Targeting adolescent depression symptoms using network-based real-time fMRI neurofeedback and mindfulness meditation

项目总结 青少年严重抑郁障碍(MDD)是一种常见且令人衰弱的疾病。目前，黄金标准治疗 仅对大约一半的患者有效，这突显了开发新干预措施的必要性， 特别是针对核心潜在机制，更有效地治疗这种反复发作的疾病。 沉思，一种对抑郁症状持续的倾向，有助于MDD的发病和 预测治疗无反应和复发。在神经层面上，沉思的特点是 默认模式网络(DMN)内的功能连接，先前的研究也一致 显示了MDD中DMN的高连接模式。有趣的是，正念冥想训练 专注于当下，可以减少持之以恒的思考、沉思的倾向和抑郁 症状。此外，我们的研究和其他研究表明，青少年可以将正念练习应用于 减少感觉到的压力，增加持续的注意力，抑制DMN的活动。尽管正念有 对一些人来说，深刻的心理健康益处，单靠正念可能不足以缓解沉思 在抑郁发作期间的倾向。也就是说，MDD症状，包括动力减弱，注意力不集中，以及 缺乏自我效能感，可能会阻碍患者在成功获得和利用正念方面的进展 改变人们对周围环境和人际关系的看法所必需的策略。直接解决这个问题 挑战，我们建议使用实时fMRI神经反馈来增强对 正念技能，以更好地针对DMN过度连接、沉思和抑郁症状。 我们开发了一种新的、基于15分钟正念的实时神经反馈(MbNF)范例 借此，人们观察大脑活动的视觉展示，并练习正念，以故意减少 DMN激活。在R61阶段，90名被诊断为MDD的青少年(年龄13-18岁)将完成45分钟的 在扫描仪外进行正念训练。测试减少DMN超级连接的目标参与度，并 最佳剂量，然后青少年将被随机接受15分钟或30分钟的MBNF治疗 (n=45/剂量组)。如果我们满足GO标准(即显著减少DMN超连通性)，那么我们将 继续到R33阶段，调查是否有MBNF的正念效果优于只有正念。因此， 120名抑郁青少年(13-18岁)的新样本将参加一项双盲随机临床试验 尝试并接受最佳MBNF剂量的正念(即，根据R61)或仅接受正念(n=60/组)。 我们将使用临床医生管理的仪器、自我报告和生态瞬时评估进行测试- 无论与单纯的正念相比，带MBNF的正念有助于更大程度地减少临床医生 评估抑郁症状(主要结果)以及反省减少(次要结果) 包括治疗后、1个月和3个月的评估。作为一个整体，mbnf直接与 精准医学倡议，如果成功，可能会彻底改变对抑郁青少年的临床护理。

PROJECT SUMMARY Adolescent major depressive disorder (MDD) is common and debilitating. Presently, gold-standard treatments are only effective for approximately half of patients, underscoring the need to develop novel interventions, particularly to target core underlying mechanisms and more effectively treat this recurrent disorder. Rumination, the tendency to perseverate about depressive symptoms, contributes to MDD onset and predicts treatment non-response and relapse. At the neural level, rumination is characterized by elevated functional connectivity within the default mode network (DMN), and prior research also has consistently demonstrated patterns of DMN hyperconnectivity in MDD. Interestingly, mindfulness meditation, which trains attentional focus to the present moment, reduces perseverative thinking, ruminative tendencies, and depression symptoms. Further, our research and others have shown that adolescents can apply mindfulness practices to decrease perceived stress, increase sustained attention, and suppress DMN activity. Although mindfulness has profound mental health benefits, for some, mindfulness alone may not be sufficient to mitigate ruminative tendencies during a depressive episode. That is, MDD symptoms, including reduced motivation, inattention, and lack of self-efficacy, may impede a patient’s progress in successfully acquiring and utilizing mindfulness strategies necessary to change perceptions about one’s environment and relationships. To directly address this challenge, we propose using real-time fMRI neurofeedback to enhance the acquisition and utilization of mindfulness skills to better target DMN hyperconnectivity, rumination, and depressive symptoms. We developed a novel, 15-minute mindfulness-based, real-time neurofeedback (mbNF) paradigm whereby people observe a visual display of their brain activity and practice mindfulness to volitionally reduce DMN activation. In the R61 phase, 90 adolescents (ages 13-18) diagnosed with MDD will complete a 45-minute mindfulness training outside the scanner. To test target engagement of reducing DMN hyperconnectivity and optimal dosing, adolescents will then be randomized to receive either a 15- or a 30-minute mbNF session (n=45/dose group). If we meet our Go criterion (i.e., significantly reducing DMN hyperconnectivity), we will then proceed to the R33 phase to investigate whether mindfulness with mbNF outperforms mindfulness only. Thus, a new sample of 120 depressed adolescents (ages 13-18) will participate in a double-blind randomized clinical trial and receive mindfulness with the optimal mbNF dose (i.e., per the R61) or mindfulness only (n=60/group). We will test–using clinician-administered instruments, self-reports, and ecological momentary assessment– whether compared to mindfulness only, mindfulness with mbNF contributes to a greater reduction in clinician assessed depression symptoms (primary outcome) as well as decreased rumination (secondary outcome) across the post-treatment, 1-month, and 3-month assessments. As a whole, mbNF is directly in line with precision medicine initiatives, and if successful, could revolutionize clinical care for depressed adolescents.