Engagement of the Rat Hindlimb Motor Cortex across Natural Locomotor Behaviors.

Contrary to cats and primates, cortical contribution to hindlimb locomotor movements is not critical in rats. However, the importance of the motor cortex to regain locomotion after neurological disorders in rats suggests that cortical engagement in hindlimb motor control may depend on the behavioral context. To investigate this possibility, we recorded whole-body kinematics, muscle synergies, and hindlimb motor cortex modulation in freely moving rats performing a range of natural locomotor procedures. We found that the activation of hindlimb motor cortex preceded gait initiation. During overground locomotion, the motor cortex exhibited consistent neuronal population responses that were synchronized with the spatiotemporal activation of hindlimb motoneurons. Behaviors requiring enhanced muscle activity or skilled paw placement correlated with substantial adjustment in neuronal population responses. In contrast, all rats exhibited a reduction of cortical activity during more automated behavior, such as stepping on a treadmill. Despite the facultative role of the motor cortex in the production of locomotion in rats, these results show that the encoding of hindlimb features in motor cortex dynamics is comparable in rats and cats. However, the extent of motor cortex modulations appears linked to the degree of volitional engagement and complexity of the task, reemphasizing the importance of goal-directed behaviors for motor control studies, rehabilitation, and neuroprosthetics. SIGNIFICANCE STATEMENT: We mapped the neuronal population responses in the hindlimb motor cortex to hindlimb kinematics and hindlimb muscle synergies across a spectrum of natural locomotion behaviors. Robust task-specific neuronal population responses revealed that the rat motor cortex displays similar modulation as other mammals during locomotion. However, the reduced motor cortex activity during more automated behaviors suggests a relationship between the degree of engagement and task complexity. This relationship emphasizes the importance of the behavioral procedure to engage the motor cortex during motor control studies, gait rehabilitation, and locomotor neuroprosthetic developments in rats.

Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury.

Severe spinal cord injury in humans leads to a progressive neuronal dysfunction in the chronic stage of the injury. This dysfunction is characterized by premature exhaustion of muscle activity during assisted locomotion, which is associated with the emergence of abnormal reflex responses. Here, we hypothesize that undirected compensatory plasticity within neural systems caudal to a severe spinal cord injury contributes to the development of neuronal dysfunction in the chronic stage of the injury. We evaluated alterations in functional, electrophysiological and neuromorphological properties of lumbosacral circuitries in adult rats with a staggered thoracic hemisection injury. In the chronic stage of the injury, rats exhibited significant neuronal dysfunction, which was characterized by co-activation of antagonistic muscles, exhaustion of locomotor muscle activity, and deterioration of electrochemically-enabled gait patterns. As observed in humans, neuronal dysfunction was associated with the emergence of abnormal, long-latency reflex responses in leg muscles. Analyses of circuit, fibre and synapse density in segments caudal to the spinal cord injury revealed an extensive, lamina-specific remodelling of neuronal networks in response to the interruption of supraspinal input. These plastic changes restored a near-normal level of synaptic input within denervated spinal segments in the chronic stage of injury. Syndromic analysis uncovered significant correlations between the development of neuronal dysfunction, emergence of abnormal reflexes, and anatomical remodelling of lumbosacral circuitries. Together, these results suggest that spinal neurons deprived of supraspinal input strive to re-establish their synaptic environment. However, this undirected compensatory plasticity forms aberrant neuronal circuits, which may engage inappropriate combinations of sensorimotor networks during gait execution.

Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion.

Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex-dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico-reticulo-spinal circuit reorganization may also improve recovery in humans.

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates.

Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species have not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than did rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys but nearly absent in rats. Our results uncover pronounced interspecies differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury reemphasizes the importance of primate models for designing clinically relevant treatments.

Multi-system neurorehabilitative strategies to restore motor functions following severe spinal cord injury.

Severe spinal cord injury (SCI) permanently abolishes motor functions caudal to the lesion. However, the neuronal machinery sufficient to produce standing and stepping is located below most SCI, and can be reactivated with training. Therefore, why do rats and humans fail to regain significant levels of motor control after a severe SCI? In this review, we argue that the lack of sustainable excitability in locomotor circuitries after SCI prevents the emergence of functional motor states during training, thus limiting the occurrence of activity-dependent plasticity in paralyzed subjects. In turn, we show that spinal rats trained with combinations of epidural electrical stimulation and monoamine agonists, which promote locomotor permissive states during rehabilitation, can regain coordinated stepping with full weight bearing capacities in the total absence of supraspinal influences. This impressive recovery of function relies on the ability of spinal circuitries to utilize multisensory information as a source of control and learning after the loss of brain input. We finally discuss the implication of these findings for the design of multi-system neurorehabilitative interventions capable of restoring some degree of function in humans with severe SCI.

Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders.

Central nervous system (CNS) disorders distinctly impair locomotor pattern generation and balance, but technical limitations prevent independent assessment and rehabilitation of these subfunctions. Here we introduce a versatile robotic interface to evaluate, enable and train pattern generation and balance independently during natural walking behaviors in rats. In evaluation mode, the robotic interface affords detailed assessments of pattern generation and dynamic equilibrium after spinal cord injury (SCI) and stroke. In enabling mode,the robot acts as a propulsive or postural neuroprosthesis that instantly promotes unexpected locomotor capacities including overground walking after complete SCI, stair climbing following partial SCI and precise paw placement shortly after stroke. In training mode, robot-enabled rehabilitation, epidural electrical stimulation and monoamine agonists reestablish weight-supported locomotion, coordinated steering and balance in rats with a paralyzing SCI. This new robotic technology and associated concepts have broad implications for both assessing and restoring motor functions after CNS disorders, both in animals and in humans.

Restoring voluntary control of locomotion after paralyzing spinal cord injury.

Half of human spinal cord injuries lead to chronic paralysis. Here, we introduce an electrochemical neuroprosthesis and a robotic postural interface designed to encourage supraspinally mediated movements in rats with paralyzing lesions. Despite the interruption of direct supraspinal pathways, the cortex regained the capacity to transform contextual information into task-specific commands to execute refined locomotion. This recovery relied on the extensive remodeling of cortical projections, including the formation of brainstem and intraspinal relays that restored qualitative control over electrochemically enabled lumbosacral circuitries. Automated treadmill-restricted training, which did not engage cortical neurons, failed to promote translesional plasticity and recovery. By encouraging active participation under functional states, our training paradigm triggered a cortex-dependent recovery that may improve function after similar injuries in humans.