Vagus nerve stimulation intensity influences motor cortex plasticity

Robert A Morrison, Daniel R Hulsey, Katherine S Adcock, Robert L Rennaker 2nd, Michael P Kilgard, Seth A Hays, Robert A Morrison, Daniel R Hulsey, Katherine S Adcock, Robert L Rennaker 2nd, Michael P Kilgard, Seth A Hays

Abstract

Background: Vagus nerve stimulation (VNS) paired with forelimb motor training enhances reorganization of movement representations in the motor cortex. Previous studies have shown an inverted-U relationship between VNS intensity and plasticity in other brain areas, such that moderate intensity VNS yields greater cortical plasticity than low or high intensity VNS. However, the relationship between VNS intensity and plasticity in the motor cortex is unknown.

Objective: In this study we sought to test the hypothesis that VNS intensity exhibits an inverted-U relationship with the degree of motor cortex plasticity in rats.

Methods: Rats were taught to perform a lever pressing task emphasizing use of the proximal forelimb musculature. Once proficient, rats underwent five additional days of behavioral training in which low intensity VNS (0.4 mA), moderate intensity VNS (0.8 mA), high intensity VNS (1.6 mA), or sham stimulation was paired with forelimb movement. 24 h after the completion of behavioral training, intracortical microstimulation (ICMS) was used to document movement representations in the motor cortex.

Results: VNS delivered at 0.8 mA caused a significant increase in motor cortex proximal forelimb representation compared to training alone. VNS delivered at 0.4 mA and 1.6 mA failed to cause a significant expansion of proximal forelimb representation.

Conclusion: Moderate intensity 0.8 mA VNS optimally enhances motor cortex plasticity while low intensity 0.4 mA and high intensity 1.6 mA VNS fail to enhance plasticity. Plasticity in the motor cortex exhibits an inverted-U function of VNS intensity similar to previous findings in auditory cortex.

Keywords: Cortical reorganization; ICMS; Motor cortex; Motor training; Plasticity; Vagus nerve stimulation.

Conflict of interest statement

Conflict of Interest Disclosures

MPK has a financial interesting in MicroTransponder, Inc., which is developing VNS for stroke and tinnitus. All other authors declare no conflicts of interest.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1.. Lever Pressing Task and Experimental…
Figure 1.. Lever Pressing Task and Experimental design.
(A) Illustration of rat performing the lever pressing task. The stimulating cable plugged into the headmounted -connector, the subcutaneous stimulation leads and nerve cuff, and the vagus nerve are shown. (B) Representative trial depicting a double press. (C) Timeline of experimental design.
Figure 2.. Moderate intensity VNS enhances plasticity…
Figure 2.. Moderate intensity VNS enhances plasticity in motor cortex.
(A) Moderate intensity 0.8 mA VNS paired with forelimb motor training significantly increases the movement representation of the proximal forelimb in motor cortex compared to equivalent motor training without VNS (Sham). Low intensity 0.4 mA VNS and high intensity 1.6 mA VNS both fail to increase proximal forelimb representation compared to Sham. (B) No difference was observed in the area of distal forelimb representation across groups, indicating that VNS-dependent plasticity is specific to the trained movement. (C) No change in the total area of motor cortex was observed across groups. Circles depict individual subjects. Bars represent mean ± SEM. * denotes significant differences using Bonferroni-corrected p

Figure 3.. Average motor cortex movement representations.

Figure 3.. Average motor cortex movement representations.

(A) Cumulative representations from all ICMS maps expressed…

Figure 3.. Average motor cortex movement representations.
(A) Cumulative representations from all ICMS maps expressed as a percentage of representations observed at each electrode penetration for each group. (B) Average percentage of the total map devoted to each movement representation. Moderate intensity 0.8 mA VNS paired with forelimb training significantly increases the amount of motor cortex that represents the proximal forelimb compared equivalent training paired with high intensity 1.6 mA VNS.

Figure 4.. Amount of training or stimulation…

Figure 4.. Amount of training or stimulation cannot explain moderate intensity VNS-dependent enhancement of plasticity.

Figure 4.. Amount of training or stimulation cannot explain moderate intensity VNS-dependent enhancement of plasticity.
(A) No difference in the total number of stimulations received was observed across groups. (B) Additionally, no difference in the timing between stimulations was observed across groups. Together, these findings indicate that differences in the amount of stimulation or the timing between stimulations cannot account for the increased in proximal forelimb representation driven by moderate intensity 0.8 mA VNS. Circles depict individual subjects. Bars represent mean ± SEM.

Figure 5.. Model of the Inverted-U relationship…

Figure 5.. Model of the Inverted-U relationship between VNS intensity and cortical plasticity.

One potential…

Figure 5.. Model of the Inverted-U relationship between VNS intensity and cortical plasticity.
One potential explanation to account for the inverted-U relationship between VNS intensity and enhancement of plasticity relies on engagement of two opposing processes. At low stimulation intensities, VNS fails to drive sufficient activation of a low-threshold, pro-plasticity process (red) and thus fails to drive plasticity. At moderate stimulation intensities, VNS activates the low-threshold pro-plasticity process and avoids activation of a high-threshold, anti-plasticity process (blue), resulting in robust enhancement of plasticity. At high stimulation intensities, the anti-plasticity process dominates and prevents effective enhancement of plasticity.
Figure 3.. Average motor cortex movement representations.
Figure 3.. Average motor cortex movement representations.
(A) Cumulative representations from all ICMS maps expressed as a percentage of representations observed at each electrode penetration for each group. (B) Average percentage of the total map devoted to each movement representation. Moderate intensity 0.8 mA VNS paired with forelimb training significantly increases the amount of motor cortex that represents the proximal forelimb compared equivalent training paired with high intensity 1.6 mA VNS.
Figure 4.. Amount of training or stimulation…
Figure 4.. Amount of training or stimulation cannot explain moderate intensity VNS-dependent enhancement of plasticity.
(A) No difference in the total number of stimulations received was observed across groups. (B) Additionally, no difference in the timing between stimulations was observed across groups. Together, these findings indicate that differences in the amount of stimulation or the timing between stimulations cannot account for the increased in proximal forelimb representation driven by moderate intensity 0.8 mA VNS. Circles depict individual subjects. Bars represent mean ± SEM.
Figure 5.. Model of the Inverted-U relationship…
Figure 5.. Model of the Inverted-U relationship between VNS intensity and cortical plasticity.
One potential explanation to account for the inverted-U relationship between VNS intensity and enhancement of plasticity relies on engagement of two opposing processes. At low stimulation intensities, VNS fails to drive sufficient activation of a low-threshold, pro-plasticity process (red) and thus fails to drive plasticity. At moderate stimulation intensities, VNS activates the low-threshold pro-plasticity process and avoids activation of a high-threshold, anti-plasticity process (blue), resulting in robust enhancement of plasticity. At high stimulation intensities, the anti-plasticity process dominates and prevents effective enhancement of plasticity.

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