Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA
Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA
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DOI：
10.1016/j.neuroimage.2019.04.007
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发表时间：
2019-07-15
期刊：
影响因子：
5.7
通讯作者：
Mehta, Mitul A.
中科院分区：
文献类型：
--
作者：
Dipasquale, Ottavia;Selvaggi, Pierluigi;Mehta, Mitul A.
药理学功能磁共振成像的主要局限性之一是它无法提供化合物主要作用的分子洞察，留下了一个关于药物作用和血流动力学反应之间关系的开放性问题。本研究的目的是研究3,4-亚甲基二氧基甲基苯丙胺（MDMA）对功能连通性（FC）的急性影响，采用一种新的多模态方法（受体富集分析功能连通性的目标-反应）。考虑到MDMA的5 -羟色胺能作用，这种方法丰富了静息状态（rs-） fMRI分析中5 -羟色胺受体分布密度的分子信息。20名健康受试者参加了这项双盲、安慰剂对照的交叉研究。四种5-羟色胺受体（5-HT1A、5-HT1B、5-HT2A和5-HT4）及其转运体（5- httt）的高分辨率体内图谱被用作两步多元回归分析的模板，以估计反映安慰剂和MDMA下与每个靶点相关的全脑连接行为的空间图。结果表明，MDMA给药后发生显著变化的网络是由5-HTT和5-HT1A分布密度图所通知的网络，这是该化合物的主要靶点。5- ht1a功能图谱的变化也与MDMA的药代动力学水平和MDMA诱导的与意识改变状态问卷精神体验亚量表相关的5- ht2a功能图谱的FC变化有关。通过利用5 -羟色胺受体在大脑中体素分布的分子数据丰富rs-fMRI分析，我们发现MDMA对FC的影响可以通过其主要靶点的分布来理解。这一结果支持了该方法表征大脑对MDMA与5 -羟色胺能受体结合的功能反应的特异性的能力，为定义新化合物表征的新指纹铺平了道路，并有可能进一步了解对治疗的反应。
One of the main limitations of pharmacological fMRI is its inability to provide a molecular insight into the main effect of compounds, leaving an open question about the relationship between drug effects and haemodynamic response. The aim of this study is to investigate the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on functional connectivity (FC) using a novel multimodal method (Receptor-Enriched Analysis of functional Connectivity by Targets - REACT). This approach enriches the resting state (rs-) fMRI analysis with the molecular information about the distribution density of serotonin receptors in the brain, given the serotonergic action of MDMA.Twenty healthy subjects participated in this double-blind, placebo-controlled, crossover study. A high-resolution in vivo atlas of four serotonin receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and its transporter (5-HTT) was used as a template in a two-step multivariate regression analysis to estimate the spatial maps reflecting the whole-brain connectivity behaviour related to each target under placebo and MDMA.Results showed that the networks exhibiting significant changes after MDMA administration are the ones informed by the 5-HTT and 5-HT1A distribution density maps, which are the main targets of this compound. Changes in the 5-HT1A-enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT2A-enriched maps correlated with the spiritual experience subscale of the Altered States of Consciousness Questionnaire.By enriching the rs-fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, we showed that MDMA effects on FC can be understood through the distribution of its main targets. This result supports the ability of this method to characterise the specificity of the functional response of the brain to MDMA binding to serotonergic receptors, paving the way to the definition of a new fingerprint in the characterization of new compounds and potentially to a further understanding to the response to treatment.