Identification of functional network nodes in temporal lobe epilepsy
Human Cognitive and Systems Neuroscience
Final Report Abstract
Mesial temporal lobe epilepsy (MTLE) is the most common form of drug-resistant epilepsy in adults. In MTLE, seizures typically originate in brain areas deep within the temporal lobe (e.g., the hippocampus or the amygdala). Surgical resection of the epileptic brain region is often the only way to control seizures. However, only about one-third of patients remain seizure-free after surgery, highlighting the urgent need for new therapeutic strategies. One alternative treatment option is deep brain stimulation (DBS). Despite clinical practice, little is known about the brain-wide effects and mechanisms of different DBS parameters. Especially in MTLE with hippocampal sclerosis (HS), there is a high variability in the DBS response rate. For the development of new therapies, it is crucial to understand seizure propagation patterns in epileptic networks and to investigate the effects of seizure-interfering protocols. Because MTLE patients have variable pathologies and there are limited opportunities for MRI monitoring, especially during seizures or DBS, studies in animal models are crucially needed. In this project, we used an MTLE mouse model that precisely reflects the human MTLE pathology and allows a comprehensive analysis of epileptic networks in combination with different neuronal activity modulation techniques. We investigated spontaneous and evoked seizure dynamics and seizureinterfering protocols in freely moving epileptic animals with intracranial EEG recordings and in anesthetized epileptic animals with functional MRI (fMRI). We studied seizure interference with optogenetic inhibition and low-frequency stimulation (LFS), translated our findings to electrical stimulation, and investigated brain-wide effects of different DBS parameters. Our main findings were: (1) While optogenetic inhibition of pyramidal cells in the contralateral hippocampus prevents the propagation of epileptic activity, optogenetic LFS (1 Hz) of entorhinal afferents in the sclerotic hippocampus prevents seizure generation. (2) This seizure suppression can also be achieved by electrical LFS in the hippocampus, which is effective for several weeks without desensitization. (3) While there was no change in the brain-wide activation pattern with increasing stimulation amplitudes, the stimulation frequency had a strong influence, with low frequencies inducing a local response and high frequencies causing a brain-wide spread of activation. (4) 10 min LFS reduced hippocampal excitability. These preclinical studies provided new insights into DBS mechanisms in particular about seizure dynamics and stimulation protocols in experimental epilepsy.
Publications
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Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy. eLife, 9.
Paschen, Enya; Elgueta, Claudio; Heining, Katharina; Vieira, Diego M.; Kleis, Piret; Orcinha, Catarina; Häussler, Ute; Bartos, Marlene; Egert, Ulrich; Janz, Philipp & Haas, Carola A.
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LFP datasets: Open Science Framework
Paschen et al.
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Preclinical MRI in Neurological Diseases - Development of MRI Methods for Non-Invasive Investigation of Experimental Epilepsy. Dissertation.
Schwaderlapp N.
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Python scripts: eLife
Paschen et al.
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fMRI comparison of optogenetic and electrical stimulation in the mouse hippocampus. 23rd Annual Meeting of the German Section of the ISMRM. Zurich, Switzerland.
Molochidis N.; Paschen E.; Haas C. & Schwaderlapp N.
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Hippocampal low-frequency stimulation and its effect on spatial memory in a mouse model of mesial temporal lobe epilepsy. 50th Annual Meeting of the Society for Neuroscience, Chicago, United States
Paschen E.; Kleis P.; Link J.; Vieira D. M.; Heining K.; Janz P.; Egert U.; Häussler U. & Haas C. A.
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Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy. 14th Göttingen Meeting of the German Neuroscience Society, Göttingen, Germany
Paschen E.; Kleis P.; Link J.; Vieira D. M.; Heining K.; Janz P.; Egert U.; Häussler U. & Haas C. A.
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Hippocampal low-frequency stimulation and its effect on spatial memory in a mouse model of mesial temporal lobe epilepsy. 22nd International Winter Neuroscience Conference (IWNC), Sölden, Austria
Paschen E.; Kleis P.; Link J.; Vieira D. M.; Heining K.; Janz P.; Egert U.; Häussler U. & Haas C. A.
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Hippocampal low-frequency stimulation and its effects on learning and memory in a mouse model of epilepsy. 51st Annual Meeting of the Society for Neuroscience, San Diego, United States
Paschen E.; Kleis P.; Link J.; Häussler U. & Haas C. A.
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LFP datasets and Python scripts: G-Node
Kleis et al.
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Long-term in vivo application of a potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus. BMC Biology, 20(1).
Kleis, P.; Paschen, E.; Häussler, U.; Bernal, Sierra Y. A. & Haas, C. A.
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Physiological and Behavioral Implications of Neuromodulation in Experimental Epilepsy. Dissertation. Faculty of Biology, University of Freiburg.
Paschen, E.
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Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI. Cold Spring Harbor Laboratory.
Schwaderlapp, Niels; Paschen, Enya; LeVan, Pierre; von Elverfeldt, Dominik & Haas, Carola
