Fatigue Resistibility and Stimulus Strength Using Intraspinal Microstimulation vs. Intramuscular Stimulation in a Rat Model: Case Study

Spinal Cord Injury is a devastating injury that has drastic effects on an individual’s daily living activities. The current devices and methods of direct muscle, peripheral nerve cuff, and epidural stimulation are bulky, easily fatigable, require large stimulation parameters, and/ or difficult to use. Intraspinal Micro stimulation (ISMS) suggests a more fatigue resistant method at lower stimulation parameters that will help restore locomotion, bladder control, and sexual function in an individual. The research conducted herein shows ISMS evokes a linear positive relationship between stimulus strength and muscle contraction force that is comparable to clinically used methods of Intramuscular stimulation. Research has also shown that fatigue resistance appears to be similar in the two stimulation parameters. The study concludes that ISMS compares to clinically used methods and therefore suggests potential of this method to help Spinal Cord Injury victims to help aid in activities of daily living

Inducing Neural Plasticity After Spinal Cord Injury To Recover Impaired Voluntary Movement

Spinal cord injury (SCI) is often an incapacitating neural injury most commonly caused by a traumatic blow to the spine. A SCI causes damage to the axons that carry sensory and motor signals between the brain and spinal cord, and in turn, the rest of the body. Depending on the severity and location of a SCI, many corticospinal axons and other descending motor pathways can remain intact. Moderate spontaneous functional recovery occurs in patients and animal models following incomplete SCI. This recovery is linked to changes occurring via the remaining pathways and throughout the entire nervous system, which is generally referred to as neuronal plasticity. It has been shown that plasticity can be induced via electrical stimulation of the brain and spinal cord targeting specific descending pathways, which can further improve impaired motor function. Most importantly, it has been shown that activity dependent stimulation (ADS), which is based on mechanisms of spike timing-dependent plasticity, can strengthen remaining pathways and promote functional recovery in various preclinical injury models of the central nervous system. The purpose of this dissertation was to determine if precisely-timed stimulation of the spinal cord triggered by the firing of neurons in the hindlimb motor cortex would result in potentiation of corticospinal connections as well as enhance hindlimb motor recovery after spinal cord contusion. In order to achieve this, we needed to determine the optimal neurophysiological conditions which would allow activity dependent stimulation (ADS) to facilitate enhanced communication between the cerebral cortex and spinal cord motor neurons. Thus, this dissertation project investigated three specific aims. The first study determined the effects of a contusive spinal cord injury on spinal motor neuron activity, corticospinal coupling, and conduction time in rats. It was discovered that spinal cord responses could still be evoked after spinal cord contusion, most likely via the cortico-reticulo-spinal pathway. The second study determined the optimal spike-stimulus delay for increasing synaptic efficacy in descending motor pathways using an ADS paradigm in an acute, anesthetized rat model of SCI. It was discovered that bouts of ADS conditioning can increase synaptic efficacy in intact descending motor pathways, as measured by cortically evoked activity in the spinal cord, after SCI. The third study determined whether spike-triggered intraspinal microstimulation (ISMS), using optimized spike-stimulus delays, results in improved motor performance in an ambulatory rat model of SCI. It was determined that ADS therapy can enhance the behavioral recovery of locomotor function after spinal cord injury. The results from this study indicate that activity-dependent stimulation is an effective treatment for behavioral recovery following a moderate spinal cord contusion in the rodent. The implications of these results have the potential to lead to a novel treatment for a variety of neurological disease and disorders

Interactions Between Baclofen and DC-induced Plasticity of Afferent Fibers within the Spinal Cord

The aims of the study were to compare effects of baclofen, a GABA B receptor agonist commonly used as an antispastic drug, on direct current (DC) evoked long-lasting changes in the excitability of afferent fibers traversing the dorsal columns and their terminal branches in the spinal cord, and to examine whether baclofen interferes with the development and expression of these changes. The experiments were performed on deeply anesthetized rats by analyzing the effects of DC before, during and following baclofen administration. Muscle and skin afferent fibers within the dorsal columns were stimulated epidurally and changes in their excitability were investigated following epidural polarization by 1.0\u20131.1 \u3bcA subsequent to i.v. administration of baclofen. Epidural polarization increased the excitability of these fibers during post-polarization periods of at least 1 h. The facilitation was as potent as in preparations that were not pretreated with baclofen, indicating that the advantages of combining epidural polarization with epidural stimulation would not be endangered by pharmacological antispastic treatment with baclofen. In contrast, baclofen-reduced effects of intraspinal stimulation combined with intraspinal polarization (0.3 \u3bcA) of terminal axonal branches of the afferents within the dorsal horn or in motor nuclei, whether administered ionophoretically or intravenously. Effects of DC on monosynaptically evoked synaptic actions of these fibers (extracellular field potentials) were likewise reduced by baclofen. The study thus provides further evidence for differential effects of DC on afferent fibers in the dorsal columns and the preterminal branches of these fibers and their involvement in spinal plasticity

The role of functional neuroanatomy of the lumbar spinal cord in effect of epidural stimulation

© 2017 Cuellar, Mendez, Islam, Calvert, Grahn, Knudsen, Pham, Lee and Lavrov. In this study, the neuroanatomy of the swine lumbar spinal cord, particularly the spatial orientation of dorsal roots was correlated to the anatomical landmarks of the lumbar spine and to the magnitude of motor evoked potentials during epidural electrical stimulation (EES). We found that the proximity of the stimulating electrode to the dorsal roots entry zone across spinal segments was a critical factor to evoke higher peak-topeak motor responses. Positioning the electrode close to the dorsal roots produced a significantly higher impact on motor evoked responses than rostro-caudal shift of electrode from segment to segment. Based on anatomical measurements of the lumbar spine and spinal cord, significant differences were found between L1-L4 to L5-L6 segments in terms of spinal cord gross anatomy, dorsal roots and spine landmarks. Linear regression analysis between intersegmental landmarks was performed and L2 intervertebral spinous process length was selected as the anatomical reference in order to correlate vertebral landmarks and the spinal cord structures. These findings present for the first time, the influence of spinal cord anatomy on the effects of epidural stimulation and the role of specific orientation of electrodes on the dorsal surface of the dura mater in relation to the dorsal roots. These results are critical to consider as spinal cord neuromodulation strategies continue to evolve and novel spinal interfaces translate into clinical practice

Cortical control of intraspinal microstimulation to restore motor function after paralysis

Phd ThesisSpinal cord injury (SCI) is a devastating condition affecting the quality of life of many otherwise healthy patients. To date, no cure or therapy is known to restore functional movements of the arm and hand, and despite considerable effort, stem cell based therapies have not been proven effective. As an alternative, nerves or muscles below the injury could be stimulated electrically. While there have been successful demonstrations of restoration of functional movement using muscle stimulation both in humans and non-human primates, intraspinal microstimulation (ISMS) could bear benets over peripheral stimulation. An extensive body of research on spinal stimulation has been accumulated – however, almost exclusively in non-primate species. Importantly, the primate motor system has evolved to be quite different from the frog’s or the cat’s – two commonly studied species –, reecting and enabling changes in how primates use their hands. Because of these functional and anatomical differences, it is fair to assume that also spinal cord stimulation will have different effects in primates. is question – what are the movements elicited by ISMS in the macaque – will be addressed in chapters and . Chronic intraspinal electrode implants so far have been difficult to realise. In chapter we describe a novel use of oating microelectrode arrays (FMAs) as chronic implants in the spinal cord. Compared to implanted microwires or other arrays, these FMAs have the benet of a high electrode density combined with different lengths of electrodes. We were able to maintain these arrays in the cord for months and could elicit movements at low thresholds throughout. If we could build a neural prosthesis stimulating the spinal cord, how would it be controlled? Remarkable progress has been recently achieved in the eld of brain-machine interfaces (BMIs), for example enabling patients to control robotic arms with neural signals recorded from chronically implanted electrodes. Chapter of this thesis examines an approach that combines ISMS with cortical control in a macaque model for upper limb paralysis for the rst time and shows that there is a behavioural improvement. We have devised an experiment in which a monkey trained to perform a grasp-and-pull task receives a temporary cortically induced paralysis of the hand reducing task performance. At the same time, cortical recordings from a different area allow us to control ISMS at sites evoking hand movements – thus partially restoring function. Finally, in appendix A we describe a system we developed in order to introduce automated positive reinforcement training (aPRT) both at the breeding facility and in our animal houses. is system potentially reduces time spent on training animals, adds enrichment to the monkeys’ home environment, and allows for suitability screening of monkeys for behavioural neuroscience experiments

Forelimb force direction and magnitude independently controlled by spinal modules in the macaque

腕の自由自在な動きをつくりだす多機能な神経細胞群の発見 --運動の方向と大きさを同時にコントロールする神経メカニズムの解明--. 京都大学プレスリリース. 2020-10-14.Primates aren't quite frogs. 京都大学プレスリリース. 2020-10-19.Modular organization of the spinal motor system is thought to reduce the cognitive complexity of simultaneously controlling the large number of muscles and joints in the human body. Although modular organization has been confirmed in the hindlimb control system of several animal species, it has yet to be established in the forelimb motor system or in primates. Expanding upon experiments originally performed in the frog lumbar spinal cord, we examined whether costimulation of two sites in the macaque monkey cervical spinal cord results in motor activity that is a simple linear sum of the responses evoked by stimulating each site individually. Similar to previous observations in the frog and rodent hindlimb, our analysis revealed that in most cases (77% of all pairs) the directions of the force fields elicited by costimulation were highly similar to those predicted by the simple linear sum of those elicited by stimulating each site individually. A comparable simple summation of electromyography (EMG) output, especially in the proximal muscles, suggested that this linear summation of force field direction was produced by a spinal neural mechanism whereby the forelimb motor output recruited by costimulation was also summed linearly. We further found that the force field magnitudes exhibited supralinear (amplified) summation, which was also observed in the EMG output of distal forelimb muscles, implying a novel feature of primate forelimb control. Overall, our observations support the idea that complex movements in the primate forelimb control system are made possible by flexibly combined spinal motor modules

Ventral root or dorsal root ganglion microstimulation to evoke hindlimb motor responses

Functional electrical stimulation is an important therapeutic tool for improving the quality of life of patients following spinal cord injury. Investigators have developed neural interfaces of varying invasiveness and implant location to stimulate neurons and evoke motor responses. Here we present an alternative interface with the ventral roots (VR) or dorsal root ganglia (DRG). We designed preliminary electrophysiology experiments to evaluate the performance of these interfaces, wherein we stimulated lumbar VR or DRG through a penetrating single-wire microelectrode while recording fixed endpoint force and bipolar electromyograms of hindlimb muscles. Data from rat experiments provided evidence for selectivity for target muscles, graded force recruitment, and nontrivial force magnitudes of up to 1 N. Electrophysiology experiments in cats produced similar results to those in rats. In addition, we developed a computational model to estimate the size and quantity of fibers recruited as a function of stimulus amplitude. This model confirmed electrophysiology results showing differences in the thresholds to detect activity in response to VR versus DRG stimulation. The model also provided insights into the mechanisms by which DRG stimulation is more likely to recruit smaller fibers than larger fibers. Finally, we discuss further work to develop and evaluate these potential interfaces

Stimulation électrique de la moelle épinière lombaire pour déclencher la marche chez le chat spinal

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

The Role of Functional Neuroanatomy of the Lumbar Spinal Cord in Effect of Epidural Stimulation

In this study, the neuroanatomy of the swine lumbar spinal cord, particularly the spatial orientation of dorsal roots was correlated to the anatomical landmarks of the lumbar spine and to the magnitude of motor evoked potentials during epidural electrical stimulation (EES). We found that the proximity of the stimulating electrode to the dorsal roots entry zone across spinal segments was a critical factor to evoke higher peak-to-peak motor responses. Positioning the electrode close to the dorsal roots produced a significantly higher impact on motor evoked responses than rostro-caudal shift of electrode from segment to segment. Based on anatomical measurements of the lumbar spine and spinal cord, significant differences were found between L1-L4 to L5-L6 segments in terms of spinal cord gross anatomy, dorsal roots and spine landmarks. Linear regression analysis between intersegmental landmarks was performed and L2 intervertebral spinous process length was selected as the anatomical reference in order to correlate vertebral landmarks and the spinal cord structures. These findings present for the first time, the influence of spinal cord anatomy on the effects of epidural stimulation and the role of specific orientation of electrodes on the dorsal surface of the dura mater in relation to the dorsal roots. These results are critical to consider as spinal cord neuromodulation strategies continue to evolve and novel spinal interfaces translate into clinical practice