Cognitive and neural mechanisms of cognitive-behavioral therapy for avoidant/restrictive food intake disorder

摘要 回避性/限制性食物摄入障碍(ARFID)影响3%的儿童和青少年 在营养缺乏、补充剂依赖和心理社会障碍方面。ARFID遵循慢性 当然，而且没有循证治疗。ARFID的标志特征是避免食物，这可能 通过极端程度的食物新恐惧症和/或恐惧回路的过度激活来维持 食物暗示。我们的团队已经开发出一种手动认知行为疗法(CBT-AR)，它直接针对 食物新恐惧症(认知机制)和恐惧回路(神经机制)都能减少对食物的回避 (临床结果)。与NIMH的实验治疗学方法一致，在这一探索性/发展性 分阶段R61/R33，我们将利用一个多学科的专家团队来治疗ARFID，神经 食物诱因的作用机制，并对临床试验进行统计分析，进行随机化研究 CBT-AR对照试验。首先，为了建立目标参与度，我们将随机选择50名年轻人(10-18岁) ARFID与CBT-AR的每周15次会议(通过远程医疗)与营养咨询的比率为1：1，以建立 目标交战。我们选择营养咨询作为我们的主动对照，因为它不包括 关键的CBT-AR干预暴露，因此不太可能与我们的目标机制接触。我们 假设，与营养咨询相比，随机接受CBT-AR治疗的患者将显示出显著的 食物新恐惧症(认知机制)和恐惧回路(神经机制)的更大降低 标准化fMRI食物线索范例(初级感兴趣区：前扣带回皮质)对食物线索的反应 [ACC]；继发性感兴趣区：杏仁核、眶前皮质[OFC])。我们还将检查食物的每周变化 新恐惧症(认知机制)，以确定进一步受益停止的会话次数，并使用 该优化剂量的CBT-AR适用于R33。如果我们能够展示R33，我们将继续讨论R33 CBT-AR组从治疗前到治疗后和治疗后之间的至少d=0.40减少- CBT-AR与营养咨询在两种食物新恐惧症(认知性)中至少d=0.40的组差异 机制)或恐惧回路(去/不去ROI：ACC；神经机制)。接下来，我们将随机抽取70名青年 (10-18岁)以1：1的方式服用ARFID，达到CBT-AR的最佳剂量或相同的疗程数 进行营养咨询，以复制目标参与并建立目标验证。我们假设， 与营养咨询相比，随机接受CBT-AR的患者将表现出明显更大的减少 在食物避免方面，这些食物避免的减少将通过食物的减少来调节 新恐惧症(认知机制)和恐惧回路(神经机制)激活。如果成功，则 建议的干预(CBT-AR)可以填补ARFID患者未得到满足的重要需求，并为 为更大规模的疗效和有效性试验提供了途径。

ABSTRACT Avoidant/restrictive food intake disorder (ARFID) affects 3% of children and adolescents and results in nutritional deficiencies, supplement dependence, and psychosocial impairment. ARFID follows a chronic course, and has no evidence-based treatment. The hallmark feature of ARFID is food avoidance, which may be maintained by extreme levels of food neophobia and/or hyperactivation of fear circuitry in response to food cues. Our team has developed a manualized cognitive-behavioral therapy (CBT-AR) that directly targets both food neophobia (cognitive mechanism) and fear circuitry (neural mechanism) to reduce food avoidance (clinical outcome). In line with NIMH’s experimental therapeutics approach, in this exploratory/developmental phased R61/R33, we will leverage a multidisciplinary team of experts in the treatment of ARFID, neural mechanisms of food motivation, and statistical analysis of clinical trials to conduct a mechanistic randomized controlled trial of CBT-AR. First, to establish target engagement, we will randomize 50 youth (ages 10-18yo) with ARFID in a 1:1 ratio to 15 weekly sessions (via telehealth) of CBT-AR vs. nutrition counseling to establish target engagement. We chose nutrition counseling as our active control because it does not include the crucial CBT-AR intervention of exposure, and is therefore unlikely to engage our target mechanisms. We hypothesize that, compared to nutrition counseling, patients randomized to CBT-AR will show significantly greater decreases in food neophobia (cognitive mechanism) and fear circuitry (neural mechanism) in response to food cues during a standardized fMRI food cue paradigm (primary ROI: anterior cingulate cortex [ACC]; secondary ROIs: amygdala, orbitofrontal cortex [OFC]). We will also examine weekly change in food neophobia (cognitive mechanism) to identify the number of sessions at which further benefit ceases, and use this optimized dose of CBT-AR for the R33. We will move on to the R33 if we are able to demonstrate a reduction of at least d=.40 in the CBT-AR group from pre- to post-treatment AND a post-treatment between- group difference of at least d=.40 in CBT-AR vs. nutrition counseling in either food neophobia (cognitive mechanism) OR fear circuitry (Go/No-Go ROI: ACC; neural mechanism). Next, we will randomize 70 youth (ages 10-18yo) with ARFID in a 1:1 fashion to the optimized dose of CBT-AR or the same number of sessions of nutrition counseling to replicate target engagement and establish target validation. We hypothesize that, compared to nutrition counseling, patients randomized to CBT-AR will exhibit significantly greater reductions in food avoidance, and that these reductions in food avoidance will be mediated by reductions in food neophobia (cognitive mechanism) and fear circuitry (neural mechanism) activation. If successful, the proposed intervention (CBT-AR) could fill an important unmet need for those living with ARFID and pave the way for larger-scale efficacy and effectiveness trials.