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

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.

SUBMITTER: Gan Z

PROVIDER: S-EPMC8102487 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThis study was aimed to summarize and analyze the quality of the available evidence in systematic reviews (SRs) of repetitive transcranial magnetic stimulation (rTMS) on the non-motor cortex (non-M1) for neuropathic pain (NP) through an evidence mapping approach.MethodsWe follow the Global Evidence Mapping (GEM) methodology. Searches were conducted in PubMed, EMBASE, Epistemonikos, and the Cochrane Library. The study type was restricted to SRs with or without meta-analysis. All literature published before January 23, 2021, were included. The methodological quality of the included SRs was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR-2). Data were extracted according to a defined population-intervention-comparison-outcome (PICO) framework from primary studies that included SRs. The same PICO was categorized into PICOs according to interventions (stimulation target, frequency, number of sessions (short: 1-5 sessions, medium: 5-10 sessions, and long: >10 sessions)) and comparison (sham rTMS or other targets). The evidence mapping was presented in tables and a bubble plot.ResultsA total of 23 SRs were included. According to the AMSTAR-2, 20 SRs scored "very low" in terms of methodological quality, 2 SRs scored "low," and 1 SR scored "high." A total of 17 PICOs were extracted. The dorsolateral prefrontal cortex (DLPFC) is the most studied of the non-motor cortex targets. PICOs of DLPFC, premotor cortex (PMC), frontal cortex, and secondary somatosensory cortex (S2) were mainly categorized with a "potentially better" conclusion. High-frequency (5-20 Hz) rTMS of non-M1 usually lead to "potentially better" conclusions.ConclusionsDLPFC, PMC, frontal cortex, and S2 seem to be promising new targets for rTMS treatment of certain NP. Evidence mapping is a useful and reliable methodology to identify and present the existing evidence gap that more research efforts are necessary in order to highlight the optimal stimulation protocols for non-M1 targets and standardize parameters to fill the evidence gaps of rTMS. Further investigation is advised to improve the methodological quality and the reporting process of SRs.

Project description:IntroductionRepetitive transcranial magnetic stimulation (rTMS) is used to induce long-lasting changes (aftereffects) in cortical excitability, which are often measured via single-pulse TMS (spTMS) over the motor cortex eliciting motor-evoked potentials (MEPs). rTMS includes various protocols, such as theta-burst stimulation (TBS), paired associative stimulation (PAS), and continuous rTMS with a fixed frequency. Nevertheless, subsequent aftereffects of rTMS are variable and seem to fail repeatability. We aimed to summarize standard rTMS procedures regarding their test-retest reliability. Hereby, we considered influencing factors such as the methodological quality of experiments and publication bias.MethodsWe conducted a literature search via PubMed in March 2023. The inclusion criteria were the application of rTMS, TBS, or PAS at least twice over the motor cortex of healthy subjects with measurements of MEPs via spTMS as a dependent variable. The exclusion criteria were measurements derived from the non-stimulated hemisphere, of non-hand muscles, and by electroencephalography only. We extracted test-retest reliability measures and aftereffects from the eligible studies. With the Rosenthal fail-safe N, funnel plot, and asymmetry test, we examined the publication bias and accounted for influential factors such as the methodological quality of experiments measured with a standardized checklist.ResultsA total of 15 studies that investigated test-retest reliability of rTMS protocols in a total of 291 subjects were identified. Reliability measures, i.e., Pearson's r and intraclass correlation coefficient (ICC) applicable from nine studies, were mainly in the small to moderate range with two experiments indicating good reliability of 20 Hz rTMS (r = 0.543) and iTBS (r = 0.55). The aftereffects of rTMS procedures seem to follow the heuristics of respective inhibition or facilitation, depending on the protocols' frequency, and application pattern. There was no indication of publication bias and the influence of methodological quality or other factors on the reliability of rTMS.ConclusionThe reliability of rTMS appears to be in the small to moderate range overall. Due to a limited number of studies reporting test-retest reliability values and heterogeneity of dependent measures, we could not provide generalizable results. We could not identify any protocol as superior to the others.

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

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