Efficacy of a new charge-balanced biphasic electrical stimulus in the isolated sciatic nerve and the hippocampal slice

Most deep brain stimulators apply rectangular monophasic voltage pulses. By modifying the stimulus shape, it is possible to optimize stimulus efficacy and find the best compromise between clinical effect, minimal side effects and power consumption of the stimulus generator. In this study, we compared the efficacy of three types of charge-balanced biphasic pulses (CBBPs, nominal duration 100 μs) in isolated sciatic nerves and in in vitro hippocampal brain slices of the rat. Using these two models, we tested the efficacy of several stimulus shapes exclusively on axons (in the sciatic nerve) and compared the effect with that of stimuli in the more complex neuronal network of the hippocampal slice by considering the stimulus-response relation. We showed that (i) adding an interphase gap (IPG, range 100-500 μs) to the CBBP enhances stimulus efficacy in the rat sciatic nerve and (ii) that this type of stimuli (CBBP with IPG) is also more effective in hippocampal slices. This benefit was similar for both models of voltage and current stimulation. In our two models, asymmetric CBBPs were less beneficial. Therefore, CBBPs with IPG appear to be well suited for application to DBS, since they enhance efficacy, extend battery life and potentially reduce harmful side effects

Stimulation cérébrale profonde : développement d'un prototype pour étude chez le petit animal

La stimulation cérébrale profonde (SCP) est une procédure chirurgicale utilisée dans le traitement de divers contextes pathologiques. Ce système, composé d’électrodes implantées dans une région cible du cerveau et d’un neurostimulateur reliés par un fil, permet de délivrer un courant électrique dans une région voulue du cerveau. À ce jour, les mécanismes d’action de la SCP et les effets cellulaires qu’elle engendre demeurent mal connus. Cette problématique découle du fait qu’il existe peu de prototypes de micro-stimulation dans le domaine de la recherche, sans compter que ceux-ci ne répondent pas bien aux critères de cette recherche. Mes travaux de maîtrise visaient donc à développer un système de microstimulation pouvant être utilisé chez la souris et de développer et valider toutes les techniques nécessaires à l’implantation de ce système chez la souris. Au terme de ces travaux, nous avons développé un système de micro-stimulation : 1) utilisable chez la souris 2) pour des protocoles de stimulation chronique de longue durée (jusqu’à 1 mois), 3) possédant des paramètres électriques, semblables à ceux utilisés chez l’humain en clinique, 4) pouvant être ajustés à différents contextes pathologiques. Nous avons aussi développé toutes les techniques nécessaires à son implantation chez la souris. Cet outil novateur permettra d’approfondir notre connaissance des mécanismes d’action et des mécanismes cellulaires sous-jacents aux effets de la SCP et pourra mener, à long terme, à l’identification de nouvelles cibles thérapeutiques.Deep brain stimulation (DBS) is a surgical procedure used in the treatment of various pathologies. This system, composed of electrodes implanted in a target area in the brain and of a neurostimulator connected by a wire, allows the delivery of an electrical current in a specific area in the brain. To this day, mechanisms of action and cellular effects resulting from DBS remain poorly understood because of a lack of micro-stimulation tools available in the domain and by the fact that these tools do not properly address requirements of this research. To address this challenge, the objectives of my master’s research were to develop a micro-stimulation system usable in mice and to develop and validate required techniques to make this system work in small-sized rodents. Through this study, we have developed a micro-stimulation system that is : 1) usable in mice, 2) able to sustain a long term chronic stimulation (up to 1 month), 3) similar to those used in human in terms of electrical parameters and 4) offering the possibility of adjusting those parameters to various pathological contexts. We also developed the required techniques for its use in mice. This novel tool will allow to deepen our knowledge on the mechanisms of action and cellular mechanisms underlying DBS effects and possibly lead to the identification of new therapeutic targets

Optimal strategies for electrical stimulation with implantable neuromodulation devices

Electrical stimulation (ES) is a neuromodulation technique that uses electrical pulses to modulate the activity of excitable cells to provide a therapeutic effect. Many past and present ES applications use rectangular current waveforms that have been well studied and are easy to generate. However, an extensive body of scientific literature describes different stimulation waveforms and their potential benefits. A key measure of stimulation performance is the amplitude required to reach a certain percentual threshold of activation, as it directly influences important ES parameters such as energy consumption per pulse and charge density. The research summarized in this thesis was conducted to re-examine some of the most-commonly suggested ES waveform variations in a rodent in-vivo nerve-muscle preparation. A key feature of our experimental model is the ability to test stimulation with both principal electrode configurations, monopolar and bipolar, under computer control and in randomized order. Among the rectangular stimulation waveforms, we investigated the effect of interphase gaps (IPGs), asymmetric charge balanced pulses, and subthreshold conditioning pre-pulses. For all these rectangular waveforms, we surprisingly observed opposite effects in the monopolar compared to the bipolar stimulation electrode configuration. The rationale for this consistent observation was identified by analyzing electroneurograms (ENGs) of the stimulated nerve. In the monopolar configuration, biphasic pulses first evoked compound action potentials (eCAPs) as a response to the first field transition. In the bipolar electrode configuration, that is the mode in which many contemporary ES devices, including the envisioned miniaturized electroceuticals, operate, eCAPs were first elicited at the return electrode in response to the middle field transition of biphasic pulses. As all rectangular waveform variations achieve their effect by modulating the amplitude and timing of cathodic (excitatory) and anodic (inhibitory) field transitions, the inverted current profile at the bipolar return electrode explains these observed opposite effects. Further we investigated the claimed benefits of non-rectangular, Gaussian stimulation waveforms in our animal model. In our study only moderate energy savings of up to 17% were observed, a finding that is surprising in light of the predicted range of benefits of up to 60% energy savings with this novel waveform in question. Additionally, we identified a major disadvantage in terms of substantially increased maximum instantaneous power requirements with Gaussian compared to rectangular stimuli. We examined physiological changes in fast twitch muscle following motor nerve injury, and optimal stimulation strategies for activation of denervated muscle. While a high frequency doublet has previously been identified to enhance stimulation efficiency of healthy fast twitch muscle, an effect that has been termed “doublet effect”, we here show that this benefit is gradually lost in muscle during denervation. Lastly, the effect of long duration stimulation pulses, that are required to activate denervated muscle, on nerve is examined. We show that these long pulses can activate nerves up to three times when the three field transition within the biphasic pulses are separated by more than (i.e., when the phase width is above) the refractory period of that nerve. This observation challenges state-of-the-art computational models of extracellular nerve stimulation that do not seem to predict such multiple activations. Further, an undesired up to threefold co-activation of innervated structures nearby the denervated stimulation target warrants further research to study whether these co-activations can be lessened with alternative stimulation waveforms such as ramped sawtooth pulses