Evidence-based treatments for children with persistent post-concussion symptoms (PPCS) are few and limited. Common PPCS complaints such as sleep disturbance and fatigue could be ameliorated via the supplementation of melatonin, which has significant neuroprotective and anti-inflammatory properties. This study aims to identify neural correlates of melatonin treatment with changes in sleep disturbances and clinical recovery in a pediatric cohort with PPCS. We examined structural and functional neuroimaging (fMRI) in 62 children with PPCS in a randomized, double-blind, placebo-controlled trial of 3 mg or 10 mg of melatonin (NCT01874847). The primary outcome was the total youth self-report Post-Concussion Symptom Inventory (PCSI) score after 28 days of treatment. Secondary outcomes included the change in the sleep domain PCSI score and sleep-wake behavior (assessed using wrist-worn actigraphy). Whole-brain analyses of (1) functional connectivity (FC) of resting-state fMRI, and (2) structural gray matter volumes via voxel-based morphometry were assessed immediately before and after melatonin treatment and compared with placebo to identify neural effects of melatonin treatment. Increased FC of posterior default mode network (DMN) regions with visual, somatosensory, and dorsal networks was detected in the melatonin groups over time. The FC increases also corresponded with reduced wake periods (r = -0.27, p = 0.01). Children who did not recover (n = 39) demonstrated significant FC increases within anterior DMN and limbic regions compared with those who did recover (i.e., PCSI scores returned to pre-injury level, n = 23) over time, (p = 0.026). Increases in GM volume within the posterior cingulate cortex were found to correlate with reduced wakefulness after sleep onset (r = -0.32, p = 0.001) and sleep symptom improvement (r = 0.29, p = 0.02). Although the melatonin treatment trial was negative and did not result in PPCS recovery (with or without sleep problems), the relationship between melatonin and improvement in sleep parameters was linked to changes in function-structure within and between brain regions interacting with the DMN.

中文翻译：

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褪黑激素治疗小儿脑震荡后睡眠恢复的神经相关性：随机对照试验。

针对持续脑震荡后症状 (PPCS) 儿童的循证治疗很少且有限。通过补充具有显着神经保护和抗炎特性的褪黑激素，可以改善常见的 PPCS 主诉，例如睡眠障碍和疲劳。本研究旨在确定褪黑激素治疗与 PPCS 儿科队列中睡眠障碍和临床恢复变化的神经相关性。我们在 3 毫克或 10 毫克褪黑激素 (NCT01874847) 的随机、双盲、安慰剂对照试验中检查了 62 名 PPCS 儿童的结构和功能神经影像学 (fMRI)。主要结果是治疗 28 天后青少年自我报告的脑震荡后症状清单 (PCSI) 总分。次要结果包括睡眠领域 PCSI 评分和睡眠-觉醒行为（使用腕戴活动记录仪评估）的变化。在褪黑激素治疗前后立即评估 (1) 静息态 fMRI 的功能连接 (FC) 和 (2) 基于体素的结构灰质体积的全脑分析，并与安慰剂进行比较以确定褪黑激素的神经影响治疗。随着时间的推移，在褪黑激素组中检测到具有视觉、体感和背侧网络的后默认模式网络 (DMN) 区域的 FC 增加。FC 的增加也与减少的唤醒时间相对应（(2) 在褪黑激素治疗前后立即评估通过基于体素的形态计量学的结构灰质体积，并与安慰剂进行比较，以确定褪黑激素治疗的神经影响。随着时间的推移，在褪黑激素组中检测到具有视觉、体感和背侧网络的后默认模式网络 (DMN) 区域的 FC 增加。FC 的增加也与减少的唤醒时间相对应（(2) 在褪黑激素治疗前后立即评估通过基于体素的形态计量学的结构灰质体积，并与安慰剂进行比较，以确定褪黑激素治疗的神经影响。随着时间的推移，在褪黑激素组中检测到具有视觉、体感和背侧网络的后默认模式网络 (DMN) 区域的 FC 增加。FC 的增加也与减少的唤醒时间相对应（r =  -0.27，p =  0.01）。与恢复的儿童相比，未恢复的儿童 ( n  = 39) 在前 DMN 和边缘区域内的 FC 显着增加（即 PCSI 评分恢复到受伤前的水平，n  = 23）随着时间的推移，（p =  0.026） . 发现后扣带皮层内 GM 体积的增加与入睡后清醒程度降低（r =  -0.32 ，p =  0.001）和睡眠症状改善（r =  0.29 ，p = 0.02）。尽管褪黑激素治疗试验是否定的并且没有导致 PPCS 恢复（有或没有睡眠问题），但褪黑激素与睡眠参数改善之间的关系与与 DMN 相互作用的大脑区域内部和之间的功能结构变化有关。