Misaki Masaya, Young Kymberly D, Tsuchiyagaito Aki, Savitz Jonathan, Guinjoan Salvador M
Laureate Institute for Brain Research, Tulsa, OK, USA.
Oxley College of Health and Natural Sciences, The University of Tulsa, Tulsa, OK, USA.
Mol Psychiatry. 2025 Jun;30(6):2707-2717. doi: 10.1038/s41380-024-02880-3. Epub 2024 Dec 26.
Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (t = -4.404, d = -0.704, p < 0.001) but not in the control group (t = -1.609, d = -0.430, p = 0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype: F = 8.735, p = 0.005; feedback response subtype: F = 5.326, p = 0.008; subtypes' interaction: F = 3.471, p = 0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.
重度抑郁症（MDD）因其高患病率以及给个人和医疗系统带来的巨大负担，构成了一项重大的公共卫生挑战。实时功能磁共振成像神经反馈（rtfMRI-NF）显示出有望成为治疗这种疾病的方法，尽管其作用机制仍不清楚。本研究调查了rtfMRI-NF训练期间的全脑反应模式，以解释MDD临床疗效的个体间差异。我们分析了来自先前rtfMRI-NF研究的95名MDD参与者（67名实验组，28名对照组）的数据，这些研究旨在通过积极的自传体记忆回忆来增加左侧杏仁核的激活。实验组观察到显著的症状减轻（t = -4.404，d = -0.704，p < 0.001），而对照组未观察到（t = -1.609，d = -0.430，p = 0.111）。然而，左侧杏仁核的激活并不能解释临床疗效的差异。为了阐明临床效果背后的大脑训练过程，我们检查了神经反馈程序两个关键阶段的全脑激活模式：自我调节期的激活，以及对反馈信号呈现的瞬时反应。通过一个涉及特征选择、流形提取和交叉验证聚类的系统过程，我们确定了两种调节激活亚型和三种对反馈信号的大脑反应亚型。这些亚型与临床效果显著相关（调节亚型：F = 8.735，p = 0.005；反馈反应亚型：F = 5.326，p = 0.008；亚型间相互作用：F = 3.471，p = 0.039）。与显著症状减轻相关的亚型的特征是控制区域（包括外侧前额叶区域）选择性增加，以及与自我参照思维相关区域（如默认模式区域）减少。这些发现表明，训练期间的大规模大脑活动对临床疗效比神经反馈目标区域本身的激活水平更为关键。根据这些模式调整神经反馈训练可以显著提高其治疗效果。
