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.

Neural activity regulates autoimmune diseases through the gateway reflex

“…Our findings are in contrast with previous studies that suggested an anti-inflammatory role of the vagus nerve in murine and rat colitis models (Ghia et al 2006(Ghia et al , 2007Meregnani et al 2011) or murine postoperative ileus (de Jonge et al 2005). These studies are in parallel with promising results of bioelectronic medicine targeting the vagus nerve of patients with rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease (Merrill et al 2006;Schwartz et al 2008;González et al 2019;Engineer et al 2019;Koopman et al 2016;Bonaz et al 2016). The discrepancy is most likely due to the fact that the activated vagus fibers are different.…”

An implant for long-term cervical vagus nerve stimulation in mice

“…In addition to its approved use in treatment-resistant epilepsy [1] and depression [2], vagus nerve stimulation (VNS) may provide new treatment options for a wide range of illnesses. Long-term VNS is currently being explored in the treatment of brain disorders, such as tinnitus [3,4], stroke [5,6], and Alzheimer's disease [7,8], as well as peripheral organ and systemic diseases, including heart failure [9], cardiac arrhythmias [10][11][12][13], pulmonary hypertension [14,15], rheumatoid arthritis [16], Crohn's disease [17], and lupus [18]. The relatively recent discovery that the VN modulates the inflammatory response [19][20][21][22] might broaden the range of future indications for VNS, as inflammation is implicated in many common chronic diseases, such as type 2 diabetes, obesity, and atherosclerosis [23][24][25][26].…”

Stress and Tinnitus; Transcutaneous Auricular Vagal Nerve Stimulation Attenuates Tinnitus-Triggered Stress Reaction

“…Maladaptive plasticity is thought to be involved in many medical entities, particularly in illnesses such as phantom pain, dystonias and tinnitus ( Flor et al, 2001 ; Engineer et al, 2011 ; Kilgard, 2012 ). In addition, enhancement of neuronal plasticity through VNS has been shown to improve functional recovery in animal models and patients with stroke-induced upper limb paresis ( Dawson et al, 2016 ; Engineer et al, 2019 ) and in animal models of spinal cord injury ( Ganzer et al, 2018 ). BDNF, norepinephrine and serotonin have been suggested to play a key role in this enhanced plasticity ( Hulsey et al, 2017 ).…”