Deep brain stimulation in the medial septum attenuates temporal lobe epilepsy via entrainment of hippocampal theta rhythm

Abstract

Aims Temporal lobe epilepsy (TLE), often associated with cognitive impairment, is one of the most common types of medically refractory epilepsy. Deep brain stimulation (DBS) shows considerable promise for the treatment of TLE. However, the optimal stimulation targets and parameters of DBS to control seizures and related cognitive impairment are still not fully illustrated. Methods In the present study, we evaluated the therapeutic potential of DBS in the medial septum (MS) on seizures and cognitive function in mouse acute and chronic epilepsy models. Results We found that DBS in the MS alleviated the severity of seizure activities in both kainic acid‐induced acute seizure model and hippocampal‐kindled epilepsy model. DBS showed antiseizure effects with a wide window of effective stimulation frequencies. The antiseizure effects of DBS were mediated by the hippocampal theta rhythm, as atropine, which reversed the DBS‐induced augmentation of the hippocampal theta oscillation, abolished the antiseizure effects of DBS. Further, in the kainic acid‐induced chronic TLE model, DBS in the MS not only reduced spontaneous seizures, but also improved behavioral performance in novel object recognition. Conclusion DBS in the MS is a promising approach to attenuate TLE probably through entrainment of the hippocampal theta rhythm, which may be therapeutically significant for refractory TLE treatment.

The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies

“…This is suggested because optogenetic gamma stimulation of PV-positive neurons in the MS during memory retrieval rescued impaired spatial memory in an AD mouse model (J20-APP) (Etter et al, 2019). The MS theta-rhythm stimulation also improved novel object recognition and spatial learning in chronic epileptic models and a traumatic brain injury model in rodents (Lee et al, 2015(Lee et al, , 2017Wang et al, 2021). The theta oscillations in the septo-hippocampal axis can be induce by VNS as well as less invasive stimulation (Broncel et al, 2018).…”

“…The original idea that theta rhythm activities in the septo-hippocampal axis suppress or oppose epileptic seizures came from the fact that seizure occurrence is less during arousal and REM states ( Ng and Pavlova, 2013 ), when theta band activities dominate. Animal experiments demonstrated that theta rhythm stimulation of the MS increased seizure threshold (decreased seizure susceptibility) in rat and mouse models of TLE ( Izadi et al, 2019 ; Wang et al, 2021 ). Studies with optogenetic technology suggested that cholinergic tone in the HPC originated from the MS, which decreases during ictal periods, was crucial for the anti-seizure effects of the MS stimulation ( Wang et al, 2020b ; Takeuchi et al, 2021a ).…”

“…The MS stimulation has been shown to be effective in rodent models of TLE with and without obvious damages of HPC (chronic intrahippocampal kainite model, HPC electrical kindling model), which correspond to human epilepsy with and without sclerosis ( Wang et al, 2020b , 2021 ; Hristova et al, 2021 ; Takeuchi et al, 2021a ). In addition, the MS stimulation has been shown to improve cognitive alterations, which are often comorbid in epilepsy, in animal models of TLE ( Izadi et al, 2019 ; Wang et al, 2021 ).…”

The Medial Septum as a Potential Target for Treating Brain Disorders Associated with Oscillopathies

“…This is suggested because optogenetic gamma stimulation of PV-positive neurons in the MS during memory retrieval rescued impaired spatial memory in an AD mouse model (J20-APP) (Etter et al, 2019). The MS theta-rhythm stimulation also improved novel object recognition and spatial learning in chronic epileptic models and a traumatic brain injury model in rodents Wang et al, 2021). The theta oscillations in the septo-hippocampal axis can be induce by VNS as well as less invasive stimulation (Broncel et al, 2018).…”

“…The original idea that theta rhythm activities in the septo-hippocampal axis suppress or oppose epileptic seizures came from the fact that seizure occurrence is less during arousal and REM states (Ng and Pavlova, 2013), when theta band activities dominate. Animal experiments demonstrated that theta rhythm stimulation of the MS increased seizure threshold (decreased seizure susceptibility) in rat models of TLE (Izadi et al, 2019;Wang et al, 2021). Studies with optogenetic technology suggested that cholinergic tone in the HPC originated from the MS mediated the anti-seizure effects of the MS stimulation (Wang et al, 2020b;Takeuchi et al, 2021).…”