Background and Purpose—Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke.
Methods—Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl–Meyer Assessment-Upper Extremity).
Results—Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl–Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, −0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl–Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6).
Conclusions—This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed.
Arm weakness is common after stroke, and its treatment is recognized as an area of considerable need.1 Approximately 85% of patients with stroke present with arm weakness,2 and 60% of stroke survivors with nonfunctional arms at 1 week do not recover function by 6 months.3Current treatment for arm weakness typically comprises intensive, task-specific, and repetitive rehabilitative interventions or occasionally methods such as constraint-induced movement therapy and electric neurostimulation.4 A recent meta-analysis and large-scale trials show the effects of current treatments for arm weakness to be modest.5,6 Novel and more effective treatments are needed. Improvement in arm function should improve quality of life for stroke survivors, reduce comorbidities associated with loss of independence, and reduce cost to the healthcare system.7
Intensive training has been shown to facilitate a range of neuroplastic brain events.8 It is possible that augmentation of neuroplasticity to promote reorganization of neural networks is required to more fully recover motor function.9 However, no practical and effective method exists to achieve this and even if such changes occur, it is unclear whether they are clinically meaningful or long term. This study is a preliminary investigation of an intervention designed to promote specific neuroplasticity; vagus nerve stimulation (VNS) paired with movement to drive task-specific plasticity in the motor cortex.10–12 VNS activates neurons in the basal forebrain and locus coeruleus and results in release of acetylcholine and norepinephrine, respectively, which are known to facilitate reorganization of cortical networks.13 We recently demonstrated in a rat model of ischemic stroke that pairing forelimb rehabilitation with VNS significantly increases recovery of forelimb speed and strength when compared with rehabilitation alone.14,15 Our subsequent studies demonstrated that VNS paired with rehabilitative training also improves recovery in a rat model of intracerebral hemorrhage,16 and that precise timing of VNS with specific motor movements yields optimal recovery.17
We hypothesize that VNS paired with upper-limb rehabilitation therapy will result in greater recovery of arm function than rehabilitation alone in adults with chronic ischemic stroke. We performed the first-in-human evaluation of VNS paired with upper-limb rehabilitation after ischemic stroke. The main objective of the study was to evaluate the safety and feasibility of paired VNS therapy after stroke and to provide clinical data for sample size calculations for larger studies. […]