Mimicking CA3 Temporal Dynamics Controls Limbic Ictogenesis

SIMPLE SUMMARY: Mesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most often refractory to medications. Electrical deep brain stimulation (DBS) has proved effective in controlling seizures in animal models and in drug-refractory MTLE patients. However, there is still no unifying framework for DBS parameters, which are obtained by trial-and-error and based on arbitrary, fixed stimulation frequencies rather than on physiologically relevant patterns. Interictal activity may present the key to devising personalized and physiologically relevant DBS strategies. Interictal activity occurs between seizures and is a hallmark of the hyperexcitability of the epileptic brain; depending on the underlying mechanisms and site of origin, it may promote seizures (pro-ictogenic) or dampen them (anti-ictogenic). In this work, we address the possibility of controlling seizure activity by means of electrical stimulation fashioned as a surrogate interictal pattern known to be anti-ictogenic. We show that this approach can effectively control seizure activity while delivering fewer electrical pulses than fixed-frequency stimulation. Thus, mimicking the temporal dynamics of an anti-ictogenic interictal pattern may represent a straightforward, personalized and more efficient DBS strategy to ameliorate drug-refractory epilepsy. Our work heralds a paradigm shift toward physiologically meaningful rather than arbitrary DBS parameters. ABSTRACT: Mesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most unresponsive to medications. Electrical deep brain stimulation (DBS) of the hippocampus has proved effective in controlling seizures in epileptic rodents and in drug-refractory MTLE patients. However, current DBS paradigms implement arbitrary fixed-frequency or patterned stimuli, disregarding the temporal profile of brain electrical activity. The latter, herein included hippocampal spontaneous firing, has been shown to follow lognormal temporal dynamics. Here, we present a novel paradigm to devise DBS protocols based on stimulation patterns fashioned as a surrogate brain signal. We focus on the interictal activity originating in the hippocampal subfield CA3, which has been shown to be anti-ictogenic. Using 4-aminopyridine-treated hippocampus-cortex slices coupled to microelectrode array, we pursue three specific aims: (1) address whether lognormal temporal dynamics can describe the CA3-driven interictal pattern, (2) explore the possibility of restoring the non-seizing state by mimicking the temporal dynamics of this anti-ictogenic pattern with electrical stimulation, and (3) compare the performance of the CA3-surrogate against periodic stimulation. We show that the CA3-driven interictal activity follows lognormal temporal dynamics. Further, electrical stimulation fashioned as a surrogate interictal pattern exhibits similar efficacy but uses less pulses than periodic stimulation. Our results support the possibility of mimicking the temporal dynamics of relevant brain signals as a straightforward DBS strategy to ameliorate drug-refractory epilepsy. Further, they herald a paradigm shift in neuromodulation, wherein a compromised brain signal can be recreated by the appropriate stimuli distribution to bypass trial-and-error studies and attain physiologically meaningful DBS operating modes.