Drug-Responsive Inhomogeneous Cortical Modulation by Direct Current Stimulation.

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.

Direct current stimulation induces mGluR5-dependent neocortical plasticity.

OBJECTIVE: To obtain insights into mechanisms mediating changes in cortical excitability induced by cathodal transcranial direct current stimulation (tDCS). METHODS: Neocortical slices were exposed to direct current stimulation (DCS) delivered through Ag/AgCl electrodes over a range of current orientations, magnitudes, and durations. DCS-induced cortical plasticity and its receptor dependency were measured as the change in layer II/III field excitatory postsynaptic potentials by a multielectrode array, both with and without neurotransmitter receptor blockers or allosteric modulators. In vivo, tDCS was delivered to intact mice scalp via surface electrodes. Molecular consequences of DCS in vitro or tDCS in vivo were tested by immunoblot of protein extracted from stimulated slices or the neocortex harvested from stimulated intact mice. RESULTS: Cathodal DCS in vitro induces a long-term depression (DCS-LTD) of excitatory synaptic strength in both human and mouse neocortical slices. DCS-LTD is abolished with an mGluR5 negative allosteric modulator, mechanistic target of rapamycin (mTOR) inhibitor, and inhibitor of protein synthesis. However, DCS-LTD persists despite either γ-aminobutyric acid type A receptor or N-methyl-D-aspartate receptor inhibition. An mGluR5-positive allosteric modulator, in contrast, transformed transient synaptic depression resultant from brief DCS application into durable DCS-LTD. INTERPRETATION: We identify a novel molecular pathway by which tDCS modulates cortical excitability, and indicate a capacity for synergistic interaction between tDCS and pharmacologic mGluR5 facilitation. The findings support exploration of cathodal tDCS as a treatment of neurologic conditions characterized by aberrant regional cortical excitability referable to mGluR5-mTOR signaling. Ann Neurol 2016;80:233-246.