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An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke.

ABSTRACT: We have previously shown the safety and feasibility of vagus nerve stimulation (VNS) paired with upper-limb rehabilitation after ischemic stroke. In this exploratory study, we assessed whether clinical and brain MRI variables predict response to treatment. We used data from two completed randomised and blinded clinical trials (N?=?35). All participants had moderate to severe upper-limb weakness and were randomised to 6-weeks intensive physiotherapy with or without VNS. Participants had 3?T brain MRI at baseline. The primary outcome was change in Fugl-Meyer Assessment, upper-extremity score (FMA-UE) from baseline to the first day after therapy completion. We used general linear regression to identify clinical and brain MRI predictors of change in FMA-UE. VNS-treated participants had greater improvement in FMA-UE at day-1 post therapy than controls (8.63?±?5.02 versus 3.79?±?5.04 points, t?=?2.83, Cohen's d?=?0.96, P?=?0.008). Higher cerebrospinal fluid volume was associated with less improvement in FMA-UE in the control but not VNS group. This was also true for white matter hyperintensity volume but not after removal of an outlying participant from the control group. Responders in the VNS group had more severe arm impairment at baseline than responders to control. A phase III trial is now underway to formally determine whether VNS improves outcomes and will explore whether these differ in people with more severe baseline upper-limb disability and cerebrovascular disease.

SUBMITTER: Dickie DA

PROVIDER: S-EPMC6828969 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke.

Dickie David Alexander DA Kimberley Teresa Jacobson TJ Pierce David D Engineer Navzer N Tarver W Brent WB Dawson Jesse J

Scientific reports 20191104 1

We have previously shown the safety and feasibility of vagus nerve stimulation (VNS) paired with upper-limb rehabilitation after ischemic stroke. In this exploratory study, we assessed whether clinical and brain MRI variables predict response to treatment. We used data from two completed randomised and blinded clinical trials (N = 35). All participants had moderate to severe upper-limb weakness and were randomised to 6-weeks intensive physiotherapy with or without VNS. Participants had 3 T brain ...[more]

PMID: 31685853

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Project description:Background:Vagus nerve stimulation (VNS) paired with a motor task improves motor outcome in rat stroke models. It is hypothesised that VNS delivered during rehabilitation will improve upper limb function compared to control rehabilitation therapy. Two pilot clinical studies demonstrated acceptable safety and feasibility of VNS paired with rehabilitation for improved upper limb function after stroke. Participants who received rehabilitation paired with VNS demonstrated clinically meaningful improvements in motor function that exceed gains seen among controls who received similar rehabilitation without VNS. These preliminary data support a larger pivotal trial. Methods:VNS-REHAB (VNS-Rehabilitation) is a pivotal, multi-site, double-blinded, randomised trial designed to evaluate safety and efficacy of VNS paired with upper limb rehabilitation after ischaemic stroke. The study will include up to 120 participants with upper limb weakness due to stroke nine months to 10 years prior. All participants will be implanted with a VNS device and randomised to receive either Active (0.8 mA) or Control VNS (0.0 mA) paired with upper limb rehabilitation. All participants receive 18 sessions of in-clinic therapy for six weeks, followed by a home-based therapy for three months. The rehabilitation therapy involves progressive, functionally based and intensive practice of hand and arm tasks. VNS is delivered during each movement repetition. After blinded follow-up is completed, the Active vagus nerve stimulation group continues with home-based Active VNS and the Control group receive six weeks of in-clinic therapy with Active VNS followed by home-based Active VNS. The primary efficacy endpoint will be the difference in Fugl-Meyer assessment-upper extremity scores between the Active VNS and Control VNS groups at the end of six weeks of in-clinic therapy. Additional secondary endpoints will also be measured. Safety will be assessed with analysis of adverse events and device complications during study participation. Discussion:This pivotal trial will determine whether VNS paired with rehabilitation is a safe and effective treatment for improving arm function after stroke.Trial Registration: ClinicalTrials.gov, NCT03131960. Registered on 27 April 2017.

Project description:Neonates born premature or who suffer brain injury at birth often have oral feeding dysfunction and do not meet oral intake requirements needed for discharge. Low oral intake volumes result in extended stays in the hospital (>2 months) and can lead to surgical implant and explant of a gastrostomy tube (G-tube). Prior work suggests pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke, and transcutaneous auricular VNS (taVNS) has emerged as promising noninvasive form of VNS. Pairing taVNS with bottle-feeding rehabilitation may improve oromotor coordination and lead to improved oral intake volumes, ultimately avoiding the need for G-tube placement. We investigated whether taVNS paired with oromotor rehabilitation is tolerable and safe and facilitates motor learning in infants who have failed oral feeding. We enrolled 14 infants [11 premature and 3 hypoxic-ischemic encephalopathy (HIE)] who were slated for G-tube placement in a prospective, open-label study of taVNS-paired rehabilitation to increase feeding volumes. Once-daily taVNS was delivered to the left tragus during bottle feeding for 2 weeks, with optional extension. The primary outcome was attainment of oral feeding volumes and weight gain adequate for discharge without G-tube while also monitoring discomfort and heart rate (HR) as safety outcomes. We observed no adverse events related to stimulation, and stimulation-induced HR reductions were transient and safe and likely confirmed vagal engagement. Eight of 14 participants (57%) achieved adequate feeding volumes for discharge without G-tube (mean treatment length: 16 ± 6 days). We observed significant increases in feeding volume trajectories in responders compared with pre-stimulation (p < 0.05). taVNS-paired feeding rehabilitation appears safe and may improve oral feeding in infants with oromotor dyscoordination, increasing the rate of discharge without G-tube, warranting larger controlled trials.

Project description:Implanted vagus nerve stimulation (VNS) delivered concurrently with upper limb rehabilitation has been shown to improve arm function after stroke. Transcutaneous auricular VNS (taVNS) offers a non-invasive alternative to implanted VNS and may provide similar therapeutic benefit. There is much discussion about the optimal approach for combining VNS and physical therapy, as such we sought to determine whether taVNS administered during robotic training, specifically delivered during the premotor planning stage for arm extension movements, would confer additional motor improvement in patients with chronic stroke. Thirty-six patients with chronic, moderate-severe upper limb hemiparesis (>6 months; mean Upper Extremity Fugl-Meyer score = 25 ± 2, range 13-48), were randomized to receive 9 sessions (1 h in length, 3x/week for 3 weeks) of active (N = 18) or sham (N = 18) taVNS (500 ms bursts, frequency 30 Hz, pulse width 0.3 ms, max intensity 5 mA, ∼250 stimulated movements per session) delivered during robotic training. taVNS was triggered by the onset of a visual cue prior to center-out arm extension movements. Clinical assessments and surface electromyography (sEMG) measures of the biceps and triceps brachii were collected during separate test sessions. Significant motor improvements were measured for both the active and sham taVNS groups, and these improvements were robust at 3 month follow-up. Compared to the sham group, the active taVNS group showed a significant reduction in spasticity of the wrist and hand at discharge (Modified Tardieu Scale; taVNS = -8.94% vs. sham = + 2.97%, p < 0.05). The EMG results also demonstrated significantly increased variance for the bicep peak sEMG amplitude during extension for the active taVNS group compared to the sham group at discharge (active = 26.29% MVC ± 3.89, sham = 10.63% MVC ± 3.10, mean absolute change admission to discharge, p < 0.01), and at 3-month follow-up, the bicep peak sEMG amplitude was significantly reduced in the active taVNS group (P < 0.05). Thus, robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. taVNS administered during premotor planning of movement may play a role in improving coordinated activation of the agonist-antagonist upper arm muscle groups by mitigating spasticity and increasing motor control following stroke. Clinical Trial Registration: www.ClinicalTrials.gov, identifier (NCT03592745).

Project description:Loss of sensory function is a common consequence of neurological injury. Recent clinical and preclinical evidence indicates vagus nerve stimulation (VNS) paired with tactile rehabilitation, consisting of delivery of a variety of mechanical stimuli to the hyposensitive skin surface, yields substantial and long-lasting recovery of somatosensory function after median and ulnar nerve transection and repair. Here, we tested the hypothesis that a specific component of the tactile rehabilitation paired with VNS is necessary for recovery of somatosensory function. In a second experiment in a separate cohort, we investigated whether VNS paired with tactile rehabilitation could improve skilled forelimb motor function. Elements of the study design, including planned sample size, assessments, and statistical comparisons, were preregistered prior to beginning data collection (https://osf.io/3tm8u/). Animals received a peripheral nerve injury (PNI) causing chronic sensory loss. Eight weeks after injury, animals were given a VNS implant followed by six weeks of tactile rehabilitation sessions consisting of repeated application of one of two distinct mechanical stimuli, a filament or a paintbrush, to the previously denervated forepaw. VNS paired with either filament indentation or brushing of the paw significantly improved recovery of forelimb withdrawal thresholds after PNI compared to tactile rehabilitation without VNS. The effect size was twice as large when VNS was paired with brushing compared to VNS paired with point indentation. An independent replication in a second cohort confirmed that VNS paired with brush restored forelimb withdrawal thresholds to normal. These rats displayed significant improvements in performance on a skilled forelimb task compared to rats that did not receive VNS. These findings support the utility of pairing VNS with tactile rehabilitation to improve recovery of somatosensory and motor function after neurological injury. Additionally, this study demonstrates that the sensory characteristics of the rehabilitation paired with VNS determine the degree of recovery.

Project description:Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed. Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drug-refractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated "ON" and nonstimulated "OFF" periods and between responder (R) and nonresponder (NR) patients. Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of ∼50% was documented. We analyzed the synchronization in EEG time series during "ON" and "OFF" periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients. Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p < 0.05). No significant differences in MST were observed between R and NR patients. Conclusion: The correlation between VNS-induced interictal EEG time-series desynchronization and decrease in seizure frequency suggested that VNS therapeutic impact might be related to changes in interictal functional connectivity. Impact statement Electroencephalography (EEG) desynchronization has been proposed to be a mechanism for antiepileptic effect of vagus nerve stimulation (VNS). We measured interictal EEG time-series synchronization during stimulated (ON) and nonstimulated (OFF) periods in epileptic patients treated by VNS. Phase lag index differences between ON and OFF periods were measured in delta, theta, and beta bands only in responder patients. To our knowledge, our study is the first to statistically correlate interictal cortical desynchronization during ON periods with reduction in seizure frequency. Our result supports the hypothesis that the antiseizure effect of VNS is mediated by cortical desynchronization.

Dataset Information

An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke.

Publications

An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke.

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