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Restoration of walking ability is an area of great interest in the rehabilitation of persons with spinal cord injury. Because many cortical, subcortical, and spinal neural centers contribute to locomotor function, it is important that intervention strategies be designed to target neural elements at all levels of the neuraxis that are important for walking ability. While to date most strategies have focused on activation of spinal circuits, more recent studies are investigating the value of engaging supraspinal circuits. Despite the apparent potential of pharmacological, biological, and genetic approaches, as yet none has proved more effective than physical therapeutic rehabilitation strategies. By making optimal use of the potential of the nervous system to respond to training, strategies can be developed that meet the unique needs of each person. To complement the development of optimal training interventions, it is valuable to have the ability to predict future walking function based on early clinical presentation, and to forecast responsiveness to training. A number of clinical prediction rules and association models based on common clinical measures have been developed with the intent, respectively, to predict future walking function based on early clinical presentation, and to delineate characteristics associated with responsiveness to training. Further, a number of variables that are correlated with walking function have been identified. Not surprisingly, most of these prediction rules, association models, and correlated variables incorporate measures of volitional lower extremity strength, illustrating the important influence of supraspinal centers in the production of walking behavior in humans.

Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.

In human spinal cord injury, the neuronal mechanisms mediating the improvement of locomotor function in response to intensive treadmill training are not well understood. In this study, we examined if such recovery is mediated, in part, by increases in residual corticospinal drive to muscles of the leg during walking. To do this, we measured the coherence of electromyogram (EMG) activity between two antagonist muscles (intermuscular coherence), specifically at frequencies between 24 and 40 Hz, which is thought to indicate common drive to two muscles from corticospinal inputs. In 12 subjects with incomplete spinal cord injury, intermuscular coherence was measured between hamstrings and vastus lateralis EMG that was activated during walking on a motorized treadmill. Before training, appreciable coherence in the 24-40 Hz frequency band was only present in subjects with moderate volitional motor strength in their leg muscles (n = 8 subjects) compared with subjects with little or no leg muscle strength (n = 4 subjects), reconfirming that 24-40 Hz frequency coherence is likely mediated by common supraspinal inputs. After training, increases in 24-40 Hz coherence only occurred in the eight subjects with moderate leg muscle strength who also exhibited improvements in locomotor recovery as assessed by the 21 point WISCI II scale (termed responders). In contrast, development of intermuscular coherence in the 24-40 Hz frequency band did not occur in the four subjects with absent or weak muscle strength. These subjects also did not improve in their locomotor ability as reflected in unchanging WISCI II scores (termed nonresponders). Lower-frequency coherence (5-18 Hz), which is thought to contain common drive from spinal inputs, did not change in either group. In a subset of subjects that were previously assessed with transcranial magnetic stimulation (TMS) before and after training (n = 5 responders and 3 nonresponders), there was a significant and positive relationship between increases in 24-40 Hz coherence and increases in evoked muscle responses to TMS of the primary motor cortex. Taken together, increases in higher-frequency EMG coherence in subjects with residual voluntary muscle strength and its parallel relation to changes in TMS-evoked responses provides further evidence that improvements in locomotor function from treadmill training are mediated, in part, by increases in corticospinal drive to muscles of the leg during walking.

In this study, we examined if several months of intensive locomotor training increases the function of spared corticospinal tract pathways after chronic spinal cord injury (SCI) in association with the recovery of locomotor function. Transcranial magnetic stimulation (TMS) at incrementing levels of intensity was applied over the motor cortex supplying either the tibialis anterior or vastus lateralis muscles, and the resulting peak-to-peak amplitude of the motor-evoked potentials (MEPs) were measured to obtain a recruitment curve both before and after training. In the majority of subjects (7/8), 3-5 mo of daily intensive training increased the responses to TMS in at least one of the leg muscles tested (9/13). On average, across all muscles tested MEP(max), which was evoked at high stimulation intensities, increased by 46% and MEP(h), which was evoked at intermediate stimulation intensities, increased by 45% (both significantly different from 0), indicating an increase in corticospinal tract connectivity from training. The slope of the sigmoid function fit to the recruitment curve increased by 24% after training (significantly different), indicating an expansion and/or increased excitability of corticospinal circuits supplying muscles to the lower leg. We also observed that the average duration of the silent period measured at MEP(max) increased after training from 130 to 178 ms, suggesting that training had effects on cortical circuits thought to mediate this long-lasting inhibition. The percentage increase in MEP(max) was positively and significantly correlated to the degree of locomotor recovery as assessed by the WISCI II score, the distance a subject could walk in 6 min, and the amplitude of the locomotor EMG activity, suggesting that the corticospinal tract, in part, mediated the functional locomotor recovery produced from training.

Inhibitory feedback from sensory pathways is important for controlling movement. Here, we characterize, for the first time, a longlatency, inhibitory spinal pathway to ankle flexors that is activated by low-threshold homonymous afferents. To examine this inhibitory pathway in uninjured, healthy participants, we suppressed motorevoked potentials (MEPs), produced in the tibialis anterior (TA), by a prior stimulation to the homonymous common peroneal nerve (CPN). The TA MEP was suppressed by a triple-pulse stimulation to the CPN, applied 40, 50, and 60 ms earlier and at intensities of 0.5- 0.7 times motor threshold (average suppression of test MEP was 33%). Whereas the triple-pulse stimulation was below M-wave and H-reflex threshold, it produced a long-latency inhibition of background muscle activity, approximately 65-115 ms after the CPN stimulation, a time period that overlapped with the test MEP. However, not all of the MEP suppression could be accounted for by this decrease in background muscle activity. Evoked responses from direct activation of the corticospinal tract, at the level of the brain stem or thoracic spinal cord, were also suppressed by low-threshold CPN stimulation. Our findings suggest that low-threshold muscle and cutaneous afferents from the CPN activate a long-latency, homonymous spinal inhibitory pathway to TA motoneurons. We propose that inhibitory feedback from spinal networks, activated by low-threshold homonymous afferents, helps regulate the activation of flexor motoneurons by the corticospinal tract. [ABSTRACT FROM AUTHOR]

In this update, the authors will discuss evidence for both spinal and brain regulation of walking in humans. They will consider the sensory control of walking in young babies and spinal cord-injured adults, two models with weak descending input from the brain, to suggest that subcortical structures are important in shaping walking behavior. Based on evidence from development, the authors suggest that the primitive pattern of walking seen in babies forms the base upon which additional features are added by supraspinal input as independent walking develops. Increasing evidence suggests the motor cortex is important in the control of level-ground walking in adults, in contrast to quadrupeds. This brain input seems particularly important for distal flexors in the leg. Finally, the authors will consider evidence that the recovery of walking after incomplete spinal cord injuries is dependent on the presence of descending input from the motor cortex and our ability to strengthen that input. These findings imply that training methods for improving walking after injury to the nervous system must promote the involvement of both spinal and brain circuits. [ABSTRACT FROM AUTHOR]