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: 10544325
• 负责人: GABRIEL S DICHTER
• 金额: $ 75.82万
• 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/10544325
• 关键词: Address; Anhedonia; Behavior; Biological; Brain; Clinical Trials; Corpus striatum structure; Data; Depressive Syndromes; Diagnostic; Dimensions; 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; Mental Depression; Mental disorders; Modeling; Molecular; Mood Disorders; Moods; Morbidity - disease rate; Participant; Pathogenesis; Perimenopause; Phase; Placebo Control; Placebos; Positron-Emission Tomography; Predisposition; Psychoses; Raclopride; Randomized; Research; Rewards; Risk; Sampling; Severities; Stratification; Symptoms; Withdrawal; Woman; Work; biomarker identification; design; dopamine D3 receptor; dopamine system; experimental group; functional disability; improved; mesolimbic system; molecular imaging; mortality; neural; neuromechanism; neurotransmission; novel; placebo group; pre-clinical; psychotic; recruit; 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.

项目摘要 情感障碍在女性中非常普遍，并且与明显的发病率有关 死亡率，特别是在生殖过渡时期，包括过渡到 绝经。阐明情感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，具有多种病因。因此，针对的研究 确定生物标志物以改善易感性和疾病课程的预测 情感障碍的治疗反应产生了不一致的结果。我们建议 通过研究最初存在的症状来应对这一挑战 过渡，因此具有共同的内分泌触发因素。我们相信研究一个相对 具有相似生物学症状发作的生物学机制的均匀的参与者将会 增加阐明围层症状症状的发病机理的可能性。这 提案将同时使用正电子发射断层扫描和功能磁性 共振成像（PET-MR）检查与奖励相关的纹状体激活之间的关系 通过fMRI和滋补和质谱纹状体DA活性测量 围层临床发作严重程度不同（PO）的妇女的经诊断样本 Anhedonia和精神病。具体目标1将研究PO Anhedonia和 通过fMRI和补品测量的精神病症状严重程度和与奖励相关的纹状体激活 通过[11C] raclopride PET测量的质谱DA活性。具体目标2将检查 相对于安慰剂，由于雌二醇给药而减少的甲基菌降低之间的关系 PET-MR指标的变化与奖励处理有关。特定目标3将检查关系 与安慰剂相对于雌二醇引起的PO精神病降低与PET-MR的变化之间 与奖励处理有关的指标。我们的中心假设是中唇多巴胺 系统在PO Anhedonia和精神病中的奖励处理过程中受到损害 雌二醇给药将与神经反应的标准化有关 通过fMRI和纹状体多巴胺的功能测量，通过PET测量 fMRI和PET测量的纹状体功能的变化将与大小有关 PO Anhedonia和精神病症状严重程度的变化。这个项目的结果将 增加我们对全面和精神病脆弱性的理解 过渡并有可能实现验证的分子成像目标以将来使用 围绝经内核障碍精神疾病的新型治疗方法的机械临床试验。