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Experimental Epilepsy ResearchDepartment of Neurosurgery

Brain-wide effects of hippocampal low-frequency stimulation in experimental epilepsy

Figure 1: Electrical stimulation of the sclerotic hippocampus during fMRI in a MTLE mouse model. (A) Setup. (B) Cryo-coil compatible implantation. (C) Carbon electrode (d=~2 mm). (D) T2-weighted MRI (spin-echo RARE). (E) LFP recording during fMRI with three different 10 Hz-stimulation currents. 600µA induced an epileptic seizure.

Funded by the German Research Foundation (HA 1443/11-1) and the Center for Basics in Neuromodulation, Freiburg

Funding to Prof. Dr. Haas and Prof. Dr. Elverfeldt

Project Description

Mesial temporal lobe epilepsy (MTLE) is the most frequent form of drug-resistant epilepsy in adults. In MTLE, seizures typically originate from brain areas located deep within the temporal lobe (e.g. the hippocampus or the amygdala). Surgical resection of the epileptic brain areas often represents the only way to control seizures. However, only about one third of patients who have undergone curative surgery remain seizure-free, indicating that epileptic regions may extend far beyond the operated areas and demonstrating the urgent need for new therapeutic strategies. One alternative relies on deep brain stimulation (DBS) which has already been applied successfully in neurological disorders such as Parkinson’s disease or depression. In MTLE with hippocampal sclerosis (HS, characterized by neuronal cell loss and glial scarring), the stimulation of the sclerotic focus at low frequencies represents a promising approach. However, little is known about the effects of low-frequency stimulation (LFS) on a brain-wide scale. Based on previous results and in collaboration with Prof. Dr. D. von Elverfeldt and Dr. N. Schwaderlapp (Dept. of Radiology - Medical Physics) we will investigate the effects of 1 and 10 Hz stimulation on brain-wide activity using functional magnetic resonance imaging (fMRI, Figure 1A). For this purpose, we optimize the surgical implantation procedure to fit implanted mice into a mouse-specific cryo-coil (Figure 1B), build MRI compatible carbon electrodes (Figure 1C) that don’t introduce noise during the scan (Figure 1D), and stimulate the hippocampus at 10 Hz (Figure 1E). In the proposed project, we aim at identifying brain-wide networks critically involved in seizure spread, and thus, facilitate targeted therapeutic intervention Therefore, we will apply electrical stimulation in the sclerotic hippocampus of chronically epileptic mice during fMRI. First, we will stimulate at 10 Hz with a stepwise increase of the applied current until a seizure occurs (Figure 1E). Secondly, we will investigate the underlying functional networks during 1 Hz stimulation at a reasonable current that does not induce epileptiform activity. Thirdly, we will combine 1 Hz (20-30 min) with the previously identified pro-epileptic 10 Hz stimulation to identify potential differences in the activity dynamics. State-of-the-art analytical tools for fMRI data will enable us to describe the interactions between hyperactive brain areas, and to identify central network hubs on a whole-brain scale. We will also use LFP recordings in order to validate the electrical stimulation (Figure 1E). We expect that the difference to BOLD signals in control mice will be critical to identify epileptic networks promoting seizure spread specifically in the reorganized epileptic brain. This project will largely extend the current knowledge regarding DBS and network interactions in MTLE, and therefore, could bring new insights for novel therapeutic interventions.

In collaboration with Prof. Dr. Dominik von Elverfeldt and Dr. Niels Schwaderlapp (Dept. of Radiology, Medical Physics, Medical Center - University of Freiburg)