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Mechanisms underlying motor recovery from a subcortical stroke in nonhuman primates

English title Mechanisms underlying motor recovery from a subcortical stroke in nonhuman primates
Applicant Bloch Jocelyne
Number 185385
Funding scheme Project funding (Div. I-III)
Research institution Service de Neurochirurgie CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurophysiology and Brain Research
Start/End 01.06.2019 - 31.05.2023
Approved amount 588'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Physiology : other topics

Keywords (6)

reaching and grasping; corticospinal tract; subcortical stroke; nonhuman primate; neuroplasticity; neurorehabilitation

Lay Summary (French)

Lead
Dans notre projet, nous nous intéressons aux AVC affectant la région sous-corticale mais épargnant le cortex cérébral. Ces AVC représentent un quart de tous les AVC ischémiques et hémorragiques et ils sont particulièrement intéressants, car le cortex cérébral est complètement épargné.
Lay summary

Les accidents vasculaires cérébraux (AVC) ischémiques et hémorragiques affectant le tractus cortico-spinal engendrent souvent des déficits moteurs dramatiques persistants. A l’heure actuelle, malgré une réhabilitation bien menée, environ 65% des patients restent définitivement incapables d’utiliser efficacement leur bras et main atteinte dans les activités de la vie quotidienne. Une des raisons pour laquelle le développement de stratégies pharmacologiques et de protocoles de rééducation efficaces est limité, est que les mécanismes engendrant la récupération ne sont pas tous compris et ceci est en partie dû au manque de modèles animaux reproduisant correctement les différents sous-types d’AVC. 

Dans ce projet, tout d’abord, nous développerons un nouveau modèle de lésion sous-corticale chez le primate non humain, qui cible la partie de la capsule interne où passe le tractus pyramidal lié aux mouvements du membre supérieur tout en épargnant les régions corticales motrices, prémotrices et sensitives.L’épargne corticale nous permettra de mettre en place des techniques avancées d'enregistrements électrophysiologiques corticaux pour étudier les mécanismes de récupération. Nos hypothèses mécanistiques seront confirmées par des inactivations corticales induites par des techniques chemogénétiques. 

Le but ultime de notre projet étant d’utiliser les connaissances issues de ces enregistrements pour ensuite développer des stratégies pharmacologiques et de neuromodulations ciblées potentialisant la récupération. 

 

Direct link to Lay Summary Last update: 19.04.2019

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Abstract

The problem: Stroke is a devastating neurological condition, often causing severe functional deficits that dramatically diminish the quality of life of affected individuals. Subcortical stroke constitutes 25% of all the ischemic and hemorrhagic strokes. Despite this high prevalence, surprisingly little is known on the mechanisms that can mediate partial motor recovery after such injuries. Preclinical and clinical studies suggested that this recovery involves compensatory anatomical and functional changes in brain regions with preserved corticofugal or corticospinal projections, but the specifically involved regions and their respective contribution to movement planning and execution remain enigmatic. Objectives: Our goal is to decipher the longitudinal changes in anatomical connectivity and movement-related circuit dynamics across the non-affected and affected cerebral cortex during recovery from a subcortical stroke, and to demonstrate the causal contribution of the circuits identified as pivotal in the recovery. Our ultimate goal is to design spatiotemporal neuromodulation therapies that reinforce the activity of these pivotal circuits during rehabilitation to augment recovery in humans. Methods: Macaca Fascicularis will be implanted with intracortical microelectrode arrays inserted into the hand region of the primary motor cortex (M1) and premotor cortex ventral (PMv) bilaterally, and in the somatosensory cortex (S1) and premotor cortex dorsal (PMd) in the affected hemisphere. Neural activity will be recorded while the monkeys are performing well-controlled basic and complex manual tasks under the control of a robotic arm that measures the forces applied in all the spatial directions. After baseline evaluations, the monkeys will undergo a clinically-relevant stroke within the hand region of the left internal capsule. To target this specific region, the anatomy of the brain will be visualized using magnetic resonance imaging (MRI) while the animals are secured within a personalized dental mold attached to an MRI-compatible stereotaxic frame. The Medtronic Neuronavigation Stealth Station will then be used to plan the trajectory of a medical-grade thermo-coagulator probe that will reach the internal capsule from the prefrontal cortex. This trajectory will preserve the integrity of the sensory and motor regions that may contribute to motor planning and execution. Using computational frameworks, we will study changes in movement-related circuit dynamics throughout recovery from the stroke. These analyses will be completed with longitudinal functional and structural MRI scans. fMRI will enable monitoring alterations in the dynamics of cortical resting-state networks. Brain connectivity will be studied using novel diffusion tensor imaging (DTI) sequences that can identify microstructural changes. These multimodal longitudinal analyses will inform the design of chemogenetic inactivation experiments in additional monkeys. Using judicious combinations of viral vectors to express DREADDs in neurons based on their synaptic projections and location, we will probe the functional role of the neuronal projections identified as pivotal in recovery. Since DREADD silencing is transient, testing will be repeated before and throughout recovery. Virus-mediated tracing of axons and synapses from the identified neurons will allow the tridimensional visualization of their connectome, then confronted to the outcomes of DTI analyses. Impact: This project will identify some of the key functional and anatomical mechanisms that support a partial motor recovery from a prevalent type of stroke in primate species. Comparable experiments are conducted in human patients by our collaborators, thus establishing a realistic framework to conceive spatiotemporal neuromodulation therapies that augment recovery following stroke in humans.
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