Cortical neuroprosthesis-mediated functional ipsilateral control of locomotion in rats with incomplete spinal cord injury

Control of voluntary limb movement is predominantly attributed to the contralateral motor cortex. Nevertheless, increasing evidence suggests the involvement of ipsilateral cortical networks in this process. Ipsilateral control particularly emerges in motor tasks requiring bilateral coordination, which is an essential characteristic of locomotion. Here, we combined a unilateral thoracic spinal cord injury (SCI) with a cortical neuroprosthetic intervention that uncovered a functional role of the ipsilateral cortex in rat movement. In all rats, after SCI, ipsilesional cortex excitation promoted a bilateral synergy, whereby the elevation of the contralateral foot was complemented by ipsilateral hindlimb extension. In two animals, we found that stimulation of a medial cortical sub-region modulated ipsilateral hindlimb flexion. Ipsilateral cortical stimulation delivered after SCI alleviated multiple locomotor and postural deficits. These results establish a causal link between cortical activation and a remarkably fine and proportional ipsilateral control of hindlimb movement, a potential target for future neuroprosthetic technology.

Noradrenergic Components of Locomotor Recovery Induced by Intraspinal Grafting of the Embryonic Brainstem in Adult Paraplegic Rats

Intraspinal grafting of serotonergic (5-HT) neurons was shown to restore plantar stepping in paraplegic rats. Here we asked whether neurons of other phenotypes contribute to the recovery. The experiments were performed on adult rats after spinal cord total transection. Grafts were injected into the sub-lesional spinal cord. Two months later, locomotor performance was tested with electromyographic recordings from hindlimb muscles. The role of noradrenergic (NA) innervation was investigated during locomotor performance of spinal grafted and non-grafted rats using intraperitoneal application of α2 adrenergic receptor agonist (clonidine) or antagonist (yohimbine). Morphological analysis of the host spinal cords demonstrated the presence of tyrosine hydroxylase positive (NA) neurons in addition to 5-HT neurons. 5-HT fibers innervated caudal spinal cord areas in the dorsal and ventral horns, central canal, and intermediolateral zone, while the NA fiber distribution was limited to the central canal and intermediolateral zone. 5-HT and NA neurons were surrounded by each other’s axons. Locomotor abilities of the spinal grafted rats, but not in control spinal rats, were facilitated by yohimbine and suppressed by clonidine. Thus, noradrenergic innervation, in addition to 5-HT innervation, plays a potent role in hindlimb movement enhanced by intraspinal grafting of brainstem embryonic tissue in paraplegic rats.

Distributed Motor Control of Limb Movements in Rat Motor and Somatosensory Cortex: The Sensorimotor Amalgam Revisited

Which areas of the neocortex are involved in the control of movement, and how is motor cortex organized across species? Recent studies using long-train intracortical microstimulation demonstrate that in addition to M1, movements can be elicited from somatosensory regions in multiple species. In the rat, M1 hindlimb and forelimb movement representations have long been thought to overlap with somatosensory representations of the hindlimb and forelimb in S1, forming a partial sensorimotor amalgam. Here we use long-train intracortical microstimulation to characterize the movements elicited across frontal and parietal cortex. We found that movements of the hindlimb, forelimb, and face can be elicited from both M1 and histologically defined S1 and that representations of limb movement types are different in these two areas. Stimulation of S1 generates retraction of the contralateral forelimb, while stimulation of M1 evokes forelimb elevation movements that are often bilateral, including a rostral region of digit grasping. Hindlimb movement representations include distinct regions of hip flexion and hindlimb retraction evoked from S1 and hip extension evoked from M1. Our data indicate that both S1 and M1 are involved in the generation of movement types exhibited during natural behavior. We draw on these results to reconsider how sensorimotor cortex evolved.

Vestibular nucleus neurons respond to hindlimb movement in the conscious cat

The limbs constitute the sole interface with the ground during most waking activities in mammalian species; it is therefore expected that somatosensory inputs from the limbs provide important information to the central nervous system for balance control. In the decerebrate cat model, the activity of a subset of neurons in the vestibular nuclei (VN) has been previously shown to be modulated by hindlimb movement. However, decerebration can profoundly alter the effects of sensory inputs on the activity of brain stem neurons, resulting in epiphenomenal responses. Thus, before this study, it was unclear whether and how somatosensory inputs from the limb affected the activity of VN neurons in conscious animals. We recorded brain stem neuronal activity in the conscious cat and characterized the responses of VN neurons to flexion and extension hindlimb movements and to whole body vertical tilts (vestibular stimulation). Among 96 VN neurons whose activity was modulated by vestibular stimulation, the firing rate of 65 neurons (67.7%) was also affected by passive hindlimb movement. VN neurons in conscious cats most commonly encoded hindlimb movement irrespective of the direction of movement ( n = 33, 50.8%), in that they responded to all flexion and extension movements of the limb. Other VN neurons overtly encoded information about the direction of hindlimb movement ( n = 27, 41.5%), and the remainder had more complex responses. These data confirm that hindlimb somatosensory and vestibular inputs converge onto VN neurons of the conscious cat, suggesting that VN neurons integrate somatosensory inputs from the limbs in computations that affect motor outflow to maintain balance.

Vestibular nucleus neurons respond to hindlimb movement in the decerebrate cat

The vestibular nuclei integrate information from vestibular and proprioceptive afferents, which presumably facilitates the maintenance of stable balance and posture. However, little is currently known about the processing of sensory signals from the limbs by vestibular nucleus neurons. This study tested the hypothesis that limb movement is encoded by vestibular nucleus neurons and described the changes in activity of these neurons elicited by limb extension and flexion. In decerebrate cats, we recorded the activity of 70 vestibular nucleus neurons whose activity was modulated by limb movements. Most of these neurons (57/70, 81.4%) encoded information about the direction of hindlimb movement, while the remaining neurons (13/70, 18.6%) encoded the presence of hindlimb movement without signaling the direction of movement. The activity of many vestibular nucleus neurons that responded to limb movement was also modulated by rotating the animal's body in vertical planes, suggesting that the neurons integrated hindlimb and labyrinthine inputs. Neurons whose firing rate increased during ipsilateral ear-down roll rotations tended to be excited by hindlimb flexion, whereas neurons whose firing rate increased during contralateral ear-down tilts were excited by hindlimb extension. These observations suggest that there is a purposeful mapping of hindlimb inputs onto vestibular nucleus neurons, such that integration of hindlimb and labyrinthine inputs to the neurons is functionally relevant.