Seed-Based Resting-State Connectivity as a Neurosignature in Fibromyalgia and Depression: A Narrative Systematic Review

Betina Franceschini Tocchetto ¹ Andrea Cristiane Janz Moreira ² Álvaro De Oliveira Franco ³ Iraci Lucena da Silva Torres ⁴ Felipe Fregni ⁵ WOLNEI CAUMO ^6*

• ¹ Post-Graduate Program in Medical Sciences, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
• ² Laboratory of Pain and Neuromodulation, Pain and Palliative Care Service, Clinical Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• ³ Post-Graduate Program in Biological Sciences: Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
• ⁴ Laboratory of Pharmacology in Pain and Neuromodulation: Pre-clinical Investigations, Clinical Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• ⁵ Laboratory of Neuromodulation and Center for Clinical Research Learning, Physics and Rehabilitation Department, Center for Neuromodulation, Spaulding Rehabilitation Hospital, Charlestown, Massachusetts, United States
• ⁶ Laboratory of Pain and Neuromodulation, Pain and Palliative Care Service, Department of Surgery, School of Medicine, Clinical Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Background: Major depressive disorder (MDD) often co-occur with fibromyalgia (FM), and both conditions have been associated with impaired resting state functional connectivity (rs-FC). The present systematic review aims to summarize the evidence on rs-FC in individuals with MDD and FM compared with healthy controls and explore overlapping connectivity patterns and their relationships with clinical symptoms.Methods: A systematic search of the EMBASE, PubMed, Scopus and ScienceDirect databases was conducted according to PRISMA guidelines. Studies were included that addressed rs-FC using seed-based analysis in MDD and FM patients compared to HC. Methodological quality and risk of bias were assessed using a 13-point checklist adapted from previous neuroimaging meta-analyzes.Results: A total of 33 articles were included in the analysis (17 with MDD and 16 with FM).The sample comprised 1,877 individuals, including 947 patients and 930 controls, with a mean age of 39.83 years. The seeds were categorized into six neural networks. Shared disruptions across MDD and FM studies have been identified in key circuits, including decreased connectivity between the insula and anterior cingulate cortex (ACC), middle frontal gyrus (MFG), superior frontal gyrus (SFG), and putamen. Increased FC was observed between the dorsolateral prefrontal cortex (DLPFC) and ACC, as well as between the thalamus and precuneus. Decreased insula-ACC connectivity correlated with greater pain intensity and catastrophizing in FM and with more severe depressive symptoms in MDD. Unique patterns of rs-FC were also observed: FM-specific changes involved the periaqueductal gray, hypothalamus, and thalamus, indicating impaired pain modulation and emotional processing.In contrast, MDD-specific changes were primarily observed in the reward, salience, and default mode networks, reflecting impaired emotional regulation. The studies showed considerable heterogeneity in the selection of seeds and study designs, which limits the feasibility of metaanalyses and underlines the need for standardized methods.Findings: This study provides information about overlapping and distinct neural mechanisms in FM and MDD, suggesting potentially the presence of a potential neurosignature that reflects shared disruptions in pain and emotion regulation networks while highlighting unique pathways underlying their respective pathophysiology.