Temporal Parameters Determine the Efficacy of Vagus Nerve Stimulation Directed Neural Plasticity

Combining vagus nerve stimulation (VNS) with rehabilitation represents an emerging treatment for a range of neurological disorders, and identifying stimulation parameters that maximize the effects of VNS may provide a means to optimize this therapy. A number of prior studies show that varying the intensity of stimulation, which influences the amount of neuromodulatory activation in response to VNS, determines the strength of VNS-dependent enhancement of synaptic plasticity in cortical circuits. The impact of the temporal parameters of stimulation, such as the frequency and distribution of pulses within a stimulation train, remains underexplored. In this study, we evaluated how varying these temporal parameters impacts the magnitude of VNS-directed plasticity. In the first experiment, rats received trains of VNS at one of three moderate pulse frequencies (20, 30, or 45Hz) timed to occur with movement during training on a simple motor task. After five days of training, we evaluated the cortical movement representations using intracortical microstimulation. All three moderate pulse frequencies produced equivalent increases in the cortical representation of the paired movement compared to sham stimulation. In a second experiment, we used a similar paradigm to explore whether burst stimulation would enhance VNS-dependent plasticity. Unexpectedly, we found that both burst stimulation or a matched number of pulses distributed evenly in time failed to produce significant enhancement of plasticity compared to sham stimulation, whereas moderate pulse frequency stimulation did. These findings illustrate the importance of the temporal dynamics of stimulation in determining the effects of VNS and provide guidelines for designing novel VNS sequences.