Modulation of Neural Networks and Symptom Correlated in Fibromyalgia: A Randomized Double-blind Factorial Explanatory Clinical Trial of Home-Based Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) might modulate neural activity and promote neural plasticity. This factorial randomized clinical trial compared a-tDCS on the left dorsolateral prefrontal cortex (l-DLPFC) or sham (s-tDCS), and a-tDCS or s-tDCS on the primary motor cortex (M1) in the connectivity analyses in eight regions of interest (ROIs) across eight resting-state electroencephalography (EEG) frequencies. We included 48 women with fibromyalgia, aged 30 to 65, randomly assigned to 2:1:2:1 to receive 20 sessions during 20 minutes of a-tDCS 2mA or s-tDCS at home, over l-DLPFC or M1, respectively. EEG recordings were obtained before and after treatment with eyes open (EO) and eyes closed (EC). In the EC condition, comparing pre to post-treatment, the a-tDCS on l-DLPFC decreased the lagged coherence connectivity in the delta frequency band between the right insula and left anterior cingulate cortex (ACC) (t=-3.542, p=.048). The l-DLPFC a-tDCS compared to s-tDCS decreased the lagged coherence connectivity in the delta frequency band between the right insula and left ACC (t=-4.000, p=.017). In the EO condition, the l-DLPFC a-tDCS compared to M1 s-tDCS increased the lagged coherence connectivity between the l-DLPFC and left ACC in the theta band (t=-4.059, p=.048). Regression analysis demonstrated that the a-tDCS effect on the l-DLPFC was positively correlated with sleep quality, while a-tDCS on l-DLPFC and M1 s-tDCS were positively correlated with pain catastrophizing. The application of a-tDCS over the l-DLPFC has modulated the connectivity between various brain regions involved in the affective-attentional aspects of pain, especially at lower EEG frequencies during the resting state. These findings suggest that the effects of a-tDCS on neural oscillations could serve as a neural marker associated with its impact on fibromyalgia symptoms. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Clinical Trial Registration: identifier [[NCT03843203][1]]. ### Funding Statement The following provided support for this study: (i) Committee for the Development of Higher Education Personnel (CAPES) through the academic excellence program (PROEX) (grants doctorate scholarships to RLA, and PVS), and the post-graduation national program (PNPD) (grant to MZ, LR, and CFSA). (ii) National Council for Scientific and Technological Development (CNPq) (Grants no 420826/2018-1 and 19/2551-0000716-7 to WC). (iii) Postgraduate Research Group at the Hospital de Clínicas de Porto Alegre (FIPE-HCPA) to WC (project no. 2020-0369). (iv) Brazilian Innovation Agency (FINEP) to WC, and ILST (process no. 1245/13). (v) Foundation for the Support of Research at Rio Grande do Sul (FAPERGS) Ministry of Science and Technology. National Council for Scientific and Technological Development - (CNPq)/ Health Secretary of State of Rio Grande do Sul, Brazil (SEARS) n. 03/2017 (PPSUS) to WC (Grant no: 17/2551-0001). Study design, data collection, analysis, manuscript preparation, or publication decisions had no interference from funders. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial's protocol for the Certificate of Presentation for Ethical Appreciation (CAAE) registry number is 36995020.3.0000.5327, and the study was approved by the Research Ethics Committee at the Hospital de Clinicas de Porto Alegre (HCPA), Brazil, under registration in the Institutional Review Board (IRB) number 2020-0369. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data might be found on: https://doi.org/10.6084/m9.figshare.23542116.v1 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03843203&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F13%2F2023.07.05.23292267.atom