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

项目摘要 情感性精神障碍在女性中非常普遍，并与显著的发病率和 死亡率，特别是在生殖过渡时期，包括过渡到 更年期。解开情感性精神障碍的病理生理学是具有挑战性的，因为 抑郁综合征是异质性的，有不同的病因。因此，研究的目的是 识别生物标记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，因此有共同的内分泌触发。我们认为，学习一种相对 具有相似症状出现生物机制的同质参与者组将 增加了阐明围绝经期症状发病机制的可能性。这 提案将同时使用正电子发射断层扫描和功能磁学 磁共振成像(PET-MR)检查奖赏相关纹状体激活之间的关系 用fMRI和[11C]雷氯普利PET测量纹状体DA活性 围绝经期发病(PO)严重程度不同的妇女的跨诊断样本 快感缺乏症和精神病。具体目标1将检查PO快感缺乏症和 精神症状严重程度和奖赏相关纹状体激活的功能磁共振成像和强直波检测 用[11C]拉氯必利PET测定纹状体DA的时相活性。《特定目标2》将考察 雌激素治疗导致的快感减退与安慰剂之间的关系 与奖赏加工相关的PET-MR指标的变化。《特定目标3》将考察两国关系 与安慰剂相比，雌激素引起的PO精神病减少与PET-MR的变化之间的关系 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快感缺乏症和精神病患者在奖赏加工过程中系统受损，即 雌二醇的应用将与神经对奖励的反应正常化有关 用fMRI测量纹状体多巴胺功能，用PET测量纹状体多巴胺功能 FMRI和PET测量的纹状体功能的变化将与纹状体功能的大小相关 PO性快感缺乏和精神病症状严重程度的变化。这个项目的结果将是 增加对更年期快感缺乏和精神病易感性的了解 过渡，并有可能提供经过验证的分子成像靶点，供未来使用 围绝经期精神障碍新疗法的机械性临床试验。

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.