Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses.

Although epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-six people undergoing clinically indicated cervical spine surgery consented to mapping of motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argue for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function.NEW & NOTEWORTHY A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline and revealed differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally, indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively.

Transspinal stimulation decreases corticospinal excitability and alters the function of spinal locomotor networks.

Locomotion requires the continuous integration of descending motor commands and sensory inputs from the legs by spinal central pattern generator circuits. Modulation of spinal neural circuits by transspinal stimulation is well documented, but how transspinal stimulation affects corticospinal excitability during walking in humans remains elusive. We measured the motor evoked potentials (MEPs) at multiple phases of the step cycle conditioned with transspinal stimulation delivered at sub- and suprathreshold intensities of the spinally mediated transspinal evoked potential (TEP). Transspinal stimulation was delivered before or after transcranial magnetic stimulation during which summation between MEP and TEP responses in the surface EMG was absent or present. Relationships between MEP amplitude and background EMG activity, silent period duration, and phase-dependent EMG amplitude modulation during and after stimulation were also determined. Ankle flexor and extensor MEPs were depressed by suprathreshold transspinal stimulation when descending volleys were timed to interact with transspinal stimulation-induced motoneuron depolarization at the spinal cord. MEP depression coincided with decreased MEP gain, unaltered MEP threshold, and unaltered silent period duration. Locomotor EMG activity of bilateral knee and ankle muscles was significantly depressed during the step at which transspinal stimulation was delivered but fully recovered at the subsequent step. The results support a model in which MEP depression by transspinal stimulation occurs via subcortical or spinal mechanisms. Transspinal stimulation disrupts the locomotor output of flexor and extensor motoneurons initially, but the intact nervous system has the ability to rapidly overcome this pronounced locomotor adaptation. In conclusion, transspinal stimulation directly affects spinal locomotor centers in healthy humans.NEW & NOTEWORTHY Lumbar transspinal stimulation decreases ankle flexor and extensor motor evoked potentials (MEPs) during walking. The MEP depression coincides with decreased MEP gain, unaltered MEP threshold changes, and unaltered silent period duration. These findings indicate that MEP depression is subcortical or spinal in origin. Healthy subjects could rapidly overcome the pronounced depression of muscle activity during the step at which transspinal stimulation was delivered. Thus, transspinal stimulation directly affects the function of spinal locomotor networks in healthy humans.

Repeated cathodal transspinal pulse and direct current stimulation modulate cortical and corticospinal excitability differently in healthy humans.

Noninvasive transspinal stimulation of the thoracolumbar region, where leg motor circuits reside, produces prominent plasticity of brain and spinal cord circuits. However, reorganization of cortical and corticospinal excitability after multiple sessions (i.e. repeated) remains elusive. In this study, we investigated changes in intracortical inhibition, intracortical facilitation, and corticospinal excitability after 10 sessions of cathodal transcutaneous delivery of pulse or direct current stimulation, termed here transspinal (tsPCS, tsDCS), in resting healthy humans. tsPCS was delivered at sub- and supra-threshold intensities, while intensity for tsDCS ranged from 2.24 to 2.34 mA within a session. Intracortical inhibition and facilitation were assessed based on the tibialis anterior (TA) motor evoked potential (MEP) amplitude following subthreshold transcranial magnetic stimulation (TMS) at the conditioning-test (C-T) intervals of 1, 2, 3, 10, 15, 20, 25, and 30 ms. The TA MEP recruitment input-output curves were also assembled to establish changes in corticospinal excitability. For both transspinal stimulation protocols, the active cathodal electrode was placed over the T10 spinal process. Results indicated that repeated tsPCS did not alter intracortical inhibition or intracortical facilitation but decreased corticospinal excitability for the right M1 and increased corticospinal excitability for the left M1. tsDCS decreased intracortical inhibition, increased intracortical facilitation, did not affect the maximal MEP amplitude but increased the slope of the right TA MEP input-output curve. Neurophysiological changes may be attributed to neural mechanisms involved in learning and memory. These results support that noninvasive transspinal stimulation alters both cortical and corticospinal neural excitability in resting healthy humans.

Cortical and Subcortical Contributions to Neuroplasticity after Repetitive Transspinal Stimulation in Humans.

The objectives of this study were to establish cortical and subcortical contributions to neuroplasticity induced by noninvasive repetitive transspinal stimulation in human subjects free of any neurological disorder. To meet our objectives, before and after 40 minutes of transspinal stimulation we established changes in tibialis anterior (TA) motor-evoked potentials (MEPs) in response to paired transcranial magnetic stimulation (TMS) pulses at interstimulus intervals (ISIs) consistent with I-wave periodicity. In order to establish to what extent similar actions are exerted at the spinal cord and motor axons, changes in soleus H-reflex and transspinal evoked potential (TEP) amplitude following transspinal and group Ia afferent conditioning stimulation, respectively, were established. After 40 min of transspinal stimulation, the TA MEP consecutive peaks of facilitation produced by paired TMS pulses were significantly decreased supporting for depression of I-waves. Additionally, the soleus H-reflex and ankle TEP depression following transspinal and group Ia afferent conditioning stimulation was potentiated at intervals when both responses interacted at the spinal cord and nerve axons. These findings support the notion that repetitive transspinal stimulation decreases corticocortical inputs onto corticospinal neurons and promotes a surround inhibition in the spinal cord and nerve axons. This novel method may be a suitable neuromodulation tool to alter excitability at cortical and subcortical levels in neurological disorders.

Intensity dependent effects of transcranial direct current stimulation on corticospinal excitability in chronic spinal cord injury.

OBJECTIVE: To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) intensity on corticospinal excitability and affected muscle activation in individuals with chronic spinal cord injury (SCI). DESIGN: Single-blind, randomized, sham-controlled, crossover study. SETTING: Medical research institute and rehabilitation hospital. PARTICIPANTS: Volunteers (N = 9) with chronic SCI and motor dysfunction in wrist extensor muscles. INTERVENTIONS: Three single session exposures to 20 minutes of a-tDCS (anode over the extensor carpi radialis [ECR] muscle representation on the left primary motor cortex, cathode over the right supraorbital area) using 1 mA, 2 mA, or sham stimulation, delivered at rest, with at least 1 week between sessions. MAIN OUTCOME MEASURES: Corticospinal excitability was assessed with motor-evoked potentials (MEPs) from the ECR muscle using surface electromyography after transcranial magnetic stimulation. Changes in spinal excitability, sensory threshold, and muscle strength were also investigated. RESULTS: Mean MEP amplitude significantly increased by approximately 40% immediately after 2mA a-tDCS (pre: 0.36 ± 0.1 mV; post: 0.47 ± 0.11 mV; P = .001), but not with 1 mA or sham. Maximal voluntary contraction measures remained unaltered across all conditions. Sensory threshold significantly decreased over time after 1mA (P = .002) and 2mA (P = .039) a-tDCS and did not change with sham. F-wave persistence showed a nonsignificant trend for increase (pre: 32% ± 12%; post: 41% ± 10%; follow-up: 46% ± 12%) after 2 mA stimulation. No adverse effects were reported with any of the experimental conditions. CONCLUSIONS: The a-tDCS can transiently raise corticospinal excitability to affected muscles in patients with chronic SCI after 2 mA stimulation. Sensory perception can improve with both 1 and 2 mA stimulation. This study gives support to the safe and effective use of a-tDCS using small electrodes in patients with SCI and highlights the importance of stimulation intensity.

Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial.

Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARCEX Therapy to improve arm and hand functions in people with chronic SCI. ARCEX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARCEX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARCEX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARCEX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 .

Transcutaneous Spinal Cord Stimulation to Stabilize Seated Systolic Blood Pressure in Persons With Chronic Spinal Cord Injury: Protocol Development.

Transcutaneous spinal cord stimulation (tSCS) is an emerging therapeutic strategy to target spinal autonomic circuitry to normalize and stabilize blood pressure (BP) in hypotensive persons living with chronic spinal cord injury (SCI). Our aim is to describe our current methodological approach to identify individual tSCS parameters that result in the maintenance of seated systolic blood pressure (SBP) within a pre-defined target range. The parent study is a prospective, randomized clinical trial in which eligible participants will undergo multiple mapping sessions to optimize tSCS parameter settings to promote stable SBP within a target range of 110-120 mm Hg for males and 100-120 mm Hg for females. Parameter mapping includes cathode electrode placement site (T7/8, T9/10, T11/12, and L1/2), stimulation frequency (30, 60 Hz), current amplitudes (0-120 mA), waveform (mono- and biphasic), pulse width (1000 µs), and use of carrier frequency (0, 10 kHz). Each participant will undergo up to 10 mapping sessions involving different electrode placement sites and parameter settings. BP will be continuously monitored throughout each mapping session. Stimulation amplitude (mA) will be increased at intervals of between 2 and 10 mA until one of the following occurs: 1) seated SBP reaches the target range; 2) tSCS intensity reaches 120 mA; or 3) the participant requests to stop. Secondary outcomes recorded include 1) symptoms related to autonomic dysreflexia and orthostatic hypotension, 2) Likert pain scale, and 3) skin appearance after removal of the tSCS electrode. Clinical Trials Registration: NCT05180227.

Timing dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans it is not known whether dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.

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.

Transspinal stimulation increases motoneuron output of multiple segments in human spinal cord injury.

Targeted neuromodulation strategies that strengthen neuronal activity are in great need for restoring sensorimotor function after chronic spinal cord injury (SCI). In this study, we established changes in the motoneuron output of individuals with and without SCI after repeated noninvasive transspinal stimulation at rest over the thoracolumbar enlargement, the spinal location of leg motor circuits. Cases of motor incomplete and complete SCI were included to delineate potential differences when corticospinal motor drive is minimal. All 10 SCI and 10 healthy control subjects received daily monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at right soleus transspinal evoked potential (TEP) subthreshold and suprathreshold intensities at rest. Before and two days after cessation of transspinal stimulation, we determined changes in TEP recruitment input-output curves, TEP amplitude at stimulation frequencies of 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and TEP postactivation depression upon transspinal paired stimuli at interstimulus intervals of 60, 100, 300, and 500 ms. TEPs were recorded at rest from bilateral ankle and knee flexor/extensor muscles. Repeated transspinal stimulation increased the motoneuron output over multiple segments. In control and complete SCI subjects, motoneuron output increased for knee muscles, while in motor incomplete SCI subjects motoneuron output increased for both ankle and knee muscles. In control subjects, TEPs homosynaptic and postactivation depression were present at baseline, and were potentiated for the distal ankle or knee flexor muscles. TEPs homosynaptic and postactivation depression at baseline depended on the completeness of the SCI, with minimal changes observed after transspinal stimulation. These results indicate that repeated transspinal stimulation increases spinal motoneuron responsiveness of ankle and knee muscles in the injured human spinal cord, and thus can promote motor recovery. This noninvasive neuromodulation method is a promising modality for promoting functional neuroplasticity after SCI.

Repeated transspinal stimulation decreases soleus H-reflex excitability and restores spinal inhibition in human spinal cord injury.

Transcutaneous spinal cord or transspinal stimulation over the thoracolumbar enlargement, the spinal location of motoneurons innervating leg muscles, modulates neural circuits engaged in the control of movement. The extent to which daily sessions (e.g. repeated) of transspinal stimulation affects soleus H-reflex excitability in individuals with chronic spinal cord injury (SCI) remains largely unknown. In this study, we established the effects of repeated cathodal transspinal stimulation on soleus H-reflex excitability and spinal inhibition in individuals with and without chronic SCI. Ten SCI and 10 healthy control subjects received monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at subthreshold and suprathreshold intensities of the right soleus transspinal evoked potential (TEP). SCI subjects received an average of 16 stimulation sessions, while healthy control subjects received an average of 10 stimulation sessions. Before and one or two days post intervention, we used the soleus H reflex to assess changes in motoneuron recruitment, homosynaptic depression following single tibial nerve stimuli delivered at 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and postactivation depression following paired tibial nerve stimuli at the interstimulus intervals of 60, 100, 300, and 500 ms. Soleus H-reflex excitability was decreased in both legs in motor incomplete and complete SCI but not in healthy control subjects. Soleus H-reflex homosynaptic and postactivation depression was present in motor incomplete and complete SCI but was of lesser strength to that observed in healthy control subjects. Repeated transspinal stimulation increased homosynaptic depression in all SCI subjects and remained unaltered in healthy controls. Postactivation depression remained unaltered in all subject groups. Lastly, transspinal stimulation decreased the severity of spasms and ankle clonus. The results indicate decreased reflex hyperexcitability and recovery of spinal inhibitory control in the injured human spinal cord with repeated transspinal stimulation. Transspinal stimulation is a noninvasive neuromodulation method for restoring spinally-mediated afferent reflex actions after SCI in humans.

Neural interactions between transspinal evoked potentials and muscle spindle afferents in humans.

The objective of this study was to establish neural interactions between transspinal evoked potentials (TEPs) and muscle spindle group Ia afferents in healthy humans. Soleus H-reflexes were assessed following transspinal stimulation at conditioning-test (C-T) intervals that ranged from negative to positive 100 ms. TEPs were recorded from the right and left ankle/knee flexor and extensor muscles, and their amplitude was assessed following stimulation of soleus muscle spindle group Ia afferents at similar C-T intervals. Transspinal conditioning stimulation produced a short-latency, long-lasting soleus H-reflex depression. Excitation of muscle spindle group Ia afferents produced depression of ipsilateral ankle TEPs and medium-latency facilitation of the ipsilateral knee TEPs. At specific C-T intervals, the soleus H-reflex and ipsilateral ankle TEPs were summated based on their relative onset and duration. No changes were observed in the contralateral TEPs. These effects were exerted at both peripheral and spinal levels. Both transspinal and muscle spindle group Ia afferent stimulation produce long-lasting depression of the soleus H-reflex and TEPs, respectively. Transspinal stimulation may promote targeted neuromodulation and can be utilized in upper motoneuron lesions to normalize spinal reflex hyper-excitability and alter excitation thresholds of peripheral nerve axons.

Transspinal Direct Current Stimulation Produces Persistent Plasticity in Human Motor Pathways.

The spinal cord is an integration center for descending, ascending, and segmental neural signals. Noninvasive transspinal stimulation may thus constitute an effective method for concomitant modulation of local and distal neural circuits. In this study, we established changes in cortical excitability and input/output function of corticospinal and spinal neural circuits before, at 0-15 and at 30-45 minutes after cathodal, anodal, and sham transspinal direct current stimulation (tsDCS) to the thoracic region in healthy individuals. We found that intracortical inhibition was different among stimulation polarities, however remained unchanged over time. Intracortical facilitation increased after cathodal and anodal tsDCS delivered with subjects seated, and decreased after cathodal tsDCS delivered with subjects lying supine. Both cathodal and anodal tsDCS increased corticospinal excitability, yet facilitation was larger and persisted for 30 minutes post stimulation only when cathodal tsDCS was delivered with subjects lying supine. Spinal input/output reflex function was decreased by cathodal and not anodal tsDCS. These changes may be attributed to altered spontaneous neural activity and membrane potentials of corticomotoneuronal cells by tsDCS involving similar mechanisms to those mediating motor learning. Our findings indicate that thoracic tsDCS has the ability to concomitantly alter cortical, corticospinal, and spinal motor output in humans.

Spinal Control of Locomotion: Individual Neurons, Their Circuits and Functions.

Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle activation profiles are observed during locomotion across species. This difference may potentially be driven by a modified distribution of muscle afferents at multiple segmental levels in humans, resulting in an altered interaction between different classes of spinal interneurons. Further, different classes of spinal interneurons are likely activated or silent to some extent simultaneously in all species. Regardless of these limitations, continuous efforts on the function of spinal interneuronal circuits during mammalian locomotion will assist in delineating the neural mechanisms underlying locomotor control, and help develop novel targeted rehabilitation strategies in cases of impaired bipedal gait in humans. These rehabilitation strategies will include activity-based therapies and targeted neuromodulation of spinal interneuronal circuits via repetitive stimulation delivered to the brain and/or spinal cord.

Remodeling Brain Activity by Repetitive Cervicothoracic Transspinal Stimulation after Human Spinal Cord Injury.

Interventions that can produce targeted brain plasticity after human spinal cord injury (SCI) are needed for restoration of impaired movement in these patients. In this study, we tested the effects of repetitive cervicothoracic transspinal stimulation in one person with cervical motor incomplete SCI on cortical and corticospinal excitability, which were assessed via transcranial magnetic stimulation with paired and single pulses, respectively. We found that repetitive cervicothoracic transspinal stimulation potentiated intracortical facilitation in flexor and extensor wrist muscles, recovered intracortical inhibition in the more impaired wrist flexor muscle, increased corticospinal excitability bilaterally, and improved voluntary muscle strength. These effects may have been mediated by improvements in cortical integration of ascending sensory inputs and strengthening of corticospinal connections. Our novel therapeutic intervention opens new avenues for targeted brain neuromodulation protocols in individuals with cervical motor incomplete SCI.

Interventional repetitive I-wave transcranial magnetic stimulation (TMS): the dimension of stimulation duration.

BACKGROUND: A range of transcranial magnetic stimulation (TMS) techniques are now available to modulate human corticomotor excitability and plasticity. One presumably critical aspect of these interventions is their duration of application. OBJECTIVE: In the current study, we investigated whether doubling the duration of an intervention would offer any additional benefit, or invoke self-limiting mechanisms controlling corticomotor excitability or synaptic plasticity. METHODS: We compared (in a cross-over design) corticomotor excitability (to the first dorsal interosseous muscle) during and after a 15-minute (I15) and 30-minute (I30) TMS intervention targeting indirect (I-) wave interaction (iTMS). The interventions consisted of equi-intensity paired stimuli with an interpulse interval (IPI) of 1.5 milliseconds, corresponding to I-wave periodicity, delivered at a frequency of 0.2 Hz. RESULTS: During both the I15 and I30 interventions, paired-pulse (I-wave) motor evoked potential (iMEP) amplitude significantly increased (by 98.3% and 120.6%, respectively, last versus first minute, P = .001). The increase for I30 occurred in the first 15 minutes, and there was no further change during the remainder of the intervention. Both interventions were equally effective overall. Postintervention, single-pulse MEP amplitude increased by a mean of 91% and 106% (I15 and I30, respectively, P < .01) with no significant difference between interventions. CONCLUSIONS: We conclude that repetitive iTMS can increase corticomotor excitability after a relatively short intervention period of stimulation, and that a longer stimulation period has no additional benefit or detriment, perhaps as a result of the action of regulatory mechanisms.