Bi-rhythmic biomimetic electrical stimulation paradigm for seizure suppression

Uilki Tufa, Anya Zahra, Chiping Wu, Liang Zhang, Peter L. Carlen, and Berj L. Bardakjian 

Epilepsy affects about 300,000 Canadians. Around 25% of patients are intractable to anticonvulsant drugs, do not meet surgical criteria and have no adequate treatment. Electrical stimulation can be an effective alternative treatment. Clinical trials have demonstrated the safety of thalamic stimulation using a high frequency stimulus with limited efficacy. Our group has previously shown, in silico, the success of stimulation with a biomimetic therapeutic signal, outperforming mono-rhythmic waveforms. In this study we aim to extend our findings in vivo and investigate a thalamic continuous stimulation paradigm using a biomimetic signal, where the amplitude of a high frequency rhythm is modulated by the phase of a low frequency rhythm forming a cross-frequency coupled (CFC) waveform, to suppress seizure-like events (SLEs) in a kindled mouse model. Bipolar electrodes were implanted in the CA3 of the hippocampus and in the ipsilateral medial dorsal nucleus of the thalamus, allowing for stimulation and iEEG recordings. A webcam was used for monitoring animal motor behavior. Mice were kindled daily through unilateral CA3 stimulations, reaching convulsive SLEs. To test suppression, thalamic stimulation using a CFC waveform was applied continuously for 15 minutes, followed by hippocampal stimulation to evoke an SLE. We found a 1Hz-100Hz phase-amplitude CFC waveform to be effective in suppressing SLEs (confirmed by iEEG and video analysis) and increasing after discharge threshold. Low frequency suppression was found as a marker to assess the effective stimulus amplitude. We aim to fine tune parameters and investigate this effect in a spontaneous recurrent seizure mouse model. These findings are important in the development of therapeutic strategies for epileptic patients.