Neurostimulation of the Rat Motor System

Ce document fait la synthèse d'un ensemble de travaux concernant la nature de la plasticité neuronale et la manière dont la neurostimulation peut être utilisée pour améliorer la récupération motrice après une atteinte neurologique. Nous commençons par les principes fondamentaux généraux des neurosciences, la structure du système nerveux moteur chez l'homme et le rat, ainsi qu'une brève discussion sur les lésions neurologiques. Les sujets sont vastes et couverts avec la brièveté nécessaire, mais ils fournissent un contexte essentiel pour les chapitres suivants, présentés sous forme d'articles scientifiques. Dans le premier article, nous passons en revue le domaine de la neurostimulation sous ses aspects fondamental et clinique avec l'Accident Vasculaire Cerebral (AVC) en tant que maladie modèle pour les lésions neurologiques. Nous classifions les interventions de stimulation en trois modèles différents d'induction de la plasticité. Notre thèse centrale est qu'une meilleure compréhension des règles sous-jacentes de la plasticité, accompagnée de progrès dans une plus grande précision spatio-temporelle, est nécessaire pour faire avancer le domaine de la neurostimulation. Dans le deuxième article, nous décrivons, étape par étape, un nouveau protocole pour évaluer l'excitabilité corticospinale chez le rongeur éveillé pendant le comportement libre, ainsi que les plateformes matérielles et logicielles associées que notre équipe a développées à cette fin. L'une de ses principale caractéristique est la possibilité d'évaluer l'excitabilité corticomotrice en boucle fermée, en fonction de l'EMG, une nouvelle façon d'accroître l'uniformité des mesures sur des animaux en comportement. Cette plateforme de développement sera utile aux neuroscientifiques intéressés par l'évaluation de l'excitabilité du système nerveux chez les rongeurs éveillés par le biais d'une interrogation électrique ou optogénétique, un intermédiaire important avant les essais chez les primates non humains et éventuellement chez les humains. Dans le troisième article, nous avons utilisé cette plateforme prototype pour étudier la stimulation électrique associative appariée et le rôle de la plasticité dépendant de la synchronisation des potentiels d'action chez des rats implantés de façon chronique, sans l'influence de l'anesthésie. Nous nous sommes concentrés sur la variation systématique de l'intervalle entre la stimulation corticale et musculaire dans notre cohorte d'animaux afin de révéler l'effet de la synchronisation relative de l'activité aux niveaux cortical et spinal. Nous n'avons pas observé de potentialisation significative dans tous les intervalles de stimulation testés, mais plutôt des tendances vers des effets de type LTD dans la plupart des conditions de synchronisation. Nous discutons des raisons possibles pour lesquelles nous avons observé ces résultats. Dans le dernier article et dans le projet en cours, nous décrivons les premiers travaux prometteurs impliquant la neurostimulation optogénétique et électrique, ainsi que la réadaptation post-AVC comme tremplin pour des recherches futures. Nous concluons par une discussion générale et nous nous projetons dans l'avenir, tant à moyen qu'à long terme. La poursuite scientifique, tant sur le plan personnel que sur celui du domaine, se poursuivra, comme il se doit. Bien que ce travail soit conçu pour être lu dans un ordre séquentiel, chaque chapitre est indépendant. Collectivement, les travaux de cette thèse posent les bases et plaident en faveur d'une meilleure compréhension de la plasticité neuronale, du développement d'outils pour l'évaluer et de l'étude de ses applications pratiques pour parvenir à une meilleure récupération motrice après une lésion neurologique.This document synthesizes a body of work concerning the nature of neural plasticity and how neurostimulation may be used to improve motor recovery after neurological insult. We begin with general foundational principles in neuroscience, the structure of the nervous and motor systems in humans and rats, and a brief discussion of neurological injury. The topics are broad and covered with the necessary brevity, but provides critical context for the following chapters. In the first paper, we review the fields of neurostimulation across the clinical and basic science domains in the service of stroke as a model disease for neurological injury, framing the field in terms of three different models of plasticity induction. Our central thesis here is that enhanced understanding of the underlying rules of plasticity, accompanied with advances in greater spatiotemporal precision is necessary to move the field of neurostimulation forward. In the second paper we describe a stable, novel step-by-step protocol to assess corticospinal excitability in the awake, freely behaving rodent, and the associated hardware and software platforms that our team has developed for this purpose. A core feature enables corticomotor excitability assessment in a closed-loop, Electromyogram (EMG)-dependent manner, a novel way of increasing consistency during free behavior in untrained animals. This development platform will be of use to neuroscientists interested in assessing the excitability of the nervous system in awake, unrestrained rodents via electrical or optogenetic interrogation, an important intermediary before trials in non-human primates and eventually humans. In the third paper, we used this prototype platform to investigate electrical paired associative stimulation and the role of spike-timing-dependent plasticity in chronically implanted rats, without the influence of anaesthesia. Our focus was on systematically varying the Inter-Stimulus Interval (ISI) between cortical and muscle stimulation in our animal cohort in order to reveal the effect of relative activity timing at both the cortical and spinal levels. We did not observe significant potentiation across all of the stimulus intervals we tested, but instead observed trends towards Long-Term Depression (LTD)-like effects in the short term across most timing conditions. We discuss possible reasons why we observed these results. In the final paper and project currently in progress, we describe early promising work involving optogenetic and electrical neurostimulation, and stroke recovery as a launchpad for future investigations. We conclude with a general discussion and peer into the future, both in the medium term and the long term. The scientific pursuit, both personally and as a field will continue, as it should. Although this work is designed to be read in sequential order, each chapter stands alone. Collectively, the work in this thesis lays the groundwork and argues for a greater understanding of neural plasticity, development of tools to assess it, and study of its practical applications to achieve enhanced motor recovery after neurological injury

Antisaccadic Eye Movements as a Correlate for Response Inhibition and White Matter Integrity in Mild Traumatic Brain Injury

Antisaccades are thought to involve higher level inputs from neural centers involved in rapid eye movement inhibition and control. Previous work has demonstrated that performance on the antisaccade task can help in assessment of injury in acute and/or chronic Mild Traumatic Brain Injury (mTBI). We validated antisaccade performance in mTBI assessment against gold standard assessments of symptom burden, diffusion tensor imaging, and a neuropsychological test of response inhibition. Significant deficits in antisaccade median latency and prosaccade mean duration were found between patient groups and controls, despite overall integrity of the pupillary light reflex; the former was correlated with loss of white matter integrity in the splenium of the corpus callosum in acute mTBI. Furthermore, antisaccade median latency was also associated with poor performance on executive functioning tasks, and greater symptom burden in the acute patients. This research suggests that the antisaccade task is useful as a neurological marker for mTBI.M.Sc.2017-12-21 00:00:0

Characteristics of the King-Devick test in the assessment of concussed patients in the subacute and later stages after injury.

Although the King-Devick (K-D) test has been used frequently in assessing sports related concussion early after injury, its characteristics over time after injury and in patients with prolonged persistent symptoms are unknown. The purpose of this paper was to: evaluate the ability of the K-D Test to distinguish patients seen early after concussion from those with symptoms persisting more than 3 months compared to controls, assess changes in the K-D test times over time after concussion, and determine the relationship of K-D times to the Stroop Color and Word Test scores. We performed cross-sectional comparisons of patients with recent concussive brain injury (acute group) and those with symptoms persisting more than 3 months to healthy controls on the K-D test, the Sports Concussion Assessment Tool 3 (SCAT3), and the Stroop Color and Word Test. Longitudinal comparisons of the acute group over time within the first month after injury were also made. Post-concussive syndrome (PCS) patients had significantly higher K-D times compared to controls (p = 0.01), while the acute group did not differ from controls(p = 0.33). K-D times at the second visit for the acute group were similar to those of controls (54.7 vs. 49.6, p = 0.31). While SCAT3 scores improved over time in the acute group, the K-D scores did not change between the first and second visit (55.2 vs. 54.7, p = 0.94). K-D scores correlated significantly with the Stroop scores for all three participant groups. The K-D test is likely useful very early after concussion in conjunction with baseline scores, and while scores in PCS patients remain elevated, they can be confounded by factors such as pre-morbid depression and medication use. High correlations with Stroop scores also suggest that performance on the K-D test can by proxy provide additional insight about cognitive function and predict performance on more cognitively demanding tasks

Relationship between K-D scores and number of days between injury and test visit in the acute group.

<p>Relationship between K-D scores and number of days between injury and test visit in the acute group.</p

Summary of test scores by group and by visit.

<p>Summary of test scores by group and by visit.</p

Average K-D score for each time interval after injury in the acute group.

<p>Abbreviations: SD, standard deviation. Symbols: > =, greater than or equal to.</p

Correlations of K-D test scores with other assessment scores.

<p>Correlations of K-D test scores with other assessment scores.</p

Basic demographic characteristics of acute mTBI, PCS, and control participant groups.

<p>Basic demographic characteristics of acute mTBI, PCS, and control participant groups.</p