Granger Steven J, Jobson Sydney A, Ravichandran Caitlin, Devignes Quentin, Akman Eylül, Blackford Jennifer U, May Victor, Hammack Sayamwong E, Carlezon William A, Ressler Kerry J, Rauch Scott L, Rosso Isabelle M
Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
medRxiv. 2025 Jun 12:2025.06.05.25329085. doi: 10.1101/2025.06.05.25329085.
Posttraumatic stress disorder (PTSD) has been associated with altered arousal regulation and dysfunction of the hypothalamic-pituitary-adrenal axis, including changes in circulating cortisol and pituitary adenylate cyclaseactivating polypeptide (PACAP). Both stress-related hormones affect extended amygdala to medial prefrontal cortex (mPFC) circuit functioning, but it is unclear whether they relate to white matter microstructure connecting these regions. We examined this question in 139 trauma-exposed adults (81 female; ages 19-54) who completed the Clinician-Administered PTSD Scale, a blood draw, and diffusion magnetic resonance imaging. White matter integrity was assessed in tracts connecting the extended amygdala to mPFC, including the uncinate fasciculus, frontal parahippocampal cingulum, and bed nucleus of the stria terminalis to mPFC projections. We used both tract-average fractional anisotropy (FA) to assess the global integrity of these white matter tracts and restricted connectometry to identify spatially localized associations along specific tract segments. Neither cortisol nor PACAP levels were associated with tract-average FA in any tract. However, connectometry, using a stringent statistical T-threshold revealed distinct, region-specific associations within the dorsal cingulum: higher cortisol levels were associated with lower FA (=.002), whereas higher PACAP levels were associated with higher FA (=.01). These localized FA alterations were not significantly associated with symptom severity. These findings suggest that cortisol and PACAP levels have differing associations with microstructural integrity of the dorsal cingulum, a region implicated in emotional regulation. These results highlight how distinct stress hormone pathways may differentially impact white matter organization in PTSD and demonstrate the utility of connectometry for detecting regionally specific brain-biomarker relationships.
创伤后应激障碍（PTSD）与唤醒调节改变及下丘脑 - 垂体 - 肾上腺轴功能障碍有关，包括循环皮质醇和垂体腺苷酸环化酶激活多肽（PACAP）的变化。这两种与应激相关的激素都会影响从终纹床核到内侧前额叶皮质（mPFC）的杏仁核扩展区回路功能，但尚不清楚它们是否与连接这些区域的白质微观结构有关。我们在139名有创伤经历的成年人（81名女性；年龄19 - 54岁）中研究了这个问题，这些人完成了临床医生管理的PTSD量表、血液抽取以及扩散磁共振成像检查。我们评估了连接杏仁核扩展区与mPFC的白质完整性，包括钩束、额叶海马旁扣带以及终纹床核到mPFC投射的白质束。我们既使用了束平均分数各向异性（FA）来评估这些白质束的整体完整性，也使用了受限连接测量法来识别沿特定束段的空间局部关联。皮质醇和PACAP水平均与任何束的束平均FA无关。然而，使用严格统计T阈值的连接测量法揭示了背侧扣带内不同的、区域特异性的关联：较高的皮质醇水平与较低的FA相关（=0.002），而较高的PACAP水平与较高的FA相关（=0.01）。这些局部FA改变与症状严重程度无显著关联。这些发现表明，皮质醇和PACAP水平与背侧扣带的微观结构完整性具有不同的关联，背侧扣带是一个与情绪调节有关的区域。这些结果突出了不同的应激激素途径可能如何不同地影响PTSD中的白质组织，并证明了连接测量法在检测区域特异性脑生物标志物关系方面的实用性。
