Vagus Nerve Stimulation Intensity Regulates Targeted Plasticity

Vagus nerve stimulation (VNS) paired with motor rehabilitation enhances recovery of function after neurological injury in rats and humans. This effect is ascribed to VNS-dependent facilitation of synaptic plasticity in motor networks triggered by increases in neuromodulatory activity. Based on plasticity’s role in VNS-enhancement of rehabilitation, it is possible that greater levels of synaptic reorganization lead to greater recovery. Thus, defining stimulation strategies that maximize plasticity may provide a means to optimize the efficacy of VNS therapy, improving subsequent recovery for patients. The stimulation parameters of VNS, including intensity, frequency, and duration, can influence the level of activity in relevant neuromodulatory nuclei. However, levels of neuromodulatory activity alone are not an accurate predictor of degree of plasticity. Previous studies in auditory cortex report an inverted-U relationship between VNS intensity and plasticity, such that moderate intensity VNS yields greater cortical plasticity than low or high intensity VNS. Here, we first investigate the effects of increasing VNS intensity on motor cortex plasticity when paired with forelimb training. We demonstrate that there is an inverted-U relationship between VNS intensity and subsequent plasticity, as VNS at moderate intensities paired with forelimb training drives expansion of associated forelimb representations in motor cortex, while low and high intensities do not. We then go on to investigate VNS-mediated plasticity in jaw motor cortex using a new behavioral paradigm emphasizing the jaw musculature, demonstrating that VNS can enhance synaptic reorganization in orofacial circuits. We validate this new behavioral paradigm by re-examining the inverted-U relationship between VNS intensity and degree of plasticity, replicating our previous findings with a higher resolution and demonstrating that there is a narrower range of effective VNS intensities than previously thought. Although high intensity VNS fails to enhance plasticity when delivered alone, it is unclear whether the mechanisms engaged by high intensity VNS interact with and disrupt subsequent moderate intensity VNS. We tested the interaction of moderate and high intensity VNS trains to probe the mechanisms that may underlie VNS-dependent plasticity, showing that high intensity VNS engages mechanisms that disrupt VNS-dependent synaptic plasticity. Lastly, based on our findings that VNS can enhance synaptic plasticity in orofacial circuits, we discuss the possibility of using VNS as an adjuvant to rehabilitation for post-stroke motor speech disorders. VNS paired with upper limb rehabilitation enhances upper limb function after stroke, and our findings suggests that VNS may enhance synaptic plasticity in networks related to poststroke motor speech disorders in a similar manner. We outline the rationale for pairing VNS with rehabilitation for dyspraxia and dysphagia to enhance plasticity in orofacial circuits mediating orofacial function, which could lead to greater recovery than with just rehabilitation alone.