Independent replication of motor cortex and cervical spinal cord electrical stimulation to promote forelimb motor function after spinal cord injury in rats

Yang, Qi; Ramamurthy, Aditya; Lall, Sophia; Santos, Joshua; Ratnadurai-Giridharan, Shivakeshavan; Lopane, Madeleine; Zareen, Neela; Alexander, Heather; Ryan, Daniel; Martin, John H.; Carmel, Jason B.

doi:10.1016/j.expneurol.2019.112962

Cited by 35 publications

(38 citation statements)

References 37 publications

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“…TBS was delivered at 75 and 80% of the RMT [approximately 0.5–1.2 mA, corresponding to previous reports (Yang et al, 2019 )] for 600 pulses. Also, a final 25-min MEPs post-stimulation was recorded at 0.2 Hz at 120% RMT.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, extracted brains were fixed in paraformaldehyde and sectioned for the histological verification of electrode positioning. TBS was delivered at 75 and 80% of the RMT [approximately 0.5-1.2 mA, corresponding to previous reports (Yang et al, 2019)] for 600 pulses. Also, a final 25-min MEPs post-stimulation was recorded at 0.2 Hz at 120% RMT.…”

Section: Motor Cortex Electrical Stimulation: Ctbs and Itbsmentioning

confidence: 99%

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Continuous Theta-Burst Stimulation Intensity Dependently Facilitates Motor-Evoked Potentials Following Focal Electrical Stimulation of the Rat Motor Cortex

Fujiki

Kawasaki

Fudaba

2020

Front. Neural Circuits

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Although theta-burst stimulation (TBS) is known to differentially modify motor cortical excitability according to stimulus conditions in humans, whether similar effects can be seen in animals, in particular rats, remains to be defined. Given the importance of experimental rat models for humans, this study explored this stimulation paradigm in rats. Specifically, this study aimed to explore corticospinal excitability after TBS in anesthetized animals to confirm its comparability with human results. Both inhibitionfacilitation configurations using paired electrical stimulation protocols and the effects of the TBS paradigm on motor-evoked potentials (MEPs) in rat descending motor pathways were assessed. Paired-stimulation MEPs showed inhibition [interstimulus interval (ISI): 3 ms] and facilitation (11 ms) patterns under medetomidine/midazolam/butorphanol (MMB) anesthesia. Furthermore, while ketamine and xylazine (K/X) anesthesia completely blocked facilitation at 11-ms ISI, inhibition at a 3-ms ISI was preserved. Continuous and intermittent TBS strongly facilitated MEPs depending on stimulus intensity, persisting for up to 25 min under both MMB and K/X anesthesia. These findings are similar to the intracortical inhibition and facilitation observed in the human motor cortex using paired-pulse magnetic stimulation, particularly the glutamate-mediated facilitation phase. However, different TBS facilitatory mechanisms occur in the rat motor cortex. These different TBS facilitatory mechanisms affect the comparability and interpretations of TBS between rat and human models.

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Section: Methodsmentioning

confidence: 99%

Section: Motor Cortex Electrical Stimulation: Ctbs and Itbsmentioning

confidence: 99%

Continuous Theta-Burst Stimulation Intensity Dependently Facilitates Motor-Evoked Potentials Following Focal Electrical Stimulation of the Rat Motor Cortex

Fujiki

Kawasaki

Fudaba

2020

Front. Neural Circuits

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“…In rats, repeated pairing of intermittent theta burst cortical stimulation with trans-spinal direct current stimulation after cervical spinal cord injury results in a strengthening of novel connections in the spinal cord. Furthermore, this paired stimulation paradigm can support the recovery of dextereous forelimb movements that depend on corticospinal function (Zareen et al, 2017;Yang et al, 2019). A brief summary of rodent electrical stimulation studies can be found in Table 1.…”

Section: Functional Effects Of Electrical Stimulation On Circuit Recomentioning

confidence: 99%

Functional Electrical Stimulation and the Modulation of the Axon Regeneration Program

Jara

Agger

Hollis

2020

Front. Cell Dev. Biol.

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Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation.

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“…To assess the rats ability to manipulate, we used the Irvine, Beatties, and Bresnahan scale (Irvine et al, 2010;Irvine et al, 2014), as we have before (Yang et al, 2019). All rats were placed in a clear plastic cylinder on top of a rotating carousel so that they could be rotated in the direction of the video camera.…”

Section: Behavior Testing (Fig 10): Food Manipulation Task (Ibb)mentioning

confidence: 99%

Spinal cord associative plasticity improves forelimb sensorimotor function after cervical injury

Pal

Park

Ramamurthy

et al. 2020

Preprint

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Associative plasticity occurs when two stimuli converge on a common neural target. We sought to use the strong convergence between motor and sensory systems in the spinal cord to restore movement after spinal cord injury (SCI). We developed a paired motor cortex and dorsal spinal cord stimulation protocol to target this interaction called spinal cord associative plasticity (SCAP). Subthreshold spinal cord stimulation strongly augments motor cortex evoked potentials at the time they are paired, but only when they arrive synchronously in the spinal cord. We tested the hypothesis that this paired stimulation effect depended on cortical descending motor and spinal cord proprioceptive afferents. Selective inactivation of either of these pathways fully abrogated the paired stimulation effect. We then found that repetitive pairing in awake rats increased spinal excitability for hours after pairing ended. To apply this protocol as therapy, we optimized the parameters to promote strong and long-lasting effects. This effect was just as strong in rats with cervical SCI as in un-injured rats, demonstrating that spared connections after SCI are sufficient to support this plasticity. When 30 minutes of paired stimulation was done over 10 days, the effect of pairing was sustained for weeks. In addition, H-reflex modulation improved, showing decreased hyperreflexia that also persisted for weeks. Importantly, repetitive paired stimulation supported enhanced recovery of forelimb dexterity in rats after SCI with no augmentation of injury-induced neuropathic pain. We conclude that SCAP strengthens sensory-motor connections within the spinal cord, resulting in decreased hyperreflexia and improved forelimb function after SCI.Significance StatementDespite evidence that electrical stimulation of spared nervous system connections can facilitate recovery after SCI, strongly overlapping sensory and motor connections in the spinal cord have not been targeted for therapy. Here we demonstrate a robust paired stimulation paradigm that depends on corticofugal and proprioceptive afferent convergence in the spinal cord. The paradigm, termed SCAP for spinal cord associative plasticity, produced large-scale physiological changes in a preclinical model of cervical SCI. Importantly, SCAP caused lasting improvements in dexterity and decreased hyperreflexia in rats with SCI. Thus, we have determined the neural circuits that drive SCAP and have preclinical evidence for its efficacy to restore function after incomplete cervical SCI, the most common SCI in people.

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Independent replication of motor cortex and cervical spinal cord electrical stimulation to promote forelimb motor function after spinal cord injury in rats

Cited by 35 publications

References 37 publications

Continuous Theta-Burst Stimulation Intensity Dependently Facilitates Motor-Evoked Potentials Following Focal Electrical Stimulation of the Rat Motor Cortex

Continuous Theta-Burst Stimulation Intensity Dependently Facilitates Motor-Evoked Potentials Following Focal Electrical Stimulation of the Rat Motor Cortex

Functional Electrical Stimulation and the Modulation of the Axon Regeneration Program

Spinal cord associative plasticity improves forelimb sensorimotor function after cervical injury

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