Neural Basis of Meal Related Interoceptive Dysfunction in Anorexia Nervosa

项目总结 Sahib Khalsa博士正在申请以患者为导向的导师职业发展奖(K23)，以支持 他成长为一名独立的研究人员，描绘了内感(脑体)的病理生理学 连接)在进食障碍中。神经性厌食症(AN)的致死率是精神分裂症的两到三倍， 双相情感障碍和单相抑郁，但潜在的病理生理学和相关神经 人们对功能障碍知之甚少。期待吃饭会让人产生恐惧，这就是 诱导一种有偏见的感觉间预期信号的状态(BIAS)，其特征是 实际的联觉状态和主观的联觉体验。偏见会干扰病人的能力 为了准确地感觉到他们体内正在发生的事情，这反过来又加剧了他们对吃的恐惧，避免食物 行为，和减肥。为了确定AN中偏见的神经基础，候选人开发了一种 采用(A)使用异丙肾上腺素的感觉间调制的协议，异丙肾上腺素是一种快速的外周作用 类似于肾上腺素的交感神经药物，(B)直接实验操作进食预期，这 增加焦虑，和(C)功能磁共振成像检查大脑对 这些操控手段。体重恢复的个体(以避免潜在的混杂影响 大脑功能指标上的饥饿)与性别和BMI匹配的健康比较将进行多项 水平评估侧重于负价值域和内感。这项提案调查了 基本问题“期待进餐的状态是如何引起恐惧和身体机能失调的-- 相关信息在一封信中吗？解决它将有助于澄清行为和大脑过程，加强 在有食物供应的情况下会出现饥饿，并会导致特定的以食物为重点的恐惧 灭绝程序。卡尔萨博士的长期职业目标是了解内感的神经来源 饮食失调，并开发新的治疗方法。拟议的研究将首先完成 通过评估跨行为、生理和神经水平的内感的作用来迈向这一目标 A中的电路。该项目的培训活动将使Khalsa博士能够发展药理学方面的专门知识 功能磁共振成像方法，增加高级统计学知识，增强进食障碍方面的专业知识 治疗。卡尔萨博士组建了一支独特的导师团队，提供所需的多样性 专业知识。保卢斯博士(LIBR科学总监和主要导师)将提供精神病学和 使用感受性探针的药理学神经成像。沃尔特·凯博士将在一项 神经生物学和治疗。LIBR神经成像核心总监Jerzy Boduka博士将在 FMRI数据处理和结构/功能连通性分析。丹尼·JJ·王博士将提供 在核磁共振灌注成像和药物成像与ASL结合方面的指导。培训和相关的 研究将在LIBR进行，这是一家拥有最先进的神经成像设备的精神病学研究机构。

PROJECT SUMMARY Dr. Sahib Khalsa is applying for the Mentored Patient-Oriented Career Development Award (K23) to support his growth as an independent researcher to delineate the pathophysiology of interoception (the brain body connection) in eating disorders. Anorexia nervosa (AN) is two to three-times deadlier than schizophrenia, bipolar disorder, and unipolar depression, yet the underlying pathophysiology and associated neural dysfunctions are poorly understood. Anticipating eating a meal makes individuals with AN fearful, which induces a state of Biased Interoceptive Anticipatory Signaling (BIAS) marked by a discrepancy between the actual interoceptive state and the subjective interoceptive experience. BIAS interferes with AN patients' ability to accurately sense what is happening in their bodies, which in turn reinforces fears of eating, food avoidance behaviors, and weight loss. To determine the neural basis of BIAS in AN, the candidate has developed a protocol that employs (a) interoceptive modulation using isoproterenol, a rapid peripherally acting sympathomimetic drug akin to adrenaline, (b) direct experimental manipulation of meal anticipation, which heightens anxiety in AN, and (c) functional magnetic resonance imaging to examine the brain's response to these manipulations. Weight-restored individuals with AN (to avoid the potentially confounding effects of starvation on measures of brain function) and sex and BMI matched healthy comparisons will undergo multi- level assessments focused on the negative valence domain and interoception. This proposal investigates the basic question “how does the state of anticipating a meal induce fear and dysregulate the processing of body- relevant information in AN?” Addressing it will help to clarify the behavioral and brain processes that reinforce starvation in the presence of food availability, and will enable the development of specific food-focused fear extinction procedures. Dr. Khalsa's long-term career goal is to understand the neural sources of interoceptive dysregulation in eating disorders, and to develop novel treatments. The proposed research will accomplish first steps towards this goal by evaluating the role of interoception across levels of behavior, physiology and neural circuits in AN. The training activities of this project will allow Dr. Khalsa to develop expertise in pharmacological fMRI methodology, increased knowledge of advanced statistics, and enhanced expertise in eating disorder treatment. Dr. Khalsa has assembled a team of mentors uniquely suited to provide the required diversity of expertise. Dr. Paulus (LIBR Scientific Director and primary mentor) will provide expertise in psychiatric and pharmacological neuroimaging using interoceptive probes. Dr. Walter Kaye will provide mentorship in AN neurobiology and treatment. Dr. Jerzy Bodurka, LIBR Neuroimaging Core Director, will provide mentorship in fMRI data processing and structural/functional connectivity analyses. Dr. Danny JJ Wang will provide mentorship in perfusion MRI and the combination of pharmaco-imaging with ASL. The training and associated research will take place at LIBR, a psychiatric research institute with state-of-the-art neuroimaging facilities.