Vagus nerve stimulation (VNS) paired with rehabilitative training enhances recovery of function in models of stroke and is currently under investigation for use in chronic stroke patients. Dosing is critical in translation of pharmacological therapies, but electrical stimulation therapies often fail to comprehensively explore dosing parameters in preclinical studies. Varying VNS parameters has non-monotonic effects on plasticity in the central nervous system, which may directly impact efficacy for stroke. We sought to optimize stimulation intensity to maximize recovery of motor function in a model of ischemic stroke. The study design was preregistered prior to beginning data collection (DOI: https://doi.org/10.17605/OSF.IO/BMJEK). After training on an automated assessment of forelimb function and receiving an ischemic lesion in motor cortex, rats were separated into groups that received rehabilitative training paired with VNS at distinct stimulation intensities (sham, 0.4 mA, 0.8 mA, or 1.6 mA). Moderate-intensity VNS at 0.8 mA enhanced recovery of function compared with all other groups. Neither 0.4 mA nor 1.6 mA VNS was sufficient to improve functional recovery compared with equivalent rehabilitation without VNS. These results demonstrate that moderate-intensity VNS delivered during rehabilitation improves recovery and defines an optimized intensity paradigm for clinical implementation of VNS therapy.
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Data and Code Availability
All data and analysis code from this study have been made available on Github (https://github.com/davepruitt/OptimalDosingIntensityVNS).
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We thank Jaimee Nguyen, Ardalan Naghian, Veda Nashi, Kishan Thomala, Ankita Shankar, Joel Wright, Sangavi Manalan, Priyanka Vayalali, Anya Ali, Emmanuel Aykara, Medhi Zaidi, Jennifer Le, Nidhi Desai, Riley Dickson, Tony Castillo, Jenitta Kunjammattil, Tyler Short, Amber Ho, Shashi Obulasetty, Emad Sidiqi, and Ahmed Alshaikhsalama who assisted with rodent behavioral training.
This project was supported by the National Institute of Health R01 NS085167 (MPK) and R01 NS094384 (SAH).
Conflict of Interest
MPK is a consultant for MicroTransponder which develops VNS-related technologies.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experimental procedures were approved by the University of Texas Institutional Animal Care and Use Committee.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Pruitt, D.T., Danaphongse, T.T., Lutchman, M. et al. Optimizing Dosing of Vagus Nerve Stimulation for Stroke Recovery. Transl. Stroke Res. 12, 65–71 (2021). https://doi.org/10.1007/s12975-020-00829-6