There are many physical disabilities with a neurological origin, such as stroke and spinal cord injuries, that significantly impact a person’s mobility, physical capacity, stamina, or dexterity. In the era of personalized medicine, optimizing the treatment of these physical disabilities requires: i) accessing direct information on the neural commands that are sent to the muscles, and ii) integrating this knowledge into the development and assessment of rehabilitation and neurotechnology aimed at restoring movement. The breakthrough of our approach lies in changing the level at which we observe the control of movement, i.e., shifting focus from the level of whole muscles to the spinal (alpha) motor neurons. To achieve this, we will combine the use of dense grids of surface electromyographic (EMG) electrodes with algorithms that decode the firing activity of spinal motor neurons. By unravelling the “neural code” for movement generation, we will address critical gaps in our understanding of the control of movement in health and disease. Building on recent work from our team, we will decode the activity of large populations of motor neurons from different muscles. We will identify motor neuron synergies, defined as functional groups of motor neurons that share inputs from various supraspinal, spinal and sensory sources. In this translational project, we will examine the structure and plasticity of these synergies in both healthy controls and patients with neurological impairments (stroke, spinal cord injury). We will also enhance the electrode design to facilitate the transfer of these methods into clinical settings. Our project is structured into independent research work packages (WP), where the progression of one is not contingent on the outcomes of another: - Aim of WP 1: To identify motor neuron synergies that controls the lower limb during tasks with different mechanical and neural constraints. Hypothesis: The activity of motor neurons can be explained by the combination of robust motor neuron synergies that would define a control space with much lower dimensions than the number of recruited motor neurons. - Aim of WP 2: To determine whether motor neuron synergies can be modified in the short- and long-term by biofeedback training. We will test the hypothesis that it is possible to dissociate the activity of motor neurons represented in the same synergy after several days of training; and conversely, it is possible to dissociate the activity of motor neurons represented in different synergies with minimal training. - Aim of WP 3: To determine whether (a) motor neuron synergies differ between stroke survivors and controls; (b) changes in synergies over the course of a rehabilitation program correlate with recovery. Based on changes in neuronal connectivity at the brain level and the observed coactivation, we will test the hypotheses that (a) synergies are disorganized in stroke survivors, and (b) they can provide biomarkers of recovery. - Aim of WP 4: (a) To describe motor neuron synergies in patients with spinal cord injury who have undergone a tendon transfer, (b) to determine whether changes in synergies correlate with the improvement in active elbow extension. Hypotheses: (a) over the course of rehabilitation, motor neurons innervating the transferred muscle and its previous agonists are progressively represented in distinct synergies, and (b) the extent of these changes is correlated with the improvement in active elbow extension. - Aim of WP 5: To improve the design of the grid of surface EMG electrodes to identify larger samples of motor neurons, especially in females Hypothesis: The differences in the number of identified motor neurons between males and females are primarily attributed to variations in fat layer thickness and innervation ratio (size of the motor units). The methodological and theoretical frameworks developed in this project will set the path for future ambitious clinical studies.