Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy

Abstract

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.

In vivocharacterization and application of a novel potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus

“…spontaneous recurrent seizures associated with hippocampal sclerosis (Bouilleret et al, 1999). Most ihpKA mice have epileptiform activity that occurs in form of bursts originating in the seizure focus and propagating into the contralateral hippocampus (Meier et al, 2007; Janz et al, 2018; Paschen et al, 2020). Unexpectedly, all our PACK-injected ihpKA mice (n=5) were free of contralateral seizures already in baseline recordings before light-activation of PACK.…”

“…MTLE is usually described as a unilateral disease since the seizures arise in one hemisphere, ipsilateral to the pathological abnormality. However, in some patients and MTLE mouse models, epileptic activity propagates to the contralateral hippocampus (Gloor et al, 1993; Mintzer et al, 2004; Meier et al, 2007; Popovic et al, 2012; Paschen et al, 2020). To scrutinize the performance of PACK and investigate the contribution of the contralateral hippocampus in MTLE, we applied PACK-mediated inhibition in the well-established intrahippocampal kainate (ihpKA) mouse model.…”

Distributed brain co-processor for tracking electrophysiology and behavior during electrical brain stimulation

“…There is evidence that both low frequency (< 7 Hz) and high frequency (>100 Hz) EBS can reduce interictal epileptiform spikes and seizures, with class-1 evidence from humans supporting HF duty cycle (4) and responsive (1) stimulation. The evidence that LF stimulation can reduce interictal epileptiform spikes and seizures comes from uncontrolled human investigations (18,46,47), non-human primates (48), and rodent models (49)(50)(51)(52)(53)(54).…”

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

“…Critically, the majority of these studies focused on high frequency stimulation parameters to desynchronize neuronal output and reduce epileptiform activity. There are also a limited number of studies demonstrating that low frequency stimulation of the hippocampus ( 22 ) and amygdala ( 23 ) can reduce seizure frequency. While each of these pre-clinical and clinical findings demonstrate that feasibility of neuromodulation to reduce spontaneous seizures, there remains a critical need for the development of a novel therapeutic paradigm to treat not only seizures but also the significant cognitive impairments associated with TLE.…”