Noninvasive spinal neuromodulation to map and augment lower urinary tract function in rhesus macaques

© 2019 Elsevier Inc. Dysfunction of the lower urinary tract (LUT) is prevalent in neurological disorders, including multiple sclerosis, stroke, spinal cord injury and neurodegenerative conditions. Common symptoms include urgency, incontinence, and urinary retention. Recent advances in neuromodulation have resulted in improved treatments for overactive bladder symptoms of urgency, frequency, and nocturia. However, there are presently no treatments available for the induction of voiding to overcome urinary retention. We demonstrate that transcutaneous spinal cord stimulation (TSCS), a non-invasive intervention, applied over the thoracolumbar spine in neurologically intact rhesus macaques can activate the LUT, including activation of the bladder detrusor muscle, the urethral sphincter and pelvic floor muscles. Urodynamic studies show improved voiding efficiency and decreased post-voiding residual volumes in the bladder, while maintaining coordinated activity in the detrusor and sphincter with physiologic detrusor peak pressure, contraction duration, and urine flow rate remaining unchanged. We conclude that TSCS may represent a novel approach to activate the LUT and enable voiding in select neurological conditions

Novel Activity Detection Algorithm to Characterize Spontaneous Stepping During Multimodal Spinal Neuromodulation After Mid-Thoracic Spinal Cord Injury in Rats.

A mid-thoracic spinal cord injury (SCI) severely impairs activation of the lower limb sensorimotor spinal networks, leading to paralysis. Various neuromodulatory techniques including electrical and pharmacological activation of the spinal networks have been successful in restoring locomotor function after SCI. We hypothesized that the combination of self-training in a natural environment with epidural stimulation (ES), quipazine (Quip), and strychnine (Strych) would result in greater activity in a cage environment after paralysis compared to either intervention alone. To assess this, we developed a method measuring and characterizing the chronic EMG recordings from tibialis anterior (TA) and soleus (Sol) muscles while rats were freely moving in their home cages. We then assessed the relationship between the change in recorded activity over time and motor-evoked potentials (MEPs) in animals receiving treatments. We found that the combination of ES, Quip, and Strych (sqES) generated the greatest level of recovery followed by ES + Quip (qES) while ES + Strych (sES) and ES alone showed least improvement in recorded activity. Further, we observed an exponential relationship between late response (LR) component of the MEPs and spontaneously generated step-like activity. Our data demonstrate the feasibility and potential importance of quantitatively monitoring mechanistic factors linked to activity-dependence in response to combinatorial interventions compared to individual therapies after SCI

Growth hormone plus resistance exercise attenuate structural changes in rat myotendinous junctions resulting from chronic unloading.

Myotendinous junctions (MTJs) are specialized sites on the muscle surface where forces generated by myofibrils are transmitted across the sarcolemma to the extracellular matrix. At the ultrastructural level, the interface between the sarcolemma and extracellular matrix is highly folded and interdigitated at these junctions. In this study, the effect of exercise and growth hormone (GH) treatments on the changes in MTJ structure that occur during muscle unloading, has been analyzed. Twenty hypophysectomized rats were assigned randomly to one of five groups: ambulatory control, hindlimb unloaded, hindlimb unloaded plus exercise (3 daily bouts of 10 climbs up a ladder with 50% body wt attached to the tail), hindlimb unloaded plus GH (2 daily injections of 1 mg/kg body wt, i.p.), and hindlimb unloaded plus exercise plus GH. MTJs of the plantaris muscle were analyzed by electron microscopy and the contact between muscle and tendon was evaluated using an IL/B ratio, where B is the base and IL is the interface length of MTJ's digit-like processes. After 10 days of unloading, the mean IL/B ratio was significantly lower in unloaded (3.92), unloaded plus exercise (4.18), and unloaded plus GH (5.25) groups than in the ambulatory control (6.39) group. On the opposite, the mean IL/B ratio in the group treated with both exercise and GH (7.3) was similar to control. These findings indicate that the interaction between exercise and GH treatments attenuates the changes in MTJ structure that result from chronic unloading and thus can be used as a countermeasure to these adaptations

Effects of Rehabilitation on Perineural Nets and Synaptic Plasticity Following Spinal Cord Transection

Epidural electrical stimulation (ES) of the lumbar spinal cord combined with daily locomotor training has been demonstrated to enhance stepping ability after complete spinal transection in rodents and clinically complete spinal injuries in humans. Although functional gain is observed, plasticity mechanisms associated with such recovery remain mostly unclear. Here, we investigated how ES and locomotor training affected expression of chondroitin sulfate proteoglycans (CSPG), perineuronal nets (PNN), and synaptic plasticity on spinal motoneurons. To test this, adult rats received a complete spinal transection (T9–T10) followed by daily locomotor training performed under ES with administration of quipazine (a serotonin (5-HT) agonist) starting 7 days post-injury (dpi). Excitatory and inhibitory synaptic changes were examined at 7, 21, and 67 dpi in addition to PNN and CSPG expression. The total amount of CSPG expression significantly increased with time after injury, with no effect of training. An interesting finding was that γ-motoneurons did not express PNNs, whereas α-motoneurons demonstrated well-defined PNNs. This remarkable difference is reflected in the greater extent of synaptic changes observed in γ-motoneurons compared to α-motoneurons. A medium negative correlation between CSPG expression and changes in putative synapses around α-motoneurons was found, but no correlation was identified for γ-motoneurons. These results suggest that modulation of γ-motoneuron activity is an important mechanism associated with functional recovery induced by locomotor training under ES after a complete spinal transection

An Autonomic Neuroprosthesis: Noninvasive Electrical Spinal Cord Stimulation Restores Autonomic Cardiovascular Function in Individuals with Spinal Cord Injury

© Aaron A. Phillips et al. 2018. Despite autonomic dysfunction after spinal cord injury (SCI) being the major cause of death and a top health priority, the clinical management options for these conditions are limited to drugs with delayed onset and nonpharmacological interventions with equivocal effectiveness. We tested the capacity of electrical stimulation, applied transcutaneously over the spinal cord, to manage autonomic dysfunction in the form of orthostatic hypotension after SCI. We assessed beat-by-beat blood pressure (BP), stroke volume, and cardiac contractility (dP/dt; Finometer), as well as cerebral blood flow (transcranial Doppler) in 5 individuals with motor-complete SCI (4 cervical, 1 thoracic) during an orthostatic challenge with and without transcutaneous electrical stimulation applied at the TVII level. During the orthostatic challenge, all individuals experienced hypotension characterized by a 37 ± 4 mm Hg decrease in systolic BP, a 52 ± 10% reduction in cardiac contractility, and a 23 ± 6% reduction in cerebral blood flow (all p < 0.05), along with severe self-reported symptoms. Electrical stimulation completely normalized BP, cardiac contractility, cerebral blood flow, and abrogated all symptoms. Noninvasive transcutaneous electrical spinal cord stimulation may be a viable therapy for restoring autonomic cardiovascular control after SCI

Cortical and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with Tetraplegia.

An increasing number of studies supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes functional recovery in humans with spinal cord injury (SCI). However, the neural mechanisms contributing to these effects remain poorly understood. Here we examined motor-evoked potentials in arm muscles elicited by cortical and subcortical stimulation of corticospinal axons before and after 20 min of TESS (30 Hz pulses with a 5 kHz carrier frequency) and sham-TESS applied between C5 and C6 spinous processes in males and females with and without chronic incomplete cervical SCI. The amplitude of subcortical, but not cortical, motor-evoked potentials increased in proximal and distal arm muscles for 75 min after TESS, but not sham-TESS, in control subjects and SCI participants, suggesting a subcortical origin for these effects. Intracortical inhibition, elicited by paired stimuli, increased after TESS in both groups. When TESS was applied without the 5 kHz carrier frequency both subcortical and cortical motor-evoked potentials were facilitated without changing intracortical inhibition, suggesting that the 5 kHz carrier frequency contributed to the cortical inhibitory effects. Hand and arm function improved largely when TESS was used with, compared with without, the 5 kHz carrier frequency. These novel observations demonstrate that TESS influences cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. We hypothesized that these parallel effects contribute to further the recovery of limb function following SCI.SIGNIFICANCE STATEMENT Accumulating evidence supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes recovery of function in humans with spinal cord injury (SCI). Here, we show that a single session of TESS over the cervical spinal cord in individuals with incomplete chronic cervical SCI influenced in parallel the excitability cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. Importantly, these parallel physiological effects had an impact on the magnitude of improvements in voluntary motor output

Rostral lumbar segments are the key controllers of hindlimb locomotor rhythmicity in the adult spinal rat

The precise location and functional organization of the spinal neuronal locomotor-related networks in adult mammals remain unclear. Our recent neurophysiological findings provided empirical evidence that the rostral lumbar spinal cord segments play a critical role in the initiation and generation of the rhythmic activation patterns necessary for hindlimb locomotion in adult spinal rats. Since added epidural stimulation at the S1 segments significantly enhanced the motor output generated by L2 stimulation, these data also suggested that the sacral spinal cord provides a strong facilitory influence in rhythm initiation and generation. However, whether L2 will initiate hindlimb locomotion in the absence of S1 segments, and whether S1 segments can facilitate locomotion in the absence of L2 segments remain unknown. Herein, adult rats received complete spinal cord transections at T8 and then at either L2 or S1. Rats with spinal cord transections at T8 and S1 remained capable of generating coordinated hindlimb locomotion when receiving epidural stimulation at L2 and when ensembles of locomotor related loadbearing input were present. In contrast, minimal locomotion was observed when S1 stimulation was delivered after spinal cord transections at T8 and L2. Results were similar when the nonspecific serotonergic agonists were administered. These results demonstrate in adult rats that rostral lumbar segments are essential for the regulation of hindlimb locomotor rhythmicity. In addition, the more caudal spinal networks alone cannot control locomotion in the absence of the rostral segments around L2 even when loadbearing rhythmic proprioceptive afferent input is imposed.NEW & NOTEWORTHY The exact location of the spinal neuronal locomotor-related networks in adult mammals remains unknown. The present data demonstrate that when the rostral lumbar spinal segments (~L2) are completely eliminated in thoracic spinal adult rats, hindlimb stepping is not possible with neurochemical modulation of the lumbosacral cord. In contrast, eliminating the sacral cord retains stepping ability. These observations highlight the importance of rostral lumbar segments in generating effective mammalian locomotion

Using EMG to deliver lumbar dynamic electrical stimulation to facilitate cortico-spinal excitability

Background: Potentiation of synaptic activity in spinal networks is reflected in the magnitude of modulation of motor responses evoked by spinal and cortical input. After spinal cord injury, motor evoked responses can be facilitated by pairing cortical and peripheral nerve stimuli. Objective: To facilitate synaptic potentiation of cortico-spinal input with epidural electrical stimulation, we designed a novel neuromodulation method called dynamic stimulation (DS), using patterns derived from hind limb EMG signal during stepping. Methods: DS was applied dorsally to the lumbar enlargement through a high-density epidural array composed of independent platinum-based micro-electrodes. Results: In fully anesthetized intact adult rats, at the interface array/spinal cord, the temporal and spatial features of DS neuromodulation affected the entire lumbosacral network, particularly the most rostral and caudal segments covered by the array. DS induced a transient (at least 1 min) increase in spinal cord excitability and, compared to tonic stimulation, generated a more robust potentiation of the motor output evoked by single pulses applied to the spinal cord. When sub-threshold pulses were selectively applied to a cortical motor area, EMG responses from the contralateral leg were facilitated by the delivery of DS to the lumbosacral cord. Finally, based on motor-evoked responses, DS was linked to a greater amplitude of motor output shortly after a calibrated spinal cord contusion. Conclusion: Compared to traditional tonic waveforms, DS amplifies both spinal and cortico-spinal input aimed at spinal networks, thus significantly increasing the potential and accelerating the rate of functional recovery after a severe spinal lesion

Engaging cervical spinal circuitry with non-invasive spinal stimulation and buspirone to restore hand function in chronic motor complete patients

© 2018, The Author(s). The combined effects of cervical electrical stimulation alone or in combination with the monoaminergic agonist buspirone on upper limb motor function were determined in six subjects with motor complete (AIS B) injury at C5 or above and more than one year from time of injury. Voluntary upper limb function was evaluated through measures of controlled hand contraction, handgrip force production, dexterity measures, and validated clinical assessment batteries. Repeated measure analysis of variance was used to evaluate functional metrics, EMG amplitude, and changes in mean grip strength. In aggregate, mean hand strength increased by greater than 300% with transcutaneous electrical stimulation and buspirone while a corresponding clinically significant improvement was observed in upper extremity motor scores and the action research arm test. Some functional improvements persisted for an extended period after the study interventions were discontinued. We demonstrate that, with these novel interventions, cervical spinal circuitry can be neuromodulated to improve volitional control of hand function in tetraplegic subjects. The potential impact of these findings on individuals with upper limb paralysis could be dramatic functionally, psychologically, and economically

A Multi-modality Approach Towards Elucidation of the Mechanism for Human Achilles Tendon Bending during Passive Ankle Rotation

© 2018 The Author(s). The in vitro unconstrained Achilles tendon is nearly straight, while in vivo experiments reveal that the proximal region of the Achilles tendon, adjacent to Kager's fat pad, bends ventrally during plantarflexion but remains nearly straight during dorsiflexion. Tendon bending is an important factor in determining the displacement of the foot compared to the shortening of the muscle fibers. The objective of this study was to elucidate the various mechanisms that could cause tendon bending, which currently remain unknown. Examination of Thiel-embalmed cadavers, with preservation of native articular joint mobility, revealed that the Achilles tendon still bent ventrally even when its surrounding tissues, including the skin surface, Kager's fat pad, and distal portions of the soleus muscle were removed. Shear modulus and collagen fiber orientation were distributed homogeneously with respect to the longitudinal line of the tendon, minimizing their causative contributions to the bending. Given that tendon bending is not caused by either the nature of the deformations of the tissues surrounding the Achilles tendon or its physical properties, we conclude that it results from the geometric architecture of the Achilles tendon and its configuration with respect to the surrounding tissues