Appetite-regulating Hormones and Neurocircuitry in Anorexia Nervosa

神经性厌食症的食欲调节激素和神经回路

• 批准号: 8676505
• 负责人: Elizabeth Austen Lawson
• 金额: $ 18.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676505
• 关键词: Amygdaloid structure; Androgen Receptor; Animals; Anorexia; Anorexia Nervosa; Anxiety; Appetite Regulation; Blood; Blood specimen; Body mass index; Brain; Brain region; Clinical Research; Clinical Trials; Collaborations; Comorbidity; Consumption; Data; Desire for food; Disease; Dose; Double-Blind Method; Eating; Eating Behavior; Eating Disorders; Endocrine; Exhibits; Fasting; Feeding behaviors; Food; Functional Magnetic Resonance Imaging; Functional disorder; Funding; General Hospitals; Goals; Hamilton Rating Scale for Depression; Hippocampus (Brain); Hormonal; Hormones; Human; Hydrocortisone; Institutes; Lead; Massachusetts; Measurement; Measures; Medical; Medicine; Mental Depression; Mental disorders; Mentors; Mood Disorders; Moods; Motivation; Neuroanatomy; Neuroendocrinology; Neurosecretory Systems; Outcome; Pathway interactions; Pharmacodynamics; Phenotype; Physiological; Placebo Control; Placebos; Positioning Attribute; Procedures; Psychopathology; Randomized; Relative (related person); Research; Research Personnel; Resources; Rewards; Role; Science; Signal Transduction; Starvation; Stimulus; Stress; Symptoms; Technology; Testing; Testosterone; Therapeutic; Time; Training; Visit; Visual; Weight Gain; Woman; abstracting; aged; blood oxygen level dependent; catalyst; density; design; ghrelin; improved; instructor; interdisciplinary approach; medical complication; medical schools; mortality; neuroimaging; novel; response; reward circuitry; statistics; treatment strategy

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.

描述（由申请人提供）：项目摘要/摘要该项目采用一种新颖的多学科方法来理解内分泌因素和神经通路的食欲和厌食症的饮食行为（AN）。以自我诱发的饥饿为特征，与任何精神病患者的医学并发症，抑郁症和最高死亡率有关。治疗策略无效。饮食行为涉及的激素在AN中是异常的，现在可以使用功能性MRI（fMRI）来检查这些途径中的大脑区域。 A也与睾丸激素（T）缺陷有关，初步数据表明生理替代剂会导致体重指数增加（BMI）。对动物和人类的研究牵涉到t的喂养行为。此外，试点数据表明，fMRI在响应于食物相关的范式的涉及T缺乏症的大脑区域中被fMRI失活，这表明T可能通过直接对大脑的直接影响影响饮食行为，并且具有治疗潜力。该应用的目的是研究表型的假设，即表型的特征是激素和涉及食物动机和奖励的神经记录的异常，并且T给药可以通过调节这些途径来改善结果。将研究60名20-30岁对照的女性。在一次访问中，受试者将接受BMI的测量；激素水平的禁食（例如，生长素，PYY）；评估食欲，情绪和饮食心理病理学混乱；和fMRI带有视觉食品和非食品刺激。消耗标准化的混合餐后，将重新评估食欲和情绪，将获得激素水平的系列血液样本，并重复fMRI。在参加横截面访问的60个A中，有40个具有相对T缺乏症的A将在双盲设计中随机分配，以接收低剂量的透皮t（300mcg QD），并将在4周零6个月时返回上述过程。 Lawson博士是哈佛医学院（HMS）的医学教练，也是马萨诸塞州综合医院（MGH）的医学助理。她是MGH神经内分泌部门的工作人员，并将大部分时间用于临床研究。她在研究荷尔蒙异常方面的专业知识在调查食欲的神经循环方面的合作中，使她领导了拟议的项目。她于6月通过HMS和马萨诸塞州理工学院（MIT）完成了医学硕士学位，并计划将培训扩展到包括高级统计，神经解剖学和神经影像学技术。她受到MGH的良好支持，并且可以完全访问神经内分泌部门，临床研究中心和哈佛催化剂资源。她的联合官员，博士。安妮·克里班斯基（Anne Klibanski）和吉尔·戈德斯坦（Jill Goldstein）获得了良好的资金，并投入了劳森博士的研究方向。该项目将支持Lawson博士在临床研究中的培训，其最终目的是成为具有神经内分泌学和神经影像学技术专业知识的独立研究者，以更好地了解疾病的病理生理学。