BackgroundHeadache is a common symptom following mild traumatic brain injury (mTBI). Post-traumatic headache (PTH), a secondary headache disorder that develops after mTBI, often persists for months or years. To identify potential recovery mechanisms and prognostic biomarkers, the present study investigated whether longitudinal changes in pain-induced brain activation differ between healthy controls (HC) and PTH participants showing headache improvement and those without improvement.MethodsThirty-three participants who met International Classification of Headache Disorders, 3rd edition, criteria for acute PTH within 59 days post-mTBI and 33 HC participants were included with no significant differences in demographics. All participants underwent functional magnetic resonance imaging scans at baseline, four weeks, and 16 weeks post-enrollment using a thermal stimulation paradigm with noxious and non-painful heat stimuli. 'Painful vs. Non-Painful Heat' contrasts were generated using SPM12. PTH improvement was assessed at three months post-enrollment via electronic headache diaries. Two-sample t-tests compared the brain activation between HC and PTH at baseline. Linear mixed-effects models examined longitudinal changes for HC, PTH improvement and non-improvement groups across visits. Generalized linear models compared these groups within visits.ResultsBaseline analysis revealed several regions with significantly higher activation in acute PTH compared to HC, including bilateral postcentral gyrus, right superior temporal gyrus, right middle temporal gyrus, left inferior parietal gyrus, right superior parietal gyrus, left ventral striatum, left olfactory cortex, left gyrus rectus, and left middle occipital gyrus. Over time, the PTH improvement group demonstrated progressive normalization across all identified brain regions, whereas the non-improvement group showed only partial normalization in left ventral striatum, left olfactory cortex, and left gyrus rectus. Sustained elevated activation in specific regions distinguished PTH participants without headache improvement from those with headache improvement, suggesting potential biomarkers for persistent PTH.ConclusionsOur findings demonstrate significantly altered pain-induced brain activations in participants with acute PTH compared to HC. Longitudinal analysis revealed distinct recovery trajectories: progressive normalization in the improvement group versus persistent alterations in the non-improvement group. These neuroimaging patterns may serve as biomarkers for identifying individuals at risk for persistent PTH, with implications for early intervention and personalized treatment approaches.

Keywords: functional MRI; headache; mild traumatic brain injury; neuroimaging biomarkers; pain processing; post-traumatic headache.

背景 头痛是轻度创伤性脑损伤（mTBI）后的常见症状。创伤后头痛（PTH），一种在mTBI之后发展的继发性头痛障碍，通常会持续数月甚至数年。为了识别潜在的恢复机制和预后生物标志物，本研究调查了健康对照组（HC）与头痛改善的PTH参与者以及未见改善的PTH参与者的疼痛诱导脑激活纵向变化是否有所不同。 方法 纳入33名符合第三版国际头痛障碍分类标准并在mTBI后的59天内出现急性PTH的参与者和33名健康对照组参与者，各组在人口统计学特征上无显著差异。所有参与者在接受研究后基线、四周及十六周时均进行了使用热刺激范式的功能磁共振成像扫描，包括痛性和非疼痛性热刺激。使用SPM12生成了“痛性 vs. 非痛性热”的对比图。PTH改善情况通过电子头痛日记在入组后的三个月进行评估。两样本t检验比较了HC和PTH基线时的脑激活水平。线性混合效应模型分析了HC、头痛有改善及无改善三组参与者随访时间点上的纵向变化。广义线性模型比较了各组内每次访问的情况。 结果 基础分析显示，急性PTH与健康对照相比在多个区域具有显著更高的激活程度，包括双侧顶后回、右侧上颞回、右侧中颞回、左侧缘下回、右侧顶上回、左侧腹侧纹状体、左侧嗅皮层、左侧直回和左侧枕中回。随着时间的推移，头痛改善组在所有识别出的大脑区域均表现出逐步正常化的趋势，而非改善组仅在左侧腹侧纹状体、左侧嗅皮层及左侧直回上显示出部分正常化现象。特定区域内持续升高的激活程度将头痛无改善者与有改善者的PTH参与者区分开来，这可能作为慢性PTH的潜在生物标志物。 结论 我们的发现表明，在急性PTH参与者的疼痛诱导脑活动显著改变相比于健康对照组。纵向分析揭示了不同的恢复轨迹：头痛改善组表现出逐步正常化趋势，而非改善组则呈现出持续性变化特征。这些神经影像模式可以作为识别有持久PTH风险个体的生物标志物，并且对早期干预和个性化治疗方案具有重要意义。

关键词：功能性磁共振成像；头痛；轻度创伤性脑损伤；神经影像生物标志物；疼痛处理；创伤后头痛。