Effects of LSD on music-evoked brain activity

This single-blind placebo-controlled crossover study (n=20) investigated the effects of LSD (75μg) on altered brain activity and connectivity in response to acoustic features in music. LSD enhanced music-evoked feelings of wonder under LSD, which in turn correlated to the changes within brain networks encoding music-evoked emotions and a modulation of timbre complexity, which is thought to be a universal feature of music that conveys emotions cross-culturally.

Abstract

“Introduction: Music is a highly dynamic stimulus, and consists of distinct acoustic features, such as pitch, rhythm and timbre. Neuroimaging studies highlight a hierarchy of brain networks involved in music perception. Psychedelic drugs such as lysergic acid diethylamide (LSD) temporary disintegrate the normal hierarchy of brain functioning, and produce profound subjective effects, including enhanced music-evoked emotion. The primary objective of this study was to investigate the acute effects of LSD on music-evoked brain-activity under naturalistic music listening conditions.

Methods: 16 healthy participants were enrolled in magnetic resonance imaging (fMRI) while listening to a 7-minute music piece under eyes-closed conditions on two separate visits (LSD (75 mcg) and placebo). Dynamic time courses for acoustic features were extracted from the music excerpts, and were entered into subject-level fMRI analyses as regressors of interest. Differences between conditions were assessed at group level subsequently, and were related to changes in music-evoked emotions via correlation analyses. Psycho-physiological interactions (PPIs) were carried out to further interrogate underlying music-specific changes in functional connectivity under LSD.

Results: showed pronounced cortical and subcortical changes in music-evoked brain activity under LSD. Most notable changes in brain activity and connectivity were associated with the component timbral complexity, representing the complexity of the music’s spectral distribution, and these occurred in brain networks previously identified for music-perception and music-evoked emotion, and showed an association with enhanced music-evoked feelings of wonder under LSD.

Discussion: The findings shed light on how the brain processes music under LSD, and provide a neurobiological basis for the usefulness of music in psychedelic therapy.”

Authors: Mendel Kaelen, Romy Lorenz, Frederick Barrett, Leor Roseman, Csaba Orban, Andre Santos-Ribeiro, Matthew B Wall, Amanda Feilding, David Nutt, Suresh Muthukumaraswamy, Robin Carhart-Harris & Robert Leech

Summary

16 healthy participants were enrolled in fMRI while listening to a 7-minute music piece under eyes-closed conditions on two separate visits. Results showed that the brain processes music under LSD in a hierarchy of brain networks, and that enhanced timbral complexity is associated with enhanced music-evoked feelings of wonder.

1. Introduction

Music is a highly dynamic and multi-dimensional stimulus that involves the analysis of several acoustic features. Neuroimaging studies have highlighted a hierarchy of processes involved in music perception, including the cochlear, auditory system, multi-modal and higher-order cortical regions, and emotion.

Advances in understanding the human brain can be made by perturbing it, for example by taking psychedelic drugs. These drugs produce an altered state of consciousness that is characterised by reduced functional coupling within high-level brain networks but simultaneous increased cross-talk between low-level areas.

Studying psychedelics and music in combination may improve our understanding of changes in the brain’s processing of complex naturalistic stimuli, and may also be relevant to the therapeutic potential of these subjective effects within “psychedelic therapy”.

This study investigated the acute effects of LSD on music-evoked brain activity under naturalistic music listening conditions, and the neural correlates of emotions such as feelings of wonder and transcendence evoked by music under LSD.

2. Materials and Methods

2.1 Ethical approvals

The study was approved by the NRES committee London – West London and conducted under a Home Office license for research with schedule I drugs.

2.2 Participants

Twenty participants were recruited after successful screening and written informed consent. The participants provided full disclosure of their drug use history and were required to have at least one previous experience with a classic psychedelic drug.

2.3 Stimuli

Two excerpts from two songs by ambient artist Robert Rich were selected for the study. The music was balanced in its acousti c properties and rich in timbre, but not in rhythm.

2.4 Experiment overview and procedures

All participants received 75 g of LSD intravenously over a two-minute period. BOLD MRI scanning was performed during peak drug intensity, starting approximately 120 minutes post-dosing, and lasted for approximately 60 minutes.

Each fMRI scanning session involved three eyes-closed resting state scans, and a music-listening scan. The music was triggered by the first TR and listened to via MR compatible headphones.

2.5 Qualitative measurements

The intensity of different types of music-evoked emotion was assessed via the 25-item Geneva emotional music scale (GEMS), and a paired t-test was performed to compare ratings between conditions (LSD versus placebo) for each emotion.

2.6 Acoustic feature extraction

Acoustic features were extracted from excerpt A and B using the Music Information Retrieval (MIR) toolbox, implemented in MATLAB, and categorized into short-term features and long-term features. A principle component analysis (PCA) was performed on the acoustic features to (1) identify the main components of the music.

We first rescaled the acoustic features, then concatenated the resulting timecourses, and performed varimax rotation on the first eight principal components that explained over 90% of the variance.

To validate that the first eight PCs explained the two excerpts equally well, we correlated the predicted timecourses of the 23 acoustic features with the corresponding acoustic features for the two excerpts separately.

We split the timecourses of the rotated PCs into two parts, convolved them with a double-gamma hemodynamic response function, downsampled them to 2 s, and high-pass filtered them at 0.01 Hz.

2.7 MRI scanning

Neuroimaging was performed on a 3T GE HDx system using a gradient echo planar imaging sequence. 35 oblique axial slices were acquired in an interleaved fashion, each 3.4mm thick with zero slice gap.

2.8 fMRI pre-processing

The fMRI pre-processing pipeline consisted of four complementary imaging software packages: FMRIB Software Library (FSL), AFNI (Cox, 1996), Freesurfer (Dale et al., 1999) and Advanced Normalization Tools (ANTS). Nine nuisance regressors were obtained: six were motion-related (3 translations, 3 rotations) and three were anatomically-related (not smoothed).

2.9 fMRI data analysis

We used a standard analysis pipeline from FSL FEAT GLM to determine the effect of PC timecourses on BOLD activation. We then analysed the fMRI data with respect to eight contrasts (one contrast for each PC) and obtained paired t-test contrasts of LSD > Placebo and Placebo .

2.10 ROI selection and extraction for correlation with individual variability in reported music-evoked peak emotions

The region of interest analysis was constrained to the group-level contrast LSD>Placebo for timbral complexity, and nine ROIs were created based on previous literature. Spearman’s rank correlation tests were used to relate the changes in parameter estimates (LSD > Placebo) with changes in GEMS-ratings for music-evoked emotions for the factors wonder and transcendence.

2.11 Psychophysiological interaction analysis

We conducted two separate psychophysiological interaction (PPI) analyses for the brain regions that showed a significant relationship with music-evoked feelings of wonder. The results show that the precuneus and right inferior frontal gyrus are involved in this relationship.

3. Results

3.1 Acoustic feature extraction

Eight principal components were identified in this study, which were consistent with the components identified in other musical genres using the same method. The identified principle components were also labelled similarly to previous studies.

3.2 Effects of LSD on music-evoked brain activity

Under LSD, activation in different cortical and sub-cortical areas was altered for different acoustic components. These included decreases in the left lateral occipital cortex, increases in the bilateral thalamus, and decreases in the right lateral occipital cortex and the right middle and inferior frontal gyrus.

3.3 Effects of LSD on music-evoked emotion

We investigated changes in music-evoked brain activity under LSD, and found that music-evoked emotions were significantly higher under LSD for wonder, transcendence, power, tenderness, nostalgia, peacefulness, and joyful activation compared to placebo.

3.4 Correlation analyses between music-evoked brain activity and peak emotions

We conducted correlation analyses between changes in music-evoked peak emotions and music-evoked BOLD activity for nine ROIs. These analyses were constrained to the contrast for timbral complexity (i.e., PC3) and included structures that have been commonly identified for music perception and emotion. We found significant positive correlations between music-evoked feelings of wonder and music-evoked BOLD activation to timbral complexity within the precuneus and right inferior frontal gyrus.

3.5 Effects of psychedelics and music on functional connectivity

We conducted PPI analyses on the precuneus and right IFG to gain insight into underlying music-specific changes in functional connectivity under LSD. We found that the precuneus was more or less coupled with the right superior frontal gyrus and right auditory cortex depending on the timbral complexity of the music.

3.6 Effect of head motion

We investigated potential confounding effects of motion on our results, but did not find any significant correlations between changes in frame-wise displacement (FD) and changes in music-evoked BOLD activity for the contrast timbral complexity (LSD > Placebo) in any of the nine ROIs.

4. Discussion

This study investigated the effects of LSD on music-evoked brain activity and emotion under naturalistic listening conditions. It revealed that the right precuneus and the right inferior frontal gyrus were more active under LSD, and that this was associated with increased feelings of wonder.

4.1 Timbral complexity and the auditory-IFG network

LSD modulates the brain’s processing of timbral and spectrotemporal information in music, possibly through the planum temporale, which segregates incoming spectral signals into distinct spectrotemporal patterns. The IFG is then thought to link the perceived spectrotemporal patterns with learned representations and associations.

The IFG plays a key role in music perception and in evaluating emotional valence in acoustic information. Brain damage and experimental disruption of the IFG are linked with impairments in identifying emotional valence in voice.

The IFG is associated with emotionally salient information from different sensory modalities, and is more generally conceptualised as being part of a cognitive control network that is associated with the allocation of attentional resources for emotionally salient information.

The functional connectivity analyses revealed that the right precuneus was decoupled from the right auditory cortex and the right IFG under LSD, and that this decoupling may reflect a reduced regulatory influence of the precuneus over emotion processing within the IFG.

4.2 Timbral complexity and the limbic system

LSD produced increased BOLD activation to timbral complexity in the striatum and in the insula, which have both been consistently associated with music-evoked emotion. However, the present study did not find a relationship between music-evoked emotion and the striatum.

LSD alters the dynamics between low-level spectral properties in the music and high-level regulation of emotional associations, which may explain why people have strong emotional experiences when listening to music under psychedelics.

4.3 Possible brain mechanisms

Classic psychedelics such as LSD stimulate serotonin 2A receptors, which are expressed on deep layer V pyramidal cells. This leads to desynchronised activity within high-level brain networks and increased information exchange between brain modules that are usually more strictly functionally segregated.

The planum temporale is functionally specialised for processing distinct spectrotemporal patterns, and may be driven by increased input from top-down projecting deep layer V pyramidal cells from the IFG and insula. This may lead to an intensified emotional response to music.

4.4 The significance of timbre

LSD may target the brain’s innate tuning to timbral properties, which is why it produces especially prominent modulation of neural processing of music’s timbral complexity. This heightened responsiveness for music’s “non-verbal language” may be at the core of the intensifying effects of LSD for music-evoked emotion.

4.5 Effects of LSD on the brain’s processing of other acoustic features

The previous discussion centred around the changes observed for timbral-complexity, but several other findings must be highlighted. These include increased thalamus and decreased IFG activation in response to “fullness”, and significant BOLD signal changes in occipital cortices for various acoustic features.

4.6 Therapeutic implications

Music listening may be useful in psychedelic-assisted psychotherapy for the treatment of depression, addiction, and end-of-life care. Knowledge of how musicians use timbre to convey emotion may be useful in designing playlists for therapy.

4.7 Study limitations

The study focused on how LSD altered the neurophysiological processing of acoustic properties in music, but did not assess how these effects were perceived.

The study used a single musical genre and was limited to rich in timbre and pitch variation, but low in tempo. The most pronounced neurophysiological changes were found in the component of “timbral complexity”.

Conclusion

The present study revealed that the brain processes music under LSD in ways previously unknown, and provides new perspective on how the brain processes music under naturalistic listening conditions.