<p>The spinal cord is an information highway continuously transmitting afferent and efferent signals to and from the brain. Although spinal cord stimulation has been used for the treatment of chronic pain for decades, its potential has not been fully explored. Spinal cord stimulation has never been used with the aim to transmit relevant information to the brain. Although, various locations along the sensory pathway have been explored for generating electrical stimulation induced sensory percepts, right from peripheral nerves, to thalamus to primary somatosensory cortex, the role of spinal cord has been largely neglected. In this dissertation, I have attempted to investigate if, electrical stimulation of dorsal columns of spinal cord called as Dorsal Column Stimulation (DCS) can be used as an effective technique to communicate therapeutic and somatosensory information to the brain. </p><p>To study the long term effects of DCS, I employed the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson’s Disease (PD). Twice a week DCS for 30 minutes resulted in a dramatic recovery of weight and behavioral symptoms in rats treated with striatal infusions of 6-OHDA. The improvement in motor symptoms was accompanied by higher dopaminergic innervation in the striatum and increased cell count of dopaminergic neurons in the substantia nigra pars compacta (SNc). These results suggest that DCS has a chronic therapeutic and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients. Thus, I was able to demonstrate the long-term efficacy of DCS, as a technique for therapeutic intervention.</p><p>Subsequently, I investigated if DCS can be used as a technique to transmit artificial somatosensory information to the cortex and trained rats to discriminate multiple artificial tactile sensations. Rats were able to successfully differentiate 4 different tactile percepts generated by varying temporal patterns of DCS. As the rats learnt the task, significant changes in the encoding of this artificial information were observed in multiple brain areas. Finally, I created a Brainet that interconnected two rats: an encoder and a decoder, whereby, cortical signals from the encoder rat were processed by a neural decoder while it performed a tactile discrimination task and transmitted to the spinal cord of the decoder using DCS. My study demonstrated for the first time, a cortico-spinal communication between different organisms. </p><p>My obtained results suggest that DCS, a semi-invasive technique, can be used in the future to send prosthetic somatosensory information to the brain or to enable a healthy brain to directly modulate neural activity in the nervous system of a patient, facilitating plasticity mechanism needed for efficient recovery.</p> / Dissertation

Multielectrode arrays may have several advantages compared to the traditional single macroelectrode brain electrical stimulation technique including less tissue damage due to implantation and the ability to deliver several spatio-temporal patterns of stimulation. Prior work on cell cultures has shown that multielectrode arrays are capable of completely stopping seizure-like spontaneous bursting events through a distributed asynchronous multi-site approach. In my studies, I used a similar approach for controlling seizures in a rat model of temporal lobe epilepsy. First, I developed a new method of electroplating in vivo microelectrode arrays for durably improving their impedance. I showed that microelectrode arrays electroplated through the new technique called sonicoplating, required the least amount of voltage in current controlled stimulation studies and also produced the least amplitude and duration of stimulation artifact compared to unplated, DC electroplated or pulse-plated microelectrodes. Second, using c-fos immunohistochemistry, I showed that 16-electrode sonicoplated microelectrode arrays can activate 5.9 times more neurons in the dorsal hippocampus compared to a single macroelectrodes while causing < 77% the tissue damage. Next, through open-loop multisite asynchronous microstimulation, I reduced seizure frequency by ~50% in the rodent model of temporal lobe epilepsy. Preliminary studies aimed at using the same stimulation protocol in closed-loop responsive and predictive seizure control did not stop seizures. Finally, through an internship at Medtronic Neuromodulation, I worked on developing and implementing a rapid algorithm prototyping research tool for closed-loop human deep brain stimulation applications.

La bioélectronique est un domaine interdisciplinaire qui étudie les interconnexions et les interactions entre entités biologiques (cellules, tissus, organes) et systèmes électroniques,par l’intermédiaire du transducteur adéquat. Pour des cellules ou des tissus excitables (neurones, muscles, ...), le transducteur prend la forme d’une simple électrode, car ces tissus produisent une activité électrique spontanée ou, dans le sens inverse, peuvent être excités par un signal électrique externe. Cette communication bidirectionnelle donne lieu à deux schémas expérimentaux : l’acquisition et la stimulation. L’acquisition consiste à enregistrer, traiter et analyser les bio-signaux alors que la stimulation consiste à appliquer le courant électrique adéquat aux tissus vivants, pour déclencher une réaction. Cette thèse se concentre sur ce dernier point : deux générations de système de stimulation ont été développées, chacune basée sur un circuit intégré spécifique et adaptée à différents contextes applicatifs.Tout d’abord, le cadre scientifique a été celui du projet CENAVEX, axé sur la stimulation électrique fonctionnelle pour réhabiliter la fonction respiratoire, suite à une lésion de la moelle épinière. Ensuite, les objectifs de conception ont été étendus pour couvrir de nouveaux besoins d’application : la surveillance de l’impédance électrique in situ et l’exploration des formes d’onde de stimulation originales. Le premier pourrait être une solution pour suivre la réaction tissulaire après l’implantation d’une électrode, contribuant ainsi à la biocompatibilité à long terme des implants ; le second propose d’aller au-delà dela conventionnelle impulsion biphasique carrée et d’explorer de nouvelles formes d’ondes qui pourraient être plus efficaces en termes de consommation d’énergie, pour un effet physiologique donné.Le travail présenté dans ce manuscrit contribue à la conception, à la fabrication et au test de dispositifs de stimulation innovants. Cela a conduit au développement de deux circuits intégrés et de deux dispositifs de stimulation permettant une stimulation multicanal.Les caractérisations électriques et les validations biologiques, de la faisabilité in vitro aux expériences in vivo, ont été menées et sont décrites dans ce manuscrit. / Bioelectronics is a cross-disciplinary field that studies interconnections and interactions between biological entities (cells, tissues, organs) and electronic systems, using the adequate transducer. For excitable cells or tissues (neurons, muscles, . . . ), the transducer takes the form of a simple electrode, as these tissues produce a spontaneous electrical activity or,in the opposite way, may be excited by an external electrical signal. This bi-directional communication gives rise to two experimental schemes: acquisition and stimulation. Acquisition consists in recording, processing and analyzing bio-signals whereas stimulation consists in applying the adequate electrical current to living tissues in order to trigger a reaction. This thesis focuses on the latter: two generations of stimulation systems have been developed, both being centered on an Application Specific Integrated Circuit, and adapted to different application contexts. First, the scientific framework was given by the CENAVEX project, focusing on Functional Electrical Stimulation to rehabilitate the respiratory function, following a Spinal Cord Injury. Then, the design objectives were extended to cover new application needs:in situ electrical impedance monitoring and exploration of original stimulation wave forms.The first one could be a solution to follow the tissue reaction after electrode implantation,hence contributing to long-term biocompatibility of implants; the second one proposes to go further the conventional constant biphasic pulse and explore new wave forms that couldbe most efficient in terms of energy consumption, for a given physiological effect.The work presented in this manuscript is a contribution to the design, fabrication and test of innovative stimulation devices. It leaded to the development of two integrated circuits and two stimulation devices permitting multichannel stimulation. Both electrical characterizations and biological validations, from in vitro feasibility to in vivo experiments, have been conducted and are described in this manuscript.