Impaired central drive to plantarflexors and minimal ankle proprioceptive deficit in people with multiple sclerosis.

BACKGROUND: A common and disruptive symptom of multiple sclerosis is difficulty in walking. Deficits in ankle proprioception and in plantarflexor muscle function may contribute to these mobility issues. In this study, ankle proprioceptive ability and plantarflexor performance of people with multiple sclerosis (PwMS) were compared to healthy controls to determine whether multiple sclerosis causes impairments in these systems. METHODS: PwMS (n = 30, median EDSS 4.0, IQR 2) were compared to age- and sex-matched healthy controls (n = 30) across tests of ankle proprioception and plantarflexor muscle performance. Proprioceptive tests: detection of passive movement, reaction time and ankle joint position sense. Plantarflexor performance: strength, fatigue, recovery and voluntary activation (level of neural drive) of the plantarflexor muscles, assessed through brief and sustained fatiguing (2 min) isometric maximal voluntary contractions with nerve stimulation to evoke superimposed and resting muscle twitches. RESULTS: PwMS had unimpaired movement detection and joint position sense but had a slower reaction time to respond with plantarflexion to an imposed ankle movement (between group difference = 0.11 [95% CI; 0.05 to 0.17] s). During brief, maximal contractions PwMS produced lower torque (difference = -25.1 [-42.0 to -8.2] Nm) with reduced voluntary activation (difference = -14.6 [-25.1 to -4.1]%) but no impairment of the muscle itself (resting twitch torque difference = 0.3 [-2.8 to 2.2] Nm). At the end of the fatiguing contraction, neural drive decreased for PwMS (-19.5 [-27.1 to -11.9]%, p <0.0001) but not for controls (-2.5 [-6.9 to 1.8]%, p = 0.242). Fatigue did not affect the resting twitch size for controls (-1.3 [-2.7 to -0.03] Nm, p = 0.134) or PwMS (-0.1 [-1.1 to 1.0] Nm, p = 0.90). CONCLUSIONS: PwMS showed no deficit in their ability to sense ankle position or imposed movements but were slow when a motor response was required. Their plantarflexor muscles produced similar torque with electrical stimulation but voluntary strength was impaired.  Both groups experienced overall fatigue following the 2-minute maximal voluntary contraction but PwMS also had significantly reduced neural drive indicating central fatigue. PwMS showed mainly central deficits in motor output at the ankle with little impairment of proprioceptive acuity.

High-intensity, low-frequency repetitive transcranial magnetic stimulation enhances excitability of the human corticospinal pathway.

Paired corticospinal-motoneuronal stimulation (PCMS) is the repeated pairing of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation to modify corticospinal synapses; however, it has yet to be determined whether PCMS modulates cortical excitability in a manner similar to paired-associative stimulation protocols. In this study, we first examined the effects of PCMS on adductor pollicis motor evoked potentials (MEPs). In experiment 1, on 2 separate days PCMS (repetitive, high-intensity TMS and ulnar nerve stimulation pairs; 1.5-ms interstimulus interval; 0.1 Hz) was compared with control conditioning of repetitive high-intensity TMS-only stimuli (0.1 Hz). Before and after conditioning, adductor pollicis MEPs were elicited using low-intensity TMS in three different coil orientations to preferentially activate corticospinal axons directly (thus bypassing cortical effects) or indirectly (cortical effects present). Unexpectedly, similar MEP increases were seen for all orientations on both PCMS (129 to 136% of baseline) and control days (108 to 129% of baseline). Given the common factor between conditioning protocols was repeated, high-intensity TMS, further experiments were performed to characterize this repetitive TMS (rTMS) protocol. In experiment 2, an intensity dependence of the rTMS protocol was revealed by a lack of change in MEPs elicited after repetitive low-intensity TMS (0.1 Hz; P = 0.37). In experiment 3, MEP recruitment curve and paired pulse analyses showed that the high-intensity rTMS protocol increased MEPs over a range of stimulus intensities but that effects were not accompanied by changes in intracortical inhibition or facilitation (P > 0.12). These experiments reveal a novel high-intensity, low-frequency rTMS protocol for enhancing corticospinal excitability.NEW & NOTEWORTHY In this study, we present a novel, intensity-dependent repetitive transcranial magnetic stimulation (rTMS) protocol that induces lasting, plastic changes within the corticospinal tract. High-intensity rTMS at a frequency of 0.1 Hz induces facilitation of motor evoked potentials (MEPs) lasting at least 35 min. Additionally, these changes are not limited only to small MEPs but occur throughout the recruitment curve. Finally, facilitation of MEPs following high-intensity rTMS does not appear to be due to changes in intracortical inhibition or facilitation.

The effect of paired corticospinal-motoneuronal stimulation on maximal voluntary elbow flexion in cervical spinal cord injury: an experimental study.

STUDY DESIGN: Randomised, controlled, crossover study. OBJECTIVES: Paired corticospinal-motoneuronal stimulation (PCMS) involves repeatedly pairing stimuli to corticospinal neurones and motoneurones to induce changes in corticospinal transmission. Here, we examined whether PCMS could enhance maximal voluntary elbow flexion in people with cervical spinal cord injury. SETTING: Neuroscience Research Australia, Sydney, Australia. METHODS: PCMS comprised 100 pairs of transcranial magnetic and electrical peripheral nerve stimulation (0.1 Hz), timed so corticospinal potentials arrived at corticospinal-motoneuronal synapses 1.5 ms before antidromic motoneuronal potentials. On two separate days, sets of five maximal elbow flexions were performed by 11 individuals with weak elbow flexors post C4 or C5 spinal cord injury before and after PCMS or control (100 peripheral nerve stimuli) conditioning. During contractions, supramaximal biceps brachii stimulation elicited superimposed twitches, which were expressed as a proportion of resting twitches to give maximal voluntary activation. Maximal torque and electromyographic activity were also assessed. RESULTS: Baseline median (range) maximal torque was 11 Nm (6-41 Nm) and voluntary activation was 92% (62-99%). Linear mixed modelling revealed no significant differences between PCMS and control protocols after conditioning (maximal torque: p = 0.87, superimposed twitch: p = 0.87, resting twitch: p = 0.44, voluntary activation: p = 0.36, biceps EMG: p = 0.25, brachioradialis EMG: 0.67). CONCLUSIONS: Possible explanations for the lack of effect include a potential ceiling effect for voluntary activation, or that PCMS may be less effective for elbow flexors than distal muscles. Despite results, previous studies suggest that PCMS is worthy of further investigation.

Elbow angle modulates corticospinal excitability to the resting biceps brachii at both spinal and supraspinal levels.

NEW FINDINGS: What is the central question of this study? Corticospinal excitability to biceps brachii is known to modulate according to upper-limb posture. Here, cervicomedullary stimulation was used to investigate potential spinal contributions to elbow angle-dependent changes in corticospinal excitability at rest. What is the main finding and its importance? At more extended elbow angles, biceps responses to cervicomedullary stimulation were decreased, whereas cortically evoked responses (normalized to cervicomedullary-evoked responses) were increased. Results suggest decreased spinal excitability but increased cortical excitability as the elbow is placed in a more extended position, an effect that is unlikely to be attributable to cutaneous stretch receptor activation. ABSTRACT: Corticospinal excitability to biceps brachii is known to modulate according to upper-limb posture. In study 1, our aim was to investigate potential spinal contributions to this modulation and the independent effect of elbow angle. Biceps responses to transcranial magnetic stimulation (motor evoked potentials; MEPs) and electrical cervicomedullary stimulation (cervicomedullary motor evoked potentials; CMEPs) were measured at five elbow angles ranging from full extension to 130 deg of flexion. In study 2, possible contributions of cutaneous stretch receptors to elbow angle-dependent excitability changes were investigated by eliciting MEPs and CMEPs in three conditions of skin stretch about the elbow (stretch to mimic full extension, no stretch or stretch to mimic flexion). Each study had 12 participants. Evoked potentials were acquired at rest, with participants seated, the shoulder flexed 90 deg and forearm supinated. The MEPs and CMEPs were normalized to maximal compound muscle action potentials. In study 1, as the elbow was moved to more extended positions, there were no changes in MEPs (P = 0.963), progressive decreases in CMEPs (P < 0.0001; CMEPs at 130 deg flexion ∼220% of full extension) and increases in the MEP/CMEP ratio (P = 0.019; MEP/CMEP at 130 deg flexion ∼20% of full extension). In study 2, there were no changes in MEPs (P = 0.830) or CMEPs (P = 0.209) between skin stretch conditions. Therefore, although results suggest a decrease in spinal and an increase in supraspinal excitability at more extended angles, the mechanism for these changes in corticospinal excitability to biceps is not cutaneous stretch receptor feedback.

Involvement of N-methyl-d-aspartate receptors in plasticity induced by paired corticospinal-motoneuronal stimulation in humans.

Plasticity can be induced at human corticospinal-motoneuronal synapses by delivery of repeated, paired stimuli to corticospinal axons and motoneurons in a technique called paired corticospinal-motoneuronal stimulation (PCMS). To date, the mechanisms of the induced plasticity are unknown. To determine whether PCMS-induced plasticity is dependent on N-methyl-d-aspartate receptors (NMDARs), the effect of the noncompetitive NMDAR antagonist dextromethorphan on PCMS-induced facilitation was assessed in a 2-day, double-blind, placebo-controlled experiment. PCMS consisted of 100 pairs of stimuli, delivered at an interstimulus interval that produces facilitation at corticospinal-motoneuronal synapses that excite biceps brachii motoneurons. Transcranial magnetic stimulation elicited corticospinal volleys, which were timed to arrive at corticospinal-motoneuronal synapses just before antidromic potentials elicited in motoneurons with electrical brachial plexus stimulation. To measure changes in the corticospinal pathway at a spinal level, biceps responses to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were measured before and for 30 min after PCMS. Individuals who displayed a ≥10% increase in CMEP size after PCMS on screening were eligible to take part in the 2-day experiment. After PCMS, there was a significant difference in CMEP area between placebo and dextromethorphan days ( P = 0.014). On the placebo day PCMS increased average CMEP areas to 127 ± 46% of baseline, whereas on the dextromethorphan day CMEP area was decreased to 86 ± 33% of baseline (mean ± SD; placebo: n = 11, dextromethorphan: n = 10). Therefore, dextromethorphan suppressed the facilitation of CMEPs after PCMS. This indicates that plasticity induced at synapses in the human spinal cord by PCMS may be dependent on NMDARs. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation can strengthen the synaptic connections between corticospinal axons and motoneurons at a spinal level in humans. The mechanism of the induced plasticity is unknown. In our 2-day, double-blind, placebo-controlled study we show that the N-methyl-d-aspartate receptor (NMDAR) antagonist dextromethorphan suppressed plasticity induced by paired corticospinal-motoneuronal stimulation, suggesting that an NMDAR-dependent mechanism is involved.

Paired corticospinal-motoneuronal stimulation increases maximal voluntary activation of human adductor pollicis.

Paired corticospinal-motoneuronal stimulation (PCMS), which delivers repeated pairs of transcranial magnetic stimuli (TMS) and maximal motor nerve stimuli, can alter corticospinal transmission to low-threshold motoneurons in the human spinal cord. To determine whether similar changes occur for high-threshold motoneurons, we tested whether maximal voluntary activation and force can be affected by PCMS in healthy individuals. On 2 separate days, healthy participants ( n = 14) performed brief thumb adduction maximal voluntary contractions (MVCs) before and after a control protocol (TMS only) or PCMS designed to facilitate corticospinal transmission to adductor pollicis. Peripheral nerve stimulation alone was not performed. During each MVC, a superimposed twitch was elicited by a supramaximal stimulus delivered to the ulnar nerve. With muscles relaxed following the maximal contraction, a similar stimulus elicited a resting twitch. Voluntary activation was calculated as (1 - superimposed twitch/resting twitch) × 100%. Although voluntary activation decreased over time in both conditions, the decrease was less after PCMS (-0.4 ± 4.1%) than after the control protocol (-4.9 ± 4.9%; P = 0.007). This was supported by a greater increase in electromyographic response after PCMS than control (7 ± 13% vs. -3 ± 10%; P = 0.043). However, maximal force was not affected. The findings indicate a modest effect of PCMS on maximal neural drive to adductor pollicis, suggesting that PCMS can affect corticospinal transmission to high-threshold motoneurons. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation (PCMS) induces changes in the human spinal cord. To date, the reported effects of PCMS have been limited to low-threshold motoneurons and low-force tasks in healthy and spinal cord injured individuals. For the first time, we show that these plastic changes are not limited to lower threshold motoneurons, but occur across the entire motoneuron pool as demonstrated by the increases in voluntary activation and muscle activity during maximal voluntary contractions of adductor pollicis.

Concurrent electrical cervicomedullary stimulation and cervical transcutaneous spinal direct current stimulation result in a stimulus interaction.

NEW FINDINGS: What is the central question of this study? We previously showed that the motor pathway is not modified after cervical transcutaneous spinal direct current stimulation (tsDCS) applied using anterior-posterior electrodes. Here, we examine the motor pathway during stimulation. What is the main finding and its importance? We show that electrically elicited muscle responses to cervicomedullary stimulation are modified during tsDCS, whereas magnetically elicited responses are not. Modelling reveals electrical field modifications during concurrent tsDCS and electrical cervicomedullary stimulation. Changes in muscle response probably result from electrical field modifications rather than physiological changes. Care should be taken when applying electrical stimuli simultaneously. Transcutaneous spinal direct current stimulation (tsDCS) can modulate neuronal excitability within the human spinal cord; however, few studies have used tsDCS at a cervical level. This study aimed to characterize cervical tsDCS further by observing its acute effects on motor responses to transcranial magnetic stimulation and cervicomedullary stimulation. In both studies 1 and 2, participants (study 1, n = 8, four female; and study 2, n = 8, three female) received two periods of 10 min, 3 mA cervical tsDCS on the same day through electrodes placed in an anterior-posterior configuration over the neck; one period with the cathode posterior (c-tsDCS) and the other with the anode posterior (a-tsDCS). In study 1, electrically elicited cervicomedullary motor evoked potentials (eCMEPs) and transcranial magnetic stimulation-elicited motor evoked potentials (MEPs) were measured in biceps brachii and flexor carpi radialis before, during and after each tsDCS period. In study 2, eCMEPs and magnetically elicited CMEPs (mCMEPs) were measured before, during and after each tsDCS period. For study 3, computational modelling was used to observe possible interactions of cervical tsDCS and electrical cervicomedullary stimulation. Studies 1 and 2 revealed that eCMEPs were larger during c-tsDCS and smaller during a-tsDCS compared with those elicited when tsDCS was off (P < 0.05), with no changes in MEPs or mCMEPs. Modelling revealed that eCMEP changes might result from modifications of the electrical field direction and magnitude when combined with cervical tsDCS. Bidirectional eCMEP changes are likely to be caused by an interaction between cervical tsDCS and electrical cervicomedullary stimulation; therefore, care should be taken when combining such electrical stimuli in close proximity.

The effects of cervical transcutaneous spinal direct current stimulation on motor pathways supplying the upper limb in humans.

Non-invasive, weak direct current stimulation can induce changes in excitability of underlying neural tissue. Many studies have used transcranial direct current stimulation to induce changes in the brain, however more recently a number of studies have used transcutaneous spinal direct current stimulation to induce changes in the spinal cord. This study further characterises the effects following cervical transcutaneous spinal direct current stimulation on motor pathways supplying the upper limb. In Study 1, on two separate days, participants (n = 12, 5 F) received 20 minutes of either real or sham direct current stimulation at 3 mA through electrodes placed in an anterior-posterior configuration over the neck (anode anterior). Biceps brachii, flexor carpi radialis and first dorsal interosseous responses to transcranial magnetic stimulation (motor evoked potentials) and cervicomedullary stimulation (cervicomedullary motor evoked potentials) were measured before and after real or sham stimulation. In Study 2, on two separate days, participants (n = 12, 7 F) received either real or sham direct current stimulation in the same way as for Study 1. Before and after real or sham stimulation, median nerve stimulation elicited M waves and H reflexes in the flexor carpi radialis. H-reflex recruitment curves and homosynaptic depression of the H reflex were assessed. Results show that the effects of real and sham direct current stimulation did not differ for motor evoked potentials or cervicomedullary motor evoked potentials for any muscle, nor for H-reflex recruitment curve parameters or homosynaptic depression. Cervical transcutaneous spinal direct current stimulation with the parameters described here does not modify motor responses to corticospinal stimulation nor does it modify H reflexes of the upper limb. These results are important for the emerging field of transcutaneous spinal direct current stimulation.