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.

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.

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.

Changes in motor-evoked potential latency during grasping after tetraplegia.

The corticospinal pathway contributes to the control of grasping in intact humans. After spinal cord injury (SCI), there is an extensive reorganization in the corticospinal pathway; however, its contribution to the control of grasping after the injury remains poorly understood. We addressed this question by using transcranial magnetic stimulation (TMS) over the hand representation of the motor cortex to elicit motor-evoked potentials (MEPs) in an intrinsic finger muscle during precision grip and power grip with the TMS coil oriented to induce currents in the brain in the latero-medial (LM) direction to activate corticospinal axons directly and in the posterior-anterior (PA) and anterior-posterior (AP) directions to activate the axon indirectly through synaptic inputs in humans with and without cervical incomplete SCI. We found prolonged MEP latencies in all coil orientations in both tasks in SCI compared with control subjects. The latencies of MEPs elicited by AP relative to LM stimuli were consistently longer during power compared with precision grip in controls and SCI subjects. In contrast, PA relative to LM MEP latencies were similar between tasks across groups. Central conduction time of AP MEPs was prolonged during power compared with precision grip in controls and SCI participants. Our results support evidence indicating that inputs activated by AP and PA currents are engaged to a different extent during fine and gross grasping in humans with and without SCI.NEW & NOTEWORTHY The mechanisms contributing to the control of hand function in humans with spinal cord injury (SCI) remain poorly understood. Here, we demonstrate for the first time that the latency of corticospinal responses elicited by transcranial magnetic stimulation anterior-posterior induced currents, relative to latero-medial currents, was prolonged during power compared with precision grip in humans with and without SCI. Gross grasping might represent a stragegy to engage networks activated by anterior-posterior currents after SCI.

Effect of coil orientation on motor-evoked potentials in humans with tetraplegia.

KEY POINTS: Although corticospinal function changes following spinal cord injury (SCI), the extent to which we can activate the corticospinal tract after injury remains poorly understood. To address this question, we used transcranial magnetic stimulation over the hand representation of the primary motor cortex to elicit motor-evoked potentials (MEPs) using posterior-anterior and anterior-posterior induced currents in the brain and compared them with responses evoked using lateral-medial currents in participants with and without cervical incomplete SCI during small levels of index finger abduction. We found prolonged MEP latencies in all coil orientations in SCI compared to control subjects. However, the latencies of MEPs elicited by posterior-anterior and anterior-posterior compared to lateral-medial stimulation were shorter in SCI compared to controls, particularly for MEPs elicited by anterior-posterior currents. Our findings demonstrate for the first time that corticospinal responses elicited by different directions of the induced current in the brain are differentially affected after SCI. ABSTRACT: The corticospinal tract undergoes reorganization following spinal cord injury (SCI). However, the extent to which we can activate corticospinal neurons using non-invasive stimulation after injury remains poorly understood. To address this question, we used transcranial magnetic stimulation over the hand representation of the primary motor cortex to elicit motor-evoked potentials (MEPs) using posterior-anterior (PA) and anterior-posterior (AP) induced currents in the brain and compared them with the responses evoked by direct activation of corticospinal axons using lateral-medial (LM) currents. Testing was completed during small levels of index finger abduction in humans with and without (controls) cervical incomplete SCI. We found prolonged MEP latencies in individuals with SCI in all coil orientations compared to controls. However, latencies of MEPs elicited by PA and AP stimulation relative to those elicited by LM stimulation were shorter in SCI compared to control subjects. Notably, the largest difference between SCI and control subjects was present in MEPs elicited by AP currents. Using a novel controllable pulse parameter transcranial magnetic stimulation, we also found that MEPs elicited by AP currents with 30 µs compared to 60 and 120 µs pulse width had increased latency in controls but not in SCI subjects. Our findings demonstrate that differences between corticospinal responses elicited by AP and PA induced currents were not preserved in humans with tetraplegia and suggest that neural structures activated by AP currents change largely after the injury.

Prehension synergies and hand function in early-stage Parkinson's disease.

We explored the multi-digit synergies and hand performance in object manipulations and pressing tasks in patients with early-stage Parkinson's disease (PD) and healthy controls. Synergies were defined as inter-trials co-variation patterns among forces/moments produced by individual digits that stabilized a resultant mechanical variable. The subjects performed three main tasks: pressing (steady-state force production followed by a force pulse into the target), prehension (manipulation of a handheld instrumented handle imitating the action of taking a sip from a glass), and functional object manipulation (moving a glass with water as quickly and accurately as possible along a chain of targets). The PD patients were slower compared to controls in all three tasks. Patients showed smaller synergy indices in the pressing and prehension tasks. In the prehension tasks, patients showed elevated grip force at steady states with smaller grip force modulation during the handle motion. PD patients showed smaller feed-forward synergy adjustments in preparation to the quick action in the pressing and (to a smaller degree) prehension tasks. Synergy indices correlated with the time index of performance in the functional glass-with-water task, whereas none of the indices correlated with the Unified PD Rating Scale part III-motor scores. We interpret the results as pointing at an important role of subcortical structures in motor synergies and their feed-forward adjustments to action.

Effects of Parkinson's disease on optimization and structure of variance in multi-finger tasks.

We explored the role of the basal ganglia in two components of multi-finger synergies by testing a group of patients with early-stage Parkinson's disease and a group of healthy controls. Synergies were defined as co-varied adjustments of commands to individual fingers that reduced variance of the total force and moment of force. The framework of the uncontrolled manifold hypothesis was used to quantify such co-variation patterns, while average performance across repetitive trials (sharing patterns) was analyzed using the analytical inverse optimization (ANIO) approach. The subjects performed four-finger pressing tasks that involved the accurate production of combinations of the total force and total moment of force and also repetitive trials at two selected combinations of the total force and moment. The ANIO approach revealed significantly larger deviations of the experimental data planes from an optimal plane for the patients compared to the control subjects. The synergy indices computed for total force stabilization were significantly higher in the control subjects compared to the patients; this was not true for synergy indices computed for moment of force stabilization. The differences in the synergy indices were due to the larger amount of variance that affected total force in the patients, while the amount of variance that did not affect total force was comparable between the groups. We conclude that the basal ganglia play an important role in both components of synergies reflecting optimization of the sharing patterns and stability of performance with respect to functionally important variables.

A kinematic analysis of relative stability of the lower extremities between subjects with and without chronic low back pain.

Even though a number of studies have evaluated postural adjustments based on kinematic changes in subjects with low back pain (LBP), kinematic stability has not been examined for abnormal postural responses during the one leg standing test. The purpose of this study was to evaluate the relative kinematic stability of the lower extremities and standing duration in subjects with and without chronic LBP. In total, 54 subjects enrolled in the study, including 28 subjects without LBP and 26 subjects with LBP. The average age of the subjects was 37.8 ± 12.6 years and ranged from 19 to 63 years. The outcome measures included normalized holding duration and relative kinematic stability. All participants were asked to maintain the test position without visual input (standing on one leg with his/her eyes closed and with the contra lateral hip flexed 90°) for 25 s. The age variable was used as a covariate to control confounding effects for the data analyses. The control group demonstrated significantly longer holding duration times (T = -2.78, p = 0.007) than the LBP group (24.6 ± 4.2 s vs. 20.5 ± 6.7 s). For the relative kinematic stability, there was a difference in dominance side (F = 9.91, p = 0.003). There was a group interaction between side and lower extremities (F = 11.79, p = 0.001) as well as an interaction between age and dominance side (F = 7.91, p = 0.007). The relative kinematic stability had a moderate negative relationship with age (r = -0.60, p = 0.007) in subjects without LBP. Clinicians need to understand the effects of age and relative stability, which decreased significantly in the single leg holding test, in subjects with LBP in order to develop effective rehabilitation strategies.

Paired corticospinal-motoneuronal stimulation and exercise after spinal cord injury.

CONTEXT: Rehabilitation after spinal cord injury (SCI) relies on the use of exercise training, which has limited functional gains. There is a need to develop more efficient approaches to facilitate recovery after SCI. METHODS: This review focuses on a neuromodulation method where transcranial magnetic stimulation (TMS) over the primary motor cortex is paired with transcutaneous electrical stimulation over a peripheral nerve to induce plasticity at corticospinal-motoneuronal synapses. These two stimuli are applied at precise inter-stimulus intervals to reinforce corticospinal synaptic transmission using principles of spike-timing-dependent plasticity applied alone or in combination with exercise training. RESULTS: Transmission in residual corticospinal axons, assessed using TMS and maximal voluntary motor output, increased after stimulation combined with exercise training in persons with SCI. There were also significant improvements in functional outcomes, including walking speed and grasping function, which persisted after 6-9 months post stimulation. Moreover, the data suggested that the effects of the stimulation protocol can be augmented with a higher number of sessions and with multiple stimulation sites in the spinal cord. CONCLUSIONS: Voluntary movement is enhanced in people with SCI through the strengthening of corticospinal-motoneuronal synapses using paired stimulation. This neuromodulation technique represents a novel powerful strategy to facilitate functional recovery after SCI.

The Potential of Corticospinal-Motoneuronal Plasticity for Recovery after Spinal Cord Injury.

PURPOSE OF REVIEW: This review focuses on a relatively new neuromodulation method where transcranial magnetic stimulation over the primary motor cortex is paired with transcutaneous electrical stimulation over a peripheral nerve to induce plasticity at corticospinal-motoneuronal synapses. RECENT FINDINGS: Recovery of sensorimotor function after spinal cord injury largely depends on transmission in the corticospinal pathway. Significantly damaged corticospinal axons fail to regenerate and participate in functional recovery. Transmission in residual corticospinal axons can be assessed using non-invasive transcranial magnetic stimulation which combined with transcutaneous electrical stimulation can be used to improve voluntary motor output, as was recently demonstrated in clinical studies in humans with chronic incomplete spinal cord injury. These two stimuli are applied at precise inter-stimulus intervals to reinforce corticospinal synaptic transmission using principles of spike-timing dependent plasticity. SUMMARY: We discuss the neural mechanisms and application of this neuromodulation technique and its potential therapeutic effect on recovery of function in humans with chronic spinal cord injury.

Systemic effects of deep brain stimulation on synergic control in Parkinson's disease.

OBJECTIVE: We explored effects of deep brain stimulation (DBS) in patients with Parkinson's disease (PD) on the synergic control of fingers in a multi-finger force production task and of muscles in a task involving vertical posture. METHODS: The finger task involved the four fingers of a hand producing accurate total force followed by a targeted quick force pulse. The postural task involved releasing a load from extended arms. The analysis of synergies was performed within the framework of the uncontrolled manifold hypothesis. RESULTS: DBS led to no significant changes in indices of stability during steady-state phases. In contrast, DBS improved indices of agility, quantified as anticipatory synergy adjustments that reduced stability of salient performance variables in preparation to their quick change. There were moderate-to-strong correlations between indices of both stability and agility measured in the multi-finger force production and multi-muscle whole-body action. CONCLUSIONS: Our results point at systemic changes in synergic control in PD. They show that DBS is effective in improving only one components of synergic control related to agility in performance being relatively ineffective for the stability component. SIGNIFICANCE: The results show systemic brain mechanisms of synergies and suggest differential effects of DBS on indices of stability and agility.

Changes in Multidigit Synergies and Their Feed-Forward Adjustments in Multiple Sclerosis.

The authors explored the changes in multidigit synergies in patients with multiple sclerosis (MS) within the framework of the uncontrolled manifold hypothesis. The specific hypotheses were that both synergy indices and anticipatory synergy adjustments prior to the initiation of a self-paced quick action would be diminished in the patients compared to age-matched controls. The MS patients and age-matched controls (n = 13 in both groups) performed one-finger and multifinger force production tasks involving both accurate steady-state force production and quick force pulses. The patients showed significantly lower maximal finger forces and a tendency toward slower force pulses. Enslaving was increased in MS, but only in the lateral fingers (index and little). Indices of multifinger synergies during steady-state force production were lower in MS, mainly due to the lower amount of intertrial variance that did not affect total force. Anticipatory synergy adjustments were significantly delayed in MS. The results show that MS leads to significant changes in multidigit synergies and feed-forward adjustments of the synergies prior to a quick action. The authors discuss possible contributions of subcortical structures to the impaired synergic control.

Finger force changes in the absence of visual feedback in patients with Parkinson's disease.

OBJECTIVES: We investigated the unintentional drift in total force and in sharing of the force between fingers in two-finger accurate force production tasks performed without visual feedback by patients with Parkinson's disease (PD) and healthy controls. In particular, we were testing a hypothesis that adaptation to the documented loss of action stability could lead to faster force drop in PD. METHODS: PD patients and healthy controls performed accurate constant force production tasks without visual feedback by different finger pairs, starting with different force levels and different sharing patterns of force between the two fingers. RESULTS: Both groups showed an exponential force drop with time and a drift of the sharing pattern towards 50:50. The PD group showed a significantly faster force drop without a change in speed of the sharing drift. These results were consistent across initial force levels, sharing patterns, and finger pairs. A pilot test of four subjects, two PD and two controls, showed no consistent effects of memory on the force drop. CONCLUSIONS: We interpret the force drop as a consequence of back-coupling between the actual and referent finger coordinates that draws the referent coordinate towards the actual one. The faster force drop in the PD group is interpreted as adaptive to the loss of action stability in PD. The lack of group differences in the sharing drift suggests two potentially independent physiological mechanisms contributing to the force and sharing drifts. SIGNIFICANCE: The hypothesis on adaptive changes in PD with the purpose to ensure stability of steady states may have important implications for treatment of PD. The speed of force drop may turn into a useful tool to quantify such adaptive changes.

Synergy as a new and sensitive marker of basal ganglia dysfunction: A study of asymptomatic welders.

BACKGROUND: Multi-digit synergies, a recently developed, theory-based method to quantify stability of motor action, are shown to reflect basal ganglia dysfunction associated with parkinsonian syndromes. In this study, we tested the hypothesis that multi-digit synergies may capture early and subclinical basal ganglia dysfunction. We chose asymptomatic welders to test the hypothesis because the basal ganglia are known to be most susceptible to neurotoxicity caused by welding-related metal accumulation (such as manganese and iron). METHODS: Twenty right-handed welders and 13 matched controls were invited to perform single- and multi-finger pressing tasks using the fingers of the right or left hand. Unified Parkinson's Disease Rating Scale and Grooved Pegboard scores were used to gauge gross and fine motor dysfunction, respectively. High-resolution (3T) T1-weighted, T2-weighted, T1 mapping, susceptibility, and diffusion tensor MRIs were obtained to reflect manganese, iron accumulation, and microstructural changes in basal ganglia. The synergy index stabilizing total force and anticipatory synergy adjustments were computed, compared between groups, and correlated with estimates of basal ganglia manganese [the pallidal index, R1 (1/T1)], iron [R2* (1/T2*)], and microstructural changes [fractional anisotropy and mean diffusivity]. RESULTS: There were no significant differences in Unified Parkinson's Disease Rating Scale (total or motor subscale) or Grooved Pegboard test scores between welders and controls. The synergy index during steady-state accurate force production was decreased significantly in the left hand of welders compared to controls (p=0.004) but did not reach statistical significance in the right hand (p=0.16). Anticipatory synergy adjustments, however, were not significantly different between groups. Among welders, higher synergy indices in the left hand were associated significantly with higher fractional anisotropy values in the left globus pallidus (R=0.731, p<0.001) but not with the pallidal index, R1, or R2* values in the basal ganglia. CONCLUSIONS: These data suggest that multi-digit synergy metrics may serve as preclinical markers for basal ganglia dysfunction in welders and other populations at risk for neurodegenerative diseases involving parkinsonian symptoms. This finding may have important clinical, scientific, and public/occupational health implications.

Three-dimensional kinematic analysis of pelvic and lower extremity differences during trunk rotation in subjects with and without chronic low back pain.

OBJECTIVE: To investigate three-dimensional angular changes of the pelvis and lower extremities during trunk axial rotation in subjects with and without chronic low back pain (LBP). DESIGN: Repeated-measures design. PARTICIPANTS: Thirty volunteers participated in the study (15 with LBP, 15 without LBP). The mean age of the subjects was 44 (standard deviation 15.8) years (range 27 to 63 years). MAIN OUTCOME MEASURES: All participants were asked to perform five sets of axial trunk rotation activities with a bar in a standing position. The outcome measures included three-dimensional rotational angles of the pelvis and lower extremities (foot, calf and thigh). RESULTS: The angular change of the pelvis in the sagittal plane differed between subjects with and without LBP (P=0.03). There were no significant differences in angular changes of the lower extremities in the frontal and transverse planes between groups. CONCLUSIONS: The angular change of the pelvis in the sagittal plane differed significantly between groups. Further research is needed to investigate the three-dimensional characteristics of biomechanical and neuromuscular aspects in subjects with LBP.