Biomarkers of Interoceptive Awareness in Adolescent Anorexia Nervosa

描述（由申请人提供）： (03)生物标志物发现和验证一般挑战领域和03-MH-101精神障碍生物标志物特定挑战主题。 神经性厌食症（AN）是一种可怕而令人困惑的疾病。一般来说，饮食失调是女性残疾的十大原因之一，而AN是任何精神疾病的最高死亡率，相对于年龄匹配的队列，由于自杀而死亡的风险增加了57倍。尽管有这些发人深省的统计数据，AN最大的谜团之一是，患病的个体对这种疾病的珍视。他们报告说，饥饿时“感觉好多了”。相比之下，在患病之前，大多数AN患者被诊断为焦虑症，并经历胃肠道症状水平升高-与内脏敏感性增加相关的病症。值得注意的是，严重饥饿的AN主要发生在青春期，一个脆弱的时期的神经成熟和修改。事实上，AN的过程是值得注意的“关键时期”的干预。如果在青春期早期至中期的脆弱发育窗口期不进行积极的治疗，AN症状改善的可能性显着降低。这些证据表明，对身体内部状态变化的敏感性（即内感受性敏感性）存在于AN患者的发病前，青春期的生物学改变可能会增强躯体敏感性，在此期间的饥饿可能会抑制躯体体验，并且在此期间大脑神经回路的关键改变可能对形成障碍过程至关重要。在75名青少年（25名处于神经性厌食症营养不良的急性状态，25名神经性厌食症体重恢复，25名典型发展对照）的样本中，我们将完成以下目标。我们将：1）表征来自上胃肠道和内感受皮层的内感受信号传导的差异，2）表征内感受皮层的前额叶皮层调制的差异，以及3）表征眶额皮层对皮层活动和与内感受皮层的连通性的调制的作用的差异。通过研究神经激活和心理物理反应的模式，改变作为饥饿的功能，并与内感受性的敏感性，我们可以制定新的假设与饥饿相关的生物学变化是加强这一组，并得出新的治疗目标。 公共卫生相关声明：神经性厌食症（AN）是一种可怕而令人困惑的疾病。一般来说，饮食失调是女性残疾的十大原因之一，而AN是任何精神疾病的死亡率最高的，相对于年龄匹配的队列，自杀死亡的风险增加了57倍。尽管有这些发人深省的统计数据，AN最大的谜团之一是，患病的个体对这种疾病的珍视。他们报告说，饥饿时“感觉好多了”。相比之下，在患病之前，大多数AN患者被诊断患有焦虑症，并经历胃肠道症状水平升高，-与对身体变化的敏感性增加相关的条件（例如，当你做错事时感觉到肠道中的坑，或者当你担心某事时感觉到肠道中的蝴蝶）。事实上，对这些内部感觉的敏感性（称为内感受性敏感性）的影响远远超出了神经性厌食症。内感受敏感性与情感记忆的强度有关，我们可以理解他人的深度，并且可能与情感学习的强度有关。由于青春期是大脑和身体发生深刻变化的时期，这一发育时期可能是研究个体在这种敏感性和定义病理发展的界限方面如何不同的关键窗口。事实上，AN的严重饥饿主要始于青春期。因此，这一时期的营养不良可能产生特别深远的负面影响。事实上，AN的过程是值得注意的“关键时期”的干预。如果在青春期早期至中期的脆弱发育窗口期不进行积极的治疗，AN症状改善的可能性显着降低。使用功能性神经成像，我们将检查大脑中的神经回路，这可能有助于我们识别可能导致神经性厌食症患者对内部身体状态敏感性困难的大脑区域，以及这些区域与典型发育中的青少年有何不同。通过研究神经激活和心理物理反应的模式，改变作为饥饿的功能，并与内感受性的敏感性，我们可以制定新的假设与饥饿相关的生物学变化，是加强这一组，并得出新的治疗目标，为那些神经性厌食症和更好地了解青春期的过渡身心连接。

DESCRIPTION (provided by applicant): (03) Biomarker Discovery and Validation general challenge Area and the 03-MH-101 Biomarkers in mental disorders specific challenge topic. Anorexia nervosa (AN) is a terrifying and perplexing disorder. Eating disorders, in general, rank among the top ten causes for disability among women, while AN has the highest mortality rate of any psychiatric disorder with a 57 fold increased risk of death due to suicide relative to an age- matched cohort. Despite these sobering statistics, one of the greatest mysteries of AN is that the ill state is prized by the individuals afflicted with this disorder. They report 'feeling better' while starved. In contrast, prior to the ill state, the majority with AN are diagnosed with an anxiety disorder and experience elevated levels of gastrointestinal symptoms, - conditions associated with increased visceral sensitivity. Notably, the severe starvation of AN principally onsets during adolescence, a vulnerable period of neural maturation and modification. Indeed, the course of AN is notable for a 'critical period' of intervention. The likelihood of improvement in symptoms of AN diminishes markedly if aggressive treatment is not undertaken during the vulnerable developmental window of early to middle adolescence. This body of evidence suggests that sensitivity to change in the internal state of the body (i.e. interoceptive sensitivity) exists premorbidly in those with AN, that biological alterations during adolescence may potentiate somatic sensitivity, that starvation during this period may dampen somatic experience, and that critical alterations in brain neural circuitry during this period may be crucial in shaping disorder course. In a sample of 75 adolescents (25 in the acute state of malnourishment of anorexia nervosa, 25 weight-restored from anorexia nervosa, and 25 typically developing controls), we will complete the following aims. We will: 1) characterize differences in interoceptive signaling from the upper GI tract and the interoceptive cortex, 2) characterize the differences in prefrontal cortical modulation of interoceptive cortex, and 3) characterize differences in the role of orbitofrontal cortex on modulation of cortical activity and connectivity with interoceptive cortex. By studying patterns of neural activation and psychophysical response that alter as a function of starvation and are associated with interoceptive sensitivity, we can formulate novel hypotheses on biological changes associated with starvation that are reinforcing for this group and derive novel treatment targets. PUBLIC HEALTH RELEVANCE STATEMENT: Anorexia nervosa (AN) is a terrifying and perplexing disorder. Eating disorders, in general, rank among the top ten causes for disability among women, while AN has the highest mortality rate of any psychiatric disorder with a 57 fold increased risk of death due to suicide relative to an age-matched cohort. Despite these sobering statistics, one of the greatest mysteries of AN is that the ill state is prized by the individuals afflicted with this disorder. They report 'feeling better' while starved. In contrast, prior to the ill state, the majority with AN are diagnosed with an anxiety disorder and experience elevated levels of gastrointestinal symptoms, - conditions associated with increased sensitivity to body changes (e.g. sensing the pit in your gut when you have done something wrong or the butterflies in your gut when you are worried about something). In fact, sensitivity to these internal sensations (called interoceptive sensitivity) has profound implications well beyond anorexia nervosa. Interoceptive sensitivity is associated with the strength of emotional memories, the depth with which we can understand others, and may be associated with the strength of emotional learning. As adolescence is a time of profound brain and body change, this developmental period may be a key window to study how individuals differ in this sensitivity and the boundaries that define pathological development. In fact, the severe starvation of AN principally begins during adolescence. Thus, malnourishment during this period may have particularly profound negative effects. In fact, the course of AN is notable for a 'critical period' of intervention. The likelihood of improvement in symptoms of AN diminishes markedly if aggressive treatment is not undertaken during the vulnerable developmental window of early to middle adolescence. Using functional neuroimaging we will examine neural circuits in the brain that may help us to identify brain regions that may contribute to difficulties with sensitivity to internal bodily states in those with anorexia nervosa and how these differ from typically developing adolescents. By studying patterns of neural activation and psychophysical response that alter as a function of starvation and are associated with interoceptive sensitivity, we can formulate novel hypotheses on biological changes associated with starvation that are reinforcing for this group and derive novel treatment targets for those with anorexia nervosa and better understand the transitioning mind-body connection of adolescence.