1. 2025;28;E115-E127Gray Matter Alterations in Medication Overuse Headache: A Voxel-Based Morphometry Meta-Analysis
   Meta-Analysis
   Weiming Luo, MD, Yuke Teng, MD, Xingyao Chen, MM, Nuo Chen, MD, Xinyue Zhang, MD, Jun Zhou, MD, Siyuan Tao, MD, Peng Lai, MD, Qian Song, PhD, Xinyu Hao, PhD, Fanrong Liang, PhD, Zhaoxuan He, PhD, and Zhengjie Li, MD.

BACKGROUND: Medication overuse headache (MOH) is a secondary headache disorder associated with the chronic use of pain-relieving medications, leading to significant alterations in brain structure and function. Previous studies have shown inconsistent findings in gray matter (GM) changes in MOH patients, making it necessary to conduct a comprehensive meta-analysis to synthesize these results.

OBJECTIVES: The objective is to conduct a thorough review and meta-analysis of the consistency among voxel-based morphometry (VBM) neuroimaging studies that focus on MOH.

STUDY DESIGN: Systematic review and meta-analysis.

SETTING: This meta-analysis examined all VBM studies that involved the whole-brain alterations of MOH.

METHODS: A comprehensive search of neuroimaging studies was conducted across 6 databases, including EMBASE, PubMed, Web of Science, Wan-Fang Database, China National Knowledge Infrastructure (CNKI), and Chongqing VIP, covering publications from the inception thereof to December 1, 2023. Two independent researchers performed quality assessment, data extraction, and study selection. Researchers performed a thorough examination of GM data in MOH, utilizing both activation likelihood estimation (ALE) and Anisotropic effect size-signed differential mapping (AES-SDM). Additionally, the research included clinical variables correlation analysis and subgroup analysis.

RESULTS: A total of 8 studies were selected for analysis based on stringent screening criteria, resulting in the inclusion of 378 patients (comprising 191 patients with MOH and 187 healthy patients). The 2 different neuroimaging meta-analysis methods both revealed that MOH patients had increased amounts of GM in their cerebellar vermis, left red nuclei, and right medial dorsal nuclei. Additionally, MOH patients showed reductions in the GM of their left superior frontal gyri, left inferior frontal gyri, right precunei, and bilateral middle frontal gyri. Correlation analysis findings indicated that numerous cerebral areas were linked to clinical variables of MOH, including the duration of the condition, frequency of headaches, and patient age. MOH patients using different medications exhibited partially inconsistent GM alterations.

LIMITATIONS: The limited number of neuroimaging studies and the variability in methodologies across studies might have affected the robustness of the findings. Future research should address these gaps by exploring both structural and functional neuroimaging in diverse MOH subtypes.

CONCLUSION: Significant alterations in GM across various brain regions associated with pain processing, modulation, and reward have been observed in association with MOH. These observations contribute to a better understanding of the neural mechanisms underlying MOH and may potentially guide the development of specific therapeutic strategies. Additional studies are required to investigate whether GM changes can serve as potential biomarkers for diagnosing and treating MOH.

KEY WORDS: Medication overuse headache, MRI, neuroimaging, gray matter, voxel-based morphometry, neuroimagers meta-analysis