The Computational Role of Corticostriatal Circuits in Binge-Eating Disorder Symptoms and Severity

项目总结/摘要 暴饮暴食症（BED）在美国比任何其他饮食失调症都更常见，并且与 高发病率、残疾率和自杀率。因为大约一半的卧床患者仍然 在目前的一线治疗后出现症状，迫切需要确定基于大脑的因素， 使BED症状永久化，并且可以作为新治疗的机制靶点。当前理论 模型认为，反复出现的，令人痛苦的，失控的暴饮暴食的特点床后出现， 从腹侧到背侧皮质纹状体回路控制决策的转变，以及相应的转变 从目标导向到习惯行为。然而，患有BED的个体同时出现以下情况： 看似矛盾的决策问题-冲动和毅力-以及广泛的 暴饮暴食的严重性迄今为止的神经生物学研究未能解释这种人内结合 认知缺陷或这种人与人之间的症状差异。这个R21项目的目标是测试一个 BED的神经计算模型，提供了症状和严重程度的更全面的说明。 这个模型扩展了以前的理论，并将行为与皮质纹状体回路的有效连接联系起来 潜在的决策。具体来说，这项研究结合了行为的计算模型， 用神经连接的动态因果模型（DCM）来检查是否有异常的内部和之间， 回路动力学与BED中的认知和临床症状特征有关。我们将比较有效的连通性 在两种决策模式下，28名成人BED患者与28名组匹配的健康对照者的数据。我们 将测试两个总体预测，这两个预测是由我们对皮质纹状体回路动力学的模拟得出的， 相关行为：1）在BED患者中，异常的回路内动力学，特别是过稳定性（高 在背侧和腹侧皮质纹状体回路内的"增益"），导致初始证据的过度加权（导致 冲动），并促进对环境变化不敏感的选择（坚持）; 2)在患有BED的个体中，异常的回路间动力学，特别是其中一个回路的过度影响， 皮质纹状体回路在另一个（背侧腹侧或反之亦然），促进更严重的暴食。这些 模型预测可以解释冲动，失控的暴饮暴食的开始，为什么患有BED的人 尽管饱胀和痛苦，仍然继续暴饮暴食（即，顽固），以及为什么有些人与床 比其他人更有可能更频繁地开始暴饮暴食。因此，数据从这个证明- 概念试点研究将证实一种新的BED症状神经计算模型， 改变神经回路动力学，而不仅仅是神经激活，在床上。此外，数据将支持一个 未来的R01应用程序侧重于在更广泛的诊断范围内测试模型， 暴饮暴食。这项工作最终可以为基于电路的目标提供新的干预措施， 打断根深蒂固的暴饮暴食模式

PROJECT SUMMARY/ABSTRACT Binge-eating disorder (BED) is more common than any other eating disorder in the US and is associated with high rates of medical morbidity, disability, and suicidality. As roughly half of patients with BED remain symptomatic after current first-line treatments, there is a critical need to identify brain-based factors that perpetuate BED symptoms and that may serve as mechanistic targets for novel treatments. Current theoretical models posit that the recurrent, distressing, and out-of-control overeating that characterizes BED arises after a transition from ventral to dorsal corticostriatal circuit control over decision-making, and a corresponding shift from goal-oriented to habitual behavior. However, individuals with BED present with a co-occurrence of seemingly contradictory decision-making problems—impulsivity and perseveration—and a wide range of binge-eating severity. Neurobiological research to date has failed to account for this within-person combination of cognitive deficits or this between-person variability in symptoms. The goal of this R21 project is to test a neurocomputational model of BED that provides a more comprehensive account of symptoms and severity. This model expands on previous theories and links behavior to effective connectivity in corticostriatal circuits underlying decision-making. Specifically, the proposed study combines computational modeling of behavior with dynamic causal modeling (DCM) of neural connectivity to examine whether aberrant within- and between- circuit dynamics relate to cognitive and clinical symptom profiles in BED. We will compare effective connectivity of 28 adults with BED to that of 28 group-matched healthy controls during two decision-making paradigms. We will test two overarching predictions that are informed by our simulations of corticostriatal circuit dynamics and associated behavior: 1) In individuals with BED, aberrant within-circuit dynamics, specifically overstability (high “gain”) within dorsal and ventral corticostriatal circuits, result in overweighting of initial evidence (leading to impulsivity) and promote choice selections that are insensitive to changes in the environment (perseveration); 2) In individuals with BED, aberrant between-circuit dynamics, specifically an over-influence of one corticostriatal circuit on the other (dorsal on ventral or vice-versa), promote more severe binge eating. These model predictions can explain the impulsive, out-of-control initiation of binge eating, why individuals with BED continue to binge eat despite fullness and distress (i.e., perseverate), and why some individuals with BED are more likely than others to more frequently initiate binge eating episodes. As such, data from this proof-of- concept pilot study will substantiate a novel neurocomputational model of BED symptoms and characterize alterations in neural circuit dynamics, not just neural activation, in BED. In addition, the data will support a future R01 application focused on testing the model among a wider diagnostic spectrum of individuals who binge eat. This work can ultimately inform new interventions with circuit-based targets to more effectively interrupt entrenched patterns of binge eating.