Characterizing the neural substrates of irritability in women: an experimental neuroendocrine model

表征女性烦躁的神经基础：实验性神经内分泌模型

• 批准号: 9981834
• 负责人: Crystal Edler Schiller
• 金额: $ 19.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981834
• 关键词: Acute; Address; Affective; Affective Symptoms; Aggressive behavior; Amygdaloid structure; Anger; Behavioral; Behavioral Sciences; Biological; Brain; Brain region; Childbirth; Corpus striatum structure; Depressed mood; Dimensions; Disease; Endocrine; Equipment and supply inventories; Etiology; Evaluation; Event; Exhibits; Female; Foundations; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hormonal; Hormonal Change; Hormones; Individual; Irritable Mood; Logistics; Measures; Medial; Mediating; Mediation; Mental Depression; Mental disorders; Modeling; Mood Disorders; Moods; Mothers; National Institute of Mental Health; Neuronal Dysfunction; Neurosecretory Systems; Outcomes Research; Pathway interactions; Patient Self-Report; Perimenopause; Perinatal; Personality; Phenotype; Physiological; Postpartum Period; Predisposition; Pregnancy; Protocols documentation; Psychosocial Stress; Research; Research Design; Rewards; Stimulus; Subgroup; Symptoms; System; Time Study; Trauma; Ventral Striatum; Woman; Work; anxiety symptoms; attentional bias; behavior test; brain behavior; cortico-limbic circuits; depressive symptoms; hormone sensitivity; improved; neural circuit; neuropsychiatric disorder; peripartum depression; premenstrual dysphoric disorder; relating to nervous system; reproductive hormone; response; reward processing; trait

Irritability, defined as a predisposition to exhibit anger, is a prominent, defining symptom of perinatal depression (PND) and many other neuropsychiatric disorders. Despite the near ubiquity of irritability across disorders, the neural dysfunction underlying the vulnerability to, onset of, and exacerbation of irritability is understudied and poorly understood. The proposed study involves experimentally manipulating reproductive hormones in nonpregnant, euthymic women to create a scaled down version of the changes that occur during pregnancy and the postpartum period. This endocrine manipulation paradigm, which we have shown provokes irritability in past studies, will be used to examine the neurocircuitry underlying irritability under baseline and hormone challenge conditions among women who are hormone sensitive (HS+; n=15) and non-hormone sensitive (HS-; n=15). The long-term goal of this research is to advance our understanding of the neural systems underlying both the triggering of and susceptibility to irritability in women. The objective of the current project is to examine whether HS+ show differences in the behavioral activation system relative to HS- under baseline and hormone challenge conditions using functional magnetic resonance imaging (fMRI) and behavioral tests. Our central hypothesis is that reproductive hormone changes are associated with dysregulated threat and reward processing and consequent irritability in HS+. The rationale for the proposed study is that employing a scaled down model of puerperal hormonal events permits the identification of a group of individuals homogeneous for hormone sensitivity (HS+), hence creating the best opportunity for disentangling the specific changes in brain function due to reproductive hormones (i.e., HS-) from those accompanying reproductive hormone-precipitated affective dysfunction (i.e., HS+). Because women will act as their own controls across time, this study design also allows for a powerful evaluation of state and trait variables that may contribute to irritability, including both threat and reward processing. Identifying both state and trait markers of irritability, and disentangling them from the effects of reproductive hormones on brain and behavior, will allow for the identification of neural substrates of irritability susceptibility that can be investigated across neuropsychiatric disorders. We plan to accomplish the objectives of this application by pursuing the following specific aims: to determine the extent to which irritability is characterized by 1) dysfunctional threat processing and 2) dysfunctional reward processing during reproductive hormone challenge relative to baseline in HS+ and HS-. We expect that, relative to baseline, HS+ women will show greater behavioral approach during threat and frustration as well as dysregulation in brain regions responsible for threat and reward processing during hormone challenge, relative to baseline, compared with HS-. The expected outcome of this research is the identification of neural circuits underlying both the susceptibility to and mediation of irritability.

易怒，定义为表现出愤怒的倾向，是围产期的一个突出的，明确的症状， 抑郁症（PND）和许多其他神经精神疾病。尽管在美国， 神经功能障碍是易激惹、发作和恶化的基础， 研究不足，理解不深。这项拟议中的研究涉及实验性地操纵生殖 激素在非怀孕，正常的妇女创造一个缩小版本的变化发生在 怀孕和产后期间。这种内分泌操纵模式，我们已经表明， 在过去的研究中，将被用来检查基线下的易怒的神经回路， 激素敏感（HS+; n=15）和非激素女性中的激素挑战状况 敏感（HS-; n=15）。这项研究的长期目标是促进我们对神经系统的理解。 系统的潜在触发和敏感性的女性易怒。当前的目标 项目是检查HS+是否显示行为激活系统相对于HS-下的差异 使用功能性磁共振成像（fMRI）的基线和激素激发条件， 行为测试我们的中心假设是生殖激素的变化与 HS+中的威胁和奖励处理失调以及随之而来的易怒。建议的理由 一项研究是，采用一个缩小模型的产后激素事件允许识别一组 激素敏感性（HS+）同质的个体，因此为 解开由于生殖激素引起的脑功能的具体变化（即，HS-）从那些 伴随的生殖障碍诱发的情感功能障碍（即，HS+）。因为女性会充当 他们自己的控制随着时间的推移，这项研究设计也允许一个强大的评估状态和特质 可能导致易怒的变量，包括威胁和奖励处理。识别两个状态 以及易怒的特征标记，并将它们与生殖激素对大脑和大脑的影响分开， 行为，将允许识别神经基板的易激惹性，可以调查 跨神经精神疾病我们计划通过以下方式实现本申请的目标： 以下具体目标：确定烦躁的特征在多大程度上表现为1）功能失调的威胁 与基线相比，生殖激素激发期间的奖励处理功能障碍 HS+和HS-。我们预计，相对于基线，HS+女性将表现出更大的行为方法 以及负责威胁和奖励的大脑区域的失调 处理激素挑战期间，相对于基线相比，HS-。预期的结果是， 研究是确定神经回路的基础上的敏感性和调解的易怒。