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

摘要 青春期抑郁症与破坏性的临床和心理社会结局有关，许多儿童 抑郁症患者对现有的治疗方法没有反应。凭借其低成本、最小副作用和 晨光疗法(LT)对成人抑郁症的疗效，有望成为一种非药物治疗 青春期抑郁症。然而，身体和大脑的成熟差异会改变青少年的反应 因此，至关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/或随年龄变化。光调制 情绪通过表达黑素的视网膜神经节细胞，它将光信号从视网膜传递到亚 皮质边缘结构支持威胁(杏仁核)和奖励(纹状体)的处理。抗抑郁作用 成年人的LT通过使用与黑素结合的蓝光来增强。蓝色增强的LT减少了与威胁相关的 健康成年人杏仁核活动和奖赏相关纹状体活动增加，以及黑素-边缘环路 光在小鼠模型中的抗抑郁作用。因此，类似于其他有效的抑郁症治疗方法， 对消极(威胁)和积极(奖励)神经情感机制的调节可能推动 灯。青少年比成年人对蓝光表现出更高的黑色素敏感性，因此可能会经历更多 蓝光对情感脑功能的显著影响。如果这一概念得到支持，它可能会通知优化 治疗剂量LT治疗青春期抑郁症。在MRI扫描仪接合内提供的光曝光 以成人神经情感性抑郁为靶点，为探索这一治疗途径提供了一条有效途径 青春期。使用这种方法，我们建议检验以下假设：急性暴露于黑素- 使用蓝光(与红光相比)将稳定抑郁症患者的神经情感缺陷，而这些效应 对于青少年来说，蓝光会比年轻人更强。我们将招收40名12-17岁的青少年和40名 患有抑郁症的年轻人(18-30岁)。作为一项治疗探索，我们将检查内部- 扫描仪强光照射对情感脑功能(脑血流量，fMRI)的影响。对黑色素敏感的人 用瞳孔测量法和参与者的发育、眼睛、行为和临床指数进行评估 收集到的特征。我们的主要目标将测试蓝光将稳定在负值的假设(目标1： (威胁)和积极(目标2：奖励)抑郁参与者的神经情感缺陷比红色更严重 这些影响会因发育阶段的不同而不同(青少年与成人)。探索性分析将1) 检查黑色素敏感度解释年龄差异的程度光调制的大脑功能和2) 应用高维建模方法确定发育、眼部、行为和临床特征 这解释了蓝光下神经情感参与的个体差异。了解以下方面的影响 发展，以及其他因素，对光的治疗机制将提供经验基础 优化青春期抑郁症的长期治疗方案，从而提高疗效、易用性和实际遵守情况。

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.