Appetite-regulating Hormones and Neurocircuitry in Anorexia Nervosa

描述(由申请人提供)：项目摘要/摘要本项目采用一种新颖的、多学科的方法来了解神经性厌食症(AN)患者食欲和进食行为背后的内分泌因素和神经回路。以自我诱导的饥饿为特征的AN与医疗并发症、抑郁症和所有精神疾病中死亡率最高的疾病有关。治疗策略一直无效。参与进食行为的激素在AN中是异常的，这些通路中的大脑区域现在可以使用功能磁共振成像(FMRI)的动态范式进行检查。AN还与睾酮(T)缺乏有关，初步数据表明，生理替代会导致身体质量指数(BMI)的增加。在动物和人类身上的研究表明，T与进食行为有关。此外，试点数据显示，在T缺乏的大脑区域，功能磁共振成像对食物相关范式的反应是低活性的，这表明T可能通过对大脑的直接影响影响饮食行为，并具有治疗AN的潜力。这项应用的目的是调查这样一种假设，即AN表型的特征是与食物动机和奖励有关的激素和神经回路的异常，并且T管理通过调节这些途径来改善结果。60名患有AN的女性和20名年龄在20-30岁之间的对照组女性将被研究。在一次访问中，受试者将接受BMI测量；空腹抽血检测激素水平(例如，Ghrelin，PYY)；评估食欲、情绪和饮食紊乱的精神病理学；以及视觉食物和非食物刺激的功能磁共振成像。在食用了标准的混合餐后，将重新评估食欲和情绪，获取系列血液样本以检测激素水平，并重复功能磁共振成像。在参与横断面访问的60名AN中，40名相对T缺乏的AN将采用双盲设计随机接受小剂量透皮治疗(300mcg，qd)，并在4周和6个月后返回重复上述程序。劳森博士是哈佛医学院(HMS)的医学讲师和马萨诸塞州综合医院(MGH)的医学助理。她是麻省理工学院神经内分泌科的工作人员，大部分时间都致力于临床研究。她在研究荷尔蒙异常方面的专业知识，以及研究食欲神经回路的既定合作，使她有能力领导这个拟议的项目。她于6月份通过HMS和麻省理工学院(MIT)完成了医学硕士学位，并计划扩大她的培训范围，将高级统计学、神经解剖学和神经成像技术包括在内。她得到了MGH的良好支持，并拥有充分的神经内分泌科、临床研究中心和哈佛大学催化剂资源。她的联合导师安妮·克利班斯基博士和吉尔·戈尔茨坦博士资金充足，对劳森博士的研究方向进行了投资。该项目将支持劳森博士在临床研究方面的培训，最终目标是成为一名独立的调查员，拥有将神经内分泌学和神经成像技术相结合的专业知识，以更好地了解疾病的病理生理学。

DESCRIPTION (provided by applicant): Project Summary/Abstract This project takes a novel, multidisciplinary approach to understanding endocrine factors and neurocircuitry underlying appetite and eating behavior in anorexia nervosa (AN). AN, characterized by self-induced starvation, is associated with medical complications, depression, and the highest mortality of any psychiatric disease. Treatment strategies have been ineffective. Hormones involved in eating behavior are abnormal in AN, and brain regions in these pathways can now be examined with dynamic paradigms using functional MRI (fMRI). AN is also associated with testosterone (T) deficiency, and preliminary data indicates that physiologic replacement leads to an increase in body mass index (BMI). Studies in animals and humans implicate T in feeding behavior. Moreover, pilot data demonstrate hypoactivation by fMRI in brain regions implicated in T deficiency in response to a food-related paradigm, suggesting that T may influence eating behavior through direct effects on the brain, and has therapeutic potential in AN. The goal of this application is to investigate the hypothesis that the AN phenotype is characterized by abnormalities in hormones and neurocircuitry involved in food motivation and reward, and that T administration improves outcomes by modulating these pathways. 60 women with AN and 20 controls aged 20-30 will be studied. During a single visit, subjects will undergo measurement of BMI; a fasting blood draw for hormone levels (eg, ghrelin, PYY); assessment of appetite, mood and disordered eating psychopathology; and fMRI with visual food and non-food stimuli. After consumption of a standardized mixed meal, appetite and mood will be reassessed, serial blood samples will be obtained for hormone levels, and fMRI will be repeated. Of the 60 AN who participate in the cross-sectional visit, 40 AN with relative T deficiency will be randomized in a double-blind design to receive low-dose transdermal T (300mcg qd), and will return to repeat the above procedures at 4 weeks and 6 months. Dr. Lawson is an Instructor in Medicine at Harvard Medical School (HMS) and Assistant in Medicine at Massachusetts General Hospital (MGH). She is on staff in the Neuroendocrine Unit at MGH and devotes the majority of her time to clinical research. Her expertise in studying hormonal abnormalities in AN and established collaboration investigating the neurocircuitry of appetite positions her to lead the proposed project. She completed her Masters of Medical Science through HMS and Massachusetts Institute of Technology (MIT) in June, and plans to expand her training to include advanced statistics, neuroanatomy and neuroimaging technology. She is well-supported by MGH and has full access to Neuroendocrine Unit, Clinical Research Center and Harvard Catalyst resources. Her co-mentors, Drs. Anne Klibanski and Jill Goldstein, are well-funded and invested in the direction of Dr. Lawson's research. This project will support Dr. Lawson's training in clinical research, with the ultimate goal of becoming an independent investigator with an expertise in combining neuroendocrinology and neuroimaging technology to better understand pathophysiology of disease.