Deep brain stimulation for seizure suppression in experimental epilepsy

• Applicant: Professorin Dr. Carola A. Haas
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511199316

Mesial temporal lobe epilepsy (MTLE) is the most frequent form of drug-resistant epilepsy in adults, in which seizures typically originate from temporal lobe structures such as the hippocampus or entorhinal cortex. Surgical resection of the epileptic focus currently represents the only curative approach for pharmacoresistant patients. However, in cases with multiple seizure foci or high risk for resection-related complications, surgery is impossible, demonstrating an urgent need for new therapeutic avenues. One promising approach to alleviate intractable seizures is deep brain stimulation (DBS) at high frequencies (100-200 Hz). Commonly, high-frequency stimulation (HFS) is applied either continuously, discontinuously, or on-demand. However, HFS has low seizure-suppressive efficacy in MTLE patients with hippocampal sclerosis (HS), presumably due to extensive neuronal loss and glial scarring. Low-frequency stimulation (LFS) represents an alternative approach, which was applied in small cohort studies including pharmacoresistant patients with HS.In the proposed project, we build on our previous preclinical findings that identified 1 Hz LFS of entorhinal afferents as a promising approach for seizure suppression. Therefore, our aim is to optimize target structures and stimulation parameters for DBS and assess potential cognitive side effects. To this end, we will use an established mouse model for MTLE with HS, which closely reflects the human pathology. Firstly, we will apply optogenetic tools to identify the most suitable neuronal population for seizure-suppressive LFS in the entorhinal-hippocampal circuit. In a second step, we will translate our findings to electrical stimulation. We will compare the three commonly used HFS configurations (continuous, discontinuous, and on-demand) to LFS with the final aim to establish long-lasting seizure control. Finally, we will determine the influence of LFS on cognitive performance with standardized behavioral tests for mobility and anxiety, as well as learning and memory. Taken together, our project will largely extend the current knowledge regarding DBS for the treatment of intractable epilepsy and therefore, could introduce LFS as a promising approach for seizure control in MTLE.

• DFG Programme: Research Grants