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. Prior studies show that varying the intensity of stimulation, which influences activity of the locus coeruleus and nucleus basalis in response to VNS, determines the strength of VNS-dependent enhancement of synaptic plasticity in cortical circuits. Objective: The impact of the temporal parameters of stimulation, such as 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 1 of 3 moderate pulse frequencies (20, 30, or 45 Hz) concurrent with a simple motor task. After 5 days of training, we evaluated cortical movement representations using intracortical microstimulation. In a second experiment, we used a similar paradigm to explore whether burst stimulation (125 ms of 30 Hz pulses, repeated 4 times over 2000 ms), would enhance VNS-dependent plasticity.

All 3 moderate pulse frequencies produced equivalent increases in cortical representation of the paired movement compared to sham stimulation. Unexpectedly, 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.