Neuro-affective response to light in depressed adolescents and young adults

摘要 青少年抑郁症与毁灭性的临床和心理社会结果有关，许多儿童 抑郁症患者对现有的治疗方法没有反应。由于其成本低，副作用最小， 在成人抑郁症的疗效，早晨明亮的光疗法（LT）有希望作为一种非药物治疗， 青春期抑郁症然而，身体和大脑的成熟差异可以改变青少年的反应 因此，重要的第一步是确定治疗机制是否 成人对LT的潜在抗抑郁反应转化为青少年和/或随年龄而变化。 情绪通过表达黑视素的视网膜神经节细胞，它将光信号从视网膜传递到亚视网膜， 支持威胁（杏仁核）和奖励（纹状体）处理的皮层边缘结构。抗抑郁作用 通过使用黑视蛋白参与的蓝光来增强成人的LT。蓝色增强型LT减少了与威胁相关的 杏仁核活动，并增加健康成年人的奖励相关纹状体活动，以及黑视素-边缘回路 在小鼠模型中光的抗抑郁作用的基础。因此，类似于其他有效的抑郁症治疗， 负性（威胁）和正性（奖励）神经情感机制的调节可能会驱动 光青少年对蓝光的黑视素敏感性高于成年人，因此可能会经历更多 蓝光对大脑情感功能的显著影响。如果这一概念得到支持，它可以告知优化的 LT治疗青少年抑郁症的剂量。在MRI扫描仪内提供的光暴露 神经情感性抑郁症的目标，提供了一种有效的方法来探索这一治疗途径， 青春期使用这种方法，我们建议测试假设，急性暴露于黑视素- 蓝光（与红光相比）可以稳定抑郁症患者的神经情感缺陷， 青少年对蓝光的反应比年轻人更强烈。我们将招募40名青少年（12- 17岁）和40名 年轻人（18- 30岁）患有抑郁症。作为一种治疗探针，我们将研究内部的直接影响- 扫描仪强光照射对大脑情感功能（脑血流，功能磁共振成像）的影响。黑视素敏感性将 通过瞳孔测量以及参与者发育、眼部、行为和临床指标进行评估 收集的特征。我们的主要目标将测试蓝光将稳定负的假设（目标1： 威胁）和积极（目标2：奖励）的神经情感缺陷在抑郁症的参与者在更大程度上比红色 这些影响将因发育阶段（青少年与成人）而异。探索性分析将1） 检查黑视敏感度解释年龄差异的程度光调制脑功能和2） 应用高维建模方法来识别发育、眼部、行为和临床特征 解释了蓝光引起的神经情感参与的个体差异。了解影响 发展，和其他因素，对光的治疗机制将提供经验基础， 优化了LT治疗青少年抑郁症的方案，从而提高了疗效、易用性和实际依从性。

ABSTRACT Adolescent depression is associated with devastating clinical and psychosocial outcomes, and many pediatric depression patients do not respond to existing treatments. With its low cost, minimal side effect profile and efficacy in adult depression, morning bright light therapy (LT) holds promise as a non-medication treatment for adolescent depression. However, maturational differences in the body and brain can alter adolescents’ response to therapeutic doses of adult treatments.Thus, essential first step is to establish whether therapeutic mechanisms underlying antidepressant response to LT in adults translate to adolescents and/or vary with age.Light modulates mood through melanopsin-expressing retinal ganglion cells, which convey light signals from the retina to sub- cortical limbic structures supporting threat (amygdala) and reward (striatum) processing. Antidepressant effects of LT in adults is enhanced by using melanopsin-engaging blue light. Blue-enhanced LT reduces threat-related amygdala activity and increases reward-related striatal activity in healthy adults, and melanopsin-limbic circuits underlie antidepressant effects of light in murine models. Thus, akin to other effective depression treatments, modulation of negative (threat) and positive (reward) neuro-affective mechanisms likely drive clinical benefits of light. Adolescents show higher melanopsin sensitivity to blue light than adults and thus may experience more pronounced effects of blue light on affective brain function. If this notion is supported, it could inform optimized therapeutic dosing of LT for adolescent depression. Light exposures delivered within an MRI scanner engage neuro-affective depression targets in adults, offering an efficient way to probe this therapeutic pathway in adolescence. Using this approach, we propose to test the hypothesis that acute exposure to melanopsin- engaging blue light (vs red light) will stabilize neuro-affective deficits in depressed individuals, and these effects will be stronger for blue light in adolescents than young adults. We will enroll 40 adolescents (12-17yr) and 40 young adults (18-30yr) with depression. As a therapeutic probe, we will examine the direct impact of within- scanner bright light exposures on affective brain function (cerebral blood flow, fMRI). Melanopsin sensitivity will be assessed with pupillometry, and indices of participant developmental, ocular, behavioral and clinical characteristics collected. Our primary aims will test the hypothesis that blue light will stabilize negative (Aim 1: threat) and positive (Aim 2: reward) neuro-affective deficits in depressed participants to a greater extent than red light, and that these effects will vary by developmental stage (adolescent vs adult). Exploratory analyses will 1) examine the extent which melanopic sensitivity explains age differences light-modulated brain function and 2) apply a high-dimensional modeling approach to identify developmental, ocular, behavioral, and clinical features that account for individual differences in neuro-affective engagement by blue light. Understanding the impact of development, and other factors, on therapeutic mechanisms of light will provide an empirical basis for building optimized LTprotocols for adolescent depression,thus increasingefficacy,ease of use, and real-word adherence.