitro, we suggest a therapeutic potential of NMDAR antagonists to augment transcranial cathodal DCS efficiency. Funding: Translational Research Program of Boston Children's Hospital