Examining the Effects of Estradiol on Neural and Molecular Response to Rewards in Perimenopausal-Onset Anhedonia and Psychosis

检查雌二醇对围绝经期快感缺失和精神病患者奖励的神经和分子反应的影响

• 批准号: 10348271
• 负责人: GABRIEL S DICHTER
• 金额: $ 77.11万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348271
• 关键词: Address; Anhedonia; Behavior; Biological; Biological Markers; Brain; Clinical Trials; Corpus striatum structure; Data; Depressive Syndromes; Distress; Dopamine; Dopamine Antagonists; Double-Blind Method; Endocrine; Ensure; Estradiol; Estrogen Therapy; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Future; Grant; Impairment; Incidence; Magnetic Resonance Imaging; Measures; Menopause; Mental Depression; Mental disorders; Modeling; Molecular; Mood Disorders; Moods; Morbidity - disease rate; Participant; Pathogenesis; Perimenopause; Phase; Placebo Control; Placebos; Play; Positron-Emission Tomography; Predisposition; Psychoses; Raclopride; Randomized; Research; Rewards; Risk; Role; Sampling; Severities; Stratification; Symptoms; Time; Withdrawal; Woman; Work; design; dimensional analysis; dopamine D3 receptor; dopamine system; experimental group; functional disability; improved; mesolimbic system; molecular imaging; mortality; neuromechanism; neurotransmission; novel; placebo group; pre-clinical; recruit; relating to nervous system; reproductive; response; reward anticipation; reward circuitry; reward processing; targeted imaging; treatment response

Project Summary Affective disorders are highly prevalent in women and associated with significant morbidity and mortality, particularly during times of reproductive transition, including the transition to menopause. Unraveling the pathophysiology of affective disorders is challenging because depressive syndromes are heterogeneous and have diverse etiologies. Thus, studies aimed at identifying biomarkers to improve the prediction of susceptibility and illness course as well as treatment response in affective disorders have yielded inconsistent results. We propose to address this challenge by studying symptoms that initially present during the menopause transition and thus have a common endocrine trigger. We believe that studying a relatively homogeneous group of participants with similar biological mechanisms of symptom onset will increase the likelihood of elucidating the pathogenesis of perimenopausal-onset symptoms. This proposal will use simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR) to examine relations between reward-related striatal activation measured by fMRI and tonic and phasic striatal DA activity measured by [11C]raclopride PET in a transdiagnostic sample of women with varying severities of perimenopausal-onset (PO) anhedonia and psychosis. Specific Aim 1 will examine associations between PO anhedonia and psychosis symptom severity and reward-related striatal activation measured by fMRI and tonic and phasic striatal DA activity measured by [11C]raclopride PET. Specific Aim 2 will examine relations between anhedonia reductions due to estradiol administration, relative to placebo, and changes in PET-MR metrics related to reward processing. Specific Aim 3 will examine relations between PO psychosis reductions due to estradiol, relative to placebo, and changes in PET-MR metrics related to reward processing. Our central hypotheses are that the mesolimbic dopamine system is impaired during reward processing in PO anhedonia and psychosis, that the effects of estradiol administration will be associated with normalization of neural responses to rewards measured by fMRI and striatal dopamine functioning measured by PET, and that the degree of change in striatal functioning measured by fMRI and PET will be associated with the magnitude of change in PO anhedonia and psychosis symptom severity. The results of this project will increase our understanding of anhedonia and psychosis vulnerability during the menopause transition and have the potential to deliver validated molecular imaging targets to use in future mechanistic clinical trials of novel treatments for perimenopausal-onset psychiatric disorders.

项目概要 情感障碍在女性中非常普遍，并且与显着的发病率和相关性相关。 死亡率，特别是在生殖过渡时期，包括向 绝经。阐明情感障碍的病理生理学具有挑战性，因为 抑郁综合征具有异质性并且有不同的病因。因此，研究旨在 识别生物标志物以改善易感性和病程的预测以及 情感障碍的治疗反应产生了不一致的结果。我们建议 通过研究更年期最初出现的症状来应对这一挑战 转变，因此具有共同的内分泌触发因素。我们认为，研究相对 具有相似症状发生生物学机制的同质参与者群体将 增加阐明围绝经期症状发病机制的可能性。这 该提案将使用同时正电子发射断层扫描和功能磁 磁共振成像（PET-MR）检查奖赏相关纹状体激活之间的关系 通过 fMRI 测量，强直和阶段性纹状体 DA 活性通过 [11C]雷氯必利 PET 测量 具有不同严重程度的围绝经期发作 (PO) 的女性的跨诊断样本 快感缺失和精神病。具体目标 1 将检查 PO 快感缺乏与 通过功能磁共振成像和强直测量精神病症状的严重程度和奖励相关的纹状体激活 和通过[11C]雷氯必利 PET 测量的阶段性纹状体 DA 活性。具体目标 2 将审查 相对于安慰剂，雌二醇给药引起的快感缺乏减少之间的关系，以及 与奖励处理相关的 PET-MR 指标发生变化。具体目标 3 将检查关系 相对于安慰剂，雌二醇导致 PO 精神病减少与 PET-MR 变化之间的关系 与奖励处理相关的指标。我们的中心假设是中脑边缘多巴胺 PO 快感缺失和精神病的奖励处理过程中系统受到损害， 雌二醇的施用将与奖励的神经反应正常化相关 通过 fMRI 测量和通过 PET 测量纹状体多巴胺功能，并且 通过 fMRI 和 PET 测量的纹状体功能的变化将与幅度相关 PO 快感缺失和精神病症状严重程度的变化。该项目的成果将 增加我们对更年期快感缺失和精神病脆弱性的了解 转变并有潜力提供经过验证的分子成像目标以供将来使用 围绝经期精神疾病新疗法的机制临床试验。