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）是一种严重且往往难治的精神疾病，但人们对可能作为开发新型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项挑战与该疾病的显着组内异质性有关。例如，《精神疾病诊断与统计手册》包括 AN 的两种亚型 - 限制性 (AN-R) 和暴食/泻食 (AN-BP)，它们在暴食或泻食（即自我诱发的呕吐或暴食）的存在方面有所不同。 滥用泻药、利尿剂或灌肠剂）。尽管有一些证据表明 AN-R 和 AN-BP 是不同的，但区分这些群体的机制仍然难以捉摸。此外，AN-BP 和神经性贪食症 (BN) 之间的相似点和区别强调需要确定 AN-R、AN-BP 和 BN 共有且独特的过程。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 谱系中症状表现的异质性与认知不灵活性的两个方面的显着性变化联系起来 - 注意力转移（即在两个抽象之间转移注意力的能力） 刺激维度）和逆转学习（即根据强化意外事件的变化而改变行为的能力）。重要的是，注意力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 僵化作为 AN 的假定生物标志物受到了广泛关注，但之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，并且研究结果好坏参半。这项研究的假设是，AN 的异质性可以通过识别介导注意力转移的额扣带回环路和介导逆转学习的额纹状体环路功能改变的不同方面来阐明。因此，本研究将使用扫描仪之外的行为任务（即来自剑桥神经心理学测试自动电池的内维度/外维度转移任务和概率逆转学习任务）和功能性磁共振成像以及概念相关的神经认知探针来评估和分离整个 AN-BN 谱中注意力设定转移和逆转学习的行为和神经方面。将招募四组年龄在 18-55 岁之间的参与者： 1）无暴食或暴食史的 AN-R（n = 30）； 2) AN-BP (n = 30); 3) 没有 AN 病史的 BN (n = 30)； 4) 精神健康的对照组 (n = 30)。这项研究具有创新性和重要意义，是首次检验注意力的单独贡献。 对 AN-BN 谱中表型异质性的设置转移和逆转学习。研究结果将对饮食失调的神经生物学模型以及针对亚组特异性病理生理过程的新型干预措施的开发产生重要影响。

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.