Regulation of Human Respiration by Electrical Stimulation.

Epidural spinal cord stimulation (SCS) is currently regarded as a breakthrough procedure for enabling movement after spinal cord injury (SCI), yet one of its original applications was for spinal spasticity. An emergent method that activates similar target neural structures non-invasively is transcutaneous SCS. Its clinical value for spasticity control would depend on inducing carry-over effects, because the surface-electrode-based approach cannot be applied chronically. We evaluated single-session effects of transcutaneous lumbar SCS in 12 individuals with SCI by a test-battery approach, before, immediately after and 2 h after intervention. Stimulation was applied for 30 min at 50 Hz with an intensity sub-threshold for eliciting reflexes in lower extremity muscles. The tests included evaluations of stretch-induced spasticity (Modified Ashworth Scale [MAS] sum score, pendulum test, electromyography-based evaluation of tonic stretch reflexes), clonus, cutaneous-input-evoked spasms, and the timed 10 m walk test. Across participants, the MAS sum score, clonus, and spasms were significantly reduced immediately after SCS, and all spasticity measures were improved 2 h post-intervention, with large effect sizes and including clinically meaningful improvements. The effect on walking speed varied across individuals. We further conducted a single-case multi-session study over 6 weeks to explore the applicability of transcutaneous SCS as a home-based therapy. Self-application of the intervention was successful; weekly evaluations suggested progressively improving therapeutic effects during the active period and carry-over effects for 7 days. Our results suggest that transcutaneous SCS can be a viable non-pharmacological option for managing spasticity, likely working through enhancing pre- and post-synaptic spinal inhibitory mechanisms, and may additionally serve to identify responders to treatments with epidural SCS.

Epidural spinal cord stimulation by means of chronically implanted electrodes was carried out on 121 patients with pain of varied benign organic etiology. In 116 patients, the pain was confined to the back and lower extremities and, of these, 56 exhibited the failed-back syndrome. Most patients were referred by a pain management service because of failure of conventional pain treatment modalities. Electrodes were implanted at varying sites, dictated by the location of pain. A total of 140 epidural implants were used: 76 unipolar, 46 Resume electrodes, 12 bipolar, and six quadripolar. Patients were followed for periods ranging from 6 months to 10 years, with a mean follow-up period of 40 months. Forty-eight patients (40%) were able to control their pain by neurostimulation alone. A further 14 patients (12%), in addition to following a regular stimulation program, needed occasional analgesic supplements to achieve 50% or more relief of the prestimulation pain. Pain secondary to arachnoiditis or perineural fibrosis following multiple intervertebral disc operations, when predominantly confined to one lower extremity, seemed to respond favorably to this treatment. Uniformly good results were also obtained in lower-extremity pain secondary to multiple sclerosis. Pain due to advanced peripheral vascular disease of the lower limbs was well controlled, and amputation below the knee was delayed for up to 2 years in some patients. Pain due to cauda equina injury, paraplegic pain, phantom-limb pain, pure midline back pain without radiculopathy, or pain due to primary bone or joint disease seemed to respond less well. Patients who responded to preliminary transcutaneous electrical nerve stimulation generally did well with electrode implants. Notable complications included wound infection, electrode displacement or fracturing, and fibrosis at the stimulating tip of the electrode. Three patients in this series died due to unrelated causes. Epidural spinal cord stimulation has proven to be an effective and safe means of controlling pain on a long-term basis in selected groups of patients. The mechanism of action of stimulation-produced analgesia remains unclear; further studies to elucidate it might allow spinal cord stimulation to be exploited more effectively in disorders that are currently refractory to this treatment modality.

The task-dependent frequency of common neural drive to muscles has important applications for motor rehabilitation therapies. While it is well established that muscle dynamics influence the synchronicity of neural drive, the modulation of this coherence between static and dynamic movements remains unclear. Transcutaneous electrical spinal cord stimulation (TESCS) is believed to enhance spinal cord excitability, potentially improving brain-muscle communication; however, its effect on common neural drive to muscles has not yet been reported. This study aimed to investigate differences in intermuscular coherence (IMC) frequency between static and dynamic movement tasks and determine whether it is feasible to enhance it by TESCS. Participants performed static and dynamic hand grip tasks at different timepoints with respect to stimulation, set to 80% tolerable intensity. Surface EMG signals were recorded from the flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) muscles during each trial to determine beta- (15-30 Hz) and gamma- (30-48 Hz) band intermuscular coherence. The sum of IMC (IMC area ) was significantly greater (p B = 0.018, p D = 0.0183, p IM = 0.0172, p 5 = 0.0206, p 10 = 0.0183, p 15 = 0.0172) in the gamma-band for the dynamic task compared to the static task at every timepoint (before TESCS, during TESCS and immediately, 5-min, 10-min, and 15-min after TESCS) which may reflect a mechanism of increased efficiency of corticospinal interactions and could have implications for the types of movements that should be performed while receiving TESCS. There was no immediate measurable effect of TESCS on IMC area at any timepoint in the beta-band (p = 0.25, p = 0.31) or gamma-band (p = 0.52, p = 0.73) for either the static or dynamic task respectively. This could be explained by corticospinal networks already working at maximum capacity in able-bodied individuals or that a longer duration of TESCS is required to elicit a measurable effect. While the intra-task difference in beta- and gamma-band IMC area between static and dynamic tasks was statistically significant (p IM = 0.0275, p 5 = 0.0275, p 15 = 0.0031) at timepoints after stimulation, we did not find direct evidence that TESCS influenced this beta-gamma interaction. Thus, further investigation is needed to establish any causal relationship.

Transcutaneous electrical stimulation is a relatively new technique to evoke spinal reflexes in lower limb muscles. The advantage of this technique is that the spinal reflex responses can be obtained from multiple lower limb muscles simultaneously. However, repeatability of spinal reflexes evoked by transcutaneous spinal cord stimulation between days has not been evaluated. We aimed to examine repeatability of recruitment properties of the spinal reflexes evoked by transcutaneous spinal cord stimulation. Recruitment curves of the spinal reflexes evoked by transcutaneous spinal cord stimulation of 8 lower limb muscles (i.e., foot, lower leg, and thigh muscles) of 20 males were measured on two consecutive days. To confirm that responses were caused by activation of the sensory fiber, a double-pulse stimulation with 50 ms inter-pulse interval was delivered. Peak-to-peak amplitude of the first response was calculated for each muscle when no response was observed in the second response owing to post-activation depression. For comparison with the spinal reflexes evoked by transcutaneous spinal cord stimulation, the recruitment curves of the H-reflex amplitude of the soleus of 9 males were measured. Threshold intensity and maximal slope of the recruitment curves were calculated, and inter-day repeatability of the properties was quantified using intraclass correlation coefficients. For the spinal reflexes evoked by transcutaneous spinal cord stimulation, the intraclass correlation coefficient values of threshold intensity and maximal slope for each muscle ranged from 0.487 to 0.874 and from 0.471 to 0.964, respectively. Regarding the soleus H-reflex, the intraclass correlation coefficients of threshold intensity and maximal slope were 0.936 and 0.751, respectively. The present data showed that repeatability of the recruitment properties of the spinal reflexes evoked by transcutaneous spinal cord stimulation in the lower limb was moderate to high. Measurement of the spinal reflexes evoked by transcutaneous spinal cord stimulation would be useful for longitudinal neurophysiological studies.

PurposeElectrical epidural spinal cord stimulation (SCS) is used as a treatment for chronic pain as well as to partially restore motor function after a spinal cord injury. Monitoring the spinal cord activity during SCS with fMRI could provide important and objective measures of integrative responses to treatment. Unfortunately, spinal cord fMRI is severely challenged by motion and susceptibility artifacts induced by the implanted electrode and bones. This pilot study introduces multi‐band sweep imaging with Fourier transformation (MB‐SWIFT) technique for spinal cord fMRI during SCS in rats. Given the close to zero acquisition delay and high bandwidth in 3 dimensions, MB‐SWIFT is demonstrated to be highly tolerant to motion and susceptibility‐induced artifacts and thus holds promise for fMRI during SCS.MethodsMB‐SWIFT with 0.78 × 0.78 × 1.50 mm3 spatial resolution and 3‐s temporal resolution was used at 9.4 Tesla in rats undergoing epidural SCS at different frequencies. Its performance was compared with spin echo EPI. The origin of the functional contrast was also explored using suppression bands.ResultsMB‐SWIFT was tolerant to electrode‐induced artifacts and respiratory motion, leading to substantially higher fMRI sensitivity than spin echo fMRI. Clear stimulation frequency‐dependent responses to SCS were detected in the rat spinal cord close to the stimulation site. The origin of MB‐SWIFT fMRI signals was consistent with dominant inflow effects.ConclusionfMRI of the rat spinal cord during SCS can be consistently achieved with MB‐SWIFT, thus providing a valuable experimental framework for assessing the effects of SCS on the central nervous system.

This study is a survey of the overall clinical results achieved with our pain treatment method, percutaneous epidural low-frequency (1.6-8.0 Hz) spinal cord stimulation. It examines the relationship between the effectiveness of epidural spinal cord stimulation (ESCS) and diseases or sites of pain. Continuous indwelling of the catheter electrodes in the posterior epidural space ranged from 3 to 67 days, and the duration of percutaneous ESCS varied from less than 1 wk to more than 1 yr. Complete pain relief (100%) was achieved during stimulation in 11.5% of the patients (52 of 454). Complete (100%) to partial (more than 30%) pain relief occurred in 71.1% of the patients. In six (1.3%) patients pain was aggravated by stimulation. Analgesics and/or sedatives were discontinued completely after treatment in 52 patients (11.5%) and reduced in 263 patients (57.9%). The number of patients who rated pain relief better than 50% was significantly more in carcinoma/sarcoma and causalgia (P < 0.001), and significantly less in postherpetic neuralgia and thromboangitis obliterans/arterial sclerosis obliterans (P < 0.001) than the average in all diseases. There was a significantly high responsiveness to ESCS in female patients in comparison to male patients (P < 0.05). Pain in the head/face, neck/upper extremities, and trunk responded more to ESCS than pain in the lower extremities. Alleviation of pain by ESCS was lower when the verbal pain score was high. There were no major complications in percutaneous ESCS. Thus, we have demonstrated that pain-alleviating effects of ESCS varies significantly by disease and site of pain, and that this simple percutaneous method can be used for a relatively long period.

Epidural stimulation (ES) of the lumbosacral spinal cord has been used to facilitate standing and voluntary movement after clinically motor-complete spinal-cord injury. It seems of importance to examine how the epidurally evoked potentials are modulated in the spinal circuitry and projected to various motor pools. We hypothesized that chronically implanted electrode arrays over the lumbosacral spinal cord can be used to assess functionally spinal circuitry linked to specific motor pools. The purpose of this study was to investigate the functional and topographic organization of compound evoked potentials induced by the stimulation. Three individuals with complete motor paralysis of the lower limbs participated in the study. The evoked potentials to epidural spinal stimulation were investigated after surgery in a supine position and in one participant, during both supine and standing, with body weight load of 60%. The stimulation was delivered with intensity from 0.5 to 10 V at a frequency of 2 Hz. Recruitment curves of evoked potentials in knee and ankle muscles were collected at three localized and two wide-field stimulation configurations. Epidural electrical stimulation of rostral and caudal areas of lumbar spinal cord resulted in a selective topographical recruitment of proximal and distal leg muscles, as revealed by both magnitude and thresholds of the evoked potentials. ES activated both afferent and efferent pathways. The components of neural pathways that can mediate motor-evoked potentials were highly dependent on the stimulation parameters and sensory conditions, suggesting a weight-bearing-induced reorganization of the spinal circuitries.

Intraspinal microstimulation and epidural spinal cord stimulation can be considered as the technique to restore function following spinal cord injury through further research. In this paper, the automatic brain stereotaxic instrument was used to electrically stimulate the lumbosacral spinal cord (T12-L2 spinal segments) in rats. The motor function regions under intraspinal microstimulation and epidural spinal cord stimulation were measured. Threshold currents and coordinate sites of related motions were recorded. Comparative analysis revealed that the threshold current required for epidural stimulation to induce hindlimb motion was greater. Although the distribution of motor function regions measured by these two methods differed in the type of motion, the segment distribution of each motion were roughly the same. Therefore, if conditions permit, epidural stimulation can be used instead of intraspinal microstimulation to reduce secondary damage to the spinal cord. This provides a reference for locating stimulation sites for epidural spinal cord stimulation.

Epidural Spinal Cord Stimulation with a Multiple Electrode Paddle Lead Is Effective in Treating Intractable Low Back Pain

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.

Ischemic vascular disease of the upper extremity represents a difficult therapeutic problem wherein medical treatment often fails. Epidural spinal cord stimulation has been shown to be an effective alternative in severe peripheral arterial disease. Although this method has been used for nearly two decades only limited experience exists in Raynaud's phenomenon of the upper limbs. In addition objective parameters to prove therapeutic success are not well defined. Herein we describe a patient with severe primary Raynaud's phenomenon over several years who had significant pain relief and complete healing of ischemic digital ulcerations after spinal cord stimulation. Pain level was evaluated using a visual rating scale before and after surgery. Microcirculatory parameters were assessed before and after spinal cord stimulation by capillary microscopy and laser Doppler anemometry. Significant improvement of red blood cell velocity, capillary density, and capillary permeability was demonstrated. At follow-up 18 months after surgery the patient had no complaints and all ulcerations of her fingertips had healed. Spinal cord stimulation appears to be an effective treatment in severe cases of Raynaud's phenomenon and we recommend its use in the case of failed medical therapy. Pain rating and capillary microscopy enable one to assess and visualize the effects of spinal cord stimulation.

Chapter 18 - The posterior root-muscle reflex

Transcutaneous stimulation is a neuromodulation method that is efficiently used for recovery after spinal cord injury and other disorders that are accompanied by motor and sensory deficits. Multiple aspects of transcutaneous stimulation optimization still require testing in animal experiments including the use of pharmacological agents, spinal lesions, cell recording, etc. This need initially motivated us to develop a new approach of transvertebral spinal cord stimulation (SCS) and to test its feasibility in acute and chronic experiments on rats. The aims of the current work were to study the selectivity of muscle activation over the lower thoracic and lumbosacral spinal cord when the stimulating electrode was located intravertebrally and to compare its effectiveness to that of the clinically used transcutaneous stimulation. In decerebrated rats, electromyographic activity was recorded in the muscles of the back (m. longissimus dorsi), tail (m. abductor caudae dorsalis), and hindlimb (mm. iliacus, adductor magnus, vastus lateralis, semitendinosus, tibialis anterior, gastrocnemius medialis, soleus, and flexor hallucis longus) during SCS with an electrode placed alternately in one of the spinous processes of the VT12–VS1 vertebrae. The recruitment curves for motor and sensory components of the evoked potentials (separated from each other by means of double-pulse stimulation) were plotted for each muscle; their slopes characterized the effectiveness of the muscle activation. The electrophysiological mapping demonstrated that transvertebral SCS has specific effects to the rostrocaudally distributed sensorimotor network of the lower thoracic and lumbosacral cord, mainly by stimulation of the roots that carry the sensory and motor spinal pathways. These effects were compared in the same animals when mapping was performed by transcutaneous stimulation, and similar distribution of muscle activity and underlying neuroanatomical mechanisms were found. The experiments on chronic rats validated the feasibility of the proposed stimulation approach of transvertebral SCS for further studies.

Lower urinary tract (LUT) dysfunction arising from injury and disease remain a clinical challenge due to unavailability of pharmacological treatments. Neuromodulation devices developed to tackle these disorders, such as sacral stimulators, are non‐selective for a single nerve with numerous off‐target effects while also stimulating the afferent and efferent population in a nerve. Here, we investigate whether epidural spinal cord stimulation (SCS) and microstimulation of dorsal root ganglion (DRG) through penetrating microarrays, can selectively activate and control reflexes relevant to LUT function. We demonstrate that custom high‐density epidural arrays and Utah arrays in the DRG can selectively access pelvic and pudendal innervation, and can modulate LUT function.To determine the effects of stimulation on peripheral nerve recruitment, α‐chloralose anesthetized male cats (SCS: n=6, DRG: n=4) were instrumented with nerve cuffs on the pelvic nerve as well as the pudendal nerve and its branches. High‐density epidural electrodes were placed corresponding to the lumbosacral (L6 and L7 laminae) and sacral (S1 laminae) spinous processes. In separate DRG experiments, 32‐channel high‐density penetrating Utah arrays were implanted in the S1, S2 and S3 DRG. We stimulated epidurally and within the DRG while recording compound action potentials in nerve cuffs. Functional effects of stimulation were measured using intravesical and transurethral catheters to measure bladder and urethral pressures respectively across various stimulus amplitudes and frequencies.All the instrumented nerves could be selectively recruited with both DRG and SCS stimulation, although not every nerve was selectivity recruited in every animal. The stimulation amplitude to evoke functional responses was higher (SCS: 600–1000 μA, DRG: 20–45 μA) than the minimum threshold to evoke antidromic activity in nerve cuffs. SCS and DRG stimulation both evoked bladder parasympathetic contractions similar to direct stimulation of the pelvic nerve. In several trials, stimulation through the same epidural electrode during cystometry, low frequency (3 Hz) stimulation evoked a continence reflex resulting in a suppression of detrusor activity, while high frequency (33 Hz) stimulation evoked a micturition reflex resulting in high intravesical pressures. Isovolumetric and filling cystometry was performed to confirm the action of these reflexes.SCS and DRG stimulation can selectively activate pelvic and pudendal innervation, and elicit micturition and continence reflexes.Support or Funding InformationR01 NS088184 and OT2OD024908. Craig H. Neilsen Foundation Award 476681

Transcutaneous electrical spinal cord stimulation (SсТS) was carried out in different phases of the stepping cycle in order to control the kinematic parameters of the step in healthy subjects walking on a treadmill. ScTS during the swing phase at the T11–T12 level activated the flexor motor pools and caused a change in the motion amplitude in the hip, knee and ankle joints, as well as increased the height of leg elevation. ScTS at the stance phase at the L1–L2 level, addressed to the extensor motor pools, did not affect the kinematics of stepping movements. A shift in the start of T11–T12 stimulation to 100–150 ms before the initiation of the swing phase or its prolongation by 100 ms after the end of the swing phase caused significant changes in the kinematics of stepping movements. Essential for the start of stimulation is the moment of pushing the leg off the support a little earlier than beginning of the swing phase . Prolongation of the stimulation period in the swing phase allows to increase ankle join flexion The choice of the optimal algorithm of phase-dependent ScTS for the activation of flexor and extensor motor pools during the stepping cycle increases the efficiency of stimulation in motor function rehabilitation techniques.