Development of an Activity-Dependent Epidural Stimulation System in Freely Moving Spinal Cord Injured Rats: A Proof of Concept Study

Rascoe, Avi; Sharma, Pawan; Shah, Prithvi

doi:10.3389/fnins.2018.00472

Cited by 8 publications

(12 citation statements)

References 60 publications

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“…The number of days of post‐surgical care required was based on our experience with these surgeries, as has been published previously (Rascoe et al . 2018; Richards et al . 2019).…”

Section: Methodsmentioning

confidence: 99%

In vivoelectrophysiological mechanisms underlying cervical epidural stimulation in adult rats

Sharma

Shah

2021

The Journal of Physiology

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Key points To electrophysiologically determine the predominant neural structures activated with cervical epidural stimulation (ES), well‐established electrophysiological protocols (single‐pulse, paired‐pulse and multiple frequency stimulation) were delivered at rest, during motor activity and under anaesthesia in adult rats. Cervical ES resulted in spinal evoked motor responses with three different waveforms – early response (ER), middle response (MR) and late response (LR). ERs remained unmodulated by repeated stimulation protocols. In contrast, MRs and LRs were modulated by repeated stimulation protocols and volitional motor activity. ERs are consequential to the direct activation of motor efferents; MRs are secondary to type‐I sensory afferent activation and LRs result from the engagement of wider spinal interneuronal circuitry with potential influence from supraspinal pathways. Evidence from this work is fundamental in enhancing our understanding of cervical ES, and critical in refining the design of neuromodulation‐based rehabilitative strategies and in the construction of neuroprosthetics. Abstract Epidural stimulation (ES) of the lumbar spinal cord has demonstrated significant improvements in various physiological functions after a traumatic spinal cord injury in humans. Electrophysiological evidence from rodent, human and computational studies collectively suggest that the functional recovery following lumbar ES is mediated via direct activation of sensory afferent fibres. However, the mechanisms underlying cervical ES have not been comprehensively studied, which greatly limits our understanding of its effectiveness in restoring upper limb function. In this work, we determined the predominant neural structures that are activated with cervical ES using in vivo cervical spinal evoked motor responses (SEMRs). Standard electrophysiological protocols (single‐pulse, paired‐pulse and multiple frequency stimulation) were implemented in 11 awake and anaesthetized rats in four experimental stages. Three distinct types of cervical SEMRs were identified based on latency of their appearance: early response (ER), middle response (MR) and late response (LR). ERs remained unmodulated by repeated stimulation protocols. MRs and LRs were modulated by repeated stimulation protocols and volitional motor activity. Except for LRs being completely abolished under urethane, ketamine or urethane anaesthesia did not affect the appearance of cervical SEMRs. Our data, backed by literature, suggest that ERs are secondary to the direct activation of motor efferents, MRs are elicited by activation of type‐I sensory afferents and LRs result from the engagement of interneuronal circuitry with potential influence from supraspinal pathways. The gathered information paves the way to designing motor rehabilitation strategies that can utilize cervical ES to recover upper limb function following neurological deficits.

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“…The number of days of post‐surgical care required was based on our experience with these surgeries, as has been published previously (Rascoe et al . 2018; Richards et al . 2019).…”

Section: Methodsmentioning

confidence: 99%

In vivoelectrophysiological mechanisms underlying cervical epidural stimulation in adult rats

Sharma

Shah

2021

The Journal of Physiology

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“…No secondary effects (such as pain or spasticity) have been reported (173,177,178). Future directions pursue to develop neuromodulatory "closed-loop" systems and brain-computerspinal interfaces (163,167,(179)(180)(181), where the stimulation is directly controlled by endogenous biological signals that highly correlate with intentionality, instead of being applied by the experimenter/therapist.…”

Section: Cervical Neuromodulation To Regain Manual Dexteritymentioning

confidence: 99%

When Spinal Neuromodulation Meets Sensorimotor Rehabilitation: Lessons Learned From Animal Models to Regain Manual Dexterity After a Spinal Cord Injury

Flores

López-Santos

García-Alías

2021

Front. Rehabilit. Sci.

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Electrical neuromodulation has strongly hit the foundations of spinal cord injury and repair. Clinical and experimental studies have demonstrated the ability to neuromodulate and engage spinal cord circuits to recover volitional motor functions lost after the injury. Although the science and technology behind electrical neuromodulation has attracted much of the attention, it cannot be obviated that electrical stimulation must be applied concomitantly to sensorimotor rehabilitation, and one would be very difficult to understand without the other, as both need to be finely tuned to efficiently execute movements. The present review explores the difficulties faced by experimental and clinical neuroscientists when attempting to neuromodulate and rehabilitate manual dexterity in spinal cord injured subjects. From a translational point of view, we will describe the major rehabilitation interventions employed in animal research to promote recovery of forelimb motor function. On the other hand, we will outline some of the state-of-the-art findings when applying electrical neuromodulation to the spinal cord in animal models and human patients, highlighting how evidences from lumbar stimulation are paving the path to cervical neuromodulation.

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“…All surgeries were performed under aseptic conditions with rats deeply anesthetized with isoflurane gas (1.0-2.5% via facemask as needed) on a heated table to maintain body temperature at 37 0 C as described previously (Rascoe et al ., 2018; Richards et al ., 2019). After surgery, rats were placed in an incubator until fully recovered and administered antibiotics (Enrofloxacin, 40 mg/kg) and analgesics (Buprenex, 0.03 mg/kg) as needed for up to 5 days.…”

Section: Methodsmentioning

confidence: 99%

Cervical Spinal Cord Modulation with Repeated Epidural Stimulation in Healthy Adult Rats

Sharma

Rampursaud

Shah

2022

Preprint

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The effects of spinal epidural stimulation (ES) in regaining various physiological functions after a spinal cord injury (SCI) are well documented. Spinal evoked motor responses (SEMR) are commonly utilized experimental outcomes in longitudinal pre-clinical and human studies to reflect the in-vivo physiological changes in neural networks secondary to a neurological insult or neuro-rehabilitative treatments utilizing ES. However, it remains unknown if the repeated exposure to ES during SEMRs testing itself modulates the spinal cord physiology and hence the SEMRs characteristics. To address this issue, cervical ES was delivered to the healthy adult rats' cervical cord using standard stimulation paradigms during multiple sessions (~17 hours that spanned across 100 days). Cervical SEMR and electromyography (EMG) activity from forelimb muscles during a reaching & grasping task were collected before and after 100 days. We noted persistent increase in the cervical SEMR and forelimb muscle activity during reaching & grasping task relative to baseline at the end of the stimulation period indicating increased spinal and cortical excitability. Findings from the present work suggests that cervical SEMRs are amenable to modulation by routine ES testing protocols, with prominent changes in the mono and poly synaptic component of evoked responses. Additionally, since multiple testing sessions of cervical ES alone increases the excitability of the intact spinal cord, we suggest that SEMR data be used with caution to infer the physiological status of the spinal circuitry in longitudinal studies involving multiple SEMR testing sessions. Our findings also recommend involving appropriate control groups, motor behavior correlates, and practicing caution while utilizing normalization methods to allow meaningful functional interpretation of SEMR profiles following a SCI.

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Development of an Activity-Dependent Epidural Stimulation System in Freely Moving Spinal Cord Injured Rats: A Proof of Concept Study

Cited by 8 publications

References 60 publications

In vivoelectrophysiological mechanisms underlying cervical epidural stimulation in adult rats

In vivoelectrophysiological mechanisms underlying cervical epidural stimulation in adult rats

When Spinal Neuromodulation Meets Sensorimotor Rehabilitation: Lessons Learned From Animal Models to Regain Manual Dexterity After a Spinal Cord Injury

Cervical Spinal Cord Modulation with Repeated Epidural Stimulation in Healthy Adult Rats

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