Vohryzek Jakub, Cabral Joana, Lord Louis-David, Fernandes Henrique M, Roseman Leor, Nutt David J, Carhart-Harris Robin L, Deco Gustavo, Kringelbach Morten L
Department of Psychiatry, University of Oxford, Oxford, UK.
Center for Music in the Brain, Aarhus University, Aarhus, Denmark.
Brain Commun. 2024 Feb 15;6(2):fcae049. doi: 10.1093/braincomms/fcae049. eCollection 2024.
Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.
裸盖菇素治疗抑郁症已开始显示出前景，但目前尚不清楚其潜在的因果机制。在此，我们利用接受裸盖菇素（10毫克和25毫克，间隔7天）治疗抑郁症的应答者和非应答者的不同结果，以深入了解与恢复健康脑动力学相关的区域和网络。我们使用大规模脑模型来拟合治疗前应答者和非应答者静息时的时空脑动力学。对这些模型进行系统扰动的动态敏感性分析，使我们能够识别出与从抑郁脑状态转变为健康脑状态相关的特定脑区。将样本分为治疗应答者（抑郁症状减轻>50%）和非应答者，使我们能够识别出与这种变化相关的一部分区域。有趣的是，这些区域与5-羟色胺2a和5-羟色胺1a血清素受体的密度图相关，裸盖菇素的活性代谢物裸盖菇素对其具有相当的亲和力，并且在这些区域它作为完全至部分激动剂起作用。血清素传递长期以来一直与抑郁症相关，我们的研究结果为脑区通过裸盖菇素从抑郁症中恢复的作用提供了因果机制证据。
