Serotonin 2A receptor signaling underlies LSD-induced alteration of the neural response to dynamic changes in music

In this secondary analysis, the experience of music was altered by LSD (100μg) (tonal-tracking bias) as recorded by blood oxygen level-dependent (BOLD) signal in this double-blind, placebo-controlled study (n=25).

Abstract

“Classic psychedelic drugs (serotonin 2A, or 5HT_2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT_2A antagonist ketanserin, to investigate the role of 5HT_2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT_2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT_2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.”

Authors: Frederick S. Barrett, Katrin H. Preller, Marcus Herdener, Petr Janata & Franz X. Vollenweider 

Notes

The study analysed data from the participants involved in a trial from Preller et al. (2017).

This study was supported in part by the Usona Institute and the Heffter Research Institute.

Summary

Serotonin 2A, or 5HT2A, receptor agonists have notable effects on music listening. These effects include an altered neural response to the time-varying tonal structure of music, as well as increased emotionality, connectedness, and meaningfulness in response to music.

Introduction

Classic psychedelic drugs, including psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), have substantial effects on perception, cognition, and emotional experience, including the perception of music.

Psychedelics alter the perception of sensory stimuli, such as music, but also alter the functioning of brain areas involved in processing the meaningfulness of stimuli, such as memory, emotions, self-referential processing, and visualization.

Music has played a key role in psychedelic therapy and research for many decades, and is currently used in best practices for safe conduct of a session.

Neurochemical effects of music listening on stress, immunity, and social affiliation have been demonstrated, and music listening has been specifically shown to lead to dopamine release and drive reward circuitry. There are very few empirical studies that have investigated the opposite direction.

Music is a complex stimulus that varies in time in a number of dimensions. Tonality is an important cognitive schema for shaping expectations during music listening.

Changes in the pattern of activation on a toroidal surface can be collectively described and computationally modeled as changes in the tonal center of a musical selection. This model represents concepts in music theory, cognitive psychology, and the pitch statistics of western music.

A torus can be used to represent the tonal center of a piece of music at any given point in time, and the rate at which the tonal center changes over time can be calculated using a sliding window. Using spherical harmonic analysis, a timecourse of toroidal (4-dimensional) representation can be decomposed into 34 spatially orthogonal patterns with associated weight vectors, and these weight vectors can be used to regress fMRI blood oxygen level-dependent (BOLD) activity measured while an individual was listening to a piece of music.

The current report applies TT analysis of BOLD signal collected while participants listened to both personally meaningful and nonmeaningful music.

Methods

This is a secondary analysis of data published elsewhere (Preller et al. 2017). The description below refers only to those measures and procedures investigated in the current report.

Participants

Twenty-five participants were recruited through advertisements placed in local universities in Zürich, Switzerland. They underwent a screening visit, and were excluded if they had a history of psychiatric disorders or a history of major psychiatric disorders in first-degree relatives. Participants were asked to abstain from alcohol and drugs for 2 weeks prior to the study, and from smoking for 60 min before the study. Urine tests were used to verify the absence of drug and alcohol use, and pregnancy was excluded.

Study Design

In a double-blind, randomized, full cross-over design, participants received either placebo+placebo, placebo + LSD, or ketanserin+LSD after pretreatment with placebo or ketanserin. The fMRI music paradigm was conducted 100 min after treatment with placebo or LSD.

Music Paradigm

Participants listened to personally meaningful songs, neutral songs, and personally meaningless songs while BOLD fMRI signal was acquired. After listening to each identified 20 s musical excerpt, participants completed a pre-task questionnaire (PTQ) and answered questions about how personally meaningful the song was to them.

To select the meaningless music played during fMRI acquisition, participants were presented with 4 music excerpts and asked to rate each excerpt on a scale of 1 to 4. The music excerpts presented during practice trials and fMRI acquisitions on test days were different from those presented at the screening visit.

Six neutral music excerpts were matched to the 6 songs provided by the participant using the “search for similar music” function of music aggregator website, Last.fm. The participants were not familiar with the songs and the excerpts were created using Audacity 2.1.2.

Participants performed 3 practice trials before drug administration to familiarize themselves with the task. The practice trials consisted of the least meaningful music excerpts.

During fMRI data acquisition and practice sessions, participants were presented with 10 musical excerpts and rated their meaningfulness of the music. There were 30 blocks in total and 10 excerpts per condition. Participants listened to excerpts of music through MR-compatible in-ear headphones, shielded by soundproof circumaural headphones, and responded using a 4-button response box. They were asked to close their eyes during music presentation, and compliance to this instruction was monitored online using eye tracking.

MR Data Acquisition and Preprocessing

MR data were acquired on a Philips Achieva 3.0T whole-body scanner using a whole-brain gradient-echo planar imaging sequence and a standard T1-weighted 3D magnetization-prepared rapid gradient-echo (MP-RAGE) sequence. The images were analyzed using SPM12 and one participant was excluded due to having gross motion.

TT Analysis

Custom MATLAB scripts were used to generate 34 toroidal surface basis functions that were used as TT regressors in subsequent TT analyses. These models were fit to the residuals of a general linear model.

Two models were fit to the residuals of the base model: one for analysis of music conditions, and one for analysis of drug effects. The interaction of drug condition and stimulus condition on TT within the brain was not significant.

Monte Carlo simulation was used to identify voxels with TT bias, which was assessed by calculating the ratio of the F-statistics describing the variance explained by tonality regressors in each given condition.

Cluster mass thresholding was used to identify brain areas that showed TT at the group level for each pair of drug conditions and for musical stimulus condition. Average TT bias across participants was calculated for each experimental condition in each significant group-level TT cluster.

Comparing TT Between Meaningful and Nonmeaningful Music Listening Conditions, Across all Drug Conditions

TT bias is determined by comparing the amount of variance explained by TT regressors in one condition (for instance, personally meaningful music) to the amount of variance explained by TT regressors in another condition (for instance, nonmeaningful music).

Brain activity in several regions was significantly associated with the time-varying tonal structure of music, and a greater amount of variance was explained in these regions by TT regressors for personally meaningful music than by TT regressors for nonmeaningful music.

Comparing TT Between Drug Conditions

The neural response to time-varying tonal structure of music was tested for LSD and 5HT2A receptor signaling.

Placebo vs. LSD: Brain activity in temporal, frontal, cingulate, insular, parietal, occipital, and cerebellar cortex was significantly associated with TT regressors during placebo and LSD conditions. A significant TT bias toward stronger TT during LSD was identified in the left anterior insula.

Brain activity in the temporal, frontal, cingulate, insular, parietal, occipital, and cerebellar cortex was significantly associated with TT regressors during LSD and Ket + LSD. A significant TT bias toward stronger TT was identified in the left mid and posterior-cingulate cortex and left superior occipital gyrus during Ket + LSD.

Brain activity in the temporal, frontal, cingulate, insular, and occipital regions was significantly associated with TT regressors during placebo and Ket + LSD. However, TT bias towards Ket + LSD was observed in the left insula, left inferior frontal gyrus, and left superior temporal gyrus.

Discussion

This study utilized music, pharmacological intervention, and a computational model of the time-varying tonal structure of music to investigate the role of LSD in altering the neural response to music.

LSD, Auditory Processing, Self-Relevance, and the Neural Response to Music

LSD increased TT in a number of brain regions, including a subregion of the right superior temporal gyrus (Brodmann area 21) that is responsive to lyrical content in music. This increase may be a mechanism or a product of the effects of LSD on increased meaning while listening to music.

Brain regions responsive to language and tonality, including bilateral inferior frontal gyrus pars orbitalis, showed TT bias for LSD compared with placebo and compared to Ket + LSD. This suggests that LSD may influence neural function in higher-order association cortices that respond to pitch, semantics, and memory.

Medial prefrontal brain regions associated with autobiographical memory showed TT bias toward LSD compared to placebo and Ket + LSD, which supports a potential benefit of LSD during psychotherapy.

The angular gyrus was shown to exhibit TT bias both for LSD compared with placebo and Ket + LSD, and for personally meaningful stimuli compared with other stimuli. This may account for the increased salience and emotional impact of musical stimuli during the effects of LSD.

LSD increases TT bias in brain areas that respond to music and speech, and also in areas associated with memory and emotion. This suggests that LSD supports a deeper or more integrated experience of music.

Although the calcarine sulcus exhibited TT bias toward placebo compared with LSD, it did not exhibit TT bias toward personally meaningful compared to other musical stimuli. This suggests that TT bias may depend on aspects of psychedelic experience that were not well-controlled or characterized within the current study.

The Role of 5HT2A Signaling in the Neural Response to the Time-Varying Tonal Structure of Music

The 5HT2A receptor is the primary receptor mechanism of action of classic psychedelics, including LSD. LSD caused effects in multiple brain regions, including the superior, middle, and inferior frontal gyri, temporal pole and superior temporal gyrus, angular gyrus, and the amygdala.

The Unknown Role of Other Receptor Signaling Mechanisms in the Neural Response to the Time-Varying Tonal Structure of Music

Ketanserin and LSD manipulations can help us to understand the role of 5HT2A receptor signaling in TT, but some curious effects were found in the current data that cannot be attributed simply to 5HT2A receptor signaling.

Ketanserin alone has been shown to reduce neural response to fearful emotional stimuli and to increase the response to low-risk negative outcomes in risk-taking individuals. The current findings are not likely due to effects expected from ketanserin alone.

Conclusion

LSD and ketanserin were used to demonstrate that 5HT2A receptor signaling altered the coupling of activity in brain areas that support an overall musical experience with patterns of change in the tonal structure of that music. This finding is important because music listening is used to provide psychological support during research.