Noninvasive Transcranial Focal Stimulation Via Tripolar Concentric Ring Electrodes Lessens Behavioral Seizure Activity of Recurrent Pentylenetetrazole Administrations in Rats

Abstract

Epilepsy affects approximately one percent of the world population. Antiepileptic drugs are ineffective in approximately 30% of patients and have side effects. We have been developing a noninvasive transcranial focal electrical stimulation with our novel tripolar concentric ring electrodes as an alternative/complementary therapy for seizure control. In this study we demonstrate the effect of focal stimulation on behavioral seizure activity induced by two successive pentylenetetrazole administrations in rats. Seizure onset latency, time of the first behavioral change, duration of seizure, and maximal seizure severity score were studied and compared for focal stimulation treated (n = 9) and control groups (n = 10). First, we demonstrate that no significant difference was found in behavioral activity for focal stimulation treated and control groups after the first pentylenetetrazole administration. Next, comparing first and second pentylenetetrazole administrations, we demonstrate there was a significant change in behavioral activity (time of the first behavioral change) in both groups that was not related to focal stimulation. Finally, we demonstrate focal stimulation provoking a significant change in seizure onset latency, duration of seizure, and maximal seizure severity score. We believe that these results, combined with our previous reports, suggest that transcranial focal stimulation may have an anticonvulsant effect.

Improving the Accuracy of Laplacian Estimation with Novel Variable Inter-Ring Distances Concentric Ring Electrodes

“…In particular, since “negative Laplacian is approximately proportional to cortical (or dura) surface potential” [ 38 ], every application currently utilizing Laplacian signals such as, for example, tEEG [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 20 , 21 ] may benefit from more accurate Laplacian estimation since it improves estimation of the cortical potentials. Moreover, other potential advantages of variable inter-ring distances CREs need to be investigated including, for example, improved control of the electric field used for seizure attenuation compared to the one that current transcranial focal stimulation applied via constant inter-ring distances TCREs can offer [ 17 , 18 , 19 , 20 ]. It should be noted that variable inter-ring distances CREs do not cause any inherent growth in the size of the electrode compared to their constant inter-ring distances counterparts since all CRE configurations considered and modeled had the same dimensions.…”

“…Compared to EEG with conventional disc electrodes ( Figure 1 A) Laplacian EEG via TCREs (tEEG) have been shown to have significantly better spatial selectivity (approximately 2.5 times higher), signal-to-noise ratio (approximately 3.7 times higher), and mutual information (approximately 12 times lower) [ 12 ]. Because of such unique capabilities, TCREs have found numerous applications in a wide range of areas including brain–computer interface [ 13 , 14 ], seizure onset detection [ 15 , 16 ], seizure attenuation using transcranial focal stimulation applied via TCREs [ 17 , 18 , 19 , 20 ], detection of high-frequency oscillations and seizure onset zones [ 21 ], etc . These EEG-related applications of TCREs, as well as recent applications related to electroenterograms [ 22 , 23 ], electrocardiograms [ 11 , 24 , 25 , 26 ], and electrohysterograms [ 27 ], suggest the potential of CRE technology in noninvasive electrophysiology, as well as the need for further improvement of CRE design.…”

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats

“…The reasoning behind using a single set of TFS parameters was threefold. First, the same set of parameters has been proven effective in attenuating acute pilocarpine- and pentylenetetrazole-induced seizures [ 4 , 6 – 8 , 26 ] and our aim was to keep the safety testing studies [ 12 , 13 , 23 ] consistent with the studies assessing the anticonvulsant effect of TFS. For example, in a previous study [ 4 ], a range of TFS frequencies (200, 300, 500, and 750 Hz), two pulse durations (200 and 300 μ s), and two current intensities (50 and 60 mA) were tested in an assessment of the effect of TFS on pilocarpine-induced status epilepticus in rats using a ramp stimulation protocol and no combination of TFS parameters yielded significantly better results than the parameter set used in the current study.…”

“…Previously, it has been shown that tEEG, Laplacian electroencephalography (EEG) via TCRE configuration, is superior to conventional EEG with disc electrodes since the tEEG has significantly better spatial selectivity, signal-to-noise ratio, and mutual information [ 3 ]. Because of such unique capabilities, TCREs have found numerous applications in a wide range of areas including, in particular, seizure attenuation using transcranial focal stimulation (TFS) applied via TCREs [ 4 – 8 ]. Unlike electrical stimulation via conventional disc electrodes that is usually applied across the head, TFS via TCRE has a much more uniform current density and focuses the stimulation directly below the electrodes [ 9 ].…”

“…Unlike electrical stimulation via conventional disc electrodes that is usually applied across the head, TFS via TCRE has a much more uniform current density and focuses the stimulation directly below the electrodes [ 9 ]. Previously, TFS has been shown to attenuate acute seizures [ 4 ] and reduce the convulsive expression and amino acid release in the hippocampus [ 5 ] during a pilocarpine-induced status epilepticus and reduce both electrographic [ 6 , 7 ] and behavioral [ 7 , 8 ] seizure activity in pentylenetetrazole-induced seizure model that is widely used for testing both seizure susceptibility and screening of new antiepileptic drugs [ 10 ].…”