Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Abstract

Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery. The development of adjunctive strategies that broadly support plasticity to facilitate the benefits of rehabilitative interventions has the potential to improve treatment of a wide range of neurological disorders. Recently, stimulation of the vagus nerve in conjunction with rehabilitation has emerged as one such potential targeted plasticity therapy. Vagus nerve stimulation (VNS) drives activation of neuromodulatory nuclei that are associated with plasticity, including the cholinergic basal forebrain and the noradrenergic locus coeruleus. Repeatedly pairing brief bursts of VNS sensory or motor events drives robust, event-specific plasticity in neural circuits. Animal models of chronic tinnitus, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and post-traumatic stress disorder benefit from delivery of VNS paired with successful trials during rehabilitative training. Moreover, mounting evidence from pilot clinical trials provides an initial indication that VNS-based targeted plasticity therapies may be effective in patients with neurological diseases and injuries. Here, I provide a discussion of the current uses and potential future applications of VNS-based targeted plasticity therapies in animal models and patients, and outline challenges for clinical implementation.

Keywords: Neuroplasticity; Rehabilitation; Stroke; Tinnitus; Vagal nerve stimulation; Vagus nerve stimulation.

Fig. 1

Vagus nerve stimulation (VNS)-dependent enhancement of plasticity in cortical circuits. (A) (i) Presentation of a tone drives activity in the auditory cortex (green). (ii) Temporally precise release of neuromodulators (blue), such as that induced by VNS, paired with this activity drives plasticity. (iii) After repeated tone presentation paired with VNS, map reorganization results in an increased representation of the paired tone [32]. Previously subthreshold inputs (light green) drive activity after pairing with VNS. (B) (i) Activity within neurons of the motor cortex results in movement of the shoulder. (ii) Release of neuromodulators paired with movement drives plasticity in the motor cortex. (iii) Following repetitive shoulder movement paired with VNS, the number of circuits representing shoulder movement in the motor cortex is increased [36]. The large rectangles represent topographical organization of the auditory and motor cortices, and the activity of neurons is represented within each individual box. Dark green denotes suprathreshold action potential firing, light green denotes subthreshold depolarization, and gray denotes no response. Figure adapted from [3]

Fig. 2

Model of vagus nerve stimulation (VNS)-based targeted plasticity therapies. (A) (i) In tinnitus, auditory neurons are hyperactive and the tonotopic map is distorted. (ii) Presentation of tones excluding the tinnitus frequency paired with VNS drives adaptive plasticity within the auditory system. (iii) Activity within the auditory system is renormalized after targeted plasticity therapy, demonstrating that VNS paired with sensory rehabilitation can reverse maladaptive plasticity [32]. (B) (i) Following a stroke, circuits controlling movement are damaged resulting in impaired function. (ii) Motor rehabilitation paired with VNS drives robust neural plasticity in motor cortex. (iii) After targeted plasticity therapy, the number of circuits controlling the previously impaired movement are increased, leading to enhanced recovery of motor function [–61, 66]. Figure adapted from [3]

Fig. 3

Model of rehabilitation and neural plasticity. (A) During rehabilitation, repeated practice in conjunction with engagement (i.e., motivation and attention) yields improvements in function. (B) Neural activity coincident with neuromodulator release synergistically combine to drive neural plasticity. Targeted plasticity therapies provide precisely timed, nonadapting neuromodulator release paired with neural activity resulting from rehabilitation to facilitate plasticity and enhance recovery