1. 2022;25;1-13Gray Matter Abnormalities in Patients with Chronic Primary Pain: A Coordinate-Based Meta-Analysis
   Meta-Analysis
   Zuxing Wang, MD, Minlan Yuan, PhD, Jun Xiao, BS, Lili Chen, BS, Xiaoyun Guo, PhD, Yikai Dou, PhD, Fugui Jiang, MD, Wenjiao Min, PhD, and Bo Zhou, PhD.

BACKGROUND: Many structural magnetic resonance imaging (MRI) studies have used voxel-based morphometry (VBM) to identify gray matter abnormalities in patients with chronic primary pain (CPP), but the findings have been inconsistent.

OBJECTIVES: To identify (a) gray matter differences between CPP patients or female patients and healthy individuals and (b) the effects of symptom duration and pain scores on gray matter.

STUDY DESIGN: We conducted a meta-analysis.

METHODS: VBM studies in PubMed, Cochrane Library, and Google Scholar, from November 2005 to June 2020, were thoroughly collected and carefully reviewed. Manual searches were performed using title and citation information. Gray matter VBM study comparing adult patients (18-65 years) with CPP to healthy controls was reviewed, and results, presented in Talairach or Montreal Neurological Institute coordinates, were included. The t value, peak coordinates, and basic clinical information of each study were reported in detail. Anisotropic effect-size signed differential mapping was used for voxel-based meta-analyses.

RESULTS: Patients with CPP had decreased gray matter in the left anterior cingulate (z value = 2.950, P < 0.001), right median cingulate (z value = 1.858, P = 0.001), and the insula bilaterally (left: z value = 2.441, P < 0.001; right: z value = 2.113, P < 0.001 ), and increased gray matter in the right striatum (z value = 1.194, P < 0.001). Subgroup meta-analysis showed female patients with CPP also had decreased gray matter in the left anterior cingulate gyrus (z value = 2.622, P < 0.001). Meta-regression analyses revealed that pain symptom duration was positively associated with a large right brain region (z value = 2.110, P < 0.001), a negative association between pain symptom duration and gray matter was found in the right anterior cingulate (z value = 1.969, P < 0.001) and right middle frontal gyrus (z value = 1.849, P < 0.001).

LIMITATIONS: Due to the lack of data from male patients, we were unable to perform a male subgroup analysis; therefore, we cannot thoroughly explore the difference in CPP from the perspective of gender.

CONCLUSION: We identified gray matter changes in CPP patients and female patients, as well as a close relationship between CPP and mental disorders. With the chronicity of pain leads to changes in relevant brain regions, which makes treatment more challenging and may have synergistic effects with affective disorders. More prospective longitudinal structural MRI studies of CPP examining the associations between those variables and gray matter in a larger population should be conducted. Additional prospective longitudinal structural MRI studies of CPP with larger sample sizes to confirm the relationships between these variables and gray matter are needed as well as gender differences of CPP in brain structure and function.

KEY WORDS: Chronic primary pain, gray matter difference, SDM meta-analysis, gender difference, mental disorder