Neuroplasticity of Ipsilateral Cortical Motor Representations, Training Effects and Role in Stroke Recovery

This thesis examines the contribution of the ipsilateral hemisphere to motor control with the aim of evaluating the potential of the contralesional hemisphere to contribute to motor recovery after stroke. Predictive algorithms based on neurobiological principles emphasize integrity of the ipsilesional corticospinal tract as the strongest prognostic indicator of good motor recovery. In contrast, extensive lesions placing reliance on alternative contralesional ipsilateral motor pathways are associated with poor recovery. Within the predictive algorithms are elements of motor control that rely on contributions from ipsilateral motor pathways, suggesting that balanced, parallel contralesional contributions can be beneficial. Current therapeutic approaches have focussed on the maladaptive potential of the contralesional hemisphere and sought to inhibit its activity with neuromodulation. Using Transcranial Magnetic Stimulation I seek examples of beneficial plasticity in ipsilateral cortical motor representations of expert performers, who have accumulated vast amounts of deliberate practise training skilled bilateral activation of muscles habitually under ipsilateral control. I demonstrate that ipsilateral cortical motor representations reorganize in response to training to acquisition of skilled motor performance. Features of this reorganization are compatible with evidence suggesting ipsilateral importance in synergy representations, controlled through corticoreticulopropriospinal pathways. I demonstrate that ipsilateral plasticity can associate positively with motor recovery after stroke. Features of plastic change in ipsilateral cortical representations are shown in response to robotic training of chronic stroke patients. These findings have implications for the individualization of motor rehabilitation after stroke, and prompt reappraisal of the approach to therapeutic intervention in the chronic phase of stroke

Cerebellar Modules and Their Role as Operational Cerebellar Processing Units

The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give their insights on the structure and function of cerebellar modules, with the aim of providing an up-to-date review of the extensive literature on this subject. Starting with an historical perspective indicating that the basis of the modular organization is formed by matching olivocorticonuclear connectivity, this is followed by consideration of anatomical and chemical modular boundaries, revealing a relation between anatomical, chemical, and physiological borders. In addition, the question is asked what the smallest operational unit of the cerebellum might be. Furthermore, it has become clear that chemical diversity of Purkinje cells also results in diversity of information processing between cerebellar modules. An additional important consideration is the relation between modular compartmentalization and the organization of the mossy fiber system, resulting in the concept of modular plasticity. Finally, examination of cerebellar output patterns suggesting cooperation between modules and recent work on modular aspects of emotional behavior are discussed. Despite the general consensus that the cerebellum has a modular organization, many questions remain. The authors hope that this joint review will inspire future cerebellar research so that we are better able to understand how this brain structure makes its vital contribution to behavior in its most general form

Flexor Dysfunction Following Unilateral Transient Ischemic Brain Injury Is Associated with Impaired Locomotor Rhythmicity

Functional motor deficits in hemiplegia after stroke are predominately associated with flexor muscle impairments in animal models of ischemic brain injury, as well as in clinical findings. Rehabilitative interventions often employ various means of retraining a maladapted central pattern generator for locomotion. Yet, holistic modeling of the central pattern generator, as well as applications of such studies, are currently scarce. Most modeling studies rely on cellular neural models of the intrinsic spinal connectivity governing ipsilateral flexor-extensor, as well as contralateral coupling inherent in the spinal cord. Models that attempt to capture the general behavior of motor neuronal populations, as well as the different modes of driving their oscillatory function in vivo is lacking in contemporary literature. This study aims at generating a holistic model of flexor and extensor function as a whole, and seeks to evaluate the parametric coupling of ipsilateral and contralateral half-center coupling through the means of generating an ordinary differential equation representative of asymmetric central pattern generator models of varying coupling architectures. The results of this study suggest that the mathematical predictions of the locomotor centers which drive the dorsiflexion phase of locomotion are correlated with the denervation-type atrophy response of hemiparetic dorsiflexor muscles, as well as their spatiotemporal activity dysfunction during in vivo locomotion on a novel precise foot placement task. Moreover, the hemiplegic solutions were found to lie in proximity to an alternative task-space solution, by which a hemiplegic strategy could be readapted in order to produce healthy output. The results revealed that there are multiple strategies of retraining hemiplegic solutions of the CPG. This solution may modify the hemiparetic locomotor pattern into a healthy output by manipulating inter-integrator couplings which are not damaged by damage to the descending drives. Ultimately, some modeling experiments will demonstrate that the increased reliance on intrinsic connectivity increases the stability of the output, rendering it resistant to perturbations originating from extrinsic inputs to the pattern generating center

Understanding motor control in humans to improve rehabilitation robots

Recent reviews highlighted the limited results of robotic rehabilitation and the low quality of evidences in this field. Despite the worldwide presence of several robotic infrastructures, there is still a lack of knowledge about the capabilities of robotic training effect on the neural control of movement. To fill this gap, a step back to motor neuroscience is needed: the understanding how the brain works in the generation of movements, how it adapts to changes and how it acquires new motor skills is fundamental. This is the rationale behind my PhD project and the contents of this thesis: all the studies included in fact examined changes in motor control due to different destabilizing conditions, ranging from external perturbations, to self-generated disturbances, to pathological conditions. Data on healthy and impaired adults have been collected and quantitative and objective information about kinematics, dynamics, performance and learning were obtained for the investigation of motor control and skill learning. Results on subjects with cervical dystonia show how important assessment is: possibly adequate treatments are missing because the physiological and pathological mechanisms underlying sensorimotor control are not routinely addressed in clinical practice. These results showed how sensory function is crucial for motor control. The relevance of proprioception in motor control and learning is evident also in a second study. This study, performed on healthy subjects, showed that stiffness control is associated with worse robustness to external perturbations and worse learning, which can be attributed to the lower sensitiveness while moving or co-activating. On the other hand, we found that the combination of higher reliance on proprioception with \u201cdisturbance training\u201d is able to lead to a better learning and better robustness. This is in line with recent findings showing that variability may facilitate learning and thus can be exploited for sensorimotor recovery. Based on these results, in a third study, we asked participants to use the more robust and efficient strategy in order to investigate the control policies used to reject disturbances. We found that control is non-linear and we associated this non-linearity with intermittent control. As the name says, intermittent control is characterized by open loop intervals, in which movements are not actively controlled. We exploited the intermittent control paradigm for other two modeling studies. In these studies we have shown how robust is this model, evaluating it in two complex situations, the coordination of two joints for postural balance and the coordination of two different balancing tasks. It is an intriguing issue, to be addressed in future studies, to consider how learning affects intermittency and how this can be exploited to enhance learning or recovery. The approach, that can exploit the results of this thesis, is the computational neurorehabilitation, which mathematically models the mechanisms underlying the rehabilitation process, with the aim of optimizing the individual treatment of patients. Integrating models of sensorimotor control during robotic neurorehabilitation, might lead to robots that are fully adaptable to the level of impairment of the patient and able to change their behavior accordingly to the patient\u2019s intention. This is one of the goals for the development of rehabilitation robotics and in particular of Wristbot, our robot for wrist rehabilitation: combining proper assessment and training protocols, based on motor control paradigms, will maximize robotic rehabilitation effects

The Slippery Slope Between Falling And Recovering: An Examination Of Sensory And Somatic Factors Influencing Recovery After A Slip

Background: Slips and falls account for large rates of injury and mortality in multiple populations. During an unexpected slip, sensory mechanisms are responsible for signaling the slip to the central nervous system, and a series of corrective responses is generated to arrest the slip and prevent a fall. While previous research has examined the corrective responses elicited, the answer of how these systems break down during a fall remains elusive. Purpose: To examine differences in postural control (slip detection), lower extremity corrective responses (slip recovery), and cortical control of the slip recovery response between individuals who fall and those who recover. Methods: One hundred participants were recruited for this study (50 males & 50 females). Participant’s gait kinematics and kinetics were collected during normal gait (NG) and an unexpected slip (US). The slip was classified as a fall or recovery, and by slip severity. Once classified, postural control, reaction times, corrective moments, and cortical contribution were examined between groups using ANOVAs and independent t-tests. Additionally, prediction equations for slip outcome, and slip severity were created using a binary logistic regression model. Slip Detection Results: Postural sway when the proprioceptive (OR = 0.02, CI: 0.01-1.34) and vestibular (OR = 0.60, CI: 0.26-1.39) systems are stressed were negatively associated with odds of falling. While postural sway when the visual system was stressed (OR = 3.18, CI: 0.887-11.445) was positively associated with odds of falling. Slip Recovery Results: Increased time to peak hip extension (OR = 1.006, CI: 1.00-1.01) and ankle dorsiflexion (OR = 1.005, CI: 1.00-1.01) moments increased the odds of falling. While the average ankle moment was negatively associated with falling (OR = 0.001, CI: 0.001-0.005). Cortical Contribution Results: Spectral power in the Piper frequency band was increased in US trials compared to NG. Further, fallers exhibited an increase in cortical activity compared to those who recovered. Conclusions: Rapid lower extremity corrective responses appear critical in arresting the slip and preventing a fall, and the temporal nature of this response may depend on slip detection and subsequent response selection. Moreover, our results suggest that more severe slips may require increased activation of higher centers of the motor cortex

Impact of Spasticity on Balance Control During Quiet Standing in Persons Post-Stroke

Statement of the problem: Balance impairments and falls are common among people with stroke. Muscle spasticity is also common and may influence balance control. However, the effect of spasticity on balance control among people with stroke is not well understood. Methods: Twenty-seven post-stroke individuals with low or high spasticity at the ankle completed quiet standing trials with eyes open and closed. Balance control was measured by estimating centre of pressure (COP) movement and trunk sway. Results: Individuals with high spasticity had greater COP velocity, trunk sway velocity, and trunk sway velocity frequency, particularly in the eyes closed condition. These effects were predominantly in the mediolateral direction (vision by group interaction effects p= 0.033, p= 0.037, and p= 0.015 respectively). Main effect of group revealed that individuals with high spasticity had higher mediolateral mean power frequency measures (p= 0.045). Conclusion: Individuals with high spasticity post-stroke demonstrated greater balance control challenges especially in absence of vision. Furthermore, these challenges were specifically noted in the frontal plane

Effects of overground walking with a robotic exoskeleton on lower limb muscle synergies

Les exosquelettes robotisés de marche (ERM) représentent une intervention prometteuse dans le domaine de la réadaptation locomotrice. Sur le plan clinique, les ERM facilitent la mise en application de principes de neuroplasticité. Jusqu'à présent, la majorité des études analysant les effets de l’ERM a été menée avec des ERM fournissant une assistance robotique complète le long d’une trajectoire de mouvements prédéfinie des membres inférieurs (MI) de façon à reproduire la marche de façon quasi parfaite à très basse vitesse. La nouvelle génération d’ERM, maintenant disponible sur le marché, propose de nouveaux modes de contrôles qui permettent, entre autres, une liberté de mouvement accrue aux MIs (c.-à-d. trajectoire non imposée) et une possibilité d’offrir une assistance ou résistance aux mouvements de différentes intensités surtout pendant la phase d’oscillation du cycle de marche. Cependant, les effets de ces modes de contrôles sur la coordination musculaire des MI pendant la marche au sol avec l’ERM, caractérisé via l’extraction de synergies musculaires (SM), restent méconnus. Cette thèse mesure et compare les caractéristiques des SM (c.-à-d. nombre, profils d’activation, composition musculaire et contribution relative des muscles) pendant la la marche au sol sans ou avec un ERM paramétré avec six différents modes de contrôle chez des individus en bonne santé (articles #1 et #2) et d’autres ayant une lésion médullaire incomplète (LMI) (article #3). Les signaux électromyographiques (EMG) des différents muscles clés des MI, enregistrés lors de la marche, ont été utilisés afin d’extraire les SM avec un algorithme de factorisation matricielle non négative. La similarité des cosinus et les coefficients de corrélation ont caractérisé les similitudes entre les caractéristiques des SM. Les résultats montrent que: 1) les profils d'activation temporelle et le nombre de SM sont modifiés en fonction de la vitesse de marche avec, entre autres une augmentation de la vitesse de marche entrainant une fusion de SM, chez les individus en bonne santé marchant sans ERM ; 2) lorsque ces derniers marchent avec un ERM, les différents modes de contrôle testés ne dupliquent pas adéquatement les SM retrouvées lors de la marche sans ERM. En fait, uniquement le mode de contrôle libérant la contrainte de trajectoire de mouvements des MIs dans le plan sagittal lors de la phase d’oscillation reproduit les principales caractéristiques des SM retrouvées pendant la marche sans ERM ; 3) le nombre et la composition musculaire des SM sont modifiés pendant la marche sans ERM chez les personnes ayant une LMI. Cependant, parmi tous les modes de contrôle étudiés, seul le mode de contrôle libérant le contrôle de la trajectoire de mouvements des MI et assistant l’oscillation du MIs (c.-à-d. HASSIST) permets l’extraction de SM similaire à celles observées chez des individus en santé lors d'une marche sans ERM. Dans l’ensemble, cette thèse a mis en évidence le fait que différentes demandes biomécaniques liées à la marche (c.-à-d. vitesse de marche, modes de contrôle de l’ERM) modifient le nombre et les caractéristiques de SM chez les personnes en santé. Cette thèse a également confirmé que la coordination musculaire, mise en évidence via l’analyse de SM, est altérée chez les personnes ayant une LMI et a tendance à se normaliser lors de la marche avec l’ERM paramétré dans le mode de HASSIST. Les nouvelles preuves appuieront les professionnels de la réadaptation dans le processus de prise de décision concernant la sélection du mode de contrôle des MIs lors de l’entrainement locomoteur utilisant avec un ERM.Wearable robotic exoskeletons (WRE) represent a promising rehabilitation intervention for locomotor rehabilitation training that aligns with activity-based neuroplasticity principles in terms of optimal sensory input, massed repetition, and proper kinematics. Thus far, most studies that investigated the effects of WRE have used WRE that provide full robotic assistance and fixed trajectory guidance to the lower extremity (L/E) to generate close-to-normal walking kinematics, usually at very slow speeds. Based on clinicians’ feedback, current commercially-available WRE have additional control options to be able to integrate these devices into the recovery process of individuals who have maintained some ability to walk after an injury to the central nervous system. In this context, WRE now offer additional degrees of movements for the L/E to move freely and different strategies to assist or resist movement, particularly during the gait cycle’s swing phase. However, the extent that these additional WRE control options affect L/E neuromuscular control during walking, typically characterized using muscle synergies (MSs), remains unknown. This thesis measures and compares MSs characteristics (i.e., number, temporal activation profile, and muscles contributing to a specific synergy [weightings]) during typical overground walking, with and without a WRE, in six different control modes, in abled-bodied individuals (Articles #1 and #2) and individuals with incomplete spinal cord injury (iSCI; Article #3). Surface EMG of key L/E muscles were recorded while walking and used to extract MSs using a non-negative matrix factorization algorithm. Cosine similarity and correlation coefficients characterized, grouped, and indicated similarities between MS characteristics. Results demonstrated that: 1) the number of MSs and MS temporal activation profiles in able-bodied individuals walking without WRE are modified by walking speed and that, as speed increased, specific MSs were fused or merged compared to MSs at slow speeds; 2) In able-bodied individuals walking with WRE, few WRE control modes maintained the typical MSs characteristics that were found during overground walking without WRE. Moreover, freeing the L/E swing trajectory imposed by the WRE best reproduced those MSs characteristics during overground walking without the WRE; and 3) After an iSCI, alterations to the number and the composition of MSs were observed during walking without WRE. However, of all WRE control modes that were investigated, only HASSIST (i.e., freeing WRE control over L/E swing trajectory while assisting the user’s self-selected trajectory) reproduced the number and composition of MSs found in abled-bodied individuals during overground walking without WRE. Altogether, the results of this thesis demonstrated that different walking-related biomechanical demands (i.e., walking speed) and most of the WRE control modes can alter some MSs, and their characteristics, in able-bodied individuals. This research also confirmed that impaired muscle coordination, assessed via MSs, can adapt when walking with a WRE set with specific control options (e.g., HASSIST). These MS adaptations mimicked typical MS characteristics extracted during overground walking. The evidence generated by this thesis will support the decision-making process when selecting specific L/E control options during WRE walking, allowing rehabilitation professionals to refine WRE locomotor training protocols

Reversible silencing of spinal neurons unmasks a left-right coordination continuum.

This dissertation is focused on dissecting the functional role of two anatomically-defined pathways in the adult rat spinal cord. A TetOn dual virus system was used to selectively and reversibly induce enhanced tetanus neurotoxin expression in L2 neurons that project to L5 (L2-L5) or C6 (long ascending propriospinal neurons, LAPNs). Results focus on the changes observed during overground locomotion. The dissertation is divided into four chapters. Chapter One is a focused introduction to locomotion, including its broad description, the central mechanisms of its expression, how genetic-based approaches defined these mechanisms, and the limitations in these approaches. It concludes with details of the silencing paradigm used here and a summary of the main findings. Chapter Two describes the functional consequences of silencing L2-L5 interneurons. The focus is on selective disruption of hindlimb coordination during overground locomotion, revealing a continuum from walk to hop. These changes are independent of speed, step frequency, and other spatiotemporal features of gait. Left-right alternation was restored during swimming and stereotypic exploration, suggesting a task-specific role. Silencing L2-L5 interneurons partially uncoupled the hindlimbs, allowing spontaneous shifts in coordination on a step-by-step basis. It is proposed this pathway distributes temporal information for left-right hindlimb alternation, securing effective coordination in a context-dependent manner. Chapter Three focuses on the consequences of silencing LAPNs.Three patterns of interlimb coupling are disrupted: left-right forelimb, left-right hindlimb, and contralateral hindlimb-forelimb coordination. Observed again was a context-dependent continuum from walk-to-hop, irrespective of step frequency, speed, and the salient features that define locomotion. However, instead of spontaneous shifts in coordination as observed from L2-L5 interneuron silencing, the breadth of coupling patterns expressed were maintained on a step-by-step basis. It is proposed that this ascending, inter-enlargement pathway distributes temporal information required for left-right alternation at the shoulder and pelvic girdles in a context-dependent manner. Collectively, these data suggest that L2-L5 interneurons and LAPNs are key pathways that distribute left-right patterning information throughout the neuraxis. The functional role(s) of these pathways are exquisitely gated to the context at hand, suggesting that the locomotor circuitry undergoes functional reorganization thereby endowing or masking the silencing-induced disruptions to interlimb coordination

Efficacy of Rhythmic Auditory Stimulation on Ataxia and Functional Dependence Post-Cerebellar Stroke

Ataxia, from Greek meaning, “lack of order,” is described as irregular movement and discoordination of body, gait, eyes, and speech. Ataxia is associated with cerebellar damage due to stroke and other cerebellar pathologies. Ataxia frequently results in functional impairment. Standard physical and occupational therapies in stroke rehabilitation facilitate motor recovery, especially within 90 days. However, many patients experience movement derangements beyond this time frame. Rhythmic auditory stimulation has been shown to be an effective intervention in chronic motor deficits like those observed after cerebellar stroke. Efficacy among patients with chronic stroke-induced ataxia is unexplored. This randomized control trial seeks to determine the benefit of rhythmic auditory stimulation over standard of care for rehabilitation of cerebellar stroke-induced ataxia. Patient progress will be assessed using validated disability and ataxia scales. It is projected that rhythmic auditory stimulation will improve ataxia and independence among patients with chronic disability post-cerebellar stroke, versus standard rehabilitation

Principles of organisation within the pathways in the brainstem and thalamus

There are few detailed studies on the pathways through the human brainstem and even fewer on those through the pons. This thesis aims to address this lack of fine detail, and used ultra-high-field magnetic resonance imaging (MRI) of human and macaque brains to identify and characterise fibre tracts connecting cortical and spinal areas as they traverse through brainstem and thalamic structures. The material in this thesis is based on a unique dataset of ultra-high-field (7 Tesla – Duke and 11, 7 Tesla – Johns Hopkins) MRI scans on postmortem specimens, on which deterministic tractography has been applied based on high-angular-resolution diffusion imaging (HARDI) and subsequently higher order tensor glyph models. The first results section of the thesis (Chapter 3) maps the descending fibre bundles associated with movement. From the motor cortical areas, the fibres of the internal capsule are traced through the crus cerebri, basilar pons and pyramids in three dimensions to reveal their organisation into functional and topographic subdivisions. While human cortico-pontine, -bulbar and -spinal tracts were traditionally considered to be dispersed, or a “melange”, I show here a much more discrete and defined organisation of these descending fibre bundles. Nine descending fibre bundles are identified and their anatomical location and terminations are described. A hitherto unknown pathway at the midline of the pons has been discovered and named herein as the Stria Pontis which connects the neocortex to the pontine tegmentum. Ten transverse fibre bundles connecting the pontine nuclei to the cerebellum are also identified. The second results section (Chapter 4) analyses the sensory pathways; the dorsal column - medial lemniscus pathway, the spinothalamic tract, the spinal trigeminal tract and the trigeminothalamic tracts. The third results section (Chapter 5) analyses the dentato-rubro-thalamic tract. The mapping identifies the superior cerebellar peduncle, the patterning of the fibres within the superior cerebellar decussation, the patterning of the fibres within the red nucleus and finally the projection of the dentato-rubro-thalamic tract from the red nucleus to the ventral lateral nucleus of the thalamus. Finally, I characterised 117 already known anatomical parts, areas and structures of the brainstem and thalamus in 3D