Altered insula connectivity under MDMA

This novel analysis of a double-blind, randomized, placebo-controlled study (n=25) investigated the effects of MDMA (100mg) on brain connectivity and found that it decreased functional connectivity insula/salience network, which was also correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA.

Abstract

“Introduction: Recent work with noninvasive human brain imaging has started to investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin-releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap.

Methods: To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired.

Results: There was decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA.

Discussion: The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations–both of which are known to be associated with insular functioning.“

Authors: Ishan C. Walpola, Timothy Nest, Leor Roseman, David Erritzoe, Amanda Feilding, David J Nutt & Robin L Carhart-Harris

Summary

Introduction

MDMA belongs to a unique class of psychoactive compounds called entactogens. It increases heart rate, blood pressure, body temperature, and causes impaired homeostatic control.

Pharmacological resting-state electroencephalography, positron emission tomography, and functional magnetic resonance imaging have begun to elucidate the immediate effects of MDMA on the human brain.

In a recent fMRI study using arterial spin labeling (ASL), decreases in cerebral blood flow were observed following MDMA administration. These decreases were correlated with subjective intensity of drug effects and positive mood.

MDMA administration decreased regional brain blood flow in the insula, a region implicated in visceral and somatosensory sensation. This finding is intriguing, as MDMA produces unusual bodily or ‘interoceptive’ effects.

We conducted a data-driven analytic approach to examine the functional interconnections between the insula and the salience network under the influence of MDMA. We found that the insula is considered an ‘integral’ hub of the salience network involved in the attribution of environmental/ bodily salience, as well as anxiety and stress.

The first randomized controlled trials of MDMA-assisted psychotherapy for treatment-resistant PTSD demonstrated decreases in both clinician- and participant-rated symptom severity. The efficacy of these interventions persisted at follow-up.

A novel analysis approach was used to re-explore a previously described resting-state fMRI data set to better understand alterations in the functional neural architecture specific to acute MDMA exposure.

The ICC allows the seed region for subsequent seed-to-voxel analysis to be defined by the contours of a resultant cluster from a contrast of interest. This allows for more accurate identification of regions with altered functional connectivity to be further interrogated using more traditional seed-based approaches.

We were interested in examining the relationship between altered insula connectivity under MDMA and two phenomenological categories: altered bodily sensation and trait anxiety. We expected that dysregulation of an insula network would be associated with greater alterations in bodily sensation and trait anxiety.

Design

This study was a novel analysis of a previously published data set. It used a within-subjects, double-blind, randomized, placebo-controlled design and used fMRI to measure global functional connectivity.

Participants

Twenty-five healthy participants with at least one previous experience with MDMA were included in the study. None had consumed MDMA in at least 48 h.

Drug Administration

MDMA was administered orally in the form of a capsule. The peak subjective effects were reported 100 min following ingestion.

Scanning Parameters and Data Acquisition

Magnetic resonance imaging was performed on a 3-Tesla Siemens Tim Trio using a 32-channel phased array head coil. BOLD-weighted functional images were acquired using a gradient echo planar imaging sequence.

fMRI images were processed using SPM12, imported into CONN: The Functional Connectivity toolbox in MATLAB, and registered to the Montreal Neurological Institute standard brain space.

To account for motion-related artifacts, we performed quality control by ‘scrubbing’ time points with excessive head motion. This approach effectively ‘removes’ outlier scans by including them as dummy-coded regressors during the de-noising procedure.

We corrected for noise from the white matter and cerebrospinal fluid using a principle component-based method and applied a band-pass filter.

Intrinsic Connectivity Contrast

To analyze whole-brain connectivity, we computed the intrinsic connectivity contrast (ICC), which quantifies the presence of connections between voxels and assigns a weight to the strength of these connections.

A seed based functional connectivity analysis was performed using a paired t-test with a significance threshold of po0.001 uncorrected, 5-voxel cluster threshold. The resulting clusters provided a global picture of functional connectivity alterations.

Follow-up Seed-To-Voxel Functional Connectivity

We used a classical seed-based functional connectivity method to examine alterations in functional connectivity profiles between conditions. We used a significant cluster located in the right insula for all subsequent analyses.

ROI-to-ROI Analysis of Primary Salience Network Hubs

We conducted a ROI-to-ROI analysis using the dorsal anterior cingulate cortex (dACC) and bilateral anterior insula (AI) as seed regions to determine if the observed alterations in salience network connectivity were exclusive to the seed regions.

Relationship between Changes in Functional Connectivity and Subjective Effects of MDMA

To explore whether insula RSFC changes were related to subjective ratings of ‘unusual bodily sensations’ following the MDMA scan or ‘trait anxiety’ preceding the scan, two correlations were tested.

Intrinsic Connectivity Contrast

The ICC (MDMA4placebo) revealed 36 clusters overlapping with the Harvard-Oxford atlas, exhibiting both increases and decreases in global functional connectivity. A right insula cluster was selected as a seed ROI for all subsequent analyses.

Follow-up Seed-To-Voxel Functional Connectivity

The functional network topography of the insula cluster was similar for placebo and MDMA, and overlapped spatially with the salience network.

Following-up seed-to-voxel resting-state functional connectivity comparisons between the MDMA and placebo conditions revealed significantly decreased connectivity between the right insula and the DLPFC.

ROI-to-ROI Analysis of Primary Salience Network Hubs

The MDMA condition showed diminished salience network connectivity compared with the placebo condition. The seeding of the dACC and AI resulted in decreased connectivity only with the left AI.

Relationship between Changes in Functional Connectivity and Subjective Effects of MDMA

The group-level results show that greater trait anxiety was associated with decreased connectivity between the right insula seed region and bilateral DLPFC, specifically the superior frontal gyrus, and greater unusual bodily sensations was associated with decreased connectivity between the right insula seed region and the anterior mid-cingulate gyrus.

Discussion

The present study employed a network theory approach to examine the impact of MDMA on voxelwise functional brain connectivity. They observed decreased connectivity in the right insular cortex, which was strikingly absent from previous fMRI analyses.

We observed decreased connectivity between the right insula seed ROI and the bilateral anterior insula and portions of the DLPFC in the MDMA condition, but not between the right AI seed ROI and the dACC.

We investigated how differences in right insula functional connectivity under MDMA (compared with placebo) might be related to individual differences in trait anxiety. We found that greater decreases in right insula functional connectivity within a dorsolateral prefrontal region – the superior frontal gyrus – in individuals who had greater trait anxiety.

Although speculative, it is intriguing to consider whether the observed decreases in salience network connectivity by MDMA might reflect the action of MDMA on a putative functional network coding trait anxiety, and might be a candidate mechanism by which MDMA operates in MDMA-assisted psychotherapy for PTSD.

MDMA is not considered generally anxiolytic, as it has been shown to increase self-reported state anxiety. It may therefore specifically target neural substrates coding trait, rather than state, anxiety.

Based on the unique phenomenology of MDMA, we hypothesized that decreased right insula-anchored salience network connectivity might be related to unusual bodily sensations, and that this decrease might be mediated by decreased integrity of a neural network important for encoding trait anxiety and supporting interoceptive awareness.

MDMA disrupts the functional circuitry supporting negative affective states, and may also give rise to subjective beliefs of unusual bodily sensations.

The salience network is important in schizophrenia and is altered by dopaminergic challenge, but serotonin mediates the majority of physiological and psychosocial effects of MDMA. A complex interaction between neuromodulators is likely to mediate salience network functioning, and increased methylation of the serotonin transporter gene predicts heightened insula reactivity and salience network connectivity. This phenomenon may have relevance for clinical syndromes such as PTSD.

Previous resting-state studies have not implicated the insula in the salience network, and studies that have demonstrated insula involvement have not directly examined functional networks. This may be due to the fact that ventromedial prefrontal cortex, hippocampus and amygdala functional connectivity with the insula is not altered under MDMA.

This study links decreased insula/salience network functional connectivity under MDMA to baseline levels of trait anxiety and changes in interoception. This may be important in understanding the neurobiological underpinnings of MDMA as a therapeutic adjunct to psychotherapy.

Limitations and Future Directions

Although the ICC method is limited by the selection of clusters of significance for follow-up seed-to-voxel functional connectivity analysis, it represents a principled approach for empirically constraining seed ROI selection for exploratory analyses in novel neuroimaging contexts.

Our study relied on self-report ratings of anxiety and bodily experience, which may be susceptible to bias. Future research should employ validated physiological measures and behavioral paradigms that probe anxiety and interoception to provide additional objective support to subjective assessments of these phenomena.

Our correlation coefficients should be interpreted with caution, as they are computed using average functional connectivity in clusters derived from the association between decreases in right insular functional connectivity and the respective subjective metrics.

We did not record physiological markers, but we can’t rule out the possibility that low-level changes in physiology (eg, tachycardia or hypertension) drove alterations in insula functional connectivity per se.

In our study, interoceptive sensibility was measured based on self-report measures, but other measures such as interoceptive accuracy or interoceptive metacognition are also important facets of interoception.

Ineffective blinding is a common problem in neuroimaging studies of substances with potent acute subjective effects, and a drug-free control condition is often favorable to enable simple between-condition comparisons.

In conclusion, decreased salience network functional connectivity following MDMA administration was linked to the experience of unusual bodily sensations and trait anxiety, and may be useful in the future treatment of major psychiatric disorders.

Acknowledgments

This research was supported by the British public service broadcast station Channel 4 and performed at the NIHR/Wellcome Trust Imperial Clinical Research Facility.