Suppression of neuropathic pain and comorbidities by recurrent cycles of repetitive transcranial direct current motor cortex stimulation in mice

Zheng Gan,Manfred Josef Oswald,Paul Vincent Naser,Rohini Kuner,Han Li

doi:10.1038/s41598-021-89122-6

Zheng Gan, Manfred Josef Oswald + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-89122-6

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Abstract

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. However, there is a major need for improving efficacy, reducing variability and understanding mechanisms. Rodent models hold promise in helping to overcome these obstacles. However, there still remains a major divide between clinical and preclinical studies with respect to stimulation programs, analysis of pain as a multidimensional sensory-affective-motivational state and lack of focus on chronic phases of established pain. Here, we employed direct transcranial M1 stimulation (M1 tDCS) either as a single 5-day block or recurring blocks of repetitive stimulation over early or chronic phases of peripherally-induced neuropathic pain in mice. We report that repeated blocks of stimulation reverse established neuropathic mechanical allodynia more strongly than a single 5-day regime and also suppress cold allodynia, aversive behavior and anxiety without adversely affecting motor function over a long period. Activity mapping revealed highly selective alterations in the posterior insula, periaqueductal gray subdivisions and superficial spinal laminae in reversal of mechanical allodynia. Our preclinical data reveal multimodal analgesia and improvement in quality of life by multiple blocks of M1 tDCS and uncover underlying brain networks, thus helping promote clinical translation.

Highlights

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain
These results demonstrate that anodal M1 transcranial direct current stimulation (tDCS) lowers the magnitude of mechanical hypersensitivity, and significantly protects against the progression of neuropathic allodynia over early stages post-nerve injury
While a majority of these studies tested epidural stimulation and were largely restricted to single stimulation sessions and the analysis of nociceptive component of pain, this study advances knowledge by (i) testing the efficacy of transcranial anodal M1 stimulation, (ii) analyzing repetitive stimulation regimes recurring over different temporal phases of neuropathic pain, (iii) testing different sensory modalities as well as affect deviations in neuropathic pain and (iv) by delineating brain regions showing changes in baseline activity after M1 stimulation from those that are recruited in mechanical allodynia

Summary

Introduction

Transcranial, minimally-invasive stimulation of the primary motor cortex (M1) has recently emerged to show promise in treating clinically refractory neuropathic pain. While there is substantial evidence for efficacy in management of certain types of pain disorders with M1 tDCS and TMS, there is considerable variability; their use in everyday clinical practice is still limited owing to scarcity of standardized treatment regimens, potential of side effects as well as lack of knowledge on underlying mechanisms and their long-term ramifications[3,6,10,11,12,14]. Suppression of progression of mechanical allodynia in neuropathic mice upon 5 cycles of anodal transcranial direct current stimulation (tDCS; Block I) of the primary motor cortex (M1) applied over early stages post-nerve injury (SNI). Data are represented as mean + /− standard error of the mean (S.E.M)

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