Cognitive Inflexibility and Phenotypic Heterogeneity in Anorexia Nervosa

描述（由申请人提供）：成人神经性厌食症（AN）是一种严重且通常难治的精神疾病，但对可能作为开发新干预措施目标的潜在机制知之甚少。推进AN病理生理学研究的一个挑战与疾病特征的大量组内异质性有关。例如，精神障碍诊断和统计手册包括AN限制（AN-R）和暴饮暴食/清除（AN-BP）的两种亚型，其在暴饮暴食或清除的存在方面不同（即，自我诱导呕吐或 滥用泻药、利尿剂或灌肠剂）发作。虽然有一些证据表明AN-R和AN-BP是不同的，但将这些组分开的机制仍然难以捉摸。此外，AN-BP和神经性贪食症（BN）之间的相似性和区别强调了识别AN-R，AN-BP和BN共享和独特的过程的必要性。因此，本研究的总体目标是测试一个概念模型，该模型将AN-BN谱中症状表现的异质性与认知能力的两个方面-注意定势转移（即，在两个抽象概念之间转移注意力能力 刺激维度）和反向学习（即，改变行为以响应强化偶然性变化的能力）。重要的是，注意定势转移和逆转学习在神经生物学上是不同的，分别与腹外侧前额叶皮层/前扣带皮层和眶额皮层/腹侧纹状体相关。认知 作为AN的假定生物标志物，可识别性受到了广泛关注，但以前的研究主要依赖于多维临床神经心理学测量，这些测量不能很好地映射到潜在的神经机制，并且结果好坏参半。本研究的指导下，在AN的异质性，可以阐明通过确定不同方面的功能改变额扣带回电路介导的注意定势转移和额纹状体电路介导的逆转学习的假设。因此，本研究将使用扫描仪外的两种行为任务（即，来自剑桥神经心理学测试自动化电池的维度内/维度外转换任务和概率反转学习任务）和功能磁共振成像与概念相关的神经认知探针，以评估和分离跨AN-BN谱的注意定势转换和反转学习的行为和神经方面。将招募四组年龄在18-55岁的参与者：1）没有暴饮暴食或排泄史的AN-R（n = 30）; 2）AN-BP（n = 30）; 3）没有AN史的BN（n = 30）;和4）精神健康对照（n = 30）。本研究是首次尝试考察注意的单独贡献，具有创新性和重要意义 集合移位和反向学习，以跨越AN-BN谱的表型异质性。研究结果将对饮食失调的神经生物学模型和针对亚组特定病理生理过程的新型干预措施的发展产生重要影响。

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) in adults is a serious and often refractory psychiatric illness, yet little is known about underlying mechanisms that might serve as targets for the development of novel interventions. One challenge in advancing research on the pathophysiology of AN relates to the substantial within-group heterogeneity that characterizes the illness. For example, the Diagnostic and Statistical Manual of Mental Disorders includes two subtypes of AN - restricting (AN-R) and binge-eating/purging (AN-BP) that differ with respect to the presence of binge eating or purging (i.e., self-induced vomiting or the misuse of laxative, diuretics or enemas) episodes. Although there is some evidence that AN-R and AN-BP are distinct, the mechanisms that separate these groups remain elusive. Moreover, similarities and distinctions between AN-BP and bulimia nervosa (BN) underscore the need to identify processes that are shared by and unique to AN-R, AN-BP and BN. Accordingly, the overall goal of this study is to test a conceptual model linking heterogeneity in symptom presentation across the AN-BN spectrum to variations in the salience of two facets of cognitive inflexibility - attentional set-shifting (i.e., the ability to shift attention between two abstract stimulus dimensions) and reversal learning (i.e., the ability to alter behavior in response to changes in reinforcement contingencies). Importantly, attentional set-shifting and reversal learning are neurobiologically distinct, with correlates in the ventrolateral prefrontal cortex/anterior cingulate cortex and orbitofrontal cortex/ventral striatum, respectively. Cognitive inflexibility has received much attention as a putative biomarker of AN, but previous studies have relied primarily on multidimensional clinical neuropsychological measures that do not map on well to underlying neural mechanisms, and findings have been mixed. This study is guided by the hypothesis that heterogeneity in AN can be elucidated by identifying distinct aspects of altered function in fronto-cingulate circuitry mediating attentional set-shifting and fronto-striatl circuitry mediating reversal learning. Thus, this study will use both behavioral tasks outside of the scanner (i.e., Intradimensional/Extradimensional shift task from the Cambridge Neuropsychological Test Automated Battery and a probabilistic reversal learning task) and functional magnetic resonance imaging with conceptually-relevant neurocognitive probes to assess and separate behavioral and neural facets of attentional set-shifting and reversal learning across the AN-BN spectrum. Four groups of participants aged 18-55 years will be recruited: 1) AN-R with no history of binge eating or purging (n = 30); 2) AN-BP (n = 30); 3) BN with no history of AN (n = 30); and 4) psychiatrically healthy controls (n = 30). This study is innovative and significant as the first effort to examine the separate contributions of attentional set-shifting and reversal learning to phenotypic heterogeneity across the AN-BN spectrum. Findings will have important implications for neurobiological models of eating disorders and the development of novel interventions designed to target subgroup-specific pathophysiological processes.