A Prospective Multicenter Post-Market Study Evaluating the Safety and Effectiveness of Cochlear Implantation in Adults With Single-Sided Deafness.

Stroke is the third-leading cause of death and disability (combined) in the world []. The 2019 Global Burden of Disease report recorded approximately 12.2 million incidents of stroke, with 143 million disability-adjusted life-years lost []. Task-specific training improves motor function post-stroke, likely by driving activity-dependent neuroplasticity []. Task-specific training leads to greater recovery in the early stage (≤ 3 months after stroke) [], corresponding to a period of heightened neuroplasticity [], compared to the chronic stage (≥ 6 months after stroke) []. This highlights the need for adjunct therapies to augment rehabilitation in chronic stroke through enhancing neuroplasticity. Vagus nerve stimulation (VNS) is an emerging neuromodulation approach that may augment rehabilitation outcomes after stroke []. Systematic reviews reported that VNS paired with upper limb motor training in people with stroke led to greater improvements in motor function compared to motor training alone [, ]. Clinically, VNS can be delivered invasively via a surgically implanted stimulator targeting the cervical vagus nerve (invasive VNS; iVNS), or non-invasively using transcutaneous auricular VNS (taVNS), applied to the external ear. Although both modalities aim to engage vagal pathways [, ], their effects are not necessarily directly comparable because stimulation sites and parameter settings differ substantially across techniques []. While iVNS delivers stimulation directly to the cervical vagus nerve and is relatively safe, taVNS is generally more accessible, costs less, and helps to avoid potential risks and complications associated with device implantation surgery [–]. Vagus nerve stimulation is thought to enhance stroke rehabilitation by engaging ascending vagal afferent pathways that modulate brain networks supporting neuroplasticity and motor learning [, ]. Unilateral VNS activates the nucleus tractus solitarius, a key brainstem relay with projections to bilateral neuromodulatory centres and widespread cortical and subcortical circuits [, ]. Through these projections, VNS can influence the release of neurotransmitters linked to synaptic plasticity, including norepinephrine, acetylcholine, and serotonin, and can also shift inhibitory signalling via GABA-mediated circuits [–]. In humans, elevated serotonergic signalling has been linked to enhanced neuroplasticity, including changes in synaptic plasticity and adult neurogenesis []. Both noradrenergic and cholinergic systems have been shown to facilitate neuroplasticity through long-term potentiation [, ]. Human studies using taVNS report changes consistent with increased engagement of GABA-related inhibitory networks [–]. By modulating these neurotransmitters, VNS may facilitate activity-dependent plasticity when paired with training [, –]. Preclinical stroke models provide complementary evidence as iVNS paired with motor training has led to a six-fold increase in synaptic connectivity in the lesioned hemisphere and behavioural gains that persist for two months beyond the stimulation period []. Together, these findings provide a mechanistic rationale for pairing VNS with task-specific training to support motor recovery. Furthermore, evidence from functional magnetic resonance imaging studies shows that taVNS activates brainstem vagal afferent projection and widespread cortical and subcortical networks [, ]. This widespread neuromodulatory effect of taVNS makes it well-suited to target motor behaviours that rely on bilateral and deeper cortical and subcortical networks, which are difficult to influence using focal, surface-targeted techniques such as repetitive transcranial magnetic stimulation or transcranial direct current stimulation.