Abstracts

Rationale: Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory method where weak electrical current is conducted to the brain via scalp electrodes. By unknown mechanisms, cathodal tDCS, in humans, predictably leads to a lasting reduction of cortical excitability, and thus may be useful in treatment of epilepsy. Previously, we demonstrated that cathodal, tDCS suppresses seizures in the rat high-dose pentylenetetrazole (PTZ) seizure model. Here, we confirm the preferential antiepileptic effect of cathodal tDCS relative to anodal tDCS, and examine the cathodal tDCS mechanism of action. In related work, we showed that long-interval paired-pulse transcranial magnetic stimulation (LI-ppTMS) can be used to measure GABAA-mediated cortical inhibition in rats, and that LI-ppTMS inhibition is acutely reduced following PTZ injection. As PTZ is a GABAA antagonist, we now combine LI-ppTMS with cathodal tDCS, to test whether cathodal tDCS enhances GABAA activation and whether loss of LI-ppTMS inihibition following PTZ injection may be reversed by cathodal tDCS.Methods: To test the antiepileptic cathodal tDCS capacity, rats (n=46) received PTZ (75mg/kg i.p.) while monitored by continuous video-EEG. Either treatment or sham tDCS was applied for 20min immediately after PTZ injection through a disc electrode on the dorsal scalp and saline-saturated sponge electrode on the ventral torso. The rats were grouped by treatment condition: cathodal 0.1mA (n=9), cathodal 1mA (n=9), anodal 0.1mA (n=10), anodal 1mA (n=8) or sham 0.0mA (n=10). Once the most potent tDCS antiepileptic treatment condition was identified, a separate group of rats (n=21) were anesthetized with sodium pentobarbital, and LI-ppTMS was applied to the left motor cortex to measure paired-pulse inhibition of the right brachioradialis motor evoked potential. Rats monitored by LI-ppTMS received PTZ (50 mg/kg i.p.) with either 1mA or sham cathodal tDCS, or saline injection with sham tDCS. The extent of LI-ppTMS inhibition was averaged during 10-min baseline recording (T1), 20-min stimulation (T2), 0-10 min after stimulation (T3) and 10-25 min after stimulation (T4).Results: 1mA cathodal tDCS was the only treatment condition to result in significant seizure and spike suppression (p<0.01) after PTZ injection, and thus we tested its effect in cortical inhibition. LI-ppTMS inhibition was unchanged relative to baseline in the saline sham tDCS group. Predictably, after PTZ injection, LI-ppTMS revealed impaired inhibition in all rats at T2, T3 and T4 (p<0.05). However, in the rats receiving PTZ and cathodal tDCS, LI ppTMS was unaffected during T3 and T4, and was enhanced relative to saline-sham tDCS at T2 (p<0.05).Conclusions: Cathodal tDCS can suppress seizures, perhaps by enhancing cortical inhibition in rats. Specifically, our data suggest that cathodal tDCS, at least in part, may work by augmenting GABAA -mediated cortical inhibition and may prophylax against such inhibition loss in the PTZ rat seizure model.