Rehabilitative Soft Exoskeleton for Rodents

Robotic exoskeletons provide programmable, consistent and controllable active therapeutic assistance to patients with neurological disorders. Here we introduce a prototype and preliminary experimental evaluation of a rehabilitative gait exoskeleton that enables compliant yet effective manipulation of the fragile limbs of rats. To assist the displacements of the lower limbs without impeding natural gait movements, we designed and fabricated soft pneumatic actuators (SPAs). The exoskeleton integrates two customizable SPAs that are attached to a limb. This configuration enables a 1 N force load, a range of motion exceeding 80 mm in the major axis, and speed of actuation reaching two gait cycles/s. Preliminary experiments in rats with spinal cord injury validated the basic features of the exoskeleton. We propose strategies to improve the performance of the robot and discuss the potential of SPAs for the design of other wearable interfaces

NEUROMECHANICAL CONTROL OF LOCOMOTION IN INTACT AND INCOMPLETE SPINAL CORD INJURED RATS

Rodent models are being extensively used to investigate the effects of traumatic injuryand to develop and assess the mechanisms of repair and regeneration. We presentquantitative assessment of 2D kinematics of overground walking and for the first time3D joint angle kinematics of all four limbs during treadmill walking in the intact and inincomplete spinal cord contusion injured (iSCI) adult female Long Evans rats. Phaserelationship between joint angles on a cycle-by-cycle basis and interlimb footfalls areassessed using a simple technique. Electromyogram (EMG) data from major flexor andextensor muscles for each of the hindlimb joints and elbow extensor muscles of theforelimbs synchronized to the 3D kinematics is also obtained in intact rats. EMG activityindicates specific relationships of the neural activity to joint angle kinematics. We findthat the ankle flexors as well as the hip and elbow extensors maintain constant burstduration with changing cycle duration. Overground walking kinematics providesinformation on stance width (SW), stride length (SL) and hindfoot rotation (Rot). SW andRot increased in iSCI rats. Treadmill walking kinematics provides information on jointangle trajectories. In iSCI rats double burst pattern in ankle angle as seen in intact ratsis lost and knee extension and range are reduced. Intra and interlimb coordination isimpaired. Left-right interlimb coordination and forelimb kinematics are not alteredsignificantly. In iSCI rats, maximum flexion of the knee during swing occurs in phasewith the hip as opposed to knee flexion preceeding hip flexion in intact rats. A mildexercise regimen in intact rats over eight weeks does not alter the kinematics

Design, implementation and validation of an exoskeletal robot for locomotion studies in rodents

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 214-226).Growing interest in robotic treatment of patients with neurological injury motivates the development of therapeutic robots for basic research into recovery. Though humans are the ultimate beneficiaries, basic research frequently involves rodent models of neurological injury, which motivates robotic devices that can interact with rats or mice. Currently, available apparatus for locomotion studies of rodents is built upon treadmills, which simplify the design and implementation but also restrict the scope of possible experiments. This is largely due to the treadmill's single-dimensional movement and the lack of accommodation for natural or voluntary movement of the animal. In order to open up new possibilities for locomotion studies in rodents, this work introduces newly developed apparatus for locomotion research in rodents. The key concept is to allow maximal freedom of voluntary movement of the animal while providing forceful interaction when necessary. Advantages and challenges of the proposed machine over other existing designs are discussed. Design and implementation issues are presented and discussed, emphasizing their impact on free, voluntary, movement of the animal. A live-animal experiment was conducted to verify the design principles. Unconstrained natural movement of the animal was compared with movement with the overground robot attached. The compact, overground design and backdrivable implementation of this robot allow novel experiments that involve open-space, free (or interactive) locomotion of the animal.by Yun Seong Song.Ph.D

Kinematic analysis of spinal cord injury animals treated with a neurotrophin-infused scaffold and body weight supported treadmill training

Spinal Cord Injury (SCI) is a condition that affects around 250,000 Americans with no cure. Existing treatments rely on physical therapies such as body weight support treadmill training (BWSTT). Treatments currently being researched include the use of implantable cells and biomaterials. Our study investigated the changes in locomotive gait and range of motion via a combinational treatment using a bioengineered scaffold [poly (N-isopropyl acrylamide) polyethylene glycol (PNIPAAm-g-PEG) with BDNF and NT-3] and rehabilitation training using BWSTT in a clinically relevant contusion SCI animal model. Five different groups of animals (Sham, Injury, BWSTT, Implant, and Combinational) were tested on a treadmill with BWSTT at three different BWS (75%, 65%, and 55%) and two different speeds (7 cm/s and 10 cm/s). Using three motion capture cameras, kinematic data were acquired and analyzed to study functional recovery in these groups. Our results show some kinematic recovery in the Combination therapy and BWSTT animals. Step height, length, and number of steps were significantly higher in these groups of animals. The obtained data warrant further studies that aim to investigate the efficacy of different biomaterial implants and combinational therapies

Afferent information modulates spinal network activity in vitro and in preclinical animal models

Primary afferents are responsible for the transmission of peripheral sensory information to the spinal cord. Spinal circuits involved in sensory processing and in motor activity are directly modulated by incoming input conveyed by afferent fibres. Current neurorehabilitation exploits primary afferent information to induce plastic changes within lesioned spinal circuitries. Plasticity and neuromodulation promoted by activity-based interventions are suggested to support both the functional recovery of locomotion and pain relief in subjects with sensorimotor disorders. The present study was aimed at assessing spinal modifications mediated by afferent information. At the beginning of my PhD project, I adopted a simplified in vitro model of isolated spinal cord from the newborn rat. In this preparation, dorsal root (DR) fibres were repetitively activated by delivering trains of electrical stimuli. Responses of dorsal sensory-related and ventral motor-related circuits were assessed by extracellular recordings. I demonstrated that electrostimulation protocols able to activate the spinal CPG for locomotion, induced primary afferent hyperexcitability, as well. Thus, evidence of incoming signals in modulating spinal circuits was provided. Furthermore, a robust sensorimotor interplay was reported to take place within the spinal cord. I further investigated hyperexcitability conditions in a new in vivo model of peripheral neuropathic pain. Adult rats underwent a surgical procedure where the common peroneal nerve was crushed using a calibrated nerve clamp (modified spared nerve injury, mSNI). Thus, primary afferents of the common peroneal nerve were activated through the application of a noxious compression, which presumably elicited ectopic activity constitutively generated in the periphery. One week after surgery, animals were classified into two groups, with (mSNI+) and without (mSNI-) tactile hypersensitivity, based on behavioral tests assessing paw withdrawal threshold. Interestingly, the efficiency of the mSNI in inducing tactile hypersensitivity was halved with respect to the classical SNI model. Moreover, mSNI animals with tactile hypersensitivity (mSNI+) showed an extensive neuroinflammation within the dorsal horn, with activated microglia and astrocytes being significantly increased with respect to mSNI animals without tactile hypersensitivity (mSNI-) and to sham-operated animals. Lastly, RGS4 (regulator of G protein signaling 4) was reported to be enhanced in lumbar dorsal root ganglia (DRGs) and dorsal horn ipsilaterally to the lesion in mSNI+ animals. Thus, a new molecular marker was demonstrated to be involved in tactile hypersensitivity in our preclinical model of mSNI. Lastly, we developed a novel in vitro model of newborn rat, where hindlimbs were functionally connected to a partially dissected spinal cord and passively-driven by a robotic device (Bipedal Induced Kinetic Exercise, BIKE). I aimed at studying whether spinal activity was influenced by afferent signals evoked during passive cycling. I first demonstrated that BIKE could actually evoke an afferent feedback from the periphery. Then, I determined that spinal circuitries were differentially affected by training sessions of different duration. On one side, a short exercise session could not directly activate the locomotor CPG, but was able to transiently facilitate an electrically-induced locomotor-like activity. Moreover, no changes in reflex or spontaneous activity of dorsal and ventral networks were promoted by a short training. On the other side, a long BIKE session caused a loss in facilitation of spinal locomotor networks and a depression in the area of motor reflexes. Furthermore, activity in dorsal circuits was long-term enhanced, with a significant increase in both electrically-evoked and spontaneous antidromic discharges. Thus, the persistence of training-mediated effects was different, with spinal locomotor circuits being only transiently modulated, whereas dorsal activity being strongly and stably enhanced. Motoneurons were also affected by a prolonged training, showing a reduction in membrane resistance and an increase in the frequency of post-synaptic currents (PSCs), with both fast- and slow-decaying synaptic inputs being augmented. Changes in synaptic transmission onto the motoneuron were suggested to be responsible for network effects mediated by passive training. In conclusion, I demonstrated that afferent information might induce changes within the spinal cord, involving both neuronal and glial cells. In particular, spinal networks are affected by incoming peripheral signals, which mediate synaptic, cellular and molecular modifications. Moreover, a strong interplay between dorsal and ventral spinal circuits was also reported. A full comprehension of basic mechanisms underlying sensory-mediated spinal plasticity and bidirectional interactions between functionally different spinal networks might lead to the development of neurorehabilitation strategies which simultaneously promote locomotor recovery and pain relief

Effet de l'entraînement locomoteur sur la récupération des fonctions locomotrices chez la souris paraplégique

Une blessure à la moelle épinière (BME) est un traumatisme qui endommage les fibres nerveuses permettant la communication entre le cerveau et le reste du corps. La prévalence d'une BME est d'environ 1.3 million de Nord-Américains. Il n'existe malheureusement aucune cure pour réparer la moelle épinière lésée. La principale conséquence d'une BME est une perte des fonctions sensorielles et motrices volontaires, sous le niveau de la lésion (ex, lésion thoracique entraîne paraplégie). Les patients souffrent également de problèmes de santé qui se développent progressivement. Des problèmes immunitaires, métaboliques, hormonaux, cardiovasculaires, musculaires, osseux et mentaux apparaîtront chez une majorité de patients. Le manque de connaissance lié au développement de ces troubles de santé constitue la problématique de recherche au coeur de cette thèse. Le but de cette thèse est de mieux comprendre l'étendue de ces problèmes de santé, et de concevoir un traitement novateur pour diminuer, voire prévenir, certains de ces problèmes. En se sens, les objectifs sont : 1) De terminer la caractérisation des ces problèmes chez notre modèle animal. 2) De bien établir les conséquences fonctionnelles de la plasticité neuronale sous-lésionnelle sur le système moteur et locomoteur. 3) D'établir le rôle précis des récepteurs 5-HT2 dans l'activation pharmacologique des circuits spinaux locomoteurs in vivo. 4) De déterminer les effets de substances aux propriétés anaboliques sur le système musculaire et locomoteur. 5) D'évaluer les effets de d'un entraînement seul, puis d'une approche multidisciplinaire combinant l'entraînement locomoteur, l'administration d'agents aux propriétés anaboliques et d'activateurs des réseaux locomoteurs spinaux, sur les dérèglements des systèmes locomoteur, musculaire et osseux

A Computational Approach for the Design of Epidural Electrical Spinal Cord Stimulation Strategies to Enable Locomotion after Spinal Cord Injury

Spinal cord injury (SCI) is a major cause of paralysis with currently no effective treatment. Epidural electrical stimulation (EES) of the lumbar spinal cord has been shown to restore locomotion in animal models of SCI, but has not yet reached the same level of efficacy in humans. The mechanisms through which EES promotes locomotion, and the causes underlying these inter-species differences remain largely unknown, although essential to fully exploit the therapeutic potential of this neuromodulation strategy. Here, we addressed these questions using a deductive approach based on computer simulations and hypothesis-driven experiments, and proposed complementary strategies to enhance the current efficacy of EES-based therapies. In the first part of this thesis, we studied the mechanisms through which EES enables locomotion in rat models of SCI. Performing simulations and behavioral experiments, we provided evidence that EES modulates proprioceptive afferents activity, without interfering with the ongoing sensory signals. We showed that this synergistic interaction allows muscle spindle feedback circuits to steer the unspecific excitation delivered by EES to functionally relevant pathways, thus allowing the formation of locomotor patterns. By leveraging this understanding, we developed a stimulation strategy that allowed adjusting lesion-specific gait deficits, hence increasing the therapeutic efficacy of EES. In the second part of this thesis, we evaluated the influence of trunk posture on proprioceptive feedback circuits during locomotion, and thus on the effect of EES, in rat models of SCI. By combining modeling and experiments, we showed that trunk orientation regulates leg proprioceptive signals, as well as the motor patterns produced during EES-induced stepping. We exploited these results to develop a control policy that by automatically regulating trunk orientation significantly enhanced locomotor performance. In the last part of this thesis, we investigated the causes underlying species-specific effects of EES. Hypothesis-driven simulations suggested that in humans continuous EES blocks the proprioceptive signals traveling along the recruited fibers. We corroborated this prediction by performing experiments in rats and people with SCI. In particular, we showed that EES disrupts the conscious perception of leg movements, as well as the afferent modulation of sensorimotor circuits in humans, but not in rats. We provide evidence that in humans, due to this phenomenon, continuous EES can only facilitate locomotion to a limited extent. This was insufficient to provide clinically relevant improvements in the tested participants. Finally, we proposed two sensory-compliant stimulation strategies that might overcome these limitations, and thus augment the therapeutic efficacy of EES. In this thesis we elucidated key mechanisms through which EES promotes locomotion, we exposed critical limitations of continuous EES strategies when applied to humans, and we introduced complementary strategies to maximize the efficacy of EES therapies. These findings have far-reaching implications in the development of future strategies and technologies supporting the recovery of locomotion in people with SCI using EES