The efficacy of standard rehabilitative therapy for improving upper limb functions after stroke is limited; thus, alternative strategies are needed. Vagus nerve stimulation (VNS) paired with rehabilitation is a promising approach, but the invasiveness of this technique limits its clinical application. Recently, a noninvasive method to stimulate vagus nerve has been developed. The aim of the present study was to explore whether noninvasive VNS combined with robotic rehabilitation can enhance upper limb functionality in chronic stroke. Safety and efficacy of this combination have been assessed within a proof-of-principle, double-blind, semirandomized, sham-controlled trial. Fourteen patients with either ischemic or haemorrhagic chronic stroke were randomized to robot-assisted therapy associated with real or sham VNS, delivered for 10 working days. Efficacy was evaluated by change in upper extremity Fugl–Meyer score. After intervention, there were no adverse events and Fugl–Meyer scores were significantly better in the real group compared to the sham group. Our pilot study confirms that VNS is feasible in stroke patients and can produce a slight clinical improvement in association to robotic rehabilitation. Compared to traditional stimulation, noninvasive VNS seems to be safer and more tolerable. Further studies are needed to confirm the efficacy of this innovative approach.
Upper limb impairment is a common consequence of stroke with a deep impact on patient’s quality of life. Since the efficacy of standard rehabilitative therapy is limited, alternative strategies are needed. Robot-assisted rehabilitation can be useful in stroke patients because it allows an intensive as well as task-specific training characterized by high repetition of movements in a strongly motivating environment [1–3]. Several studies have explored the possibility to potentiate the effect of robotic therapy by the association with noninvasive human brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), that can induce neuroplasticity via long-term potentiation-/depression- (LTP-/LTD-) like phenomena . Although intriguing, the evidence in support of this strategy remains low [5, 6]. Indeed, the literature analysis of the published data seems to demonstrate that the association of rTMS with robotic training has the same clinical gain derived from robotic therapy alone. Moreover, rTMS is contraindicated in patients who suffered from haemorrhagic stroke for the risk of inducing seizures . For these reasons, there is great interest in the development of alternative techniques of neuromodulation that can foster the effect of robotic therapy.
Vagus nerve stimulation (VNS) is approved as adjunctive treatment for refractory epilepsy and depression but is currently under investigation for a wide range of neurological diseases . In particular, recent studies have demonstrated that VNS paired with rehabilitation significantly improves forelimb strength and movement speed in rat models of ischemic  and haemorrhagic stroke . VNS is believed to enhance the benefits of rehabilitation by promoting neuroplasticity . Preliminary data  have showed that such approach is also feasible in patients; however, the diffusion of this technique is limited by its invasiveness. Indeed, VNS requires the surgical implantation of a stimulator of the cervical branch of the vagus nerve. Recently, it has been proposed a noninvasive technique that consists of transcutaneous stimulation of the vagus nerve (tVNS) in external auditory channel at the inner side of the tragus. Both neuroimaging  and neurophysiological  studies have demonstrated that the effect of tVNS on brain activity is quite similar to the effect induced by traditional, invasive VNS.
The aim of the present study was to explore whether tVNS can enhance the benefit induced by robotic rehabilitation on motor function of the upper limb in chronic stroke. Safety and efficacy of this combination have been assessed within a proof-of-principle, double-blind, semirandomized, sham-controlled trial. […]