Differential brainstem connectivity according to sex and menopausal status in healthy male and female individuals.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Lisa A Kilpatrick, Arpana Church, David Meriwether, Swapna Mahurkar-Joshi, Vince W Li, Jessica Sohn, Juliana Reist, Jennifer S Labus, Tien Dong, Jonathan P Jacobs, Bruce D Naliboff, Lin Chang, Emeran A Mayer
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引用次数: 0

Abstract

Background: Brainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus, right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants.

Methods: Resting-state fMRI was performed in 47 healthy male (age, 31.2 ± 8.0 years), 53 healthy premenopausal female (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal female participants (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 males and 17 females (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis.

Results: Left LCC-executive control network connectivity showed an overall sex difference (p = 0.02), with higher connectivity in females than in males; however, this was mainly due to differences between males and premenopausal females (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal females than in males (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal females than in males (p = 0.03) and postmenopausal females (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were reliably associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal females (p < 0.01).

Conclusions: Healthy females show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than males, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal females. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.

健康男性和女性个体根据性别和绝经状态的不同脑干连通性。
背景:脑干核在皮质功能和觉醒的上升单胺能调节和球脊髓疼痛的下降调节中都起着关键作用。尽管在动物模型中已经报道了这两个系统在功能上的性别相关差异,但对人类脑干连通性的性别差异以及更年期影响还缺乏全面的了解。本研究评估了健康个体中缝背核、左右蓝斑复合体(LCC)和导水管周围灰质(PAG)在静息状态下的连通性。此外,在一部分参与者中,研究了全身雌激素水平与脑干网络连接之间的关系。方法:对47例健康男性(年龄31.2±8.0岁)、53例健康绝经前女性(年龄24.7±7.3岁;卵泡期22例,黄体期31例),绝经后女性20例(年龄54.6±7.2岁)。使用线性模型排列分析(5000个排列)来评估脑干-网络连接的差异,根据性别和绝经状态,控制年龄。男性10例,女性17例(绝经前9例;采用液相色谱-质谱/质谱法测定血浆和粪便中雌激素及雌激素代谢物水平。通过偏最小二乘分析评估雌激素水平与脑干网络连通性之间的关系。结果:左lcc -执行控制网络连通性存在总体性别差异(p = 0.02),女性的连通性高于男性;然而,这主要是由于男性和绝经前女性之间的差异(p = 0.008)。其他性别差异依赖于绝经状态:绝经后女性的pag -默认模式网络(DMN)连通性高于男性(p = 0.04),绝经前女性的pag -感觉运动网络(SMN)连通性高于男性(p = 0.03)和绝经后女性(p = 0.007)。值得注意的是,在绝经前女性中,粪便中较高的游离2-羟孕酮水平与较高的PAG-SMN和PAG-DMN连通性可靠相关(p结论:健康女性在认知控制、感觉运动功能和自我相关过程中表现出比男性更高的脑干网络连通性,这取决于她们的绝经状态。此外,与疼痛有关的2-羟酮可能调节绝经前女性PAG的连通性。这些发现可能与不同生命阶段对慢性压力敏感性疾病的不同脆弱性有关。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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