What Else Can Be Done by the Spinal Cord? A Review on the Effectiveness of Transpinal Direct Current Stimulation (tsDCS) in Stroke Recovery.

Since the spinal cord has traditionally been considered a bundle of long fibers connecting the brain to all parts of the body, the study of its role has long been limited to peripheral sensory and motor control. However, in recent years, new studies have challenged this view pointing to the spinal cord's involvement not only in the acquisition and maintenance of new motor skills but also in the modulation of motor and cognitive functions dependent on cortical motor regions. Indeed, several reports to date, which have combined neurophysiological techniques with transpinal direct current stimulation (tsDCS), have shown that tsDCS is effective in promoting local and cortical neuroplasticity changes in animals and humans through the activation of ascending corticospinal pathways that modulate the sensorimotor cortical networks. The aim of this paper is first to report the most prominent tsDCS studies on neuroplasticity and its influence at the cortical level. Then, a comprehensive review of tsDCS literature on motor improvement in animals and healthy subjects and on motor and cognitive recovery in post-stroke populations is presented. We believe that these findings might have an important impact in the future making tsDCS a potential suitable adjunctive approach for post-stroke recovery.

Characterization of interlimb interaction via transcutaneous spinal stimulation of cervical and lumbar spinal enlargements.

The use of transcutaneous electrical spinal stimulation (TSS) to modulate sensorimotor networks after neurological insult has garnered much attention from both researchers and clinicians in recent years. Although many different stimulation paradigms have been reported, the interlimb effects of these neuromodulation techniques have been little studied. The effects of multisite TSS on interlimb sensorimotor function are of particular interest in the context of neurorehabilitation, as these networks have been shown to be important for functional recovery after neurological insult. The present study utilized a condition-test paradigm to investigate the effects of interenlargement TSS on spinal motor excitability in both cervical and lumbosacral motor pools. Additionally, comparison was made between the conditioning effects of lumbosacral and cervical TSS and peripheral stimulation of the fibular nerve and ulnar nerve, respectively. In 16/16 supine, relaxed participants, facilitation of spinally evoked motor responses (sEMRs) in arm muscles was seen in response to lumbosacral TSS or fibular nerve stimulation, whereas facilitation of sEMRs in leg muscles was seen in response to cervical TSS or ulnar nerve stimulation. The decreased latency between TSS- and peripheral nerve-evoked conditioning implicates interlimb networks in the observed facilitation of motor output. The results demonstrate the ability of multisite TSS to engage interlimb networks, resulting in the bidirectional influence of cervical and lumbosacral motor output. The engagement of interlimb networks via TSS of the cervical and lumbosacral enlargements represents a feasible method for engaging spinal sensorimotor networks in clinical populations with compromised motor function.NEW & NOTEWORTHY Bidirectional interlimb modulation of spinal motor excitability can be evoked by transcutaneous spinal stimulation over the cervical and lumbosacral enlargements. Multisite transcutaneous spinal stimulation engages spinal sensorimotor networks thought to be important in the recovery of function after spinal cord injury.

Preferential activation of spinal sensorimotor networks via lateralized transcutaneous spinal stimulation in neurologically intact humans.

Transcutaneous spinal stimulation (TSS), a noninvasive technique to modulate sensorimotor circuitry within the spinal cord, has been shown to enable a wide range of functions that were thought to be permanently impaired in humans with spinal cord injury. However, the extent to which TSS can be used to target specific mediolateral spinal cord circuitry remains undefined. We tested the hypothesis that TSS applied unilaterally to the skin ~2 cm lateral to the midline of the lumbosacral spine selectively activates ipsilateral spinal sensorimotor circuitry, resulting in ipsilateral activation of downstream lower extremity neuromusculature. TSS cathodes and anodes were positioned lateral from the midline of the spine in 15 healthy subjects while supine, and the timing of TSS pulses was synchronized to recordings of lower extremity muscle activity and force. At motor threshold, left and right TSS-evoked muscle activity was significantly higher in the ipsilateral leg compared with contralateral recordings from the same muscles. Similarly, we observed a significant increase in force production in the ipsilateral leg compared with the contralateral leg. Delivery of paired TSS pulses, during which an initial stimulus was applied to one side of the spinal cord and 50 ms later a second stimulus was applied to the contralateral side, revealed that ipsilateral leg muscle responses decreased following the initial stimulus, whereas contralateral muscle responses did not decrease, indicating side-specific activation of lateral spinal sensorimotor circuitry. Our results indicate TSS can selectively engage ipsilateral neuromusculature via lumbosacral sensorimotor networks responsible for lower extremity function in healthy humans.NEW & NOTEWORTHY We demonstrate the selectivity of transcutaneous spinal stimulation (TSS), which has been shown to enable function in humans with chronic paralysis. Specifically, we demonstrate that TSS applied to locations lateral to the spinal cord can selectively activate ipsilateral spinal sensorimotor networks. We quantified lumbosacral spinal network activity by recording lower extremity muscle electromyography and force. Our results suggest lumbosacral TSS engages side-specific spinal sensorimotor networks associated with ipsilateral lower extremity function in humans.

Multi-site lumbar transcutaneous spinal cord stimulation: When less is more.

BACKGROUND: Transcutaneous spinal stimulation (TSS) has become a valuable tool for facilitating rehabilitation in individuals with neurological deficits. A significant constraint arises from the need for precise knowledge of stimulation locations to effectively apply TSS for targeted functional enhancement. METHODS: In this study, we investigate whether single-site or simultaneous multi-site stimulation over the lumbar spinal cord is advantageous for recruitment of specific motor pools projecting to lower limb muscles and generates higher leg extensor forces in neurologically intact individuals. Tests were performed in a supine position. TSS was delivered at T10-T11, T11-T12, T12-L1, and L1-L2 intervertebral spaces individually, then through all four locations simultaneously. The peak-to-peak amplitude of spinally evoked motor potentials and the forces generated by lower limb muscles were compared at the common motor threshold intensity level across all stimulation conditions. RESULTS: Recruitment of motor pools projecting to proximal and distal lower limb muscles followed their topographical rostro-caudal arrangement along the lumbosacral enlargement. Single-site stimulation, apart from the T10-T11 location, resulted in larger responses in both proximal and distal muscles while also generating higher knee-extension and plantarflexion forces when compared to multi-site stimulation. CONCLUSIONS: Both motor response and force generation were reduced when using multi-site TSS when compared to single-site stimulation. This demonstrates that the segmental effects of TSS are important to consider when performing multi-site TSS.

Transcutaneous spinal stimulation in people with and without spinal cord injury: Effect of electrode placement and trains of stimulation on threshold intensity.

Transcutaneous spinal cord stimulation (TSS) is purported to improve motor function in people after spinal cord injury (SCI). However, several methodology aspects are yet to be explored. We investigated whether stimulation configuration affected the intensity needed to elicit spinally evoked motor responses (sEMR) in four lower limb muscles bilaterally. Also, since stimulation intensity for therapeutic TSS (i.e., trains of stimulation, typically delivered at 15-50 Hz) is sometimes based on the single-pulse threshold intensity, we compared these two stimulation types. In non-SCI participants (n = 9) and participants with a SCI (n = 9), three different electrode configurations (cathode-anode); L1-midline (below the umbilicus), T11-midline and L1-ASIS (anterior superior iliac spine; non-SCI only) were compared for the sEMR threshold intensity using single pulses or trains of stimulation which were recorded in the vastus medialis, medial hamstring, tibialis anterior, medial gastrocnemius muscles. In non-SCI participants, the L1-midline configuration showed lower sEMR thresholds compared to T11-midline (p = 0.002) and L1-ASIS (p < 0.001). There was no difference between T11-midline and L1-midline for participants with SCI (p = 0.245). Spinally evoked motor response thresholds were ~13% lower during trains of stimulation compared to single pulses in non-SCI participants (p < 0.001), but not in participants with SCI (p = 0.101). With trains of stimulation, threshold intensities were slightly lower and the incidence of sEMR was considerably lower. Overall, stimulation threshold intensities were generally lower with the L1-midline electrode configuration and is therefore preferred. While single-pulse threshold intensities may overestimate threshold intensities for therapeutic TSS, tolerance to trains of stimulation will be the limiting factor in most cases.

Assessment of Dorsiflexion Ability across Tasks in Persons with Subacute SCI after Combined Locomotor Training and Transcutaneous Spinal Stimulation.

In people with spinal cord injury (SCI), transcutaneous spinal stimulation (TSS) has an immediate effect on the ability to dorsiflex the ankle, but persistent effects are not known. Furthermore, TSS has been associated with improved walking, increased volitional muscle activation, and decreased spasticity when combined with locomotor training (LT). In this study, the persistent impact of combined LT and TSS on dorsiflexion during the swing phase of walking and a volitional task in participants with SCI is determined. Ten participants with subacute motor-incomplete SCI received 2 weeks of LT alone (wash-in phase), followed by 2 weeks of either LT + TSS (TSS at 50 Hz) or LT + TSSSham (intervention phase). There was no persistent effect of TSS on dorsiflexion during walking and inconsistent effects on the volitional task. There was a strong positive correlation between the dorsiflexor ability for both tasks. There was a moderate effect of 4 weeks of LT on increased dorsiflexion during the task (d = 0.33) and walking (d = 0.34) and a small effect on spasticity (d = -0.2). Combined LT + TSS did not show persistent effects on dorsiflexion ability in people with SCI. Four weeks of locomotor training was associated with increased dorsiflexion across tasks. Improvements in walking observed with TSS may be due to factors other than improved ankle dorsiflexion.

Utilizing Neuromodulation in the Treatment of Spinal Cord Injury: An Assessment of Clinical Trials from the National ClinicalTrials.gov Database.

OBJECTIVE: Spinal cord injury (SCI) is responsible for approximately 18,000 trauma cases each year in the United States, often resulting in debilitating motor and autonomic disability. Neuromodulation is a rapidly growing field of interest in the neurosurgical field and has additionally shown promise in the treatment of SCI. This review characterizes all clinical trials to date studying neuromodulation for the treatment of SCI. METHODS: The ClinicalTrials.gov database was queried using the search terms "neuromodulation" and "spinal cord injury" on ClinicalTrials.gov. Trials were excluded if they were not yet recruiting, suspended, terminated early, or of unknown status. RESULTS: In total, 33 clinical trials were included in this study. Of the 33 trials, 8 were completed and 1 had published results. Most trials studied deficits of motor function (60%) and bladder control (37%). Fourteen studies (42.4%) utilized transcutaneous spinal stimulation, 7 (21.2%) utilized epidural electrical stimulation, and 6 (18.2%) utilized tibial nerve stimulation. There was an uptrend of clinical trials studying SCI indexed on PubMed, which was comparable to the increased number of publications indexed overall (Pearson correlation, P < 0.001). Of these, only 1 study regarding home tibial nerve stimulation for neurogenic bladder had published data, which was performed with no adverse events. CONCLUSIONS: Neuromodulation in SCI studies currently assess transcutaneous spinal stimulation, epidural electrical stimulation, and tibial nerve stimulation. There is currently 1 completed study suggesting feasibility of home neuromodulation techniques without adverse events. The results of trials that will be completed in the next few years will help dictate the potential of neuromodulation as a treatment for SCI.

The relationship between maximum tolerance and motor activation during transcutaneous spinal stimulation is unaffected by the carrier frequency or vibration.

Transcutaneous spinal stimulation (TSS) is a useful tool to modulate spinal sensorimotor circuits and has emerged as a potential treatment for motor disorders in neurologically impaired populations. One major limitation of TSS is the discomfort associated with high levels of stimulation during the experimental procedure. The objective of this study was to examine if the discomfort caused by TSS can be alleviated using different stimulation paradigms in a neurologically intact population. Tolerance to TSS delivered using conventional biphasic balanced rectangular pulses was compared to two alternative stimulation paradigms: a 5 kHz carrier frequency and biphasic balanced rectangular pulses combined with vibrotactile stimulation. In ten healthy participants, tolerance to TSS was examined using both single-pulse (0.2 Hz) and continuous (30 Hz) stimulation protocols. In both the single-pulse and continuous stimulation protocols, participants tolerated significantly higher levels of stimulation with the carrier frequency paradigm compared to the other stimulation paradigms. However, when the maximum tolerable stimulation intensity of each stimulation paradigm was normalized to the intensity required to evoke a lower limb muscle response, there were no statistical differences between the stimulation paradigms. Our results suggest that, when considering the intensity of stimulation required to obtain spinally evoked motor potentials, neither alternative stimulation paradigm is more effective at reducing discomfort than the conventional, unmodulated pulse configuration.

Posteroanterior cervical transcutaneous spinal stimulation targets ventral and dorsal nerve roots.

OBJECTIVE: We aim to non-invasively facilitate activation of spared neural circuits after cervical spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). We developed and tested a novel configuration for cervical transcutaneous spinal stimulation (cTSS). METHODS: cTSS was delivered via electrodes placed over the midline at ~T2-T4 levels posteriorly and ~C4-C5 levels anteriorly. Electromyographic responses were measured in arm and hand muscles across a range of stimulus intensities. Double-pulse experiments were performed to assess homosynaptic post-activation depression (PAD). Safety was closely monitored. RESULTS: More than 170 cTSS sessions were conducted without major safety or tolerability issues. A cathode-posterior, 2 ms biphasic waveform provided optimal stimulation characteristics. Bilateral upper extremity muscle responses were easily obtained in subjects with SCI and ALS. Resting motor threshold at the abductor pollicis brevis muscle ranged from 5.5 to 51.0 mA. As stimulus intensity increased, response latencies to all muscles decreased. PAD was incomplete at lower stimulus intensities, and decreased at higher stimulus intensities. CONCLUSIONS: Posteroanterior cTSS has the capability to target motor neurons both trans-synaptically via large-diameter afferents and non-synaptically via efferent motor axons. SIGNIFICANCE: Posteroanterior cTSS is well tolerated and easily activates upper extremity muscles in individuals with SCI and ALS.

Soleus H-reflex modulation following transcutaneous high- and low-frequency spinal stimulation in healthy volunteers.

The main aim of this work was to investigate the difference in the excitability of the soleus H-reflex in healthy volunteers following spinal transcutaneous electrical nerve stimulation (TENS) and high-frequency alternating current (HFAC) at a frequency of 10 kHz applied at the lower thoracic spinal level (T10-T12). A double-blind, randomized, crossover, controlled clinical trial was designed. Participants received three randomized interventions (TENS, 10 kHz, and sham stimulation) during 40 min. The amplitude and latency of the soleus H-reflex were registered prior to, during, and 10 min following stimulation. Twenty-four participants completed the study. A significant inhibition of H-reflex amplitude was observed following transcutaneous spinal TENS (12.7%; 95% CI 1.5-22.2%) when compared with sham stimulation (5.5%; 95% CI 3.6-14.5%; p = 0.03). An increase in H-reflex latency was also observed following transcutaneous spinal stimulation at 10 kHz (2%; 95% CI 1.4-2.5%) as compared with sham stimulation (0.7%; 95% CI 0.07-1.3%; p < 0.01). No differences were found between TENS and 10 kHz for H-reflex modulation. Transcutaneous spinal TENS and HFAC at a frequency of 10 kHz had a modulatory effect on the soleus H-reflex when compared to sham stimulation; however, no differences were found between these two interventions.

Influence of transcutaneous spinal stimulation on human LTP-like pain amplification. A randomized, double-blind study in volunteers.

OBJECTIVE: Transcutaneous spinal direct current stimulation (tsDCS) has been proven to affect nociceptive signal processing. We designed a randomized, double-blind, cross-over study to investigate whether tsDCS applied before or after inducing long-term potentiation-(LTP)-like hyperalgesia may decrease nociceptive sensitivity. METHODS: In healthy volunteers, tsDCS (2.5mA, 15min) was applied to the thoracic spine prior (n=14) or immediately following (n=12) electrical high-frequency stimulation (HFS) to the thigh, inducing hyperalgesia. Mechanical and electrical perception were assessed before HFS stimulation and at three time points following HFS stimulation (all within 90min of HFS). Subjects took part in three separate sessions to test effects of anodal, cathodal, or sham tsDCS. RESULTS: Within 60minHFS led to unilateral changes on the conditioned side: mechanical pain thresholds tended to decrease and electrical detection thresholds significantly decreased (p<0.001); pain ratings measured using the numerical rating scale (NRS) increased for electrical stimuli (p<0.01) and two categories of mechanical stimuli ("Light(8-64mN)": p=ns; "Heavy(128-512mN)": p<0.01). Irrespective of stimulation order or polarity, tsDCS could not influence nociceptive sensitivity. CONCLUSION: Hyperalgesia was adequately induced, but tsDCS had no effect on HFS-induced sensitization. SIGNIFICANCE: While tsDCS has been shown to affect pain measures, our results suggest irrespective of time of stimulation or polarity that tsDCS may be less effective in modulating pain in a sensitized state in healthy subjects.

Post-activation depression in the human soleus muscle using peripheral nerve and transcutaneous spinal stimulation.

Transcutaneous stimulation of the human lumbar spine can be used to elicit root-evoked potentials (REPs). These sensory-motor responses display notable similarities to the monosynaptic H-reflex. The purpose of this study was to compare post-activation depression of the soleus REP to that of the H-reflex, when conditioned by either an H-reflex or an REP. Paired pulses were delivered 25-200ms apart and the recovery was characterized using three levels of stimulation. In all conditions, post-activation depression was reduced during contraction as compared to rest (P<0.001). REP doublets, delivered using an inter-pulse interval of 150ms, recovered to 68±8% of control during plantarflexion and 20±6% of control at rest. During contraction, recovery of a second REP was 65% of the corresponding recovery for a second H-reflex. The recovery of an H-reflex was equivalent, when conditioned by either an H-reflex or an REP, even though the spinal stimulus activated and/or engaged more afferent and efferent fibers. Our results suggest that the additional elements activated by the spinal stimulus did not affect the recovery of the H-reflex. However, the transcutaneous spinal stimulus produced more inhibition when it was assessed using two low-intensity REPs (P<0.05) suggesting that the pathway mediating the spinally-evoked response was more susceptible to being inhibited.