Electrical epidural stimulation of the cervical spinal cord: Implications for spinal respiratory neuroplasticity after spinal cord injury

2021 ◽  
Author(s):  
Ian G Malone ◽  
Rachel L Nosacka ◽  
Marissa A Nash ◽  
Kevin J Otto ◽  
Erica A Dale
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neural Plasticity ◽  
Molecular Mechanisms ◽  
Cervical Spinal Cord ◽  
Motor Nucleus ◽  
Epidural Stimulation ◽  
Locomotor Function ◽  
Lumbosacral Spinal Cord ◽  
Cord Injury

Traumatic cervical spinal cord injury (cSCI) can lead to damage of bulbospinal pathways to the respiratory motor nuclei and consequent life-threatening respiratory insufficiency due to respiratory muscle paralysis/paresis. Reports of electrical epidural stimulation (EES) of the lumbosacral spinal cord to enable locomotor function after SCI are encouraging, with some evidence of facilitating neural plasticity. Here, we detail the development and success of EES in recovering locomotor function with consideration of stimulation parameters and safety measures to develop effective EES protocols. EES is just beginning to be applied in other motor, sensory, and autonomic systems; however, there has only been moderate success in preclinical studies aimed at improving breathing function after cSCI. Thus, we explore rationale for applying EES to the cervical spinal cord, targeting the phrenic motor nucleus for the restoration of breathing. We also suggest cellular/molecular mechanisms by which EES may induce respiratory plasticity including a brief examination of sex-related differences in these mechanisms. Finally, we suggest more attention be paid to the effects of specific electrical parameters that have been used in the development of EES protocols and how that can impact the safety and efficacy for those receiving this therapy. Ultimately, we aim to inform readers about the potential benefits of EES in the phrenic motor system and encourage future studies in this area.

scholarly journals High-frequency epidural stimulation across the respiratory cycle evokes phrenic short-term potentiation after incomplete cervical spinal cord injury

2017 ◽  
Vol 118 (4) ◽  
pp. 2344-2357 ◽  
Author(s):  
Elisa J. Gonzalez-Rothi ◽  
Kristi A. Streeter ◽  
Marie H. Hanna ◽  
Anna C. Stamas ◽  
Paul J. Reier ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
High Frequency ◽  
Muscle Activation ◽  
Cervical Spinal Cord ◽  
Cervical Spinal Cord Injury ◽  
Burst Frequency ◽  
Epidural Stimulation ◽  
Term Potentiation ◽  
Cord Injury

C2 spinal hemilesion (C2Hx) paralyzes the ipsilateral diaphragm, but recovery is possible through activation of “crossed spinal” synaptic inputs to ipsilateral phrenic motoneurons. We tested the hypothesis that high-frequency epidural stimulation (HF-ES) would potentiate ipsilateral phrenic output after subacute and chronic C2Hx. HF-ES (300 Hz) was applied to the ventrolateral C4 or T2 spinal cord ipsilateral to C2Hx in anesthetized and mechanically ventilated adult rats. Stimulus duration was 60 s, and currents ranged from 100 to 1,000 µA. Bilateral phrenic nerve activity and ipsilateral hypoglossal (XII) nerve activity were recorded before and after HF-ES. Higher T2 stimulus currents potentiated ipsilateral phasic inspiratory activity at both 2 and 12 wk post-C2Hx, whereas higher stimulus currents delivered at C4 potentiated ipsilateral phasic phrenic activity only at 12 wk ( P = 0.028). Meanwhile, tonic output in the ipsilateral phrenic nerve reached 500% of baseline values at the high currents with no difference between 2 and 12 wk. HF-ES did not trigger inspiratory burst-frequency changes. Similar responses occurred following T2 HF-ES. Increases in contralateral phrenic and XII nerve output were induced by C4 and T2 HF-ES at higher currents, but the relative magnitude of these changes was small compared with the ipsilateral phrenic response. We conclude that following incomplete cervical spinal cord injury, HF-ES of the ventrolateral midcervical or thoracic spinal cord can potentiate efferent phrenic motor output with little impact on inspiratory burst frequency. However, the substantial increases in tonic output indicate that the uninterrupted 60-s stimulation paradigm used is unlikely to be useful for respiratory muscle activation after spinal injury. NEW & NOTEWORTHY Previous studies reported that high-frequency epidural stimulation (HF-ES) activates the diaphragm following acute spinal transection. This study examined HF-ES and phrenic motor output following subacute and chronic incomplete cervical spinal cord injury. Short-term potentiation of phrenic bursting following HF-ES illustrates the potential for spinal stimulation to induce respiratory neuroplasticity. Increased tonic phrenic output indicates that alternatives to the continuous stimulation paradigm used in this study will be required for respiratory muscle activation after spinal cord injury.

Activation of SIRT1 by Hyperbaric  Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

2020 ◽  
Author(s):  
Huiqiang Chen ◽  
Mengyu Yao ◽  
Zhibo Li ◽  
Ranran Xing ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Inflammatory Cascade ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

scholarly journals Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury

2015 ◽  
Vol 112 (39) ◽  
pp. 12193-12198 ◽  
Author(s):  
Jacob G. McPherson ◽  
Robert R. Miller ◽  
Steve I. Perlmutter
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neural Plasticity ◽  
Enhanced Recovery ◽  
Cervical Spinal Cord ◽  
Spike Timing ◽  
Neurological Injury ◽  
Partial Recovery ◽  
Cord Injury ◽  
Activity Dependent

Use-dependent movement therapies can lead to partial recovery of motor function after neurological injury. We attempted to improve recovery by developing a neuroprosthetic intervention that enhances movement therapy by directing spike timing-dependent plasticity in spared motor pathways. Using a recurrent neural–computer interface in rats with a cervical contusion of the spinal cord, we synchronized intraspinal microstimulation below the injury with the arrival of functionally related volitional motor commands signaled by muscle activity in the impaired forelimb. Stimulation was delivered during physical retraining of a forelimb behavior and throughout the day for 3 mo. Rats receiving this targeted, activity-dependent spinal stimulation (TADSS) exhibited markedly enhanced recovery compared with animals receiving targeted but open-loop spinal stimulation and rats receiving physical retraining alone. On a forelimb reach and grasp task, TADSS animals recovered 63% of their preinjury ability, more than two times the performance level achieved by the other therapy groups. Therapeutic gains were maintained for 3 additional wk without stimulation. The results suggest that activity-dependent spinal stimulation can induce neural plasticity that improves behavioral recovery after spinal cord injury.

Combination Therapy With Hyperbaric Oxygen and Erythropoietin Inhibits Neuronal Apoptosis and Improves Recovery in Rats With Spinal Cord Injury

2019 ◽  
Vol 99 (12) ◽  
pp. 1679-1689 ◽  
Author(s):  
Yue Zhou ◽  
Peng Su ◽  
Zhenzhen Pan ◽  
Dong Liu ◽  
Yanping Niu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyperbaric Oxygen ◽  
Neuronal Apoptosis ◽  
Molecular Mechanisms ◽  
Rating Scale ◽  
B Cell Lymphoma ◽  
Locomotor Function ◽  
Therapeutic Benefits ◽  
Cord Injury

Abstract Background Apoptosis plays an important role in various diseases, including spinal cord injury (SCI). Hyperbaric oxygen (HBO) and erythropoietin (EPO) promote the recovery from SCI, but the relationship between apoptosis and the combination therapeutic effect is not completely clear. Objective The purpose of this study was to investigate the effects of HBO and EPO on SCI and the mechanisms that underlie their therapeutic benefits. Design The study was designed to explore the effects of HBO and EPO on SCI through a randomized controlled trial. Methods Sixty young developing female Sprague-Dawley rats were randomly divided into groups of 12 rats receiving sham, SCI, HBO, EPO, or HBO plus EPO. The SCI model was modified with the Allen method to better control consistency. HBO was performed for 1 hour per day for a total of 21 days, and EPO was given once per week for a total of 3 weeks. Both methods were performed 2 hours after SCI. Locomotor function was evaluated with the 21-point Basso-Beattie-Bresnahan Locomotor Rating Scale, an inclined-plane test, and a footprint analysis. All genes were detected by Western blotting and immunohistochemistry. The level of cell apoptosis was determined by Hoechst staining. Results The results showed that HBO and EPO promoted the recovery of locomotor function in the hind limbs of rats by inhibiting the apoptosis of neurons. During this period, the expression of B-cell lymphoma/leukemia 2 protein (Bcl-2) increased significantly, whereas the expression of Bcl-2–associated X protein (Bax) and cleaved caspase 3 decreased significantly, indicating the inhibition of apoptosis. Meanwhile, the expression of G protein–coupled receptor 17 decreased, and that of myelin basic protein increased, suggesting that there may be a potential connection between demyelination and neuronal apoptosis. Limitations The limitations of the study include deviations in the preparation of SCI models; lack of reverse validation of molecular mechanisms; absence of in vitro cell experiments; and only one time point after SCI was studied. Conclusions HBO and EPO treatments are beneficial for SCI, especially when the 2 therapies are combined.

scholarly journals Intraspinal microstimulation and diaphragm activation after cervical spinal cord injury

2017 ◽  
Vol 117 (2) ◽  
pp. 767-776 ◽  
Author(s):  
L. M. Mercier ◽  
E. J. Gonzalez-Rothi ◽  
K. A. Streeter ◽  
S. S. Posgai ◽  
A. S. Poirier ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cervical Spinal Cord ◽  
Emg Activity ◽  
Motor Nucleus ◽  
Adult Rats ◽  
Intraspinal Microstimulation ◽  
Emg Signal ◽  
Cord Injury ◽  
Diaphragm Activity

Intraspinal microstimulation (ISMS) using implanted electrodes can evoke locomotor movements after spinal cord injury (SCI) but has not been explored in the context of respiratory motor output. An advantage over epidural and direct muscle stimulation is the potential of ISMS to selectively stimulate components of the spinal respiratory network. The present study tested the hypothesis that medullary respiratory activity could be used to trigger midcervical ISMS and diaphragm motor unit activation in rats with cervical SCI. Studies were conducted after acute (hours) and subacute (5–21 days) C2 hemisection (C2Hx) injury in adult rats. Inspiratory bursting in the genioglossus (tongue) muscle was used to trigger a 250-ms train stimulus (100 Hz, 100–200 μA) to the ventral C4 spinal cord, targeting the phrenic motor nucleus. After both acute and subacute injury, genioglossus EMG activity effectively triggered ISMS and activated diaphragm motor units during the inspiratory phase. The ISMS paradigm also evoked short-term potentiation of spontaneous inspiratory activity in the previously paralyzed hemidiaphragm (i.e., bursting persisting beyond the stimulus period) in ∼70% of the C2Hx animals. We conclude that medullary inspiratory output can be used to trigger cervical ISMS and diaphragm activity after SCI. Further refinement of this method may enable “closed-loop-like” ISMS approaches to sustain ventilation after severe SCI. NEW & NOTEWORTHY We examined the feasibility of using intraspinal microstimulation (ISMS) of the cervical spinal cord to evoke diaphragm activity ipsilateral to acute and subacute hemisection of the upper cervical spinal cord of the rat. This proof-of-concept study demonstrated the efficacy of diaphragm activation, using an upper airway respiratory EMG signal to trigger ISMS at the level of the ipsilesional phrenic nucleus during acute and advanced postinjury intervals.

scholarly journals Nicotinic signaling is required for motor learning but not rehabilitation after spinal cord injury

2022 ◽  
Author(s):  
Yue Li ◽  
Edmund Hollis
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Learning ◽  
Molecular Mechanisms ◽  
Motor Behavior ◽  
Cervical Spinal Cord ◽  
Compensatory Strategies ◽  
Nicotinic Acetylcholine ◽  
Motor Circuits ◽  
Cord Injury

Currently, therapeutic intervention for spinal cord injury is limited. Many approaches rely on strengthening the remaining substrate and driving recovery through rehabilitative training. As compared to learning novel compensatory strategies, rehabilitation focuses on restoring movements lost to injury. Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning, or if it engages previously trained motor circuits without requiring novel learning. Our findings implicate the latter mechanism, as we demonstrate that nicotinic acetylcholine signaling is required for motor learning but is dispensable for the recovery of previously trained motor behavior after cervical spinal cord injury.

scholarly journals Paced breathing and phrenic nerve responses evoked by epidural stimulation following complete high cervical spinal cord injury in rats

2018 ◽  
Vol 125 (3) ◽  
pp. 687-696 ◽  
Author(s):  
Tatiana Bezdudnaya ◽  
Michael A. Lane ◽  
Vitaliy Marchenko
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Phrenic Nerve ◽  
Cervical Spinal Cord ◽  
Frequency Dependent ◽  
Epidural Stimulation ◽  
Tracheal Pressure ◽  
Cord Injury ◽  
Phrenic Nucleus ◽  
High Cervical

Spinal cord injury (SCI) at the level of cervical segments often results in life-threatening respiratory complications and requires long-term mechanical ventilator assistance. Thus restoring diaphragm activity and regaining voluntary control of breathing are the primary clinical goals for patients with respiratory dysfunction following cervical SCI. Epidural stimulation (EDS) is a promising strategy that has been explored extensively for nonrespiratory functions and to a limited extent within the respiratory system. The goal of the present study is to assess the potential for EDS at the location of the phrenic nucleus (C3–C5) innervating the diaphragm: the main inspiratory muscle following complete C1 cervical transection. To avoid the suppressive effect of anesthesia, all experiments were performed in decerebrate, C1 cervical transection, unanesthetized, nonparalyzed ( n = 13) and paralyzed ( n = 7) animals. Our results show that C4 segment was the most responsive to EDS and required the lowest threshold of current intensity, affecting tracheal pressure and phrenic nerve responses. High-frequency (200–300 Hz) EDS applied over C4 segment (C4-EDS) was able to maintain breathing with normal end-tidal CO2 level and raise blood pressure. In addition, 100–300 Hz of C4-EDS showed time- and frequency-dependent changes (short-term facilitation) of evoked phrenic nerve responses that may serve as a target mechanism for pacing of phrenic motor circuits. The present work provides the first report of successful EDS at the level of phrenic nucleus in a complete SCI animal model and offers insight into the potential therapeutic application in patients with high cervical SCI. NEW & NOTEWORTHY The present work offers the first demonstration of successful life-supporting breathing paced by epidural stimulation (EDS) at the level of the phrenic nucleus, following a complete spinal cord injury in unanesthetized, decerebrate rats. Moreover, our experiments showed time- and frequency-dependent changes of evoked phrenic nerve activity during EDS that may serve as a target mechanism for pacing spinal phrenic motor networks.

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