Background: Chronic pain conditions such as fibromyalgia syndrome (FMS) reflect maladaptive network physiology across perceptual–autonomic–immune axes, yet most treatments remain symptomatic and incompletely effective. Methods: We conducted a comprehensive systematic review to evaluate vagus nerve stimulation (VNS) and FMS within a network physiology framework. PubMed, Embase, and Cochrane CENTRAL were searched on October 24, 2025. Risk of bias was assessed using the ROB-2 tool. An iterative thematic synthesis was performed to develop an integrative conceptual framework and to identify knowledge gaps and future research directions. Results: We first summarize physiological evidence showing autonomic imbalance (e.g., decreased heart rate variability), neuroinflammatory activation, and aberrant cortical network connectivity in FMS, supporting a network-dysregulation model. We then included 6 studies (4 clinical studies and 2 protocols) on VNS effects, highlighting improvements in pain, fatigue, sleep disturbance and autonomic regulation, along with emerging mechanistic insights. Key methodological heterogeneity—such as stimulation parameters, outcome metrics, type of control arm, sham definition, and small samples—limits current interpretability. Finally, we outline a research agenda centered on network-based biomarkers, immunophenotyping, adaptive trial designs and stratification of responders, with the aim of validating taVNS as a scalable neuromodulatory intervention for FMS. Conclusions: By reframing FMS from a symptom-centric pharmacologic model to a network-centric neuromodulation approach, taVNS is a promising tool for mechanism-based therapeutics in central sensitization syndromes and chronic pain.

Background: This study aims to investigate the association between the presence and severity of non-motor symptoms (constipation, REM sleep behavior disorder [RBD], hyposmia, and depression) and the severity of motor impairment in Parkinson’s disease (PD). Methods: We used data from Parkinson’s Progression Markers Initiative (PPMI), comprising patients with established PD, prodromal PD, and healthy controls. Motor disability was evaluated with the MDS-UPDRS part III. Non-motor symptoms were assessed with standardized scales for constipation (MDS-UPDRS part I sub-item), depression (15-item GDS), RBD questionnaire (RBDQ), and hyposmia (UPSIT). The relationships between non-motor symptoms and motor severity were explored using linear regression models (adjusted for age/sex). Results: Constipation was significantly more prevalent in PD and prodromal PD and independently associated with greater motor severity in both groups (p < 0.001). Constipation also correlated with increased freezing and falls. Depressive symptoms were similar across groups, but in prodromal PD, higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as well as higher freezing and fall scores. Hyposmia was strongly reduced in PD and prodromal PD compared with controls but was not independently associated with motor severity. Higher RBDQ scores were associated with worse motor impairment in PD, but not in prodromal PD after adjustment. Conclusions: Constipation and REM sleep behavioral disorder were independent correlates of worse motor severity in prodromal and established PD, whereas depressive symptoms predicted more severe parkinsonism only within the prodromal phase.

Background: Placebo effects are well documented in Parkinson’s disease (PD) clinical trials and represent a major methodological challenge in interpreting neuromodulation studies. Although sham stimulation has been associated with clinical improvement, the magnitude, durability, and outcome specificity of placebo-related effects across non-invasive neuromodulation trials remain incompletely characterized. Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD1272381). PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library were searched from inception through September 2025. Randomized, sham-controlled trials of non-invasive neuromodulation in adults with PD were included. Results: Seventeen randomized sham-controlled trials (n = 654 participants) involving repetitive transcranial magnetic stimulation and transcranial direct current stimulation were included. Sham stimulation was associated with small but statistically significant improvements in UPDRS Part III (motor examination) at post-intervention and follow-up, whereas no significant placebo-related improvement was observed for UPDRS Total score. Placebo effects were modest and did not increase over time. In contrast, active neuromodulation produced larger and more durable improvements in both UPDRS Total and Part III, with statistically significant effects maintained at follow-up. Conclusions: Placebo effects contribute to short-term clinical improvement in non-invasive neuromodulation trials for PD, particularly for motor examination outcomes, but do not fully account for the sustained benefits observed with active stimulation. Placebo responsiveness is outcome- and time-dependent, underscoring the importance of rigorous trial design, including careful outcome selection, assessment timing, expectancy management, and comparator structures, to accurately estimate neuromodulation efficacy and support clinical translation.

Limited inclusion of ethnically diverse and socioeconomically disadvantaged populations in pain research undermines external validity, generalizability, and equity. This comprehensive review synthesized evidence on effective strategies to recruit and retain these populations in pain studies. We searched Medline, Web of Science, Embase, Scopus, and CENTRAL (12 April 2025) and included studies in which ethnically diverse and socioeconomically disadvantaged participants comprised ≥75% of the sample. Quantitative data were pooled using random-effects meta-analyses of proportions, with prespecified subgroup analyses, and qualitative findings were integrated through thematic synthesis. Certainty of evidence was evaluated using GRADE. Eighteen studies (n = 4611; 11 experimental, 5 observational, 2 qualitative), primarily from the United States and involving chronic pain, met inclusion criteria. Overall enrollment among ethnically diverse and socioeconomically disadvantaged groups was 37% (95% CI 18–58%), with significantly higher enrollment in observational studies (84%, 95% CI 78–90%) than in experimental trials (22%, 95% CI 10–36%; p < 0.001). Overall retention was 77% (95% CI 64–88%) and did not differ significantly by study design. Statewide disease-clinic networks, purposive community-leader engagement, and snowball sampling produced the highest enrollment, whereas medical-record screening yielded the lowest enrollment but the highest retention. Compensation and reminder strategies were similarly effective for retention. Thematic synthesis highlighted trust, culturally and linguistically tailored communication, hybrid and flexible visit schedules, transportation assistance, and clinician engagement as key facilitators. GRADE certainty was low for enrollment and moderate for retention. Community-engaged recruitment strategies, clinician referrals, culturally tailored materials, hybrid procedures, and modest incentives can substantially improve participation of ethnically diverse and socioeconomically disadvantaged populations in pain research. Standardized CONSORT-style reporting of recruitment/retention flowcharts according to strategy and ethnicity/socioeconomic status is essential to refine evidence-based strategies in the future.