Acute neuromodulation restores spinally-induced motor responses after severe spinal cord injury

doi:10.1016/j.expneurol.2020.113246

Experimental Neurology

Volume 327, May 2020, 113246

https://doi.org/10.1016/j.expneurol.2020.113246 Get rights and content

Abstract

Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level. Repetitive DS delivery restored the spinally-evoked motor EMG responses that were previously suppressed by a calibrated spinal cord contusion. Sham experiments without DS delivery did not allow any spontaneous recovery. Thus, DS uniquely provides the potential for a greater long-term functional recovery after paralysis.

Section snippets

Author disclosure statement

VRE, researcher on the study team hold shareholder interest in NeuroRecovery Technologies and hold certain inventorship rights on intellectual property licensed by The Regents of the University of California to NeuroRecovery Technologies and its subsidiaries. VRE, and PG, researchers on the study team hold shareholder interest in Spinex. Wentai Liu, researcher on the study team holds shareholder interest in Niche Biomedical Inc.

Acknowledgments

GT is supported by funding from the European Union‘s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie (grant agreement No 661452). This research was also funded in part by NIH U01EB007615, the Christopher & Dana Reeve Foundation, Broccoli Foundation, and Walkabout Foundation. GT is also grateful to Dr. Elisa Ius for her excellent assistance in preparing the manuscript.

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Cited by (12)

Dynamic electrical stimulation enhances the recruitment of spinal interneurons by corticospinal input
2024, Experimental Neurology
Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.
Activity-dependent plasticity and spinal cord stimulation for motor recovery following spinal cord injury
2022, Experimental Neurology
Citation Excerpt :
Acute applications of SCS may also preserve activity of spinal cord circuits by modulating the spinal networks shortly after injury. In a preclinical study, applications of epidural stimulation modulated the EMG activity in the hindlimbs even three hours after contusion injury in rats (Taccola et al., 2020). The epidural stimulation was designed to reproduce pre-recorded EMG activity of tibialis anterior and soleus EMG activity.
Spinal cord injuries lead to permanent physical impairment despite most often being anatomically incomplete disruptions of the spinal cord. Remaining connections between the brain and spinal cord create the potential for inducing neural plasticity to improve sensorimotor function, even many years after injury. This narrative review provides an overview of the current evidence for spontaneous motor recovery, activity-dependent plasticity, and interventions for restoring motor control to residual brain and spinal cord networks via spinal cord stimulation. In addition to open-loop spinal cord stimulation to promote long-term neuroplasticity, we also review a more targeted approach: closed-loop stimulation. Lastly, we review mechanisms of spinal cord neuromodulation to promote sensorimotor recovery, with the goal of advancing the field of rehabilitation for physical impairments following spinal cord injury.
Stochastic spinal neuromodulation tunes the intrinsic logic of spinal neural networks
2022, Experimental Neurology
Citation Excerpt :
A key question remains, however, regarding how specific should the networks that are involved in the practice and training be relative to those that are critical in the primary motor skill of interest (de Leon et al., 1998; Shah et al., 2013; Rejc et al., 2017). The lumbosacral spinal circuitry can be successfully activated, also when there are proximally located injuries, using short-termed and prolonged electrical stimulation of the spinal cord with varying and highly interactive combinations of stimulation parameters (“noisy” and “dynamic” stimulation; Taccola, 2011; Taccola et al., 2020a, 2020b; Howard et al., 2020). However, based on the variability of the motor output induced by spinal stimulation sub-motor threshold intensities, there are many questions remaining, including the challenge of optimizing stimulation parameters to reach and sustain the optimal outcome, particularly in realizing that the optimal is a moving target as there can be a continuous reorganization of key neuronal networks that are linked directly and/or indirectly to activity dependent-mechanisms.
The present review focuses on the physiological states of spinal networks, which are stochastically modulated by continuously changing ensembles of proprioceptive and supraspinal input resulting in highly redundant neural networks. Spinal epidural interfaces provide a platform for probing spinal network dynamics and connectivity among multiple motor pool-specific spinal networks post-injury under in vivo experimental conditions. Continuous epidural low-frequency pulses at low intensity can evoke motor responses of stochastically changing amplitudes and with an oscillatory pattern of modulation. The physiological significance of this oscillatory pattern, intrinsic to “resting” spinal networks and observed in both uninjured and injured locomotor circuits, is unclear. This neural variability among spinal networks appears to be a fundamental mechanism of the network's design and not a “noise” interfering with movement control. Data to date also suggest that the greater the level of stimulation above motor threshold, the greater the loss of modulation over the motor output that is physiologically provided by interneuronal networks, which integrate naturally occurring proprioceptive and cutaneous input generated during movement. Sub-motor threshold spinal electrical stimulation experiments demonstrate a range of functional improvements of multiple physiological systems when used in concert with sensorimotor training after spinal cord injury. Although our understanding of the systemic, cellular and molecular modulatory mechanisms that trigger these activity-dependent adaptive processes remain incomplete, some basic physiological principles have evolved, at least at the systemic and neural network levels and to some degree at the cellular level.
Transcutaneous Spinal Neuromodulation Reorganizes Neural Networks in Patients with Cerebral Palsy
2021, Neurotherapeutics
Spinal neuromodulation and activity-based rehabilitation triggers neural network reorganization and enhances sensory-motor performances involving the lower limbs, the trunk, and the upper limbs. This study reports the acute effects of Transcutaneous Electrical Spinal Cord Neuromodulation (SCONE™, SpineX Inc.) on 12 individuals (ages 2 to 50) diagnosed with cerebral palsy (CP) with Gross Motor Function Classification Scale (GMFCS) levels ranging from I to V. Acute spinal neuromodulation improved the postural and locomotor abilities in 11 out of the 12 patients including the ability to generate bilateral weight bearing stepping in a 2-year-old (GMFCS level IV) who was unable to step. In addition, we observed independent head-control and weight bearing standing with stimulation in a 10-year-old and a 4-year old (GMFCS level V) who were unable to hold their head up or stand without support in the absence of stimulation. All patients significantly improved in coordination of flexor and extensor motor pools and inter and intralimb joint angles while stepping on a treadmill. While it is assumed that the etiologies of the disruptive functions of CP are associated with an injury to the supraspinal networks, these data are consistent with the hypothesis that spinal neuromodulation and functionally focused activity-based therapies can form a functionally improved chronic state of reorganization of the spinal-supraspinal connectivity. We further suggest that the level of reorganization of spinal-supraspinal connectivity with neuromodulation contributed to improved locomotion by improving the coordination patterns of flexor and extensor muscles by modulating the amplitude and firing patterns of EMG burst during stepping.
Magnetothermal-based non-invasive focused magnetic stimulation for functional recovery in chronic stroke treatment
2023, Scientific Reports
Combined neuromodulatory approaches in the central nervous system for treatment of spinal cord injury
2021, Current Opinion in Neurology

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Short CommunicationAcute neuromodulation restores spinally-induced motor responses after severe spinal cord injury

Abstract

Section snippets

Author disclosure statement

Acknowledgments

Neuron

Neurobiol. Dis.

Exp. Neurol.

Exp. Neurol.

Prog. Neurobiol.

Neuroscience

Prog. Neurobiol.

Brain Stimul.

Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/Akt signaling pathway

Stroke

Neurotrophic factors promote and enhance locomotor recovery in untrained spinalized cats

J. Neurophysiol.

Design and fabrication of a multi-electrode array for spinal cord epidural stimulation

Conf. Proc. IEEE Eng. Med. Biol. Soc.

Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury

J. Neurotrauma

Short Communication
Acute neuromodulation restores spinally-induced motor responses after severe spinal cord injury