Biomarkers of Interoceptive Awareness in Adolescent Anorexia Nervosa

描述(由申请人提供)： (03)生物标记物发现和验证一般挑战领域和03-MH-101精神障碍生物标记物具体挑战主题。 神经性厌食症(AN)是一种可怕而令人困惑的疾病。一般来说，饮食失调是导致女性残疾的十大原因之一，而在所有精神疾病中，饮食失调的死亡率最高，与年龄匹配的队列相比，自杀死亡风险增加了57倍。尽管有这些发人深省的统计数据，但AN最大的谜团之一是，患有这种疾病的人珍视这种不良状态。他们说在挨饿的时候“感觉好多了”。相比之下，在患病之前，大多数AN患者都被诊断为焦虑症，并经历了胃肠道症状水平的升高，这些症状与内脏敏感性增加有关。值得注意的是，儿童的严重饥饿主要发生在青春期，这是神经成熟和改造的脆弱时期。事实上，在干预的“关键时期”，AN的进程是值得注意的。如果在青春期早期到中期的脆弱发育窗口期不采取积极治疗，AN症状改善的可能性显著降低。这一证据表明，AN患者对身体内部状态变化的敏感性(即内感敏感性)在发病前就存在，青春期的生物变化可能会增强躯体敏感性，这一时期的饥饿可能会抑制躯体体验，以及这一时期大脑神经回路的关键变化可能是形成障碍过程的关键。在75名青少年的样本中(25名处于神经性厌食症急性营养不良状态，25名从神经性厌食症恢复体重，25名典型的发育正常的青少年)，我们将完成以下目标。我们将：1)表征来自上消化道和内感觉皮层的内感觉信号的差异；2)表征前额叶皮质对内感觉皮质的调制的差异；3)表征眶前叶皮质在调节皮质活动和与内感觉皮质连接方面的作用的差异。通过研究神经激活和心理物理反应的模式，这些模式随着饥饿的函数而改变，并与内感敏感性相关，我们可以就与饥饿相关的生物变化提出新的假说，这些变化对这一群体是强化的，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，饮食失调是导致女性残疾的十大原因之一，而在所有精神疾病中，饮食失调的死亡率最高，与年龄匹配的队列相比，自杀死亡风险增加了57倍。尽管有这些发人深省的统计数据，但AN最大的谜团之一是，患有这种疾病的人珍视这种不良状态。他们说在挨饿的时候“感觉好多了”。相比之下，在生病之前，大多数患有AN的人被诊断为焦虑症，并经历胃肠道症状水平升高，这些症状与对身体变化的敏感度增加有关(例如，当你做错事时感觉到肠道里的凹陷，或者当你担心什么时感觉到肠道里的蝴蝶)。事实上，对这些内在感觉的敏感度(称为内感敏感度)的影响远远超出了神经性厌食症。内感敏感性与情绪记忆的强度有关，与我们理解他人的深度有关，也可能与情绪学习的强度有关。由于青春期是大脑和身体发生深刻变化的时期，这一发育期可能是研究个体在这种敏感性上的差异以及定义病理发育的界限的关键窗口。事实上，人类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会产生特别深远的负面影响。事实上，在干预的“关键时期”，AN的进程是值得注意的。如果在青春期早期到中期的脆弱发育窗口期不采取积极治疗，AN症状改善的可能性显著降低。使用功能神经成像，我们将检查大脑中的神经回路，这些回路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的大脑区域，以及这些区域与典型的发育中青少年有何不同。通过研究神经激活和心理物理反应的模式，这些模式随着饥饿的函数而改变，并与内感敏感性相关，我们可以就与饥饿相关的生物变化提出新的假说，这些假说正在加强这一群体，并为那些患有神经性厌食症的人得出新的治疗目标，并更好地理解青春期过渡的心身联系。

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.