Non-invasive Transcutaneous Spinal Cord Stimulation Programming Recommendations for the Treatment of Upper Extremity Impairment in Tetraplegia.

OBJECTIVES: This study analyzes the stimulation parameters implemented during two successful trials that used non-invasive transcutaneous spinal cord stimulation (tSCS) to effectively improve upper extremity function after chronic spinal cord injury (SCI). It proposes a framework to guide stimulation programming decisions for the successful translation of these techniques into the clinic. MATERIALS AND METHODS: Programming data from 60 participants who completed the Up-LIFT trial and from 17 participants who subsequently completed the LIFT Home trial were analyzed. All observations of stimulation amplitudes, frequencies, waveforms, and electrode configurations were examined. The incidence of adverse events and relatedness to stimulation parameters is reported. A comparison of parameter usage across the American Spinal Injury Association Impairment Scale (AIS) subgroups was conducted to evaluate stimulation strategies across participants with varying degrees of sensorimotor preservation. RESULTS: Active (cathodal) electrodes were typically placed between the C3/C4 and C6/C7 spinous processes. Most sessions featured return (anodal) electrodes positioned bilaterally over the anterior superior iliac spine, although clavicular placement was frequently used by 12 participants. Stimulation was delivered with a 10-kHz carrier frequency and typically a 30-Hz burst frequency. Biphasic waveforms were used in 83% of sessions. Average stimulation amplitudes were higher for biphasic waveforms. The AIS B subgroup required significantly higher amplitudes than did the AIS C and D subgroups. Device-related adverse events were infrequent, and not correlated with specific waveforms or amplitudes. Within the home setting, participants maintained their current amplitudes within 1% of the preset values. The suggested stimulation programming framework dictates the following hierarchical order of parameter adjustments: current amplitude, waveform type, active/return electrode positioning, and burst frequency, guided by clinical observations as required. CONCLUSIONS: This analysis summarizes effective stimulation parameters from the trials and provides a decision-making framework for clinical implementation of tSCS for upper extremity functional restoration after SCI. The parameters are aligned with existing literature and proved safe and well tolerated by participants.

Safety and Feasibility of Cervical and Thoracic Transcutaneous Spinal Cord Stimulation to Improve Hand Motor Function in Children With Chronic Spinal Cord Injury.

OBJECTIVE: In adults with cervical spinal cord injury (SCI), transcutaneous spinal stimulation (scTS) has improved upper extremity strength and control. This novel noninvasive neurotherapeutic approach combined with training may modulate the inherent developmental plasticity of children with SCI, providing even greater improvements than training or stimulation alone. Because children with SCI represent a vulnerable population, we first must establish the safety and feasibility of any potential novel therapeutic approach. The objectives of this pilot study were to determine the safety, feasibility, and proof of principle of cervical and thoracic scTS for short-term effect on upper extremity strength in children with SCI. MATERIALS AND METHODS: In this nonrandomized, within-subject repeated measure design, seven participants with chronic cervical SCI performed upper extremity motor tasks without and with cervical (C3-C4 and C6-C7) and thoracic (T10-T11) site scTS. Safety and feasibility of using cervical and thoracic sites scTS were determined by the frequency count of anticipated and unanticipated risks (eg, pain, numbness). Proof-of-principle concept was tested via change in force production during hand motor tasks. RESULTS: All seven participants tolerated cervical and thoracic scTS across the three days, with a wide range of stimulation intensities (cervical sites = 20-70 mA and thoracic site = 25-190 mA). Skin redness at the stimulation sites was observed in four of 21 assessments (19%) and dissipated in a few hours. No episode of autonomic dysreflexia was observed or reported. Hemodynamic parameters (systolic blood pressure and heart rate) remained within stable limits (p > 0.05) throughout the assessment time points at baseline, with scTS, and after the experiment. Hand-grip and wrist-extension strength increased (p < 0.05) with scTS. CONCLUSIONS: We indicated that short-term application of scTS via two cervical and one thoracic site is safe and feasible in children with SCI and resulted in immediate improvements in hand-grip and wrist-extension strength in the presence of scTS. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT04032990.

Intrathecal and Oral Baclofen Use in Adults With Spinal Cord Injury: A Systematic Review of Efficacy in Spasticity Reduction, Functional Changes, Dosing, and Adverse Events.

OBJECTIVE: To examine the efficacy, dosing, and safety profiles of intrathecal and oral baclofen in treating spasticity after spinal cord injury (SCI). DATA SOURCES: PubMed and Cochrane Databases were searched from 1970-2018 with keywords baclofen, spinal cord injury, and efficacy. STUDY SELECTION: The database search yielded 588 sources and 10 additional relevant publications. After removal of duplicates, 398 publications were screened. DATA EXTRACTION: Data were extracted using the following population, intervention, comparator, outcomes, and study designs criteria: studies including adult patients with SCI with spasticity; the intervention could be oral or intrathecal administration of baclofen; selection was inclusive for control groups, surgical management, rehabilitation, and alternative pharmaceutical agents; outcomes were efficacy, dosing, and adverse events. Randomized controlled trials, observational studies, and case reports were included. Meta-analyses and systematic reviews were excluded. DATA SYNTHESIS: A total of 98 studies were included with 1943 patients. Only 4 randomized, double-blinded, and placebo-controlled trials were reported. Thirty-nine studies examined changes in the Modified Ashworth Scale (MAS; 34 studies) and Penn Spasm scores (Penn Spasm Frequency; 19 studies), with average reductions of 1.7±1.3 and 1.6±1.4 in individuals with SCI, respectively. Of these data, a total of 6 of the 34 studies (MAS) and 2 of the 19 studies (Penn Spasm Frequency) analyzed oral baclofen. Forty-three studies addressed adverse events with muscle weakness and fatigue frequently reported. CONCLUSIONS: Baclofen is the most commonly-prescribed antispasmodic after SCI. Surprisingly, there remains a significant lack of large, placebo-controlled, double-blinded clinical trials, with most efficacy data arising from small studies examining treatment across different etiologies. In the studies reviewed, baclofen effectively improved spasticity outcome measures, with increased efficacy through intrathecal administration. Few studies assessed how reduced neural excitability affected residual motor function and activities of daily living. A host of adverse events were reported that may negatively affect quality of life. Comparative randomized controlled trials of baclofen and alternative treatments are warranted because these have demonstrated promise in relieving spasticity with reduced adverse events and without negatively affecting residual motor function.

Quadriceps Muscle Fatigue Reduces Extension and Flexion Power During Maximal Cycling.

Purpose: To investigate how quadriceps muscle fatigue affects power production over the extension and flexion phases and muscle activation during maximal cycling. Methods: Ten participants performed 10-s maximal cycling efforts without fatigue and after 120 bilateral maximal concentric contractions of the quadriceps muscles. Extension power, flexion power and electromyographic (EMG) activity were compared between maximal cycling trials. We also investigated the associations between changes in quadriceps force during isometric maximal voluntary contractions (IMVC) and power output (flexion and extension) during maximal cycling, in addition to inter-individual variability in muscle activation and pedal force profiles. Results: Quadriceps IMVC (-52 ± 21%, P = 0.002), voluntary activation (-24 ± 14%, P < 0.001) and resting twitch amplitude (-45 ± 19%, P = 0.002) were reduced following the fatiguing task, whereas vastus lateralis (P = 0.58) and vastus medialis (P = 0.15) M-wave amplitudes were unchanged. The reductions in extension power (-15 ± 8%, P < 0.001) and flexion power (-24 ± 18%, P < 0.001) recorded during maximal cycling with fatigue of the quadriceps were dissociated from the decreases in quadriceps IMVC. Peak EMG decreased across all muscles while inter-individual variability in pedal force and EMG profiles increased during maximal cycling with quadriceps fatigue. Conclusion: Quadriceps fatigue induced by voluntary contractions led to reduced activation of all lower limb muscles, increased inter-individual variability and decreased power production during maximal cycling. Interestingly, power production was further reduced over the flexion phase (24%) than the extension phase (15%), likely due to larger levels of peripheral fatigue developed in RF muscle and/or a higher contribution of the quadriceps muscle to flexion power production compared to extension power during maximal cycling.

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.

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.

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.

Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone.

KEY POINTS: In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5-HT1A ) receptors at the axon initial segment. We explored whether ingestion of the 5-HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans. Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F-wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii. Our findings suggest that activation of 5-HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones. ABSTRACT: Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5-HT1A ) receptors and inhibits generation of action potentials. We examined whether activation of 5-HT1A receptors decreases motoneurone excitability in humans by determining the effects of a 5-HT1A receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo-controlled double-blind study, 10 participants were tested on two occasions where either placebo or 20 mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F-wave area and persistence, as well as CMEP area, were significantly decreased. The mean post-pill difference in normalized F-wave areas and persistence between buspirone and placebo days was -27% (-42, -12; 95% confidence interval) and -9% (-16, -2), respectively. The mean post-pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was -31% (-60, -2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5-HT1A receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise.

Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity.

The state of areflexia and muscle weakness that immediately follows a spinal cord injury (SCI) is gradually replaced by the recovery of neuronal and network excitability, leading to both improvements in residual motor function and the development of spasticity. In this review we summarize recent animal and human studies that describe how motoneurons and their activation by sensory pathways become hyperexcitable to compensate for the reduction of functional activation of the spinal cord and the eventual impact on the muscle. Specifically, decreases in the inhibitory control of sensory transmission and increases in intrinsic motoneuron excitability are described. We present the idea that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements, pharmacology or electrical stimulation may help to recover lost spinal inhibition. This may lead to a reduction of uncontrolled activation of the spinal cord and thus, improve its controlled activation by synaptic inputs to ultimately normalize circuit function. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically, may provide the best avenue to improve residual motor function and manage spasticity after SCI.

Activation properties of trigeminal motoneurons in participants with and without bruxism.

In animals, sodium- and calcium-mediated persistent inward currents (PICs), which produce long-lasting periods of depolarization under conditions of low synaptic drive, can be activated in trigeminal motoneurons following the application of the monoamine serotonin. Here we examined if PICs are activated in human trigeminal motoneurons during voluntary contractions and under physiological levels of monoaminergic drive (e.g., serotonin and norepinephrine) using a paired motor unit analysis technique. We also examined if PICs activated during voluntary contractions are larger in participants who demonstrate involuntary chewing during sleep (bruxism), which is accompanied by periods of high monoaminergic drive. In control participants, during a slowly increasing and then decreasing isometric contraction, the firing rate of an earlier-recruited masseter motor unit, which served as a measure of synaptic input to a later-recruited test unit, was consistently lower during derecruitment of the test unit compared with at recruitment (ΔF = 4.6 ± 1.5 imp/s). The ΔF, therefore, is a measure of the reduction in synaptic input needed to counteract the depolarization from the PIC to provide an indirect estimate of PIC amplitude. The range of ΔF values measured in the bruxer participants during similar voluntary contractions was the same as in controls, suggesting that abnormally high levels of monoaminergic drive are not continually present in the absence of involuntary motor activity. We also observed a consistent "onion skin effect" during the moderately sized contractions (<20% of maximal), whereby the firing rate of higher threshold motor units discharged at slower rates (by 4-7 imp/s) compared with motor units with relatively lower thresholds. The presence of lower firing rates in the more fatigue-prone, higher threshold trigeminal motoneurons, in addition to the activation of PICs, likely facilitates the activation of the masseter muscle during motor activities such as eating, nonnutritive chewing, clenching, and yawning.

Reduction of spinal sensory transmission by facilitation of 5-HT1B/D receptors in noninjured and spinal cord-injured humans.

Activation of receptors by serotonin (5-HT1) and norepinephrine (α2) on primary afferent terminals and excitatory interneurons reduces transmission in spinal sensory pathways. Loss or reduction of descending sources of serotonin and norepinephrine after spinal cord injury (SCI) and the subsequent reduction of 5-HT1/α2 receptor activity contributes, in part, to the emergence of excessive motoneuron activation from sensory afferent pathways and the uncontrolled triggering of persistent inward currents that depolarize motoneurons during muscle spasms. We tested in a double-blind, placebo-controlled study whether facilitating 5-HT1B/D receptors with the agonist zolmitriptan reduces the sensory activation of motoneurons during an H-reflex in both noninjured control and spinal cord-injured participants. In both groups zolmitriptan, but not placebo, reduced the size of the maximum soleus H-reflex with a peak decrease to 59% (noninjured) and 62% (SCI) of predrug values. In SCI participants we also examined the effects of zolmitriptan on the cutaneomuscular reflex evoked in tibialis anterior from stimulation to the medial arch of the foot. Zolmitriptan, but not placebo, reduced the long-latency, polysynaptic component of the cutaneomuscular reflex (first 200 ms of reflex) by ∼50%. This ultimately reduced the triggering of the long-lasting component of the reflex (500 ms poststimulation to end of reflex) known to be mediated by persistent inward currents in the motoneuron. These results demonstrate that facilitation of 5-HT1B/D receptors reduces sensory transmission in both monosynaptic and polysynaptic reflex pathways to ultimately reduce long-lasting reflexes (spasms) after SCI.

Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury.

In animals, the recovery of motoneuron excitability in the months following a complete spinal cord injury is mediated, in part, by increases in constitutive serotonin (5-HT2) and norepinephrine (α1) receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents (CaPICs) without the ligands serotonin and norepinephrine below the injury. In this study we sought evidence for a similar role of constitutive monoamine receptor activity in the development of spasticity in human spinal cord injury. In chronically injured participants with partially preserved sensory and motor function, the serotonin reuptake inhibitor citalopram facilitated long-lasting reflex responses (spasms) previously shown to be mediated by CaPICs, suggesting that in incomplete spinal cord injury, functional descending sources of monoamines are present to activate monoamine receptors below the lesion. However, in participants with motor or motor/sensory complete injuries, the inverse agonist cyproheptadine, which blocks both ligand and constitutive 5-HT2/α1 receptor activity, decreased long-lasting reflexes, whereas the neutral antagonist chlorpromazine, which only blocks ligand activation of these receptors, had no effect. When tested in noninjured control participants having functional descending sources of monoamines, chlorpromazine was effective in reducing CaPIC-mediated motor unit activity. On the basis of these combined results, it appears that in severe spinal cord injury, facilitation of persistent inward currents and muscle spasms is mainly mediated by the activation of constitutive 5-HT2 and α1 receptor activity. Drugs that more selectively block these constitutively active monoamine receptors may provide better oral control of spasticity, especially in motor complete spinal cord injury where reducing motoneuron excitability is the primary goal.