The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength

Hays, Seth A.; Khodaparast, Navid; Ruiz, Andrea; Sloan, Andrew M.; Hulsey, Daniel R.; Rennaker, Robert L.; Kilgard, Michael P.

doi:10.1097/wnr.0000000000000154

Cited by 91 publications

(130 citation statements)

References 24 publications

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“…Even when initiated many weeks after stroke in rats with stable, chronic deficits, VNS paired with rehabilitative training significantly enhanced recovery of forelimb function compared with rehabilitative training without VNS. Consistent with previous studies, a matched amount of VNS that was not paired with rehabilitative training failed to improve recovery [61]. In summary, a number of preclinical studies provide proof-of-concept demonstration of efficacy for VNS paired with rehabilitative training to improve recovery of motor function after ischemic stroke.…”

Section: Preclinical and Clinical Studies For Ischemic Strokesupporting

confidence: 81%

“…Although chronic VNS is known to confer anxiolytic effects [99,100], this effect is not dependent on pairing with an extinction training regimen. Therefore, the absence of benefits of unpaired VNS is consistent with VNS therapies for sensory and motor dysfunction described above [32,59,61], and further supports enhancement of plasticity as a convergent mechanism that underlies the benefits of VNS therapy.…”

Section: Preclinical Studies For Post-traumatic Stress Disordersupporting

confidence: 73%

“…In both studies, no difference in lesion size was observed, suggesting that VNS is not conferring a neuroprotective effect but rather improving recovery by enhancing plasticity. A follow-up study provided additional evidence that neuroplasticity underlies the benefits of VNS therapy for stroke [61]. A matched amount of VNS that is not paired with rehabilitative training is less effective in restoring function than VNS that is paired with rehabilitative training, suggesting that nonspecific effects of stimulation are unlikely to underlie VNS-dependent enhancement recovery.…”

Section: Preclinical and Clinical Studies For Ischemic Strokementioning

confidence: 99%

“…VNS paired with rehabilitative training resulted in significantly improved forelimb function compared to rehabilitative training without VNS. However, VNS therapy failed to restore fully forelimb function to prelesion levels, unlike the complete recovery observed in models of ischemic stroke [59][60][61]. To determine whether recovery was limited by an insufficient amount of VNS, a cohort of rats received VNS delivered on every attempted trial rather than only successful trials, resulting in~40 % more paired stimulations during therapy.…”

Section: Preclinical Studies For Intracerebral Hemorrhagementioning

confidence: 99%

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Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Hays

2016

Neurotherapeutics

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Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery. The development of adjunctive strategies that broadly support plasticity to facilitate the benefits of rehabilitative interventions has the potential to improve treatment of a wide range of neurological disorders. Recently, stimulation of the vagus nerve in conjunction with rehabilitation has emerged as one such potential targeted plasticity therapy. Vagus nerve stimulation (VNS) drives activation of neuromodulatory nuclei that are associated with plasticity, including the cholinergic basal forebrain and the noradrenergic locus coeruleus. Repeatedly pairing brief bursts of VNS sensory or motor events drives robust, event-specific plasticity in neural circuits. Animal models of chronic tinnitus, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and post-traumatic stress disorder benefit from delivery of VNS paired with successful trials during rehabilitative training. Moreover, mounting evidence from pilot clinical trials provides an initial indication that VNS-based targeted plasticity therapies may be effective in patients with neurological diseases and injuries. Here, I provide a discussion of the current uses and potential future applications of VNS-based targeted plasticity therapies in animal models and patients, and outline challenges for clinical implementation.

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Section: Preclinical and Clinical Studies For Ischemic Strokesupporting

confidence: 81%

Section: Preclinical Studies For Post-traumatic Stress Disordersupporting

confidence: 73%

Section: Preclinical and Clinical Studies For Ischemic Strokementioning

confidence: 99%

Section: Preclinical Studies For Intracerebral Hemorrhagementioning

confidence: 99%

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Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Hays

2016

Neurotherapeutics

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“…However, delayed VNS delivered 2 hr after rehabilitative training sessions or several-fold larger amounts of VNS resulted in comparatively less improvement than precisely timed VNS 51 . Thus, future studies need to optimize both the timing and the amount of VNS to maximize therapeutic benefits.…”

mentioning

confidence: 99%

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Childs

Alvarez-Dieppa

McIntyre

et al. 2015

JoVE

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Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been maintaining the behavior. There is close correspondence between fear and human anxiety, and therefore studies of extinction learning might provide insight into the biological nature of anxiety-related disorders such as post-traumatic stress disorder, and they might help to develop strategies to treat them. Preclinical research aims to aid extinction learning and to induce targeted plasticity in extinction circuits to consolidate the newly formed memory. Vagus nerve stimulation (VNS) is a powerful approach that provides tight temporal and circuit-specific release of neurotransmitters, resulting in modulation of neuronal networks engaged in an ongoing task. VNS enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here, we provide a detailed protocol for the preparation of custom-made parts and the surgical procedures required for VNS in rats. Using this protocol we show how VNS can facilitate the extinction of conditioned fear responses in an auditory fear conditioning task. In addition, we provide evidence that VNS modulates synaptic plasticity in the pathway between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA), which is involved in the expression and modulation of extinction memory. Video LinkThe video component of this article can be found at

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Restoration of Somatosensory Function by Pairing Vagus Nerve Stimulation with Tactile Rehabilitation

Darrow

Mian

Torres

et al. 2020

Annals of Neurology

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ObjectiveSensory dysfunction is a common consequence of many forms of neurological injury, including stroke and nerve damage. Rehabilitative paradigms that incorporate sensory retraining can provide modest benefits, but the majority of patients are left with lasting sensory loss. We have developed a novel strategy that uses closed‐loop vagus nerve stimulation (VNS) paired with tactile rehabilitation to enhance synaptic plasticity and facilitate recovery of sensory function.MethodsA clinical case report provides initial evidence that a similar implementation of closed‐loop VNS paired with a tactile rehabilitation regimen could improve recovery of somatosensory function. Here, we sought to build on these promising initial clinical data and rigorously evaluate the ability of VNS paired with tactile rehabilitation to improve recovery in an animal model of chronic sensory loss. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection (https://osf.io/xsnj5/).ResultsVNS paired with tactile rehabilitation resulted in a significant and nearly complete recovery of mechanosensory withdrawal thresholds. Equivalent tactile rehabilitation without VNS failed to improve sensory function. This VNS‐dependent restoration of sensory thresholds was maintained for several months after the cessation of stimulation, illustrating long‐term benefits. Moreover, VNS paired with tactile rehabilitation resulted in significant generalized improvements in other measures of sensorimotor forepaw function.InterpretationGiven the safety and tolerability of VNS therapy, these findings suggest that incorporating VNS paired with sensory retraining into rehabilitative regimens may represent a fundamentally new method to increase recovery of sensory function after neurological injury. ANN NEUROL 2020;87:194–205

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The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength

Cited by 91 publications

References 24 publications

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Restoration of Somatosensory Function by Pairing Vagus Nerve Stimulation with Tactile Rehabilitation

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