Motor cortex inhibition as a fibromyalgia biomarker: a meta-analysis of transcranial magnetic stimulation studies

Abstract

Fibromyalgia (FM) is a common and refractory chronic pain condition with multiple clinical phenotypes. The current diagnosis is based on a syndrome identification which can be subjective and lead to under or over-diagnosis. Therefore, there is a need for objective biomarkers for diagnosis, phenotyping, and prognosis (treatment response and follow-up) in fibromyalgia. Potential biomarkers are measures of cortical excitability indexed by transcranial magnetic stimulation (TMS). However, no systematic analysis of current evidence has been performed to assess the role of TMS metrics as a fibromyalgia biomarker. Therefore, this study aims to evaluate evidence on corticospinal and intracortical motor excitability in fibromyalgia subjects and to assess the prognostic role of TMS metrics as response biomarkers in FM. We conducted systematic searches on PubMed/Medline, Embase, and Cochrane Central databases for observational studies and randomized controlled trials on fibromyalgia subjects that used TMS as an assessment. Three reviewers independently selected and extracted the data. Then, a random-effects model meta-analysis was performed to compare fibromyalgia and healthy controls in observational studies. Also, to compare active versus sham treatments, in randomized controlled trials. Correlations between changes in TMS metrics and clinical improvement were explored. The quality and evidence certainty were assessed following standardized approaches. We included 15 studies (696 participants, 474 FM subjects). The main findings were: (1) fibromyalgia subjects present less intracortical inhibition (mean difference (MD) = -0.40, 95% confidence interval (CI) -0.69 to -0.11) and higher resting motor thresholds (MD = 6.90 μV, 95% CI 4.16 to 9.63 μV) when compared to controls; (2) interventions such as exercise, pregabalin, and non-invasive brain stimulation increased intracortical inhibition (MD = 0.19, 95% CI 0.10 to 0.29) and cortical silent period (MD = 14.92 ms, 95% CI 4.86 to 24.98 ms), when compared to placebo or sham stimulation; (3) changes on intracortical excitability are correlated with clinical improvements - higher inhibition moderately correlates with less pain, depression, and pain catastrophizing; lower facilitation moderately correlates with less fatigue. Measures of intracortical inhibition and facilitation indexed by TMS are potential diagnostic and treatment response biomarkers for fibromyalgia subjects. The disruption in the intracortical inhibitory system in fibromyalgia also provides additional evidence that fibromyalgia has some neurophysiological characteristics of neuropathic pain. Treatments inducing an engagement of sensorimotor systems (e.g., exercise, motor imagery, and non-invasive brain stimulation) could restore the cortical inhibitory tonus in FM and induce clinical improvement.

Keywords: biomarkers; cortical inhibition; fibromyalgia; transcranial magnetic stimulation.

Figure 1. Study selection flow-chart.

RCT: Randomized controlled trial, SR: systematic review.

Figure 2 –. Forest plots of cross-sectional comparison.

(A) Resting motor threshold. (B) Short intracortical inhibition.

Figure 3. Forest plots of longitudinal changes.

(A) Resting motor threshold. (B) Short intracortical inhibition.

Figure 4. Pearson’s correlation betweenTMS metrics changes and clinical improvement.

Note: ICF and SICI data were extracted from 2 studies (Mhala et al. 2010 and 2011), the active intervention was M1 rTMS. MEP data was extracted from 1 study (Bement et al. 2014), the active intervention was exercise. *P < 0.05, **P < 0.01. Depr: depression; ICF: Intracortical facilitation; MEP: motor-evoked potential; Pcatas: pain catastrophizing; PT: pain threshold; SICI: short intracortical inhibition.