Plasticity of Corticospinal Neural Control after Locomotor Training in Human Spinal Cord Injury

Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result in devastating effects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axons of the damaged neurons do not regenerate spontaneously. Body-weight-supported treadmill training (BWSTT) is a therapeutic approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal and spinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood and translational neuroscience research is needed so patient-orientated rehabilitation protocols to be developed

Parallel Facilitatory Reflex Pathways from the Foot and Hip to Flexors and Extensors in the Injured Human Spinal Cord

Spinal integration of sensory signals associated with hip position, muscle loading, and cutaneous sensation of the foot contributes to movement regulation. The exact interactive effects of these sensory signals under controlled dynamic conditions are unknown. The purpose of the present study was to establish the effects of combined plantar cutaneous afferent excitation and hip movement on the Hoffmann (H) and flexion reflexes in people with a spinal cord injury (SCI). The flexion and H-reflexes were elicited through stimulation of the right sural (at non-nociceptive levels) and posterior tibial nerves respectively. Reflex responses were recorded from the ipsilateral tibialis anterior (TA) (flexion reflex) and soleus (H-reflex) muscles. The plantar cutaneous afferents were stimulated at three times the perceptual threshold (200 Hz, 24-ms pulse train) at conditioning–test intervals that ranged from 3 to 90 ms. Sinusoidal movements were imposed to the right hip joint at 0.2 Hz with subjects supine. Control and conditioned reflexes were recorded as the hip moved in flexion and extension. Leg muscle activity and sagittal-plane joint torques were recorded. We found that excitation of plantar cutaneous afferents facilitated the soleus H-reflex and the long latency flexion reflex during hip extension. In contrast, the short latency flexion reflex was depressed by plantar cutaneous stimulation during hip flexion. Oscillatory joint forces were present during the transition phase of the hip movement from flexion to extension when stimuli were delivered during hip flexion. Hip-mediated input interacts with feedback from the foot sole to facilitate extensor and flexor reflex activity during the extension phase of movement. The interactive effects of these sensory signals may be a feature of impaired gait, but when they are appropriately excited, they may contribute to locomotion recovery in these patients

Pre- and Post-alpha Motoneuronal Control of the Soleus H-reflex during Sinusoidal Hip Movements in Human Spinal Cord Injury

The aim of this study was to establish the contribution of hip-mediated sensory feedback to spinal interneuronal circuits during dynamic conditions in people with incomplete spinal cord injury (SCI). Specifically, we investigated the effects of synergistic and antagonistic group I afferents on the soleus H-reflex during imposed sinusoidal hip movements. The soleus H-reflex was conditioned by stimulating the common peroneal nerve (CPN) at short (2, 3, and 4 ms) and long (80, 100, and 120 ms) conditioning test (C-T) intervals to assess the reciprocal and pre-synaptic inhibition of the soleus H-reflex, respectively. The soleus H-reflex was also conditioned by medial gastrocnemius (MG) nerve stimulation at C-T intervals ranging from 4 to 7 ms to assess changes in autogenic Ib inhibition during hip movement. Sinusoidal hip movements were imposed to the right hip joint at 0.2 Hz by the Biodex system while subjects were supine. The effects of sinusoidal hip movement on five leg muscles along with hip, knee, and ankle joint torques were also established during sensorimotor conditioning of the reflex. Phase-dependent modulation of antagonistic and synergistic muscle afferents was present during hip movement, with the reciprocal, pre-synaptic, and Ib inhibition to be significantly reduced during hip extension and reinforced during hip flexion. Reflexive muscle and joint torque responses – induced by the hip movement – were entrained to specific phases of hip movement. This study provides evidence that hip-mediated input acts as a controlling signal of pre- and post-alpha motoneuronal control of the soleus H-reflex. The expression of these spinal interneuronal circuits during imposed sinusoidal hip movements is discussed with respect to motor recovery in humans after SCI

Transspinal stimulation increases motoneuron output of multiple segments in human spinal cord injury

Targeted neuromodulation strategies that strengthen neuronal activity are in great need for restoring sensorimotor function after chronic spinal cord injury (SCI). In this study, we established changes in the motoneuron output of individuals with and without SCI after repeated noninvasive transspinal stimulation at rest over the thoracolumbar enlargement, the spinal location of leg motor circuits. Cases of motor incomplete and complete SCI were included to delineate potential differences when corticospinal motor drive is minimal. All 10 SCI and 10 healthy control subjects received daily monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at right soleus transspinal evoked potential (TEP) subthreshold and suprathreshold intensities at rest. Before and two days after cessation of transspinal stimulation, we determined changes in TEP recruitment input-output curves, TEP amplitude at stimulation frequencies of 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and TEP postactivation depression upon transspinal paired stimuli at interstimulus intervals of 60, 100, 300, and 500 ms. TEPs were recorded at rest from bilateral ankle and knee flexor/extensor muscles. Repeated transspinal stimulation increased the motoneuron output over multiple segments. In control and complete SCI subjects, motoneuron output increased for knee muscles, while in motor incomplete SCI subjects motoneuron output increased for both ankle and knee muscles. In control subjects, TEPs homosynaptic and postactivation depression were present at baseline, and were potentiated for the distal ankle or knee flexor muscles. TEPs homosynaptic and postactivation depression at baseline depended on the completeness of the SCI, with minimal changes observed after transspinal stimulation. These results indicate that repeated transspinal stimulation increases spinal motoneuron responsiveness of ankle and knee muscles in the injured human spinal cord, and thus can promote motor recovery. This noninvasive neuromodulation method is a promising modality for promoting functional neuroplasticity after SCI

Spinal Excitability Changes after Transspinal and Transcortical Paired Associative Stimulation in Humans

Paired associative stimulation (PAS) produces enduring neuroplasticity based on Hebbian associative plasticity. This study established the changes in spinal motoneuronal excitability by pairing transcortical and transspinal stimulation. Transcortical stimulation was delivered after (transspinal-transcortical PAS) or before (transcortical-transspinal PAS) transspinal stimulation. Before and after 40 minutes of each PAS protocol, spinal neural excitability was assessed based on the amplitude of the transspinal-evoked potentials (TEPs) recorded from ankle muscles of both legs at different stimulation intensities (recruitment input-output curve). Changes in TEPs amplitude in response to low-frequency stimulation and paired transspinal stimuli were also established before and after each PAS protocol. TEP recruitment input-output curves revealed a generalized depression of TEPs in most ankle muscles of both legs after both PAS protocols that coincided with an increased gain only after transcortical-transspinal PAS. Transcortical-transspinal PAS increased and transspinal-transcortical PAS decreased the low-frequency-dependent TEP depression, whereas neither PAS protocol affected the TEP depression observed upon paired transspinal stimuli. These findings support the notion that transspinal and transcortical PAS has the ability to alter concomitantly cortical and spinal synaptic activity. Transspinal and transcortical PAS may contribute to the development of rehabilitation strategies in people with bilateral increased motoneuronal excitability due to cortical or spinal lesions

Transpinal and Transcortical Stimulation Alter Corticospinal Excitability and Increase Spinal Output

The objective of this study was to assess changes in corticospinal excitability and spinal output following noninvasive transpinal and transcortical stimulation in humans. The size of the motor evoked potentials (MEPs), induced by transcranial magnetic stimulation (TMS) and recorded from the right plantar flexor and extensor muscles, was assessed following transcutaneous electric stimulation of the spine (tsESS) over the thoracolumbar region at conditioning-test (C-T) intervals that ranged from negative 50 to positive 50 ms. The size of the transpinal evoked potentials (TEPs), induced by tsESS and recorded from the right and left plantar flexor and extensor muscles, was assessed following TMS over the left primary motor cortex at 0.7 and at 1.1× MEP resting threshold at C-T intervals that ranged from negative 50 to positive 50 ms. The recruitment curves of MEPs and TEPs had a similar shape, and statistically significant differences between the sigmoid function parameters of MEPs and TEPs were not found. Anodal tsESS resulted in early MEP depression followed by long-latency MEP facilitation of both ankle plantar flexors and extensors. TEPs of ankle plantar flexors and extensors were increased regardless TMS intensity level. Subthreshold and suprathreshold TMS induced short-latency TEP facilitation that was larger in the TEPs ipsilateral to TMS. Noninvasive transpinal stimulation affected ipsilateral and contralateral actions of corticospinal neurons, while corticocortical and corticospinal descending volleys increased TEPs in both limbs. Transpinal and transcortical stimulation is a noninvasive neuromodulation method that alters corticospinal excitability and increases motor output of multiple spinal segments in humans

Soleus H-reflex Excitability Changes in Response to Sinusoidal Hip Stretches in the Injured Human Spinal Cord

Imposed static hip stretches substantially modulate the soleus H-reflex in people with an intact or injured spinal cord while stretch of the hip flexors affect the walking pattern in lower vertebrates and humans. The aim of this study was to assess the effects of dynamic hip stretches on the soleus H-reflex in supine spinal cord injured (SCI) subjects. Sinusoidal movements were imposed on the right hip joint at 0.2 Hz by a Biodex system. H-reflexes from the soleus muscle were recorded as the leg moved in flexion or extension. Stimuli were sent only once in every hip movement cycle that each lasted 5 s. Torque responses were recorded at the hip, knee, and ankle joints. A hip phase-dependent soleus H-reflex modulation was present in all subjects. The reflex was facilitated during hip extension and suppressed during hip flexion. There were no significant differences in pre- or post-stimulus soleus background activity between the two conditions. Oscillatory responses were present as the hip was maximally flexed. Sinusoidal hip stretches modulated the soleus H-reflex in a manner similar to that previously observed following static hip stretches. The amount of reflex facilitation depended on the angle of hip extension. Further research is needed on the afferent control of spinal reflex pathways in health and disease in order to better understand the neural control of movement in humans. This will aid in the development of rehabilitation strategies to restore motor function in these patients

Transspinal Direct Current Stimulation Produces Persistent Plasticity in Human Motor Pathways

The spinal cord is an integration center for descending, ascending, and segmental neural signals. Noninvasive transspinal stimulation may thus constitute an effective method for concomitant modulation of local and distal neural circuits. In this study, we established changes in cortical excitability and input/output function of corticospinal and spinal neural circuits before, at 0–15 and at 30–45 minutes after cathodal, anodal, and sham transspinal direct current stimulation (tsDCS) to the thoracic region in healthy individuals. We found that intracortical inhibition was different among stimulation polarities, however remained unchanged over time. Intracortical facilitation increased after cathodal and anodal tsDCS delivered with subjects seated, and decreased after cathodal tsDCS delivered with subjects lying supine. Both cathodal and anodal tsDCS increased corticospinal excitability, yet facilitation was larger and persisted for 30 minutes post stimulation only when cathodal tsDCS was delivered with subjects lying supine. Spinal input/output reflex function was decreased by cathodal and not anodal tsDCS. These changes may be attributed to altered spontaneous neural activity and membrane potentials of corticomotoneuronal cells by tsDCS involving similar mechanisms to those mediating motor learning. Our findings indicate that thoracic tsDCS has the ability to concomitantly alter cortical, corticospinal, and spinal motor output in humans

Cervicothoracic Multisegmental Transpinal Evoked Potentials in Humans

The objectives of this study were to establish the neurophysiological properties of the transpinal evoked potentials (TEPs) following transcutaneous electric stimulation of the spine (tsESS) over the cervicothoracic region, changes in the amplitude of the TEPs preceded by median nerve stimulation at group I threshold, and the effects of tsESS on the flexor carpi radialis (FCR) H-reflex in thirteen healthy human subjects while seated. Two re-usable self-adhering electrodes, connected to function as one electrode (cathode), were placed bilaterally on the clavicles. A re-usable electrode (anode) was placed on the cervicothoracic region covering from Cervical 4 – Thoracic 2 and held under constant pressure throughout the experiment. TEPs were recorded bilaterally from major arm muscles with subjects seated at stimulation frequencies of 1.0, 0.5, 0.33, 0.2, 0.125, and 0.1 Hz, and upon double tsESS pulses delivered at an inter-stimulus interval of 40 ms. TEPs from the arm muscles were also recorded following median nerve stimulation at the conditioning-test (C-T) intervals of 2, 3, 5, 8, and 10 ms. The FCR H-reflex was evoked and recorded according to conventional methods following double median nerve pulses at 40 ms, and was also conditioned by tsESS at C-T intervals that ranged from −10 to +50 ms. The arm TEPs amplitude was not decreased at low-stimulation frequencies and upon double tsESS pulses in all but one subject. Ipsilateral and contralateral arm TEPs were facilitated following ipsilateral median nerve stimulation, while the FCR H-reflex was depressed by double pulses and following tsESS at short and long C-T intervals. Non-invasive transpinal stimulation can be used as a therapeutic modality to decrease spinal reflex hyper-excitability in neurological disorders and when combined with peripheral nerve stimulation to potentiate spinal output

Spinal Control of Locomotion: Individual Neurons, Their Circuits and Functions

Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle activation profiles are observed during locomotion across species. This difference may potentially be driven by a modified distribution of muscle afferents at multiple segmental levels in humans, resulting in an altered interaction between different classes of spinal interneurons. Further, different classes of spinal interneurons are likely activated or silent to some extent simultaneously in all species. Regardless of these limitations, continuous efforts on the function of spinal interneuronal circuits during mammalian locomotion will assist in delineating the neural mechanisms underlying locomotor control, and help develop novel targeted rehabilitation strategies in cases of impaired bipedal gait in humans. These rehabilitation strategies will include activity-based therapies and targeted neuromodulation of spinal interneuronal circuits via repetitive stimulation delivered to the brain and/or spinal cord