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

A double-blind, placebo-controlled study combined resting-state fMRI with a molecular atlas of serotonin receptors to examine how MDMA alters functional connectivity. Using the REACT method, the researchers found that MDMA-induced connectivity changes were specifically linked to brain regions rich in the serotonin transporter (5-HTT) and the 5-HT1A receptor, the drug's primary targets. Changes in 5-HT1A-enriched maps correlated with MDMA blood levels, while changes in 5-HT2A-enriched maps correlated with spiritual experiences reported by participants. The approach shows that MDMA's effects on brain connectivity can be explained by the distribution of its serotonergic targets, offering a new way to characterize psychoactive compounds.

Study at a glance

Abstract

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.