Abstracts

Rationale: Transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs) applied at 50 mA has been found to induce antiepileptic and neuroprotective effects in different experimental animal models (Besio et al. Epilepsia 2007, Santana-Gomez et al. Epilep. and Behav. 2015). We also have found that TFS reduces the expression of P-glycoprotein in animals with induced seizure activity. Preliminary studies on 10 healthy humans also revealed that TFS is safe. The goal of the present animal study was to determine the effects of TFS applied at low current intensity (1 mA) alone and combined with antiseizure drugs that are substrates of P-glycoprotein. The human study was to increase the number of human participants and use computer modeling to estimate the electric fields in the brain due to 50 mA TFS. Methods: Animal experiments: Male Wistar rats (250-300 g, n=10 per group) were used. Animals were administered with phenytoin (PHT, 75 mg/kg, i.p.) or phenobarbital (PB, 15 mg/kg, i.p.). One hour later they received TFS at 1 mA for 2 min. At the end of the stimulation, they were administered 3-mercaptopropionic acid (37.5 mg/kg i.p.). The latency and incidence of clonic and tonic-clonic seizures were evaluated. The results obtained were compared with animals receiving the following treatments: TFS alone, PHT or PB alone, or vehicle. Human experiments: Eleven more participants were included in the safety study for a total of 21. TFS (300 Hz, biphasic equal charge, square pulses) safety was tested on participant’s skin and behavior during three sessions (S1, S2, S3) approximately 1-week apart. At S1, participants rate each step of the electrode application process on the arm and scalp for pain (0-10, none to worst) and the experimenter rates skin erythema (Draize scale, 0-4; no change-beet red) (NuPrep cleansing gel; Ten20 EEG paste; gel + paste; gel + paste + TCRE; gel + paste + TCRE + TFS or sham (SH) for 2 mins). Baseline (BL) performance on a working memory task (WMT: 5-min each of 2-back and 3-back) is recorded before scalp TFS or SH while 16 channels of EEG are collected at 512 Hz over the left prefrontal cortex. TFS or SH is applied at F3. At S2 they perform a BL WMT, TFS or SH is delivered, then, they perform the WMT at 3 post-intervention time points (in mins: T0, T20 and T40). At S3, they perform the WMT at the 3 time points. Computer modelling: A four concentric spheres (scalp, skull, CSF, and brain) finite element model was constructed in Comsol with TCREs providing electrical stimulation through conductive paste. The electric fields were calculated due to 50 mA current applied between the outer ring and central disc of the 10 mm diameter TCRE. Results: Animal: The results obtained revealed that TFS alone did not modify the seizure activity. The administration of PHT or PB alone augmented the latency to the clonic and tonic-clonic seizures (p<0.05, respectively), effect associated with a lower incidence (p<0.01, respectively). TFS combined with PB reduce the incidence of animals with clonic and tonic seizures (p<0.05, respectively), when compared with PB alone. In contrast, TFS combined with PHT reverted the protective effect induced by PHT alone. Human: None of the participants could tell if the TFS was on. There was no damage to skin and no pain. There was no significant difference in memory or reaction time as well as electroencephalography under the TFS site. Model: The electric field at the cortical surface is estimated to be 0.13V/m by the model. Conclusions: These results indicate that TFS applied at 1 mA alone does not modify the seizure activity. However, it augments the antiseizure effects of PB, a drug that augments the GABAergic neurotransmission. In contrast, it reverts the anticonvulsant effects of PHT, a drug that blocks the sodium channels. Future experiments are essential to confirm the effects of TFS when combined with different antiseizure drugs in order to avoid side effects. The TFS appears to be safe for humans not causing skin deterioration or significant changes in memory. The 0.13V/m electric fields in the cortex should not be large enough to activate neurons but should alter neuronal activity. Funding: NSF awards 1539068 and 1701049