• Citer

Vagus nerve recording and stimulation in small animal epileptic model

par Chavez Cerda, Javier
Président du jury Delchambre, Alain
Promoteur Nonclercq, Antoine
Co-Promoteur Doguet, Pascal
Publication Non publié, 2025-03-13

Thèse de doctorat

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

Epilepsy is a chronic neurological disorder affecting approximately 70 million people worldwide, characterized by recurrent unprovoked seizures. This condition significantly impacts patients’ quality of life, often requiring lifestyle restrictions and leading to social stigma and discrimination. Unfortunately, 30% to 40% of epilepsy patients do not respond adequately to anti-epileptic drugs (AEDs), and surgical interventions are not always feasible for all cases. For these drug-resistant patients, neuromodulation techniques such as Vagus Nerve Stimulation (VNS) offer an alternative therapeutic approach. VNS has shown efficacy in reducing seizure frequency and duration, but conventional VNS operates in an open-loop mode, delivering stimulation at pre-set intervals without considering the patient’s physiological state or the occurrence of seizures, unlike a closed-loop VNS, which adapts stimulation based on real-time physiological signals. Considering this limitation, the central scientific question is: Can a closed-loop VNS enhance therapy by stimulating based on physiological variables and during seizures?This thesis investigates the development and evaluation of a closed-loop VNS system to enhance therapy by modulating stimulation based on respiration and enabling seizure detection through the vagus nerve electroneurogram (VENG). The work is structured along three complementary research axes: recording, stimulation, and analysis of vagus nerve activity in small animal epileptic models. First, regarding VENG recording, a microcuff electrode was designed and fabricated, providing a low-cost and accessible alternative to existing commercial solutions. The recorded signal in one rat confirmed the presence of respiratory and cardiac activity, supporting that the electrode’s neural recording corresponded to a VENG signal. Additionally, a chronic setup combining VENG, EEG, and video recording was developed to continuously monitor one epileptic rat over extended periods, successfully capturing spontaneous seizures.The second research line focused on breathing-synchronized VNS, where stimulation was triggered in real time by the respiratory cycle. This approach was validated in anesthetized rats, demonstrating a respiration detection sensitivity of 96.5±3.07% and a positive predictive value of 93.6±4.51%. In anesthetized epileptic rats, breathing-synchronized VNS (n=4) was compared to standard open-loop VNS (n=4) and sham stimulation (n=4). Both VNS paradigms significantly influenced autonomic parameters (heart rate and respiratory rate) and affected seizure susceptibility in induced-epileptic rats. Results show that standard and breathing-synchronized VNS significantly impact the autonomic system by modulating the heart and respiration rates, possibly causing hypoxia and hypotension, which are indirect factors that can increase seizure susceptibility.Finally, vagus nerve activity is known to be modulated by seizures and could be used as a physiological marker for seizure detection. The electrical activity of the vagus nerve before, during, and after seizures was compared in epileptic rats. Action potentials (AP) identified by template matching were sorted according to the fiber type they are deemed to originate from. During seizures, an increase in the percentage of occurrence of APs was observed for 2μm and 3μm fibers, while a decrease was observed for 4μm, 5μm-6μm, and 7μm-11μm fibers. The increase in smaller diameter sizes is believed to be linked to an increase in autonomic activity. These findings highlight the potential of vagus nerve activity as a physiological marker for seizure detection.Overall, this thesis contributes to understanding closed-loop VNS therapy, combining innovative physiological monitoring, adaptive stimulation, and neural signal analysis with the long-term goal of improving personalized treatment strategies for drug-resistant epilepsy.