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. 2023 Sep;37(9):652-661.
doi: 10.1177/15459683231197412. Epub 2023 Sep 11.

Effective Delivery of Vagus Nerve Stimulation Requires Many Stimulations Per Session and Many Sessions Per Week Over Many Weeks to Improve Recovery of Somatosensation

Andrea D Ruiz  1   2 , Kaitlyn M Malley  1   3 , Tanya T Danaphongse  1 , Fatima N Ahmad  1   3 , Clareth Mota Beltran  1   3 , Robert L Rennaker  1   2   3 , Michael P Kilgard  1   3 , Seth A Hays  1   2
Affiliations

Effective Delivery of Vagus Nerve Stimulation Requires Many Stimulations Per Session and Many Sessions Per Week Over Many Weeks to Improve Recovery of Somatosensation

Andrea D Ruiz et al. Neurorehabil Neural Repair. 2023 Sep.

Abstract

Background: Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation.

Objective: Here, we characterize the amount, intensity, frequency, and duration of VNS therapy paradigms to determine the optimal dosage for VNS-dependent enhancement of recovery in a model of peripheral nerve injury (PNI).

Methods: Rats underwent transection of the medial and ulnar nerves in the forelimb, resulting in chronic sensory loss in the paw. Eight weeks after injury, rats were implanted with a VNS cuff and received tactile rehabilitation sessions consisting of repeated mechanical stimulation of the previously denervated forepaw paired with short bursts of VNS. Rats received VNS therapy in 1 of 6 systematically varied dosing schedules to identify a paradigm that balanced therapy effectiveness with a shorter regimen.

Results: Delivering 200 VNS pairings a day 4 days a week for 4 weeks produced the greatest percent improvement in somatosensory function compared to any of the 6 other groups (One Way analysis of variance at the end of therapy, F[4 70] P = .005).

Conclusions: Our findings demonstrate that an effective VNS therapy dosage delivers many stimulations per session, with many sessions per week, over many weeks. These results provide a framework to inform the development of VNS-based therapies for sensory restoration.

Keywords: dosage; massed training; nerve injury; neurorehabilitation; spaced training; vagal nerve stimulation.

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Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MPK has a financial interest in MicroTransponder, Inc., which is developing closed-loop VNS for stroke. RLR is the co-founder and CEO of XNerve, which is developing nerve stimulation therapies. The other authors declare that no competing interests exist.

Figures

Figure 1.
Figure 1.
Experimental design and therapy schedules. The No VNS group received tactile rehabilitation without VNS stimulation. All other groups received tactile rehabilitation paired with VNS stimulation in various therapy schedules. The Moderate Weekly VNS, Intense Weekly VNS, and Intense Daily VNS explore the effects of reducing session frequency while varying the amount of VNS-touch pairings, and therapy duration. The Short Daily VNS and Rapid Moderate Daily groups explore the effects of reducing individual session time by altering amount of VNS-touch pairings or interstimulus interval between trials.
Figure 2.
Figure 2.
VNS therapy requires daily sessions over many weeks to drive somatosensory recovery. After injury, withdrawal thresholds are significantly worse in all groups, indicating chronic somatosensory impairments. The Moderate Daily VNS therapy schedule significantly improves somatosensory thresholds compared to equivalent tactile rehabilitation without VNS and all groups receiving 4 sessions of therapy. Error bars indicate mean ± standard error of the mean. *Denotes P < .05.
Figure 3.
Figure 3.
VNS requires many VNS-touch pairings per session to drive somatosensory recovery. After injury, withdrawal thresholds are significantly worse in all groups. The Moderate Daily VNS therapy schedule significantly improves somatosensory thresholds compared to equivalent tactile rehabilitation without VNS, and all groups receiving 50 stimulations per session and 2 seconds ISI. Error bars indicate mean ± standard error of the mean. *Denotes P < .05.
Figure 4.
Figure 4.
VNS efficacy cannot be linked to any single dosing factor. (A) VNS delivered in the Moderate Daily VNS schedule results in a robust improvement in recovery, whereas other VNS therapy schedules do not facilitate recovery compared to tactile therapy without stimulation. (B-H) No single factor characterized in this study can account for the effects of VNS therapy.
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