Targeted Vagus Nerve Stimulation for Rehabilitation After Stroke

Abstract

Stroke is a leading cause of disability worldwide, and in approximately 60% of individuals, upper limb deficits persist 6 months after stroke. These deficits adversely affect the functional use of the upper limb and restrict participation in day to day activities. An important goal of stroke rehabilitation is to improve the quality of life by enhancing functional independence and participation in activities. Since upper limb deficits are one of the best predictors of quality of life after stroke, effective interventions targeting these deficits may represent a means to improve quality of life. An increased understanding of the neurobiological processes underlying stroke recovery has led to the development of targeted approaches to improve motor deficits. One such targeted strategy uses brief bursts of Vagus Nerve Stimulation (VNS) paired with rehabilitation to enhance plasticity and support recovery of upper limb function after chronic stroke. Stimulation of the vagus nerve triggers release of plasticity promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex. Timed engagement of neuromodulators concurrent with motor training drives task-specific plasticity in the motor cortex to improve function and provides the basis for paired VNS therapy. A number of studies in preclinical models of ischemic stroke demonstrated that VNS paired with rehabilitative training significantly improved the recovery of forelimb motor function compared to rehabilitative training without VNS. The improvements were associated with synaptic reorganization of cortical motor networks and recruitment of residual motor neurons controlling the impaired forelimb, demonstrating the putative neurobiological mechanisms underlying recovery of motor function. These preclinical studies provided the basis for conducting two multi-site, randomized controlled pilot trials in individuals with moderate to severe upper limb weakness after chronic ischemic stroke. In both studies, VNS paired with rehabilitation improved motor deficits compared to rehabilitation alone. The trials provided support for a 120-patient pivotal study designed to evaluate the efficacy of paired VNS therapy in individuals with chronic ischemic stroke. This manuscript will discuss the neurobiological rationale for VNS therapy, provide an in-depth discussion of both animal and human studies of VNS therapy for stroke, and outline the challenges and opportunities for the future use of VNS therapy.

Keywords: neuromodulation; plasticity; rehabilitation; stroke; vagus nerve stimulation.

FIGURE 1

Vagus Nerve Stimulation-dependent recovery of motor function in rat models of stroke. (A) VNS paired with rehabilitative training significantly improves recovery of forelimb motor function compared to equivalent training without VNS in a model of cortical ischemic stroke. The top panel shows a coronal brain section with a representative ischemic lesion. Similarly, VNS paired with rehabilitative training enhances recovery of forelimb function after (B) chronic combined cortical and subcortical ischemic and (C) intracerebral hemorrhage. The symbol “^∗” indicates p < 0.05 across groups at each time point (Adapted from Hays et al., 2014a,b; Khodaparast et al., 2016).

FIGURE 2

Vagus Nerve Stimulation therapy improves recovery in a variety of models of neurological injury. A meta-analysis of recovery across a range of rat models of neurological damage demonstrates that VNS paired with rehabilitative training (VNS+Rehab) consistently improves recovery of forelimb motor function compared to equivalent rehabilitative training without VNS (Rehab Alone). The data are presented as a forest plot. Markers denote standardized mean difference for VNS+Rehab compared to Rehab Alone for each study, and horizontal lines indicate 95% confidence interval. The size of the indicator represents the number of subjects. The blue diamond represents the summary effect.

FIGURE 3

Vagus Nerve Stimulation paired with motor training enhances synaptic reorganization after stroke. Rats that receive VNS paired with motor training (red bar) after stroke demonstrated a significantly greater increase in corticospinal tract (CST) connectivity to rehabilitated muscles compared to equivalent training without VNS (blue bar). CST connectivity originating in both the ipsilesional and contralesional hemispheres was increased. These findings indicate that VNS drives large-scale reorganization in motor networks after stroke which may underlie recovery of function (Adapted from Meyers E.C. et al., 2018). ^∗ indicates p < 0.05; ^∗∗ indicates p < 0.01.

FIGURE 4

Vagus Nerve Stimulation paired with rehabilitation in the clinic and at home, (A) In-clinic rehabilitation with VNS: VNS is delivered by a therapist using a push button timed with a task-specific movement. Pressing the button delivers a brief burst of VNS (0.5 s) during an active goal-directed movement. The VNS system includes an implantable pulse generator (implanted device) that is implanted under the individual’s chest wall, an implantable lead, wireless transmitter (for communication between the device and computer) and custom programming software. (B) Home-based VNS therapy: Participants are provided a magnet (inset) to swipe over the device once before the start of each rehabilitation session to self-initiate 30 min of VNS (0.5 s burst of VNS every 10 s for 30 min). During the 30 min, participants performed at-home exercises prescribed by the therapist and adapted to their functional level and goals.

FIGURE 5

(A) Consort Diagram for the pilot study (from Kimberley et al., 2018). Twenty-two participants were enrolled in the study of which 17 were implanted. Eight participants were randomized to the VNS group and 9 to rehabilitation only (B). Clinical study flowchart. After screening and baseline evaluations, all participants were implanted with a VNS device and randomized to receive either Active (0.8 mA) or Control VNS (0.0 mA) paired with upper limb rehabilitation. Participants received 18 sessions of in-clinic therapy for 6 weeks, followed by a home-based therapy for 3 months (no VNS was delivered to either group during the 1st month of home therapy). The 3-month time point is referred to as Post-day 90. After Post-day 90, the Active VNS group continued with home-based Active VNS, and the Control group crossed over to receive 6-weeks of in-clinic therapy with Active VNS followed by home-based Active VNS, similar to the Active VNS+Rehab group. Outcome measures were evaluated at baseline, Post-day 1, Post-day 30, and Post-day 90.

FIGURE 6

(A) Fugl-Meyer assessment–upper extremity (Kimberley et al., 2018). Change in FMA-UE score at three posttreatment assessments from baseline for Active VNS (solid line) and Control VNS + Rehab (dashed line). Shaded area indicates 6 weeks of in-clinic therapy. Error bars indicated standard error of the mean (s.e.m). (B) FMA-UE responder rate (defined as FMA-UE change ≥6 points from baseline) for Active VNS (black) and Control VNS + Rehab (gray). ^∗p < 0.05, Fisher exact test.