Early Intervention via Stimulation of the Medial Septal Nucleus Improves Cognition and Alters Markers of Epileptogenesis in Pilocarpine-Induced Epilepsy.

Ali Izadi,Gregory Disse,Amber Schedlbauer,Stephen L Cowen,Katelynn Ondek,Gene G Gurkoff,Kiarash Shahlaie,Arne D Ekstrom

doi:10.3389/fneur.2021.708957

Ali Izadi, Gregory Disse + Show 6 more

Open Access

https://doi.org/10.3389/fneur.2021.708957

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Abstract

Over one-third of patients with temporal lobe epilepsy are refractory to medication. In addition, anti-epileptic drugs often exacerbate cognitive comorbidities. Neuromodulation is an FDA treatment for refractory epilepsy, but patients often wait >20 years for a surgical referral for resection or neuromodulation. Using a rodent model, we test the hypothesis that 2 weeks of theta stimulation of the medial septum acutely following exposure to pilocarpine will alter the course of epileptogenesis resulting in persistent behavioral improvements. Electrodes were implanted in the medial septum, dorsal and ventral hippocampus, and the pre-frontal cortex of pilocarpine-treated rats. Rats received 30 min/day of 7.7 Hz or theta burst frequency on days 4–16 post-pilocarpine, prior to the development of spontaneous seizures. Seizure threshold, spikes, and oscillatory activity, as well as spatial and object-based learning, were assessed in the weeks following stimulation. Non-stimulated pilocarpine animals exhibited significantly decreased seizure threshold, increased spikes, and cognitive impairments as compared to vehicle controls. Furthermore, decreased ventral hippocampal power (6–10 Hz) correlated with both the development of spikes and impaired cognition. Measures of spikes, seizure threshold, and cognitive performance in both acute 7.7 Hz and theta burst stimulated animals were statistically similar to vehicle controls when tested during the chronic phase of epilepsy, weeks after stimulation was terminated. These data indicate that modulation of the septohippocampal circuit early after pilocarpine treatment alters the progression of epileptic activity, resulting in elevated seizure thresholds, fewer spikes, and improved cognitive outcome. Results from this study support that septal theta stimulation has the potential to serve in combination or as an alternative to high frequency thalamic stimulation in refractory cases and that further research into early intervention is critical.

Highlights

Of the ∼3.4 million adults and children in the U.S diagnosed with epilepsy [1], more than half experience comorbidities such as cognitive decline [2]
All animals injected with pilocarpine experienced motor limbic seizures followed by status epilepticus
Post-hoc Bonferroni analysis demonstrated that each pilocarpine group was statistically different from vehicle controls for pilocarpine with no stimulation (Vehicle) (p < 0.0001 for all comparisons), there were no differences between pilocarpine-treated rats with no stimulation (Pilo), Fixed, or burst stimulation (Burst) groups

Summary

Introduction

Of the ∼3.4 million adults and children in the U.S diagnosed with epilepsy [1], more than half experience comorbidities such as cognitive decline [2]. For patients who do not meet surgical criteria [12], neuromodulation paradigms such as vagal nerve stimulation (VNS), deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT), and responsive neurostimulation (RNS) represent reversible and effective alternatives [13,14,15]. While these stimulation paradigms result in progressive improvements in responder rates [13,14,15,16] as compared to pharmacology alone, they do not significantly improve cognitive outcome [17]

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