Dissociated cerebellar contributions to feedforward gait adaptation.

The cerebellum is important for motor adaptation. Lesions to the vestibulo-cerebellum selectively cause gait ataxia. Here we investigate how such damage affects locomotor adaptation when performing the 'broken escalator' paradigm. Following an auditory cue, participants were required to step from the fixed surface onto a moving platform (akin to an airport travellator). The experiment included three conditions: 10 stationary (BEFORE), 15 moving (MOVING) and 10 stationary (AFTER) trials. We assessed both behavioural (gait approach velocity and trunk sway after stepping onto the moving platform) and neuromuscular outcomes (lower leg muscle activity, EMG). Unlike controls, cerebellar patients showed reduced after-effects (AFTER trials) with respect to gait approach velocity and leg EMG activity. However, patients with cerebellar damage maintain the ability to learn the trunk movement required to maximise stability after stepping onto the moving platform (i.e., reactive postural behaviours). Importantly, our findings reveal that these patients could even initiate these behaviours in a feedforward manner, leading to an after-effect. These findings reveal that the cerebellum is crucial for feedforward locomotor control, but that adaptive locomotor behaviours learned via feedback (i.e., reactive) mechanisms may be preserved following cerebellum damage.

The Immediate and Short-Term Effects of Transcutaneous Spinal Cord Stimulation and Peripheral Nerve Stimulation on Corticospinal Excitability.

Rehabilitative interventions involving electrical stimulation show promise for neuroplastic recovery in people living with Spinal Cord Injury (SCI). However, the understanding of how stimulation interacts with descending and spinal excitability remain unclear. In this study we compared the immediate and short-term (within a few minutes) effects of pairing Transcranial Magnetic Stimulation (TMS) with transcutaneous Spinal Cord stimulation (tSCS) and Peripheral Nerve Stimulation (PNS) on Corticospinal excitability in healthy subjects. Three separate experimental conditions were assessed. In Experiment I, paired associative stimulation (PAS) was applied, involving repeated pairing of single pulses of TMS and tSCS, either arriving simultaneously at the spinal motoneurones (PAS0ms) or slightly delayed (PAS5ms). Corticospinal and spinal excitability, and motor performance, were assessed before and after the PAS interventions in 24 subjects. Experiment II compared the immediate effects of tSCS and PNS on corticospinal excitability in 20 subjects. Experiment III compared the immediate effects of tSCS with tSCS delivered at the same stimulation amplitude but modulated with a carrier frequency (in the kHz range) on corticospinal excitability in 10 subjects. Electromyography (EMG) electrodes were placed over the Tibialis Anterior (TA) soleus (SOL) and vastus medialis (VM) muscles and stimulation electrodes (cathodes) were placed on the lumbar spine (tSCS) and lateral to the popliteal fossa (PNS). TMS over the primary motor cortex (M1) was paired with tSCS or PNS to produce Motor Evoked Potentials (MEPs) in the TA and SOL muscles. Simultaneous delivery of repetitive PAS (PAS0ms) increased corticospinal excitability and H-reflex amplitude at least 5 min after the intervention, and dorsiflexion force was increased in a force-matching task. When comparing effects on descending excitability between tSCS and PNS, a subsequent facilitation in MEPs was observed following tSCS at 30-50 ms which was not present following PNS. To a lesser extent this facilitatory effect was also observed with HF- tSCS at subthreshold currents. Here we have shown that repeated pairing of TMS and tSCS can increase corticospinal excitability when timed to arrive simultaneously at the alpha-motoneurone and can influence functional motor output. These results may be useful in optimizing stimulation parameters for neuroplasticity in people living with SCI.

Potentiating paired corticospinal-motoneuronal plasticity after spinal cord injury.

BACKGROUND: Paired corticospinal-motoneuronal stimulation (PCMS) increases corticospinal transmission in humans with chronic incomplete spinal cord injury (SCI). OBJECTIVE/HYPOTHESIS: Here, we examine whether increases in the excitability of spinal motoneurons, by performing voluntary activity, could potentiate PCMS effects on corticospinal transmission. METHODS: During PCMS, we used 100 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the hand representation of the primary motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the first dorsal interosseous (FDI) muscle ∼1-2 ms before antidromic potentials were elicited in motoneurons by electrical stimulation of the ulnar nerve. PCMS was applied at rest (PCMSrest) and during a small level of isometric index finger abduction (PCMSactive) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the FDI muscle before and after each protocol in humans with and without (controls) chronic cervical SCI. RESULTS: We found in control participants that MEPs elicited by TMS and electrical stimulation increased to a similar extent after both PCMS protocols for ∼30 min. Whereas, in humans with SCI, MEPs elicited by TMS and electrical stimulation increased to a larger extent after PCMSactive compared with PCMSrest. Importantly, SCI participants who did not respond to PCMSrest responded after PCMSactive and those who responded to both protocols showed larger increments in corticospinal transmission after PCMSactive. CONCLUSIONS: Our findings suggest that muscle contraction during PCMS potentiates corticospinal transmission. PCMS applied during voluntary activity may represent a strategy to boost spinal plasticity after SCI.

Grasp-specific motor resonance is influenced by the visibility of the observed actor.

Motor resonance is the modulation of M1 corticospinal excitability induced by observation of others' actions. Recent brain imaging studies have revealed that viewing videos of grasping actions led to a differential activation of the ventral premotor cortex depending on whether the entire person is viewed versus only their disembodied hand. Here we used transcranial magnetic stimulation (TMS) to examine motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) during observation of videos or static images in which a whole person or merely the hand was seen reaching and grasping a peanut (precision grip) or an apple (whole hand grasp). Participants were presented with six visual conditions in which visual stimuli (video vs static image), view (whole person vs hand) and grasp (precision grip vs whole hand grasp) were varied in a 2 × 2 × 2 factorial design. Observing videos, but not static images, of a hand grasping different objects resulted in a grasp-specific interaction, such that FDI and ADM MEPs were differentially modulated depending on the type of grasp being observed (precision grip vs whole hand grasp). This interaction was present when observing the hand acting, but not when observing the whole person acting. Additional experiments revealed that these results were unlikely to be due to the relative size of the hand being observed. Our results suggest that observation of videos rather than static images is critical for motor resonance. Importantly, observing the whole person performing the action abolished the grasp-specific effect, which could be due to a variety of PMv inputs converging on M1.

A Causal Role for Primary Motor Cortex in Perception of Observed Actions.

It has been proposed that motor system activity during action observation may be modulated by the kinematics of observed actions. One purpose of this activity during action observation may be to predict the visual consequence of another person's action based on their movement kinematics. Here, we tested the hypothesis that the primary motor cortex (M1) may have a causal role in inferring information that is present in the kinematics of observed actions. Healthy participants completed an action perception task before and after applying continuous theta burst stimulation (cTBS) over left M1. A neurophysiological marker was used to quantify the extent of M1 disruption following cTBS and stratify our sample a priori to provide an internal control. We found that a disruption to M1 caused a reduction in an individual's sensitivity to interpret the kinematics of observed actions; the magnitude of suppression of motor excitability predicted this change in sensitivity.

Subcortical control of precision grip after human spinal cord injury.

The motor cortex and the corticospinal system contribute to the control of a precision grip between the thumb and index finger. The involvement of subcortical pathways during human precision grip remains unclear. Using noninvasive cortical and cervicomedullary stimulation, we examined motor evoked potentials (MEPs) and the activity in intracortical and subcortical pathways targeting an intrinsic hand muscle when grasping a small (6 mm) cylinder between the thumb and index finger and during index finger abduction in uninjured humans and in patients with subcortical damage due to incomplete cervical spinal cord injury (SCI). We demonstrate that cortical and cervicomedullary MEP size was reduced during precision grip compared with index finger abduction in uninjured humans, but was unchanged in SCI patients. Regardless of whether cortical and cervicomedullary stimulation was used, suppression of the MEP was only evident 1-3 ms after its onset. Long-term (∼5 years) use of the GABAb receptor agonist baclofen by SCI patients reduced MEP size during precision grip to similar levels as uninjured humans. Index finger sensory function correlated with MEP size during precision grip in SCI patients. Intracortical inhibition decreased during precision grip and spinal motoneuron excitability remained unchanged in all groups. Our results demonstrate that the control of precision grip in humans involves premotoneuronal subcortical mechanisms, likely disynaptic or polysynaptic spinal pathways that are lacking after SCI and restored by long-term use of baclofen. We propose that spinal GABAb-ergic interneuronal circuits, which are sensitive to baclofen, are part of the subcortical premotoneuronal network shaping corticospinal output during human precision grip.

Aberrant crossed corticospinal facilitation in muscles distant from a spinal cord injury.

Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI.

Selective effects of baclofen on use-dependent modulation of GABAB inhibition after tetraplegia.

Baclofen is a GABAB receptor agonist commonly used to relief spasticity related to motor disorders. The effects of baclofen on voluntary motor output are limited and not yet understood. Using noninvasive transcranial magnetic and electrical stimulation techniques, we examined electrophysiological measures probably involving GABAB (long-interval intracortical inhibition and the cortical silent period) and GABAA (short-interval intracortical inhibition) receptors, which are inhibitory effects mediated by subcortical and cortical mechanisms. We demonstrate increased active long-interval intracortical inhibition and prolonged cortical silent period during voluntary activity of an intrinsic finger muscle in humans with chronic incomplete cervical spinal cord injury (SCI) compared with age-matched controls, whereas resting long-interval intracortical inhibition was unchanged. However, long-term (~6 years) use of baclofen decreased active long-interval intracortical inhibition to similar levels as controls but did not affect the duration of the cortical silent period. We found a correlation between signs of spasticity and long-interval intracortical inhibition in patients with SCI. Short-interval intracortical inhibition was decreased during voluntary contraction compared with rest but there was no effect of SCI or baclofen use. Together, these results demonstrate that baclofen selectively maintains use-dependent modulation of largely subcortical but not cortical GABAB neuronal pathways after human SCI. Thus, cortical GABA(B) circuits may be less sensitive to baclofen than spinal GABAB circuits. This may contribute to the limited effects of baclofen on voluntary motor output in subjects with motor disorders affected by spasticity.

Motor recovery after spinal cord injury enhanced by strengthening corticospinal synaptic transmission.

The corticospinal tract is an important target for motor recovery after spinal cord injury (SCI) in animals and humans. Voluntary motor output depends on the efficacy of synapses between corticospinal axons and spinal motoneurons, which can be modulated by the precise timing of neuronal spikes. Using noninvasive techniques, we developed tailored protocols for precise timing of the arrival of descending and peripheral volleys at corticospinal-motoneuronal synapses of an intrinsic finger muscle in humans with chronic incomplete SCI. We found that arrival of presynaptic volleys prior to motoneuron discharge enhanced corticospinal transmission and hand voluntary motor output. The reverse order of volley arrival and sham stimulation did not affect or decreased voluntary motor output and electrophysiological outcomes. These findings are the first demonstration that spike timing-dependent plasticity of residual corticospinal-motoneuronal synapses provides a mechanism to improve motor function after SCI. Modulation of residual corticospinal-motoneuronal synapses may present a novel therapeutic target for enhancing voluntary motor output in motor disorders affecting the corticospinal tract.

Impaired crossed facilitation of the corticospinal pathway after cervical spinal cord injury.

In uninjured humans, it is well established that voluntary contraction of muscles on one side of the body can facilitate transmission in the contralateral corticospinal pathway. This crossed facilitatory effect may favor interlimb coordination and motor performance. Whether this aspect of corticospinal function is preserved after chronic spinal cord injury (SCI) is unknown. Here, using transcranial magnetic stimulation, we show in patients with chronic cervical SCI (C(5)-C(8)) that the size of motor evoked potentials (MEPs) in a resting intrinsic hand muscle remained unchanged during increasing levels of voluntary contraction with a contralateral distal or proximal arm muscle. In contrast, MEP size in a resting hand muscle was increased during the same motor tasks in healthy control subjects. The magnitude of voluntary electromyography was negatively correlated with MEP size after chronic cervical SCI and positively correlated in healthy control subjects. To examine the mechanisms contributing to MEP crossed facilitation we examined short-interval intracortical inhibition (SICI), interhemispheric inhibition (IHI), and motoneuronal behavior by testing F waves and cervicomedullary MEPs (CMEPs). During strong voluntary contractions SICI was unchanged after cervical SCI and decreased in healthy control subjects compared with rest. F-wave amplitude and persistence and CMEP size remained unchanged after cervical SCI and increased in healthy control subjects compared with rest. In addition, during strong voluntary contractions IHI was unchanged in cervical SCI compared with rest. Our results indicate that GABAergic intracortical circuits, interhemispheric glutamatergic projections between motor cortices, and excitability of index finger motoneurons are neural mechanisms underlying, at least in part, the lack of crossed corticospinal facilitation observed after SCI. Our data point to the spinal motoneurons as a critical site for modulating corticospinal transmission after chronic cervical SCI.

Locomotor adaptation and aftereffects in patients with reduced somatosensory input due to peripheral neuropathy.

We studied 12 peripheral neuropathy patients (PNP) and 13 age-matched controls with the "broken escalator" paradigm to see how somatosensory loss affects gait adaptation and the release and recovery ("braking") of the forward trunk overshoot observed during this locomotor aftereffect. Trunk displacement, foot contact signals, and leg electromyograms (EMGs) were recorded while subjects walked onto a stationary sled (BEFORE trials), onto the moving sled (MOVING or adaptation trials), and again onto the stationary sled (AFTER trials). PNP were unsteady during the MOVING trials, but this progressively improved, indicating some adaptation. During the after trials, 77% of control subjects displayed a trunk overshoot aftereffect but over half of the PNP (58%) did not. The PNP without a trunk aftereffect adapted to the MOVING trials by increasing distance traveled; subsequently this was expressed as increased distance traveled during the aftereffect rather than as a trunk overshoot. This clear separation in consequent aftereffects was not seen in the normal controls suggesting that, as a result of somatosensory loss, some PNP use distinctive strategies to negotiate the moving sled, in turn resulting in a distinct aftereffects. In addition, PNP displayed earlier than normal anticipatory leg EMG activity during the first after trial. Although proprioceptive inputs are not critical for the emergence or termination of the aftereffect, somatosensory loss induces profound changes in motor adaptation and anticipation. Our study has found individual differences in adaptive motor performance, indicative that PNP adopt different feed-forward gait compensatory strategies in response to peripheral sensory loss.

What the "broken escalator" phenomenon teaches us about balance.

Gait adaptation is crucial for coping with varying terrain and biological needs. It is also important that any acquired adaptation is expressed only in the appropriate context. Here we review a recent series of experiments that demonstrate inappropriate expression of gait adaptation. We show that a brief period of walking onto a platform previously experienced as moving results in a large forward sway aftereffect, despite full awareness of the changing context. The adaptation mechanisms involved in this paradigm are extremely fast, just 1-2 discrete exposures to the moving platform result in the motor aftereffect. This aftereffect occurs even if subjects deliberately attempt to suppress it. However, it disappears when the location or method of gait is altered, indicating that aftereffect expression is context dependent. Conversely, making gait self-initiated increases sway during the aftereffect. This aftereffect demonstrates a profound dissociation between knowledge and action. The absence of generalization suggests a relatively simple form of motor learning, albeit involving high-level processing by cortical and cerebellar structures.

Visuo-vestibular influences on the moving platform locomotor aftereffect.

After walking onto a moving platform subjects experience a locomotor aftereffect (LAE), including a self-generated stumble, when walking again onto a stationary platform. Thus this LAE affords examination of the role of vestibular input during an internally generated postural challenge. The experiments involved walking onto the stationary sled (BEFORE trials), walking onto the moving sled (MOVING), and a second set of stationary trials (AFTER). We investigated 9 bilateral labyrinthine defective subjects (LDS) and 13 age-matched normal controls (NC) with eyes open. We repeated the experiment in 5 NC and 5 LDS but this time the AFTER trials were performed twice, first eyes closed and then on eye reopening. During MOVING trials, LDS were considerably unstable, thus confirming the established role of the vestibular system during externally imposed postural perturbations. During AFTER trials, both groups experienced an aftereffect with eyes open and closed, shown as higher approach gait velocity, a forward trunk overshoot, and increased leg EMG. However, there were no significant group differences due to the fact that stopping the forward trunk overshoot was accomplished by anticipatory EMG bursts. On eye reopening the aftereffect re-emerged, significantly larger in LDS than that in NC. The lack of group differences in AFTER trials suggests that when facing internally generated postural perturbations, as in this adaptation process, the CNS relies less on vestibular feedback and more on anticipatory mechanisms. Reemergence of the aftereffect on eye reopening indicates the existence of a feedforward visuo-contextual mechanism for locomotor learning, which is adaptively enhanced in the absence of vestibular function.