Multisite Hebbian Plasticity Restores Function in Humans with Spinal Cord Injury.

OBJECTIVE: Spinal cord injury (SCI) damages synaptic connections between corticospinal axons and motoneurons of many muscles, resulting in devastating paralysis. We hypothesized that strengthening corticospinal-motoneuronal synapses at multiple spinal cord levels through Hebbian plasticity (i.e., "neurons that fire together, wire together") promotes recovery of leg and arm function. METHODS: Twenty participants with chronic SCI were randomly assigned to receive 20 sessions of Hebbian or sham stimulation targeting corticospinal-motoneuronal synapses of multiple leg muscles followed by exercise. Based on the results from this study, in a follow-up prospective study, 11 more participants received 40 sessions of Hebbian stimulation targeting corticospinal-motoneuronal synapses of multiple arm and leg muscles followed by exercise. During Hebbian stimulation sessions, 180 paired pulses elicited corticospinal action potentials by magnetic (motor cortex) and/or electrical (thoracic spine) stimulation allowing volleys to arrive at the spinal cord 1-2 milliseconds before motoneurons were activated retrogradely via bilateral electrical stimulation (brachial plexus, ulnar, femoral, and common peroneal nerves) for biceps brachii, first dorsal interosseous, quadriceps femoris, and tibialis anterior muscles as needed. RESULTS: We found in our randomized study that participants receiving Hebbian stimulation improved their walking speed and corticospinal function to a greater extent than individuals receiving sham stimulation. In agreement, prospective study participants improved their grasping and walking, corticospinal function, and quality of life metrics, exhibiting greater improvements with more sessions that persisted 9-month post-therapy. INTERPRETATION: Our findings suggest that multisite Hebbian stimulation, informed by the physiology of the corticospinal system, represents an effective strategy to promote functional recovery following SCI. ANN NEUROL 2023;93:1198-1213.

Spasticity Predicts Motor Recovery for Patients with Subacute Motor Complete Spinal Cord Injury.

OBJECTIVE: A motor complete spinal cord injury (SCI) results in the loss of voluntary motor control below the point of injury. Some of these patients can regain partial motor function through inpatient rehabilitation; however, there is currently no biomarker to easily identify which patients have this potential. Evidence indicates that spasticity could be that marker. Patients with motor complete SCI who exhibit spasticity show preservation of descending motor pathways, the pathways necessary for motor signals to be carried from the brain to the target muscle. We hypothesized that the presence of spasticity predicts motor recovery after subacute motor complete SCI. METHODS: Spasticity (Modified Ashworth Scale and pendulum test) and descending connectivity (motor evoked potentials) were tested in the rectus femoris muscle in patients with subacute motor complete (n = 36) and motor incomplete (n = 30) SCI. Motor recovery was assessed by using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association Impairment Scale (AIS). All measurements were taken at admission and discharge from inpatient rehabilitation. RESULTS: We found that motor complete SCI patients with spasticity improved in motor scores and showed AIS conversion to either motor or sensory incomplete. Conversely, patients without spasticity showed no changes in motor scores and AIS conversion. In incomplete SCI patients, motor scores improved and AIS conversion occurred regardless of spasticity. INTERPRETATION: These findings suggest that spasticity represents an easy-to-use clinical outcome that might help to predict motor recovery after severe SCI. This knowledge can improve inpatient rehabilitation effectiveness for motor complete SCI patients. ANN NEUROL 2023.

A portable system to measure knee extensor spasticity after spinal cord injury.

BACKGROUND: The pendulum test is a quantitative method used to assess knee extensor spasticity in humans with spinal cord injury (SCI). Yet, the clinical implementation of this method remains limited. The goal of our study was to develop an objective and portable system to assess knee extensor spasticity during the pendulum test using inertial measurement units (IMU). METHODS: Spasticity was quantified by measuring the first swing angle (FSA) using a 3-dimensional optical tracking system (with external markers over the iliotibial band, lateral knee epicondyle, and lateral malleolus) and two wireless IMUs (positioned over the iliotibial band and mid-part of the lower leg) as well as a clinical exam (Modified Ashworth Scale, MAS). RESULTS: Measurements were taken on separate days to assess test-retest reliability and device agreement in humans with and without SCI. We found no differences between FSA values obtained with the optical tracking system and the IMU-based system in control subjects and individuals with SCI. FSA values from the IMU-based system showed excellent agreement with the optical tracking system in individuals with SCI (ICC > 0.98) and good agreement in controls (ICC > 0.82), excellent test-retest reliability across days in SCI (ICC = 0.93) and good in controls (ICC = 0.87). Notably, FSA values measured by both systems showed a strong association with MAS scores ( ρ  ~ -0.8) being decreased in individuals with SCI with higher MAS scores, reflecting the presence of spasticity. CONCLUSIONS: These findings suggest that our new portable IMU-based system provides a robust and flexible alternative to a camera-based optical tracking system to quantify knee extensor spasticity following SCI.

Increased paired stimuli enhance corticospinal-motoneuronal plasticity in humans with spinal cord injury.

Paired corticospinal-motoneuronal stimulation (PCMS) has been used to enhance corticospinal excitability and functional outcomes in humans with spinal cord injury (SCI). Here, we examined the effect of increasing the number of paired pulses on PCMS-induced plasticity. During PCMS, corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the hand motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the first dorsal interosseous (FDI) muscle 1-2 ms before the arrival of antidromic potentials elicited in motoneurons by electrical stimulation of the ulnar nerve. We tested motor-evoked potentials (MEPs) elicited by TMS over the hand motor cortex and electrical stimulation at the cervicomedullary junction (CMEPs) in the FDI muscle before and after 180 paired pulses (PCMS-180) followed up by another 180 paired pulses (PCMS-360) in humans with and without chronic incomplete cervical SCI. The nine-hole-peg-test (9HPT) was measured before and after PCMS paired pulses in individuals with SCI. We found that the size of MEPs and CMEPs increased after PCMS-180 in both groups compared with baseline and further increased after PCMS-360 in participants with SCI, suggesting a spinal origin for these effects. Notably, in people with SCI, the time to complete the 9HPT decreased after PCMS-180 and further decreased after PCMS-360 compared with baseline but not when the 9HPT was repeated overtime. Our findings demonstrate that increasing the number of PCMS paired pulses potentiates corticospinal excitability and voluntary motor output after SCI, likely through spinal plasticity. This proof-of-principle study suggests that increasing the PCMS dose represents a strategy to boost voluntary motor output after SCI.NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation (PCMS) has been used to enhance corticospinal excitability and functional outcomes in humans with spinal cord injury (SCI). Here, we demonstrate that 360 paired pulses resulted in larger increases in motor-evoked potential size in a hand muscle and in a better ability to complete the nine-hold-peg-test compared with 180 paired pulses in people with SCI. This proof-of-principle study suggests that increasing the PCMS dose represents a strategy to boost motor output after SCI.

Corticospinal excitability across lower limb muscles in humans.

Electrophysiological studies in nonhuman primates reported the existence of strong corticospinal output from the primary motor cortex to distal compared with proximal hindlimb muscles. The extent to which corticospinal output differs across muscles in the leg in humans remains poorly understood. Using transcranial magnetic stimulation over the leg representation of the primary motor cortex, we constructed motor evoked potential (MEP) recruitment curves to measure the resting motor threshold (RMT), maximum MEP amplitude (MEP-max), and slope in the biceps femoris, rectus femoris, tibialis anterior, soleus, and a foot muscle (i.e., abductor hallucis) in intact humans. We found that the RMT was lower and the MEP-max and slope were larger in the abductor hallucis compared with most other muscles tested. In contrast, the RMT was higher and the MEP-max and slope were lower in the biceps femoris compared to all other muscles tested. Corticospinal responses in the rectus femoris, tibialis anterior, and soleus were in between those obtained from other leg muscles, with the soleus having a higher RMT and lower MEP-max and slope than the rectus femoris and tibialis anterior. To examine the origin of increases in corticospinal excitability in the abductor hallucis, we compared short-interval intracortical inhibition (SICI) and F-waves between the abductor hallucis and tibialis anterior. SICI was similar across muscles while the F-wave amplitude was larger in the abductor hallucis compared with the tibialis anterior. These results support a nonuniform distribution of corticospinal output to leg muscles, highlighting that increases in corticospinal excitability in a foot muscle could be related to a spinal origin.NEW & NOTEWORTHY We provide evidence on how corticospinal output differs across muscles in the leg in intact humans. We found that corticospinal responses were larger in a distal intrinsic foot muscle and were smaller in the biceps femoris compared to all other muscles in the leg. Increases in corticospinal excitability to an intrinsic foot muscle could have a spinal origin.

Prevalence of spasticity in humans with spinal cord injury with different injury severity.

Spasticity is one of the most common symptoms manifested following spinal cord injury (SCI). The aim of this study was to assess spasticity in individuals with subacute and chronic SCI with different injury severity, standardizing the time and assessments of spasticity. We tested 110 individuals with SCI classified by the American Spinal Injury Association Impairment Scale (AIS) as either motor complete (AIS A and B; subacute, n = 25; chronic, n = 33) or motor incomplete (AIS C and D; subacute, n = 23; chronic, n = 29) at a similar time after injury (subacute, ∼1 mo after injury during inpatient rehabilitation and chronic, ≥1 yr after injury) using clinical (modified Ashworth scale) and kinematic (pendulum test) outcomes to assess spasticity in the quadriceps femoris muscle. Using both methodologies, we found that among individuals with subacute motor complete injuries, only a minority showed spasticity, whereas the majority exhibited no spasticity. This finding stands in contrast to individuals with subacute motor incomplete injury, where both methodologies revealed that a majority exhibited spasticity, whereas a minority exhibited no spasticity. In chronic injuries, most individuals showed spasticity regardless of injury severity. Notably, when spasticity was present, its magnitude was similar across injury severity in both subacute and chronic injuries. Our results suggest that the prevalence, not the magnitude, of spasticity differs between individuals with motor complete and incomplete SCI in the subacute and chronic stages of the injury. We thus argue that considering the "presence of spasticity" might help the stratification of participants with motor complete injuries for clinical trials.NEW & NOTEWORTHY The prevalence of spasticity in humans with SCI remains poorly understood. Using kinematic and clinical outcomes, we examined spasticity in individuals with subacute and chronic injuries of different severity. We found that spasticity in the quadriceps femoris muscle was more prevalent among individuals with subacute motor incomplete than in those with motor complete injuries. However, in a different group of individuals with chronic injuries, no differences were found in the prevalence of spasticity across injury severity.

When the whole is greater than the sum of its parts: a scoping review of activity-based therapy paired with spinal cord stimulation following spinal cord injury.

Spinal cord injury (SCI) results in both motor and autonomic impairments, which can negatively affect independence and quality of life and increase morbidity and mortality. Despite emerging evidence supporting the benefits of activity-based training and spinal cord stimulation as two distinct interventions for sensorimotor and autonomic recovery, the combined effects of these modalities are currently uncertain. This scoping review evaluated the effectiveness of paired interventions (exercise + spinal neuromodulation) for improving sensorimotor and autonomic functions in individuals with SCI. Four electronic databases were searched for peer-reviewed manuscripts (Medline, Embase, CINAHL, and EI-compedex Engineering Village) and data were independently extracted by two reviewers using pre-established extraction tables. A total of 15 studies representing 79 participants were included in the review, of which 73% were conducted within the past 5 years. Only two of the studies were randomized controlled studies, while the other 13 studies were case or case-series designs. Compared with activity-based training alone, spinal cord stimulation combined with activity-based training improved walking and voluntary muscle activation, and augmented improvements in lower urinary tract, bowel, resting metabolic rate, peak oxygen consumption, and thermoregulatory function. Spinal neuromodulation in combination with use-dependent therapies may provide greater neurorecovery and induce long-term benefits for both motor and autonomic function beyond the capacity of traditional activity-based therapies. However, evidence for combinational approaches is limited and there is no consensus for outcome measures or optimal protocol parameters, including stimulation settings. Future large-scale randomized trials into paired interventions are warranted to further investigate these preliminary findings.

Transcutaneous spinal cord stimulation combined with locomotor training to improve walking ability in people with chronic spinal cord injury: study protocol for an international multi-centred double-blinded randomised sham-controlled trial (eWALK).

STUDY DESIGN: An international multi-centred, double-blinded, randomised sham-controlled trial (eWALK). OBJECTIVE: To determine the effect of 12 weeks of transcutaneous spinal stimulation (TSS) combined with locomotor training on walking ability in people with spinal cord injury (SCI). SETTING: Dedicated SCI research centres in Australia, Spain, USA and Scotland. METHODS: Fifty community-dwelling individuals with chronic SCI will be recruited. Participants will be eligible if they have bilateral motor levels between T1 and T11, a reproducible lower limb muscle contraction in at least one muscle group, and a Walking Index for SCI II (WISCI II) between 1 and 6. Eligible participants will be randomised to one of two groups, either the active stimulation group or the sham stimulation group. Participants allocated to the stimulation group will receive TSS combined with locomotor training for three 30-min sessions a week for 12 weeks. The locomotor sessions will include walking on a treadmill and overground. Participants allocated to the sham stimulation group will receive the same locomotor training combined with sham stimulation. The primary outcome will be walking ability with stimulation using the WISCI II. Secondary outcomes will record sensation, strength, spasticity, bowel function and quality of life. TRIAL REGISTRATION: ANZCTR.org.au identifier ACTRN12620001241921.

Distinct Corticospinal and Reticulospinal Contributions to Voluntary Control of Elbow Flexor and Extensor Muscles in Humans with Tetraplegia.

Humans with cervical spinal cord injury (SCI) often recover voluntary control of elbow flexors and, to a much lesser extent, elbow extensor muscles. The neural mechanisms underlying this asymmetrical recovery remain unknown. Anatomical and physiological evidence in animals and humans indicates that corticospinal and reticulospinal pathways differentially control elbow flexor and extensor motoneurons; therefore, it is possible that reorganization in these pathways contributes to the asymmetrical recovery of elbow muscles after SCI. To test this hypothesis, we examined motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the arm representation of the primary motor cortex, maximal voluntary contractions, the StartReact response (a shortening in reaction time evoked by a startling stimulus), and the effect of an acoustic startle cue on MEPs elicited by cervicomedullary stimulation (CMEPs) on biceps and triceps brachii in males and females with and without chronic cervical incomplete SCI. We found that SCI participants showed similar MEPs and maximal voluntary contractions in biceps but smaller responses in triceps compared with controls, suggesting reduced corticospinal inputs to elbow extensors. The StartReact and CMEP facilitation was larger in biceps but similar to controls in triceps, suggesting enhanced reticulospinal inputs to elbow flexors. These findings support the hypothesis that the recovery of biceps after cervical SCI results, at least in part, from increased reticulospinal inputs and that the lack of these extra inputs combined with the loss of corticospinal drive contribute to the pronounced weakness found in triceps.SIGNIFICANCE STATEMENT Although a number of individuals with cervical incomplete spinal cord injury show limited functional recovery of elbow extensors compared with elbow flexor muscles, to date, the neural mechanisms underlying this asymmetrical recovery remain unknown. Here, we provide for the first time evidence for increased reticulospinal inputs to biceps but not triceps brachii and loss of corticospinal drive to triceps brachii in humans with tetraplegia. We propose that this reorganization in descending control contributes to the asymmetrical recovery between elbow flexor and extensor muscles after cervical spinal cord injury.

Cortical and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with Tetraplegia.

An increasing number of studies supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes functional recovery in humans with spinal cord injury (SCI). However, the neural mechanisms contributing to these effects remain poorly understood. Here we examined motor-evoked potentials in arm muscles elicited by cortical and subcortical stimulation of corticospinal axons before and after 20 min of TESS (30 Hz pulses with a 5 kHz carrier frequency) and sham-TESS applied between C5 and C6 spinous processes in males and females with and without chronic incomplete cervical SCI. The amplitude of subcortical, but not cortical, motor-evoked potentials increased in proximal and distal arm muscles for 75 min after TESS, but not sham-TESS, in control subjects and SCI participants, suggesting a subcortical origin for these effects. Intracortical inhibition, elicited by paired stimuli, increased after TESS in both groups. When TESS was applied without the 5 kHz carrier frequency both subcortical and cortical motor-evoked potentials were facilitated without changing intracortical inhibition, suggesting that the 5 kHz carrier frequency contributed to the cortical inhibitory effects. Hand and arm function improved largely when TESS was used with, compared with without, the 5 kHz carrier frequency. These novel observations demonstrate that TESS influences cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. We hypothesized that these parallel effects contribute to further the recovery of limb function following SCI.SIGNIFICANCE STATEMENT Accumulating evidence supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes recovery of function in humans with spinal cord injury (SCI). Here, we show that a single session of TESS over the cervical spinal cord in individuals with incomplete chronic cervical SCI influenced in parallel the excitability cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. Importantly, these parallel physiological effects had an impact on the magnitude of improvements in voluntary motor output.

Abnormal changes in motor cortical maps in humans with spinal cord injury.

KEY POINTS: The functional role of motor cortical reorganization following spinal cord injury (SCI) remains largely unknown. Here, we tested motor maps in a hand muscle at rest and during voluntary contraction of the hand with and without voluntary contraction of a proximal arm muscle. Motor map area in participants with SCI decreased during hand voluntary contraction and further decreased during additional contraction of a proximal arm muscle compared with rest. In contrast, motor map area in controls increased during the same motor tasks. Participants with SCI with more severe sensory deficits in the hand showed larger decreases in motor map area. Ten minutes of hand muscle-tendon vibration increased the motor map area during voluntary contraction in SCI participants. These novel findings suggest that abnormal changes in motor cortical maps during voluntary contraction after SCI can be reshaped by sensory input, knowledge that can have implications for rehabilitation. ABSTRACT: Motor cortical representations reorganize following cervical spinal cord injury (SCI). The functional role of this reorganization remains largely unknown. Using neuronavigated transcranial magnetic stimulation, we examined motor cortical maps during voluntary contraction in humans with chronic cervical SCI and age-matched controls. We constructed motor maps in the first dorsal interosseous (FDI) muscle at rest and during voluntary contraction of the FDI with and without voluntary contraction of the biceps brachi (BB). The role of sensory input into this reorganization was examined by muscle-tendon vibration. We found that, at rest, motor maps were larger in SCI (22.3 cm2 ) compared with control (12.6 cm2 , P < 0.001) participants. Motor map area increased during voluntary contraction of the FDI (120.7%) and further increased during contraction of the BB (143.9%) compared with rest in control subjects; however, motor map area decreased during voluntary contraction of the FDI (69.5%) and further decreased during contraction of the BB (55.5%) in individuals with SCI. SCI participants with larger decreases in map area during voluntary contraction of the FDI were those with larger sensory deficits in the hand and 10 min of hand muscle-tendon vibration increased motor map area. These results provide the first evidence of abnormal changes in motor cortical maps in humans with chronic SCI during voluntary contraction, suggesting that sensory input can help to reshape this reorganization.

Distinct patterns of spasticity and corticospinal connectivity following complete spinal cord injury.

KEY POINTS: Damage to corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). Here, we examined to what extent residual corticospinal connections and spasticity are present in muscles below the injury (quadriceps femoris and soleus) in humans with motor complete thoracic SCI. We found three distinct subgroups of people: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus; participants with spasticity and corticospinal responses in the quadriceps femoris only; and participants with no spasticity or corticospinal responses in either muscle. Spasticity and corticospinal responses were present in the quadriceps but never only in the soleus muscle, suggesting a proximal to distal gradient of symptoms of hyperreflexia. These results suggest that concomitant patterns of residual corticospinal connectivity and spasticity exist in humans with motor complete SCI and that a clinical examination of spasticity might be a good predictor of residual descending motor pathways in people with severe paralysis. ABSTRACT: The loss of corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). However, the extent to which residual corticospinal connections and spasticity are present across muscles below the injury remains unknown. To address this question, we tested spasticity using the Modified Ashworth Scale and transmission in the corticospinal pathway by examining motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the leg motor cortex (cortical MEPs) and by direct activation of corticospinal axons by electrical stimulation over the thoracic spine (thoracic MEPs), in the quadriceps femoris and soleus muscles, in 30 individuals with motor complete thoracic SCI. Cortical MEPs were also conditioned by thoracic electrical stimulation at intervals allowing their summation or collision. We found three distinct subgroups of participants: 47% showed spasticity in the quadriceps femoris and soleus muscles; 30% showed spasticity in the quadriceps femoris muscle only; and 23% showed no spasticity in either muscle. Although cortical MEPs were present only in the quadriceps in participants with spasticity, thoracic MEPs were present in both muscles when spasticity was present. Thoracic electrical stimulation facilitated and suppressed cortical MEPs, showing that both forms of stimulation activated similar corticospinal axons. Cortical and thoracic MEPs correlated with the degree of spasticity in both muscles. These results provide the first evidence that related patterns of residual corticospinal connectivity and spasticity exist in muscles below the injury after motor complete thoracic SCI and highlight that a clinical examination of spasticity can predict residual corticospinal connectivity after severe paralysis.

Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury.

Rehabilitative exercise in humans with spinal cord injury aims to engage residual neural networks to improve functional recovery. We hypothesized that exercise combined with non-invasive stimulation targeting spinal synapses further promotes functional recovery. Twenty-five individuals with chronic incomplete cervical, thoracic, and lumbar spinal cord injury were randomly assigned to 10 sessions of exercise combined with paired corticospinal-motor neuronal stimulation (PCMS) or sham-PCMS. In an additional experiment, we tested the effect of PCMS without exercise in 13 individuals with spinal cord injury with similar characteristics. During PCMS, 180 pairs of stimuli were timed to have corticospinal volleys evoked by transcranial magnetic stimulation over the primary motor cortex arrive at corticospinal-motor neuronal synapses of upper- or lower-limb muscles (depending on the injury level), 1-2 ms before antidromic potentials were elicited in motor neurons by electrical stimulation of a peripheral nerve. Participants exercised for 45 min after all protocols. We found that the time to complete subcomponents of the Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) and the 10-m walk test decreased on average by 20% after all protocols. However, the amplitude of corticospinal responses elicited by transcranial magnetic stimulation and the magnitude of maximal voluntary contractions in targeted muscles increased on overage by 40-50% after PCMS combined or not with exercise but not after sham-PCMS combined with exercise. Notably, behavioural and physiological effects were preserved 6 months after the intervention in the group receiving exercise with PCMS but not in the group receiving exercise combined with sham-PCMS, suggesting that the stimulation contributed to preserve exercise gains. Our findings indicate that targeted non-invasive stimulation of spinal synapses might represent an effective strategy to facilitate exercise-mediated recovery in humans with different degrees of paralysis and levels of spinal cord injury.

Imbalanced Corticospinal and Reticulospinal Contributions to Spasticity in Humans with Spinal Cord Injury.

Damage to the corticospinal and reticulospinal tract has been associated with spasticity in humans with upper motor neuron lesions. We hypothesized that these descending motor pathways distinctly contribute to the control of a spastic muscle in humans with incomplete spinal cord injury (SCI). To test this hypothesis, we examined motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the leg representation of the primary motor cortex, maximal voluntary contractions (MVCs), and the StartReact response (shortening in reaction time evoked by a startling stimulus) in the quadriceps femoris muscle in male and females with and without incomplete SCI. A total of 66.7% of the SCI participants showed symptoms of spasticity, whereas the other 33.3% showed no or low levels of spasticity. We found that participants with spasticity had smaller MEPs and MVCs and larger StartReact compared with participants with no or low spasticity and control subjects. These results were consistently present in spastic subjects but not in the other populations. Clinical scores of spasticity were negatively correlated with MEP-max and MVC values and positively correlated with shortening in reaction time. These findings provide evidence for lesser corticospinal and larger reticulospinal influences to spastic muscles in humans with SCI and suggest that these imbalanced contributions are important for motor recovery.SIGNIFICANCE STATEMENT Although spasticity is one of the most common symptoms manifested in humans with spinal cord injury (SCI) to date, its mechanisms of action remain poorly understood. We provide evidence, for the first time, of imbalanced contributions of the corticospinal and reticulospinal tract to control a spastic muscle in humans with chronic incomplete SCI. We found that participants with SCI with spasticity showed small corticospinal responses and maximal voluntary contractions and larger reticulospinal gain compared with participants with no or low spasticity and control subjects. These results were consistently present in spastic subjects but not in the other populations. We showed that imbalanced corticospinal and reticulospinal tract contributions are more pronounced in participants with chronic incomplete SCI with lesser recovery.

Vibration attenuates spasm-like activity in humans with spinal cord injury.

KEY POINTS: Cutaneous reflexes were tested to examine the neuronal mechanisms contributing to muscle spasms in humans with chronic spinal cord injury (SCI). Specifically, we tested the effect of Achilles and tibialis anterior tendon vibration on the early and late components of the cutaneous reflex and reciprocal Ia inhibition in the soleus and tibialis anterior muscles in humans with chronic SCI. We found that tendon vibration reduced the amplitude of later but not earlier cutaneous reflex in the antagonist but not in the agonist muscle relative to the location of the vibration. In addition, reciprocal Ia inhibition between antagonist ankle muscles increased with tendon vibration and participants with a larger suppression of the later component of the cutaneous reflex had stronger reciprocal Ia inhibition from the antagonistic muscle. Our study is the first to provide evidence that tendon vibration attenuates late cutaneous spasm-like reflex activity, likely via reciprocal inhibitory mechanisms, and may represent a method, when properly targeted, for controlling spasms in humans with SCI. ABSTRACT: The neuronal mechanisms contributing to the generation of involuntary muscle contractions (spasms) in humans with spinal cord injury (SCI) remain poorly understood. To address this question, we examined the effect of Achilles and tibialis anterior tendon vibration at 20, 40, 80 and 120 Hz on the amplitude of the long-polysynaptic (LPR, from reflex onset to 500 ms) and long-lasting (LLR, from 500 ms to reflex offset) cutaneous reflex evoked by medial plantar nerve stimulation in the soleus and tibialis anterior, and reciprocal Ia inhibition between these muscles, in 25 individuals with chronic SCI. We found that Achilles tendon vibration at 40 and 80 Hz, but not other frequencies, reduced the amplitude of the LLR in the tibialis anterior, but not the soleus muscle, without affecting the amplitude of the LPR. Vibratory effects were stronger at 80 than 40 Hz. Similar results were found in the soleus muscle when the tibialis anterior tendon was vibrated. Notably, tendon vibration at 80 Hz increased reciprocal Ia inhibition between antagonistic ankle muscles and vibratory-induced increases in reciprocal Ia inhibition were correlated with decreases in the LLR, suggesting that participants with a larger suppression of later cutaneous reflex activity had stronger reciprocal Ia inhibition from the antagonistic muscle. Our study is the first to provide evidence that tendon vibration suppresses late spasm-like activity in antagonist but not agonist muscles, likely via reciprocal inhibitory mechanisms, in humans with chronic SCI. We argue that targeted vibration of antagonistic tendons might help to control spasms after SCI.

Changes in motoneuron excitability during voluntary muscle activity in humans with spinal cord injury.

The excitability of resting motoneurons increases following spinal cord injury (SCI). The extent to which motoneuron excitability changes during voluntary muscle activity in humans with SCI, however, remains poorly understood. To address this question, we measured F waves by using supramaximal electrical stimulation of the ulnar nerve at the wrist and cervicomedullary motor-evoked potentials (CMEPs) by using high-current electrical stimulation over the cervicomedullary junction in the first dorsal interosseous muscle at rest and during 5 and 30% of maximal voluntary contraction into index finger abduction in individuals with chronic cervical incomplete SCI and aged-matched control participants. We found higher persistence (number of F waves present in each set) and amplitude of F waves at rest in SCI compared with control participants. With increasing levels of voluntary contraction, the amplitude, but not the persistence, of F waves increased in both groups but to a lesser extent in SCI compared with control participants. Similarly, the CMEP amplitude increased in both groups but to a lesser extent in SCI compared with controls. These results were also found at matched absolutely levels of electromyographic activity, suggesting that these changes were not related to decreases in voluntary motor output after SCI. F-wave and CMEP amplitudes were positively correlated across conditions in both groups. These results support the hypothesis that the responsiveness of the motoneuron pool during voluntary activity decreases following SCI, which could alter the generation and strength of voluntary muscle contractions.NEW & NOTEWORTHY How the excitability of motoneurons changes during voluntary muscle activity in humans with spinal cord injury (SCI) remains poorly understood. We found that F-wave and cervicomedullary motor-evoked potential amplitude, outcomes reflecting motoneuronal excitability, increased during voluntary activity compared with rest in SCI participants but to a lesser extent that in controls. These results suggest that the responsiveness of motoneurons during voluntary activity decreases following SCI, which might affect functionally relevant plasticity after the injury.

Bilateral and asymmetrical contributions of passive and active ankle plantar flexors stiffness to spasticity in humans with spinal cord injury.

Spasticity is one of the most common symptoms present in humans with spinal cord injury (SCI); however, its clinical assessment remains underdeveloped. The purpose of the study was to examine the contribution of passive muscle stiffness and active spinal reflex mechanisms to clinical outcomes of spasticity after SCI. It is important that passive and active contributions to increased muscle stiffness are distinguished to make appropriate decisions about antispastic treatments and to monitor its effectiveness. To address this question, we combined biomechanical and electrophysiological assessments of ankle plantarflexor muscles bilaterally in individuals with and without chronic SCI. Spasticity was assessed using the Modified Ashworth Scale (MAS) and a self-reported questionnaire. We performed slow and fast dorsiflexion stretches of the ankle joint to measure passive muscle stiffness and reflex-induced torque using a dynamometer and the soleus H reflex using electrical stimulation over the posterior tibial nerve. All SCI participants reported the presence of spasticity. While 96% of them reported higher spasticity on one side compared with the other, the MAS detected differences across sides in only 25% of the them. Passive muscle stiffness and the reflex-induced torque were larger in SCI compared with controls more on one side compared with the other. The soleus stretch reflex, but not the H reflex, was larger in SCI compared with controls and showed differences across sides, with a larger reflex in the side showing a higher reflex-induced torque. MAS scores were not correlated with biomechanical and electrophysiological outcomes. These findings provide evidence for bilateral and asymmetric contributions of passive and active ankle plantar flexors stiffness to spasticity in humans with chronic SCI and highlight a poor agreement between a self-reported questionnaire and the MAS for detecting asymmetries in spasticity across sides.NEW & NOTEWORTHY Spasticity affects a number of people with spinal cord injury (SCI). Using biomechanical, electrophysiological, and clinical assessments, we found that passive muscle properties and active spinal reflex mechanisms contribute bilaterally and asymmetrically to spasticity in ankle plantarflexor muscles in humans with chronic SCI. A self-reported questionnaire had poor agreement with the Modified Ashworth Scale in detecting asymmetries in spasticity. The nature of these changes might contribute to the poor sensitivity of clinical exams.

Residual descending motor pathways influence spasticity after spinal cord injury.

OBJECTIVE: Spasticity is one of the most common symptoms manifested in humans with spinal cord injury (SCI). The neural mechanisms contributing to its development are not yet understood. Using neurophysiological and imaging techniques, we examined the influence of residual descending motor pathways on spasticity in humans with SCI. METHODS: We measured spasticity in 33 individuals with motor complete SCI (determined by clinical examination) without preservation of voluntary motor output in the quadriceps femoris muscle. To examine residual descending motor pathways, we used magnetic and electrical stimulation over the leg motor cortex to elicit motor evoked potentials (MEPs) in the quadriceps femoris muscle and structural magnetic resonance imaging to measure spinal cord atrophy. RESULTS: We found that 60% of participants showed symptoms of spasticity, whereas the other 40% showed no spasticity, demonstrating the presence of 2 clear subgroups of humans with motor complete SCI. MEPs were only present in individuals who had spasticity, and MEP size correlated with the severity of spasticity. Spinal cord atrophy was greater in nonspastic compared with spastic subjects. Notably, the degree of spared tissue in the lateral regions of the spinal cord was positively correlated with the severity of spasticity, indicating preservation of white matter related to motor tracts when spasticity was present. INTERPRETATION: These results support the hypothesis that preservation of descending motor pathways influences spasticity in humans with motor complete SCI; this knowledge might help the rehabilitation and assessment of people with SCI. ANN NEUROL 2019.

Gating of Sensory Input at Subcortical and Cortical Levels during Grasping in Humans.

Afferent input from the periphery to the cortex contributes to the control of grasping. How sensory input is gated along the ascending sensory pathway and its functional role during gross and fine grasping in humans remain largely unknown. To address this question, we assessed somatosensory-evoked potential components reflecting activation at subcortical and cortical levels and psychophysical tests at rest, during index finger abduction, precision, and power grip. We found that sensory gating at subcortical level and in the primary somatosensory cortex (S1), as well as intracortical inhibition in the S1, increased during power grip compared with the other tasks. To probe the functional relevance of gating in the S1, we examined somatosensory temporal discrimination threshold by measuring the shortest time interval to perceive a pair of electrical stimuli. Somatosensory temporal discrimination threshold increased during power grip, and higher threshold was associated with increased intracortical inhibition in the S1. These novel findings indicate that humans gate sensory input at subcortical level and in the S1 largely during gross compared with fine grasping. Inhibitory processes in the S1 may increase discrimination threshold to allow better performance during power grip.SIGNIFICANCE STATEMENT Most of our daily life actions involve grasping. Here, we demonstrate that gating of afferent input increases at subcortical level and in the primary somatosensory cortex (S1) during gross compared with fine grasping in intact humans. The precise timing of sensory information is critical for human perception and behavior. Notably, we found that the ability to perceive a pair of electrical stimuli, as measured by the somatosensory temporal discrimination threshold, increased during power grip compared with the other tasks. We propose that reduced afferent input to the S1 during gross grasping behaviors diminishes temporal discrimination of sensory processes related, at least in part, to increased inhibitory processes within the S1.