Appetite-regulating Hormones and Neurocircuitry in Anorexia Nervosa

项目概述/摘要本项目采用新颖的多学科方法来了解神经性厌食症（AN）食欲和饮食行为背后的内分泌因素和神经回路。AN以自我诱导的饥饿为特征，与医学并发症、抑郁和任何精神疾病中最高的死亡率有关。治疗策略一直无效。参与进食行为的激素在AN中是异常的，现在可以使用功能磁共振成像（fMRI）动态范式检查这些通路中的大脑区域。AN也与睾酮(T)缺乏有关，初步数据表明生理性替代导致体重指数（BMI）增加。对动物和人类的研究表明，T与摄食行为有关。此外，试点数据显示，fMRI显示，在食物相关范式下，与T缺乏有关的大脑区域活性降低，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。本应用的目的是研究一种假设，即AN表型的特征是涉及食物动机和奖励的激素和神经回路异常，而T治疗通过调节这些途径来改善结果。60名患有AN的女性和20名20-30岁的对照组将被研究。在单次访问期间，受试者将接受BMI测量；空腹抽血检查激素水平（如生长素，PYY）；食欲、情绪及进食障碍精神病理评估视觉食物和非食物刺激的功能磁共振成像。在食用标准化的混合餐后，将重新评估食欲和情绪，获取一系列血液样本以检测激素水平，并重复进行功能磁共振成像。在参与横断面访问的60名AN中，40名相对T缺乏的AN将随机分为双盲设计，接受低剂量透皮T治疗（300mcg / d），并将在4周和6个月时返回重复上述程序。Lawson博士是哈佛医学院（HMS）的医学讲师和麻省总医院（MGH）的医学助理。她是MGH神经内分泌科的一名工作人员，她的大部分时间都用于临床研究。她在研究AN的激素异常方面的专业知识，以及在研究食欲神经回路方面的合作，使她能够领导这个拟议的项目。今年6月，她在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，包括高级统计学、神经解剖学和神经成像技术。她得到了MGH的大力支持，可以充分利用神经内分泌科、临床研究中心和哈佛催化剂资源。她的共同导师，博士。安妮·克里班斯基和吉尔·戈尔茨坦，在劳森博士的研究方向上投入了大量资金。该项目将支持Lawson博士在临床研究方面的培训，最终目标是成为一名独立的研究者，在神经内分泌学和神经成像技术方面具有专业知识，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.