Institute of Brain Science, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Integrated Brain Research Unit, Division of Clinical Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
Neuroimage Clin. 2021;30:102576. doi: 10.1016/j.nicl.2021.102576. Epub 2021 Jan 26.
Primary dysmenorrhea (PDM) refers to menstrual pain of which the pathological cause(s) are unknown. This study examined the associations among BDNF Val66Met polymorphisms, menstrual pain severity, and hippocampal volume among young PDM subjects. We recruited 115 PDM subjects, including severe cases (n = 66) and moderate cases (n = 44), and 117 young females (aged 20-30 years) as a control group (CON) for BDNF Val66Met genotyping and MRI examination. The assessment of hippocampal volume involved analysis at various anatomical resolutions, i.e., whole hippocampal volume, hippocampal subfields, and voxel-based morphometry (VBM) volumetric analysis. Two-way ANOVA analyses with planned contrasts and Bonferroni correction were conducted for the assessment of hippocampal volume. Linear regression was used to test for BDNF Val66Met Val allele dosage-dependent effects. We observed no main effects of group, genotype, or group-genotype interactions on bilateral whole hippocampal volumes. Significant interactions between PDM severity and BDNF Val66Met genotype were observed in the right whole hippocampus, subiculum, and molecular layer. Post-hoc analysis revealed that the average hippocampal volume of Val/Val moderate PDM subjects was greater than that of Val/Val severe PDM subjects. Note that right hippocampal volume was greater in the Val/Val group than in the Met/Met group, particularly in the right posterior hippocampal region. Dosage effect analysis revealed a positive dosage-dependent relationship between the Val allele and volume of the right whole hippocampus, subiculum, molecular layer, and VBM-defined right posterior hippocampal region in the moderate PDM subgroup only. These findings indicate that Val/Val PDM subjects are resistant to intermittent moderate pain-related stress, whereas Met carrier PDM subjects are susceptible. When confronted with years of repeated PDM stress, the hippocampus can undergo differential structural changes in accordance with the BDNF genotype and pain severity. This triad study on PDM (i.e., combining genotype with endophenotype imaging results and clinical phenotypes), underscores the potential neurobiological consequences of PDM, which may prefigure in neuroimaging abnormalities associated with various chronic pain disorders. Our results provide evidence for Val allele dosage-dependent protective effects on the hippocampal structure; however, in cases of the Val variant, these effects were modulated in accordance with the severity of menstrual pain.
原发性痛经（PDM）是指病因不明的月经疼痛。本研究探讨了 BDNF Val66Met 多态性、月经疼痛严重程度和年轻 PDM 受试者海马体积之间的关系。我们招募了 115 名 PDM 受试者，包括严重病例（n=66）和中度病例（n=44），以及 117 名年轻女性（年龄 20-30 岁）作为对照组（CON）进行 BDNF Val66Met 基因分型和 MRI 检查。海马体积的评估涉及到不同解剖分辨率的分析，即整个海马体积、海马亚区和基于体素的形态计量学（VBM）体积分析。采用双因素方差分析和计划对比及 Bonferroni 校正进行海马体积评估。线性回归用于测试 BDNF Val66Met Val 等位基因剂量依赖性效应。我们没有观察到组、基因型或组-基因型相互作用对双侧全海马体积的主要影响。在右全海马、下托和分子层观察到 PDM 严重程度和 BDNF Val66Met 基因型之间的显著相互作用。事后分析显示，中度 PDM 患者 Val/Val 纯合子的平均海马体积大于重度 PDM 患者 Val/Val 纯合子。值得注意的是，与 Met/Met 组相比，Val/Val 组的右海马体积更大，尤其是右后海马区。剂量效应分析显示，仅在中度 PDM 亚组中，右全海马、下托、分子层和 VBM 定义的右后海马区的 Val 等位基因与体积之间存在正剂量依赖性关系。这些发现表明，Val/Val PDM 患者对间歇性中度疼痛相关应激具有抵抗力，而 Met 携带者 PDM 患者则易感。当面对多年的反复 PDM 应激时，海马体可以根据 BDNF 基因型和疼痛严重程度发生不同的结构变化。这项关于 PDM 的三联研究（即结合基因型与内表型成像结果和临床表型）强调了 PDM 的潜在神经生物学后果，这可能预示着与各种慢性疼痛障碍相关的神经影像学异常。我们的研究结果提供了 Val 等位基因剂量依赖性对海马结构的保护作用的证据；然而，在 Val 变体的情况下，这些作用根据月经疼痛的严重程度而受到调节。
