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IntroductionA novel, spinal cord stimulation (SCS) system with a physiologic closed-loop (CL) feedback mechanism controlled by evoked compound action potentials (ECAPs) enables the optimization of physiologic neural dose and the accuracy of the stimulation, not possible with any other commercially available SCS systems. The report of objective spinal cord measurements is essential to increase the transparency and reproducibility of SCS therapy. Here, we report a cohort of the EVOKE double-blind randomized controlled trial treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements.Methods41 patients randomized to CL-SCS remained in their treatment allocation and were followed up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with ≥50% and ≥80% reduction in overall back and leg pain.ResultsThe performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints. Percent time stimulating above the ECAP threshold was >98%, and the ECAP dose was ≥19.3µV. Most patients obtained ≥50% reduction (83%) and ≥80% reduction (59%) in overall back and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p=0.083 and p=0.405, respectively).ConclusionThe results suggest that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS leads to durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.

Neurorecovery from locomotor training is well established in human spinal cord injury (SCI). However, neurorecovery resulting from combined interventions has not been widely studied. In this randomized clinical trial, we established the tibialis anterior (TA) flexion reflex modulation pattern when transcranial magnetic stimulation (TMS) of the primary motor cortex was paired with transcutaneous spinal cord (transspinal) stimulation over the thoracolumbar region during assisted step training. Single pulses of TMS were delivered either before (TMS-transspinal) or after (transspinal-TMS) transspinal stimulation during the stance phase of the less impaired leg. Eight individuals with chronic incomplete or complete SCI received at least 20 sessions of paired stimulation during assisted step training. Each session consisted of 240 paired stimuli delivered over 10-min blocks for 1 h during robotic-assisted step training with the Lokomat6 Pro®. Body weight support, leg guidance force and treadmill speed were adjusted based on each participant’s ability to step without knee buckling or toe dragging. Both the early and late TA flexion reflex remained unaltered after TMS-transspinal and locomotor training. In contrast, the early and late TA flexion reflexes were significantly depressed during stepping after transspinal-TMS and locomotor training. Reflex changes occurred at similar slopes and intercepts before and after training. Our findings support that targeted brain and spinal cord stimulation coupled with locomotor training reorganizes the function of flexion reflex pathways, which are a part of locomotor networks, in humans with varying levels of sensorimotor function after SCI.Trial registration number NCT04624607; Registered on November 12, 2020.

Deficits in locomotor function, including impairments in walking speed and balance, are major problems for many individuals with incomplete spinal cord injury (iSCI). However, it remains unclear which type of training paradigms are more effective in improving balance, particularly dynamic balance, in individuals with iSCI. The purpose of this study was to determine whether anodal transcutaneous spinal direct current stimulation (tsDCS) can facilitate learning of balance control during walking in individuals with iSCI. Fifteen individuals with iSCI participated in this study and were tested in two sessions (i.e., tsDCS and sham conditions). Each session consisted of 1 min of treadmill walking without stimulation or perturbation (baseline), 10 min of walking with either anodal tsDCS or sham stimulation, paired with bilateral pelvis perturbation (adaptation), and finally 2 min of walking without stimulation and perturbation (post-adaptation). The outcome measures were the dynamic balance, assessed using the minimal margin of stability (MoS), and electromyography of leg muscles. Participants demonstrated a smaller MoS during the late adaptation period for the anodal tsDCS condition compared to sham (p = 0.041), and this MoS intended to retain during the early post-adaptation period (p = 0.05). In addition, muscle activity of hip abductors was greater for the anodal tsDCS condition compared to sham during the late adaptation period and post-adaptation period (p < 0.05). Results from this study suggest that anodal tsDCS may modulate motor adaptation to pelvis perturbation and facilitate learning of dynamic balance control in individuals with iSCI.

Spinal cord stimulation enhanced restoration of motor function following spinal cord injury (SCI) in unblinded studies. To determine whether training combined with transcutaneous electrical spinal cord stimulation (tSCS), with or without systemic serotonergic treatment with buspirone (busp), could improve hand function in individuals with severe hand paralysis following SCI, we assessed ten subjects in a double-blind, sham-controlled, crossover study. All treatments—busp, tSCS, and the busp plus tSCS—reduced muscle tone and spasm frequency. Buspirone did not have any discernible impact on grip force or manual dexterity when administered alone or in combination with tSCS. In contrast, grip force, sinusoidal force generation and grip-release rate improved significantly after 6 weeks of tSCS in 5 out of 10 subjects who had residual grip force within the range of 0.1–1.5 N at the baseline evaluation. Improved hand function was sustained in subjects with residual grip force 2–5 months after the tSCS and buspirone treatment. We conclude that tSCS combined with training improves hand strength and manual dexterity in subjects with SCI who have residual grip strength greater than 0.1 N. Buspirone did not significantly improve the hand function nor add to the effect of stimulation.

The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.

Background There is growing interest in use of transcutaneous spinal stimulation (TSS) for people with neurologic conditions both to augment volitional control (by facilitating motoneuron excitability), and to decrease spasticity (by activating inhibitory networks). Various electrode montages are used during TSS, with little understanding of how electrode position influences spinal circuit activation. We sought to identify the thoracolumbar electrode montage associated with the most robust activation of spinal circuits by comparing posterior root-muscle reflexes (PRM reflexes) elicited by 6 montages. Additionally, we assessed tolerability of the stimulation during PRM reflex testing. Methods Fifteen adults with intact neurological systems participated in this randomized crossover study. PRM reflexes were evoked transcutaneously using electrode montages with dorsal–ventral (DV) or dorsal-midline (DM) current flow. DV montages included: [1] cathode over T11/T12, anodes over iliac crests (DV-I), [2] cathode over T11/T12, anodes over umbilicus (DV-U), [3] dual paraspinal cathodes at T11/12, anodes over iliac crests (DV-PI), and [4] dual paraspinal cathodes at T11/12, anodes over umbilicus (DV-PU). DM montages included: [5] cathode over T11/12, anode 5 cm caudal (DM-C), and [6] cathode over T11/12, anode 5 cm rostral (DM-R). PRM reflex recruitment curves were obtained in the soleus muscle of both lower extremities. Results Lower reflex thresholds (mA) for dominant (D) and nondominant (ND) soleus muscles were elicited in DV-U (D: 46.7[33.9, 59.4], ND: 45.4[32.5, 58.2]) and DV-I (D: 48.1[35.3, 60.8], ND: 45.4[32.5, 58.2]) montages compared to DV-PU (D: 64.3[51.4, 77.1], ND:61.7[48.8, 74.6]), DV-PI (D:64.9[52.1, 77.7], ND:61.4[48.5, 75.5]), DM-C(D:60.0[46.9, 73.1], ND:63.6[50.8, 76.5]), and DM-R(D:63.1[50.3, 76.0], ND:62.6[49.8, 75.5]). DV-U and DV-I montages demonstrated larger recruitment curve area than other montages. There were no differences in response amplitude at 120% of RT(1.2xRT) or tolerability among montages. Conclusions Differences in spinal circuit recruitment are reflected in the response amplitude of the PRM reflexes. DV-I and DV-U montages were associated with lower reflex thresholds, indicating that motor responses can be evoked with lower stimulation intensity. DV-I and DV-U montages therefore have the potential for lower and more tolerable interventional stimulation intensities. Our findings optimize electrode placement for interventional TSS and PRM reflex assessments. Clinical Trial Number: NCT04243044.

The soleus H-reflex modulation pattern was investigated during stepping following transspinal stimulation over the thoracolumbar region at 15, 30, and 50 Hz with 10 kHz carry-over frequency above and below the paresthesia threshold. The soleus H-reflex was elicited by posterior tibial nerve stimulation with a single 1 ms pulse at an intensity that the M-wave amplitudes ranged from 0 to 15% of the maximal M-wave evoked 80 ms after the test stimulus, and the soleus H-reflex was half the size of the maximal H-reflex evoked on the ascending portion of the recruitment curve. During treadmill walking, the soleus H-reflex was elicited every 2 or 3 steps, and stimuli were randomly dispersed across the step cycle which was divided in 16 equal bins. For each subject and condition, the soleus M-wave and H-reflex were normalized to the maximal M-wave. The soleus background electromyographic (EMG) activity was estimated as the linear envelope for 50 ms duration starting at 100 ms before posterior tibial nerve stimulation for each bin. The gain was determined as the slope of the relationship between the soleus H-reflex and the soleus background EMG activity. The soleus H-reflex phase-dependent amplitude modulation remained unaltered during transspinal stimulation, regardless frequency, or intensity. Similarly, the H-reflex slope and intercept remained the same for all transspinal stimulation conditions tested. Locomotor EMG activity was increased in knee extensor muscles during transspinal stimulation at 30 and 50 Hz throughout the step cycle while no effects were observed in flexor muscles. These findings suggest that transspinal stimulation above and below the paresthesia threshold at 15, 30, and 50 Hz does not block or impair spinal integration of proprioceptive inputs and increases activity of thigh muscles that affect both hip and knee joint movement. Transspinal stimulation may serve as a neurorecovery strategy to augment standing or walking ability in upper motoneuron lesions.

Placebo analgesia is a prime example of the impact that psychological factors have on pain perception. We used functional magnetic resonance imaging of the human spinal cord to test the hypothesis that placebo analgesia results in a reduction of nociceptive processing in the spinal cord. In line with behavioral data that show decreased pain responses under placebo, pain-related activity in the spinal cord is strongly reduced under placebo. These results provide direct evidence for spinal inhibition as one mechanism of placebo analgesia and highlight that psychological factors can act on the earliest stages of pain processing in the central nervous system.

Transcranial direct current stimulation (tDCS) is among the rapidly growing experimental approaches to enhance athletic performance. Likewise, novel investigations have recently addressed the effects of transcutaneous spinal Direct Current Stimulation (tsDCS) on motor functions such as reduced reaction time. The impact of tDCS, and tsDCS might be attributed to altered spontaneous neural activity and membrane potentials of cortical and corticomotoneuronal cells, respectively. Given the paucity of empirical research in non-invasive brain stimulation in sports neuroscience, especially in boxing, the present investigation studied the effects of neuromodulation on motor and cognitive functions of professional boxers. The study sample comprised 14 experienced male boxers who received random sequential real or sham direct current stimulation over the primary motor cortex (M1) and paraspinal region (corresponding to the hand area) in two sessions with a 72-h interval. Unlike sham stimulation, real stimulation improved selective attention and reaction time of the experienced boxers [enhanced selective attention ( p  < 0.0003), diminished right hand ( p  < 0.0001) and left hand reaction time ( p  < 0.0006)]. Meanwhile, the intervention left no impact on the participants’ cognitive functions ( p  > 0.05). We demonstrated that simultaneous stimulation of the spinal cord and M1 can improve the performance of experienced boxers through neuromodulation. The present study design may be extended to examine the role of neurostimulation in other sport fields.