Nutritional deficiency and dopamine: A neurodevelopmental study of starvation effects in adolescent anorexia nervosa

营养缺乏和多巴胺：饥饿对青少年神经性厌食症影响的神经发育研究

• 批准号: 10534437
• 负责人: Jonathan E Posner
• 金额: $ 76.78万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534437
• 关键词: Adolescence; Adolescent; Affect; Amino Acids; Anorexia Nervosa; Anxiety; Behavioral; Biological Factors; Body Image; Body Weight decreased; Brain; Caloric Restriction; Calories; Chronic; Clinical; Complex; Consumption; Corpus striatum structure; Data; Development; Dietary Fats; Dietary Practices; Diffusion; Disease; Disease remission; Dopamine; Eating; Food; Functional Magnetic Resonance Imaging; Individual; Intake; Knowledge; Lead; Learning; Life; Lipids; MRI Scans; Magnetic Resonance Imaging; Malnutrition; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Midbrain structure; Mood Disorders; Moods; Morbidity - disease rate; Nucleus Accumbens; Nutrient; Nutritional; Outcome; Patients; Pattern; Plasma; Play; Polyunsaturated Fatty Acids; Psychological reinforcement; Psychopathology; Records; Relapse; Research; Role; Severity of illness; Signal Transduction; Starvation; Supplementation; Symptoms; Teenagers; Testing; Translating; Tyrosine; Underweight; Youth; adolescent brain development; adolescent patient; affective disturbance; anxiety symptoms; associated symptom; brain tract; dietary restriction; dietary supplements; dopamine system; food restriction; functional MRI scan; imaging modality; mood symptom; mortality; neuromelanin; nutrition; peer; polyunsaturated fat; pre-clinical; premature; restrictive eating; severe mental illness; tractography; translational therapeutics; weight restoration; white matter

Anorexia nervosa (AN) is a severe and potentially life-threating condition that typically emerges in the teenage years. While AN is a complex disorder with myriad symptoms, caloric restriction is the central behavioral disturbance, and is characterized by a specific restriction of dietary fat. Converging data indicate that AN is associated with disturbances in the dopamine system. The dopamine system develops considerably during adolescence, and adequate nutrition plays a role in healthy brain development. Yet the effects of dietary restriction and the associated starved state that is an inherent feature of AN is poorly understood. Individuals with AN typically initiate dietary restrictions that accelerate, with mounting caloric reductions and weight loss and associated symptoms including anxiety and depression. This cascading pattern most commonly unfolds during adolescence and can lead to life-long struggles with eating, body image, and mood disturbance, if not unremitting AN. The restrictive eating pattern leads to decreased availability of many nutrients, some of which are particularly important in adolescent brain development. Here, we focus on polyunsaturated fats (PUFAs) and tyrosine which are specifically known to be critical for the functioning and development of the dopamine system. Our proposal aims to test the overarching hypothesis that among teens who develop AN, dietary restriction which is intrinsic to illness negatively impacts the dopamine (DA) system during a critical window of brain development, with enduring effects. We predict that these nutritional deficits will be associated with structural and functional disturbances in the DA system (baseline MRI scans with tractography, neuromelanin-MRI, and prediction error-fMRI). We predict that these nutritional deficits have enduring effects on the DA system even when weight restoration is successful, as evidenced by repeat MRI at 1 year. To assess the impact of being underweight, we will include individuals with atypical AN, who show all clinical features of AN but are not underweight, and 1-year longitudinal assessments will measure the enduring impact of these nutritional deficits. The proposed research has direct translational therapeutic implications – such as augmenting current treatments (including refeeding) with nutrient supplementation, thereby protecting the developing brain and curtailing the long-term negative sequelae of adolescent AN. With extant knowledge, such trials would be premature as the specific nutrients underlying AN-related starvation effects on brain development are unknown. We aim to close this gap by examining whether PUFAs and tyrosine mediate abnormalities in the DA system in adolescents with AN and atypical AN.

神经性厌食症 (AN) 是一种严重且可能危及生命的疾病，通常出现在 青少年时期。虽然 AN 是一种具有多种症状的复杂疾病，但热量限制是核心 行为障碍，其特征是对膳食脂肪的特定限制。收敛数据表明 AN 与多巴胺系统紊乱有关。多巴胺系统显着发展 在青春期，充足的营养对大脑的健康发育起着重要作用。然而饮食的影响 人们对限制和相关的饥饿状态（AN 的固有特征）知之甚少。个人 AN 通常会启动饮食限制，并加速热量减少和体重减轻 以及相关症状，包括焦虑和抑郁。这种层叠模式最常见 在青春期，如果不这样做，可能会导致终生与饮食、身体形象和情绪困扰作斗争 坚持不懈的AN。限制性饮食模式导致许多营养素的利用率下降，其中一些营养素 对青少年大脑发育尤为重要。在这里，我们重点关注多不饱和脂肪 (PUFA) 和酪氨酸，已知对多巴胺的功能和发育至关重要 系统。 我们的提案旨在检验一个总体假设，即在患有 AN 的青少年中，饮食限制 这是疾病所固有的，它会在大脑的关键窗口期对多巴胺 (DA) 系统产生负面影响 发展，影响持久。我们预测这些营养缺乏将与结构性 DA 系统的功能障碍（基线 MRI 扫描、纤维束成像、神经黑色素 MRI 和 预测误差-fMRI）。我们预测这些营养缺乏会对 DA 系统产生持久影响，甚至 当体重恢复成功时，如一年后重复 MRI 所证明的那样。评估存在的影响 体重不足，我们将包括患有非典型 AN 的个体，他们表现出 AN 的所有临床特征，但并非 体重不足和一年纵向评估将衡量这些营养的持久影响 赤字。 拟议的研究具有直接的转化治疗意义——例如增强电流 补充营养的治疗（包括重新喂养），从而保护发育中的大脑和 减少青少年 AN 的长期负面后遗症。根据现有知识，此类试验将是 为时过早，因为与 AN 相关的饥饿对大脑发育产生影响的特定营养物质是 未知。我们的目标是通过检查 PUFA 和酪氨酸是否介导 DA 异常来缩小这一差距 AN 和非典型 AN 青少年的系统。