Amyot Franck, Lynch Cillian E, Ollinger John, Werner J Kent, Silverman E, Moore Carol, Davis Cora, Turtzo L Christine, Diaz-Arrastia Ramon, Kenney Kimbra
National Intrepid Center of Excellence, Walter Reed National Military Medical Center, Bethesda, MD, United States.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Physiol. 2021 May 13;12:649901. doi: 10.3389/fphys.2021.649901. eCollection 2021.
To characterize the relationship between persistent post-traumatic headache (pPTH) and traumatic cerebrovascular injury (TCVI) in chronic traumatic brain injury (TBI). Cerebrovascular reactivity (CVR), a measure of the cerebral microvasculature and endothelial cell function, is altered both in individuals with chronic TBI and migraine headache disorder (Amyot et al., 2017; Lee et al., 2019b). The pathophysiologies of pPTH and migraine are believed to be associated with chronic microvascular dysfunction. We therefore hypothesize that TCVI may contribute to the underlying migraine-like mechanism(s) of pPTH.
22 moderate/severe TBI participants in the chronic stage (>6 months) underwent anatomic and functional magnetic resonance imaging (fMRI) scanning with hypercapnia gas challenge to measure CVR as well as the change in CVR (ΔCVR) after single-dose treatment of a specific phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, which potentiates vasodilation in response to hypercapnia in impaired endothelium, as part of a Phase2a RCT of sildenafil in chronic TBI (NCT01762475). CVR and ΔCVR measures of each participant were compared with the individual's pPTH severity measured by the headache impact test-6 (HIT-6) survey.
There was a moderate correlation between HIT-6 and both CVR and ΔCVR scores [Spearman's correlation = -0.50 ( = 0.018) and = 0.46 ( = 0.03), respectively], indicating that a higher headache burden is associated with decreased endothelial function in our chronic TBI population.
There is a correlation between PTH and CVR in chronic moderate-severe TBI. This relationship suggests that chronic TCVI may underlie the pathobiology of pPTH. Further, our results suggest that novel treatment strategies that target endothelial function and vascular health may be beneficial in refractory pPTH.
明确慢性创伤性脑损伤（TBI）中持续性创伤后头痛（pPTH）与创伤性脑血管损伤（TCVI）之间的关系。脑血管反应性（CVR）是衡量脑微血管和内皮细胞功能的指标，在慢性TBI患者和偏头痛性头痛障碍患者中均发生改变（Amyot等人，2017年；Lee等人，2019b）。pPTH和偏头痛的病理生理学被认为与慢性微血管功能障碍有关。因此，我们假设TCVI可能促成了pPTH潜在的偏头痛样机制。
22名处于慢性期（>6个月）的中度/重度TBI参与者接受了解剖学和功能磁共振成像（fMRI）扫描，通过高碳酸血症气体激发来测量CVR以及在单剂量治疗一种特定的磷酸二酯酶-5（PDE-5）抑制剂西地那非后CVR的变化（ΔCVR），西地那非可增强受损内皮对高碳酸血症的血管舒张反应，这是西地那非用于慢性TBI的2a期随机对照试验（RCT）（NCT01762475）的一部分。将每位参与者的CVR和ΔCVR测量值与通过头痛影响测试-6（HIT-6）调查测量的个体pPTH严重程度进行比较。
HIT-6与CVR和ΔCVR评分之间存在中度相关性[斯皮尔曼相关性分别为=-0.50（=0.018）和=0.46（=0.03）]，表明在我们的慢性TBI人群中，较高的头痛负担与内皮功能降低相关。
慢性中度-重度TBI中PTH与CVR之间存在相关性。这种关系表明慢性TCVI可能是pPTH病理生物学的基础。此外，我们的结果表明，针对内皮功能和血管健康的新型治疗策略可能对难治性pPTH有益。
