Corticospinal Volleys Research Articles

Is Intraoperative Muscle Motor Evoked Potential Variability due to Fluctuating Lower Motor Neuron Background Excitability?

This pilot study tests the contribution of fluctuating lower motor neuron excitability to motor evoked potential (MEP) variability. In six pediatric patients with idiopathic scoliosis and normal neurologic examination, cascades of 30 intraoperative H-reflexes (HRs) and MEPs were evoked in the soleus muscle using constant-current stimulators and recorded through surface electrodes with a 20-second interstimulus interval. First, HRs were obtained with an intensity capable of evoking the maximum response. Subsequently, MEPs were obtained with double trains and an intensity of 700 to 900 mA. Coefficients of variation (CVs) of amplitude and area under the curve from HRs and MEPs were compared using a paired two-tailed Student t test. Coefficients of correlation between the mean CVs of HR and MEP parameters were also assessed. Pooling the results from the six patients, the mean CV of amplitude from the MEP (24.6 ± 3) was significantly higher than that from the HR (3.5 ± 4.4) (P = 0.000091). The mean CV of the MEP area under the curve (21.8 ± 4.8) was also statistically significantly higher than that from the HR area under the curve (3.4 ± 4.5) (P = 0.00091). The coefficients of correlation of the mean CV of the HR amplitude and area under the curve compared with the corresponding values of the MEP were low (r = 0.29) and very low (r = 0.03), respectively. Our results suggest that fluctuations in lower motor neuron excitability may be less important than previously thought to explain the magnitude of MEP variability. The efficacy of corticospinal volleys to recruit a larger and more stable lower motor neuron population would be critical to obtain reproducible MEPs.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Pairing Transcranial Magnetic Stimulation and Loud Sounds Produces Plastic Changes in Motor Output.

Most current methods for neuromodulation target the cortex. Approaches for inducing plasticity in subcortical motor pathways, such as the reticulospinal tract, could help to boost recovery after damage (e.g., stroke). In this study, we paired loud acoustic stimulation (LAS) with transcranial magnetic stimulation (TMS) over the motor cortex in male and female healthy humans. LAS activates the reticular formation; TMS activates descending systems, including corticoreticular fibers. Two hundred paired stimuli were used, with 50 ms interstimulus interval at which LAS suppresses TMS responses. Before and after stimulus pairing, responses in the contralateral biceps muscle to TMS alone were measured. Ten, 20, and 30 min after stimulus pairing ended, TMS responses were enhanced, indicating the induction of LTP. No long-term changes were seen in control experiments which used 200 unpaired TMS or LAS, indicating the importance of associative stimulation. Following paired stimulation, no changes were seen in responses to direct corticospinal stimulation at the level of the medulla, or in the extent of reaction time shortening by a loud sound (StartReact effect), suggesting that plasticity did not occur in corticospinal or reticulospinal synapses. Direct measurements in female monkeys undergoing a similar paired protocol revealed no enhancement of corticospinal volleys after paired stimulation, suggesting no changes occurred in intracortical connections. The most likely substrate for the plastic changes, consistent with all our measurements, is an increase in the efficacy of corticoreticular connections. This new protocol may find utility, as it seems to target different motor circuits compared with other available paradigms.SIGNIFICANCE STATEMENT Induction of plasticity by neurostimulation protocols may be promising to enhance functional recovery after damage such as following stroke, but current protocols mainly target cortical circuits. In this study, we developed a novel paradigm which may generate long-term changes in connections between cortex and brainstem. This could provide an additional tool to modulate and improve recovery.

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.

Neurophysiological Changes After Paired Brain and Spinal Cord Stimulation Coupled With Locomotor Training in Human Spinal Cord Injury

Neurophysiological changes that involve activity-dependent neuroplasticity mechanisms via repeated stimulation and locomotor training are not commonly employed in research even though combination of interventions is a common clinical practice. In this randomized clinical trial, we established neurophysiological changes when transcranial magnetic stimulation (TMS) of the motor cortex was paired with transcutaneous thoracolumbar spinal (transspinal) stimulation in human spinal cord injury (SCI) delivered during locomotor training. We hypothesized that TMS delivered before transspinal (TMS-transspinal) stimulation promotes functional reorganization of spinal networks during stepping. In this protocol, TMS-induced corticospinal volleys arrive at the spinal cord at a sufficient time to interact with transspinal stimulation induced depolarization of alpha motoneurons over multiple spinal segments. We further hypothesized that TMS delivered after transspinal (transspinal-TMS) stimulation induces less pronounced effects. In this protocol, transspinal stimulation is delivered at time that allows transspinal stimulation induced action potentials to arrive at the motor cortex and affect descending motor volleys at the site of their origin. Fourteen individuals with motor incomplete and complete SCI participated in at least 25 sessions. Both stimulation protocols were delivered during the stance phase of the less impaired leg. Each training session consisted of 240 paired stimuli delivered over 10-min blocks. In transspinal-TMS, the left soleus H-reflex increased during the stance-phase and the right soleus H-reflex decreased at mid-swing. In TMS-transspinal no significant changes were found. When soleus H-reflexes were grouped based on the TMS-targeted limb, transspinal-TMS and locomotor training promoted H-reflex depression at swing phase, while TMS-transspinal and locomotor training resulted in facilitation of the soleus H-reflex at stance phase of the step cycle. Furthermore, both transspinal-TMS and TMS-transspinal paired-associative stimulation (PAS) and locomotor training promoted a more physiological modulation of motor activity and thus depolarization of motoneurons during assisted stepping. Our findings support that targeted non-invasive stimulation of corticospinal and spinal neuronal pathways coupled with locomotor training produce neurophysiological changes beneficial to stepping in humans with varying deficits of sensorimotor function after SCI.

Aspects of cortical area responsibilities while learning a visually cued spatiotemporal motor task.

Aspects of cortical area responsibilities while learning a visually cued spatiotemporal motor task.

Acute intermittent hypoxia boosts spinal plasticity in humans with tetraplegia

Paired corticospinal-motoneuronal stimulation (PCMS) elicits spinal synaptic plasticity in humans with chronic incomplete cervical spinal cord injury (SCI). Here, we examined whether PCMS-induced plasticity could be potentiated by acute intermittent hypoxia (AIH), a treatment also known to induce spinal synaptic plasticity in humans with chronic incomplete cervical SCI.During PCMS, we used 180 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation 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 the arrival of antidromic potentials elicited in motoneurons by electrical stimulation of the ulnar nerve. During AIH, participants were exposed to brief alternating episodes of hypoxic inspired gas (1 min episodes of 9% O2) and room air (1 min episodes of 20.9% O2). We examined corticospinal function by measuring motor evoked potentials (MEPs) elicited by cortical and subcortical stimulation of corticospinal axons and voluntary motor output in the FDI muscle before and after 30 min of PCMS combined with AIH (PCMS+AIH) or sham AIH (PCMS+sham-AIH). The amplitude of MEPs evoked by magnetic and electrical stimulation increased after both protocols, but most after PCMS+AIH, consistent with the hypothesis that their combined effects arise from spinal plasticity. Both protocols increased electromyographic activity in the FDI muscle to a similar extent. Thus, PCMS effects on spinal synapses of hand motoneurons can be potentiated by AIH. The possibility of different thresholds for physiological vs behavioral gains needs to be considered during combinatorial treatments.

Detecting cortical circuits resonant to high-frequency oscillations in the human primary motor cortex: a TMS-tACS study

Corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) consist of high-frequency bursts (≈667 and ≈333 Hz). However, intracortical circuits producing such corticospinal high-frequency bursts are unknown. We here investigated whether neurons activated by single TMS pulses over M1 are resonant to high-frequency oscillations, using a combined transcranial alternating current stimulation (tACS)-TMS approach. We applied 667, 333 Hz or sham-tACS and, concurrently, we delivered six single-pulse TMS protocols using monophasic or biphasic pulses, different stimulation intensities, muscular states, types and orientations of coils. We recorded motor evoked potentials (MEPs) before, during and after tACS. 333 Hz tACS facilitated MEPs evoked by biphasic TMS through a figure-of-eight coil at active motor threshold (AMT), and by monophasic TMS with anterior-to-posterior-induced current in the brain. 333 Hz tACS also facilitated MEPs evoked by monophasic TMS through a circular coil at AMT, an effect that weakly persisted after the stimulation. 667 Hz tACS had no effects. 333 Hz, but not 667 Hz, tACS may have reinforced the synchronization of specific neurons to high-frequency oscillations enhancing this activity, and facilitating MEPs. Our findings suggest that different bursting modes of corticospinal neurons are produced by separate circuits with different oscillatory properties.

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.

Non-invasive assessment of superficial and deep layer circuits in human motor cortex.

Key points The first indirect (I) corticospinal volley from stimulation of the motor cortex consists of two parts: one that originates from infragranular layer 5 and a subsequent part with a delay of 0.6 ms to which supragranular layers contribute.Non‐invasive probing of these two parts was performed in humans using a refined electrophysiological method involving transcranial magnetic stimulation and peripheral nerve stimulation.Activity modulation of these two parts during a sensorimotor discrimination task was consistent with previous results in monkeys obtained with laminar recordings. Circuits in superficial and deep layers play distinct roles in cortical computation, but current methods to study them in humans are limited. Here, we developed a novel approach for non‐invasive assessment of layer‐specific activity in the human motor cortex. We first conducted brain slice and in vivo experiments on monkey motor cortex to investigate the output timing from layer 5 (including corticospinal neurons) following extracellular stimulation. Neuron responses contained cyclical waves. The first wave was composed of two parts: the earliest part originated only from stimulation of layer 5; after 0.6 ms, stimuli to superficial layers 2/3 could also contribute. In healthy humans we then assessed different parts of the first corticospinal volley elicited by transcranial magnetic stimulation (TMS), by interacting TMS with stimulation of the median nerve generating an H‐reflex. By adjusting the delay between stimuli, we could assess the earliest volley evoked by TMS, and the part 0.6 ms later. Measurements were made while subjects performed a visuo‐motor discrimination task, which has been previously shown in monkey to modulate superficial motor cortical cells selectively depending on task difficulty. We showed a similar selective modulation of the later part of the TMS volley, as expected if this part of the volley is sensitive to superficial cortical excitability. We conclude that it is possible to segregate different cortical circuits which may refer to different motor cortex layers in humans, by exploiting small time differences in the corticospinal volleys evoked by non‐invasive stimulation.

Paired-pulse TMS mapping based on individual sulci shape, reveals corticomotor representations underpinning I-wave facilitation

Background: Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) evoke multiple corticospinal volleys, namely a direct wave (D-wave) and multiple indirect waves (I-waves). I-waves are thought to originate from monosynaptic activation of layer 5 pyramidal cells by excitatory layer 2-3 interneurons, but the spatial origin of I-waves is unknown.

Vestibulospinal and Corticospinal Modulation of Lumbosacral Network Excitability in Human Subjects.

As part of a project aimed to develop a novel, non-invasive techniques for comprehensive assessment of supraspinal-spinal connectivity in humans, the present study sought to explore the convergence of descending vestibulospinal and corticospinal pathways onto lumbosacral motor pools. Transcutaneous electrical spinal stimulation-evoked motor potentials were recorded from knee and ankle flexors and extensors in resting neurologically intact participants. Descending influences on lumbosacral motor neurons were studied using galvanic vestibular (GVS) or transcranial magnetic stimulation (TMS) to elicit descending vestibulospinal or corticospinal volleys, respectively. Facilitatory conditioning effects of descending corticospinal volleys were manifested by a significant increase of spinally evoked motor potentials in recorded knee and ankle muscles bilaterally, and were observed at the 10–30 ms conditioning-test intervals (CTIs); whereas, facilitatory conditioning effects of vestibulospinal volleys manifested at longer latencies (CTIs of 90 and 110 ms), and lasted up to 250 ms. TMS mediated volleys revealed the conditioning effects at both short and long latencies, suggestive of both direct and indirect influence. In contrast, vestibulospinally mediated conditioning effects occurred at longer latencies, consistent with this pathway’s known anatomical and functional interfaces with other descending systems including the reticulospinal pathway and, suggestively, propriospinal interneurons. Our work demonstrates the utility and sensitivity of transcutaneous spinal stimulation in human neurophysiological studies as a technique for quantitative characterization of excitatory conditioning effects in multiple lumbosacral motor pools, obtained through descending pathways. This characterization becomes critical in understanding the neuroplasticity in the central nervous system during motor learning and neurological recovery.

A reappraisal of pain-paired associative stimulation suggesting motor inhibition at spinal level

Paired associative stimulation (PAS) can modulate motor excitability and consists of delivering repeated pairs of peripheral sensory stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor cortex. Our objective was to evaluate the effect of a PAS protocol using a painful stimulation. Ten healthy volunteers underwent pain-PAS protocol consisting of 90 pairs of nociceptive stimulus over the right hand followed by an image-guided navigated TMS of the contralateral motor cortex, delivered at 0.1Hz over 15minutes. Four distinct inter-stimuli intervals (ISI) were assessed: -40ms, +10ms, +30ms and +50ms with respect to the individual pain-related evoked potential (N2 latency). The impact of pain-PAS was assessed by measuring motor evoked potentials (MEPs) amplitudes before and up to 30minutes after the pain-PAS procedure. For the "N2 latency -40ms" ISI condition, a significant decrease of MEP amplitude was observed in the immediate post-pain-PAS period. For longer ISIs, no significant changes were observed. A motor inhibition effect was produced by repetitive pairs of painful peripheral stimulation and TMS pulse delivered to the motor cortex before the afferent volley reaches the somatosensory cortex. This short ISI falls into a period of time corresponding to the cutaneous silent period, suggesting that the motor inhibition effect produced by pain-PAS could occur at spinal level. The repeated interaction of the nociceptive afferent input and the descending motor corticospinal volley could lead to reduced excitability of homonymous spinal motoneurons.

Potentiating paired corticospinal-motoneuronal plasticity after spinal cord injury

BackgroundPaired 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. MethodsDuring 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. ResultsWe 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. ConclusionsOur 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.

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.

Towards assessing corticospinal excitability bilaterally: Validation of a double-coil TMS method

BackgroundFor several decades, Transcranial magnetic stimulation (TMS) has been used to monitor corticospinal excitability (CSE) changes in various contexts. Habitually, single-coil TMS is applied over one primary motor cortex (M1), eliciting motor-evoked potentials (MEPs) in a contralateral limb muscle, usually a hand effector. However, in many situations, it would be useful to obtain MEPs in both hands simultaneously, to track CSE bilaterally. Such an approach requires stimulating both M1 concurrently while avoiding interference between the two descending stimuli. New methodWe examined MEPs obtained at rest using a double-coil TMS approach where the two M1 are stimulated with a 1ms inter-pulse interval (double-coil1ms). MEPs were acquired using double-coil1ms (MEPdouble) or single-coil (MEPsingle) TMS, at five different intensities of stimulation (100, 115, 130, 145 or 160% of the resting motor threshold, rMT). Given the 1ms inter-pulse interval in double-coil1ms trials, MEPdouble were either evoked by a 1st (MEPdouble-1) or a 2nd (MEPdouble-2) TMS pulse. ResultsAll MEPTYPE (MEPTYPE=MEPsingle, MEPdouble-1 and MEPdouble-2) were equivalent, regardless of the hand within which they were elicited, the intensity of stimulation or the pulse order. Comparison with existing methodThis method allows one to observe state-related CSE changes for the two hands simultaneously on a trial-by-trial basis. ConclusionThese results infer the absence of any neural interactions between the two cortico-spinal volleys with double-coil1ms TMS. Hence, this technique can be reliably used to assess CSE bilaterally, opening new research perspectives for scientists interested in physiological markers of activity in the motor output system.

Spike-timing-dependent plasticity in lower-limb motoneurons after human spinal cord injury.

Recovery of lower-limb function after spinal cord injury (SCI) likely depends on transmission in the corticospinal pathway. Here, we examined whether paired corticospinal-motoneuronal stimulation (PCMS) changes transmission at spinal synapses of lower-limb motoneurons in humans with chronic incomplete SCI and aged-matched controls. We used 200 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the leg representation of the motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the tibialis anterior (TA) muscle 2 ms before antidromic potentials evoked in motoneurons by electrical stimulation of the common peroneal nerve (PCMS+) or when antidromic potentials arrived 15 or 28 ms before corticospinal volleys (PCMS-) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the TA muscle before and after each stimulation protocol. After PCMS+, the size of MEPs elicited by TMS and electrical stimulation increased for up to 30 min in control and SCI participants. Notably, this was accompanied by increases in TA electromyographic activity and ankle dorsiflexion force in both groups, suggesting that this plasticity has functional implications. After PCMS-, MEPs elicited by TMS and electrical stimulation were suppressed if afferent input from the common peroneal nerve reduced TA MEP size during paired stimulation in both groups. In conclusion, PCMS elicits spike-timing-dependent changes at spinal synapses of lower-limb motoneurons in humans and has potential to improve lower-limb motor output following SCI.NEW & NOTEWORTHY Approaches that aim to enhance corticospinal transmission to lower-limb muscles following spinal cord injury (SCI) are needed. We demonstrate that paired corticomotoneuronal stimulation (PCMS) can enhance plasticity at spinal synapses of lower-limb motoneurons in humans with and without SCI. We propose that PCMS has potential for improving motor output in leg muscles in individuals with damage to the corticospinal tract.

P155 Fluctuation of motor evoked potentials and resting motor threshold over time

Introduction MEP amplitude and RMT are measures of corticospinal excitability (CSE) that are often used as baseline characteristics and outcome measures for various TMS protocols. However, marked variation in the amplitude of MEPs to consecutive stimuli reduces the reliability of these estimates. Variation in CSE over time may cause values of RMT and MEP amplitude to deviate from their initial estimates. Objectives Our aim was to assess the factors contributing to fluctuations of CSE, namely dispersion of the corticospinal volley and coil positioning. We tested the hypothesis that (i) trial-to-trial variation of MEP area is less than that of amplitude and (ii) significant changes in average MEP amplitude and RMT occur due to displacements of the stimulating coil. Materials & methods To assess fluctuations of CSE, single-pulse TMS was applied to the motor area of the dominant hemisphere and EMG recorded from the contralateral relaxed FDI muscle. RMT was defined as stimulation intensity required to evoke a response of 0.2 mV and was determined by threshold tracking. Subsequently, RMT was tracked continuously. MEPs were recorded using stimulation intensity of 120% RMT. For each protocol, ten 20-min recordings were obtained from healthy subjects. Pulses were applied every 4.6 ± 0.5 s. A navigation system was used to record coil displacement during the experiments. Results Trial-to-trial variation of MEP area was as great as that of amplitude (median normalised mean consecutive difference 0.48 (range 0.5) for both). Whilst RMT and average MEP amplitude were found to fluctuate substantially over the course of the experiment, this was not attributable to coil displacement. Conclusions Our data suggest that coil displacement and response analysis (MEP area vs amplitude) do not contribute substantially to the variability of CSE parameters. Variation in MEP responses and RMT over time has implications for TMS protocols which use estimates of the average MEP amplitude and RMT. Studies such as paired pulse and rTMS should not use a single estimate to define parameters for a long duration. Further investigations into the sources of variation will be useful to improve its control.

Physiological processes influencing motor-evoked potential duration with voluntary contraction.

Voluntary contraction leads to facilitation of motor-evoked potentials (MEPs) producing greater amplitude, shorter onset latency, and prolonged duration of the electromyography potential. Whereas hyperexcitability of spinal motoneurons and changes in descending corticospinal volleys have been proposed as putative mechanisms for changes in MEP amplitude and onset latency, a contribution of propriospinal interneurons, exerting modulatory effects on α-motoneurons, has been proposed as a potential explanation for prolongation of MEP duration. The aim of the present study is to gain further insight into the physiological processes underlying changes in MEP duration. Transcranial magnetic stimulation (TMS) studies were undertaken on 30 healthy controls, using a 90-mm circular coil, with MEPs recorded at rest and during facilitation, produced by contraction of abductor pollicis brevis. In the same experiment, short interval-intracortical inhibition (SICI) was recorded at rest. Facilitation resulted in a significant prolongation of MEP duration, which increased with stimulus intensity and was accompanied by an increase in MEP amplitude. The main effect (TMS intensity × activation state) was correlated with MEP duration (F = 10.9, P < 0.001), whereas TMS intensity (F = 30.5, P < 0.001) and activation state (F = 125.8, P < 0.001) in isolation were correlated with MEP amplitude. There was a significant inverse relationship between SICI and MEP duration at rest (R2 = 0.141, P = 0.041) and during facilitation (R2 = 0.340, P = 0.001). The present findings suggest that similar physiological processes mediate changes in the facilitated MEP duration and amplitude and that both cortical and nonpropriospinal spinal mechanisms contribute to changes in MEP duration.NEW & NOTEWORTHY Muscle contraction is associated with a significant increase in motor-evoked potential (MEP) duration and amplitude. Whereas the increase in MEP duration was linear, the amplitude increase exhibited a ceiling effect. Importantly, the MEP duration increase strongly correlated with short interval-intracortical inhibition, a biomarker of motor cortical function. This suggests that whereas similar physiological processes contribute to changes in facilitated MEP duration and amplitude, cortical mechanisms appear to contribute to MEP duration changes.

Measurement of voluntary activation based on transcranial magnetic stimulation over the motor cortex.

This article reviews the use of transcranial magnetic stimulation (TMS) over the motor cortex to make estimates of the level of voluntary drive to muscles. The method, described in 2003 (Todd et al. J Physiol 551: 661-671, 2003), uses a TMS pulse to produce descending corticospinal volleys that synaptically activate motoneurons, resulting in a muscle twitch. Linear regression of the superimposed twitch amplitude and voluntary force (or torque) can generate an "estimated" resting twitch for muscles involved in a task. This procedure has most commonly been applied to elbow flexors but also to knee extensors and other muscle groups. Data from 44 papers using the method were tabulated. We identify and discuss five major technical challenges, and the frequency with which they are addressed. The technical challenges include inadvertent activation of the cortical representation of antagonist muscles, the role of antagonist torques at the studied joint, uncertainty about the effectiveness of the TMS pulse in activating the motoneuron pool, the linearity of the voluntary force (or torque) and superimposed twitch relationship, and variability in the TMS-evoked EMG and force/torque responses. The ideal situation in which the descending corticospinal volleys recruit all of the agonist motoneurons and none of the antagonist motoneurons is unlikely to ever occur, and hence results must be carefully examined to assess the authenticity of the voluntary activation estimates in the context of the experimental design. A partial compromise lies in the choice of stimulus intensity. We also identify aspects of the procedure that require further investigation.