LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion

This placebo-controlled within-subjects study (n=10) investigated the effects of LSD (75μg) on brain activity in relation to closed-eye visual hallucinations during resting-state. Results indicated that the early visual system (i.e., retinotopically mapped regions in V1 and V3) is affected by LSD and behaves “as if” it were receiving spatially localized visual information.

Abstract

“Introduction: The question of how spatially organized activity in the visual cortex behaves during eyes‐closed, lysergic acid diethylamide (LSD)‐induced “psychedelic imagery” (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes‐closed, the brain may function “as if” there is visual input when there is none.

Methods: In this work, resting‐state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes‐closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches.

Results: Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal–horizontal and vertical–vertical) and those with incongruent specificity (horizontal–vertical and vertical–horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition.

Discussion: This result may indicate that under LSD, with eyes‐closed, the early visual system behaves as if it were seeing spatially localized visual inputs.”

Authors: Leor Roseman, Martin I. Sereno, Robert Leech, Mendel Kaelen, Csaba Orban, John McGonigle, Amanda Feilding, David J. Nutt & Robin L. Carhart‐Harris

Summary

INTRODUCTION

LSD is a psychedelic drug and classic hallucinogen. Its potent hallucinogenic properties are mediated by activation of serotonin 2A receptor (5-HT2AR) in the visual cortex.

Heinrich Kluver€ studied mescaline in the mid-1920s and proposed a mecha-€ nism by which peculiar geometric patterns could be perceived. Although it has proved difficult to empirically test Cowan’s model, decreased alpha power in the occipital areas with psilocybin, ayahuasca and LSD, increased BOLD activation in the visual cortex, increased resting-state functional connectivity between primary visual cortex and higher-level associative areas, and increased cerebral blood flow in visual areas have been observed.

The visual field is retinotopically rerepresented several times in subregions of the occipital cortex. This technique has helped identify the borders between neighboring visual regions and has also proven useful for understanding spontaneous activity within the visual system.

This study modified a previously used paradigm to focus on activity in retinotopically sensitive patches of the lower level visual cortex. The results suggest that visual stimulation drives this organized pattern of activity.

We predicted that retinotopically organized patches of V1 and V3 would have greater RSFC under LSD than under placebo, and that this effect would be consistent with previously described effects of visual stimulation and imagery.

MATERIALS AND METHODS

This study was approved by the National Research Ethics Service and conducted in accordance with the International Committee on Harmonisation Good Clinical Practice guidelines and National Health Service Research Governance Framework.

Participants

All participants provided written informed consent to participate after screening for physical and mental health. They had experience with psychedelic drugs and provided full disclosure of their drug use history.

Design

Twenty healthy participants (4 females) attended two scanning days (LSD and placebo) at least 2 weeks apart and reported subjective drug effects between 5 and 15 min postdosing. The effects approached peak intensity between 60 and 90 min postdosing. After LSD infusion, MRI scanning started approximately 70 min postdosing, and lasted for approximately 60 min. Two eyes-closed resting-state BOLD scans totaling 14 min were completed 125 min postinfusion, and the effects of LSD were stable through the scanning period.

Subjective Ratings

All participants reported eyes-closed psychedelic imagery, and completed the 11 factor altered states of consciousness questionnaire at the end of each dosing day.

Anatomical Scans

A 3T GE HDx system was used to perform 3D magnetization prepared fast-spoiled gradient echo scans with 1 mm isotropic voxel resolution.

BOLD fMRI Data Acquisition: Eyes-Closed Resting State

Two sequences of BOLD-weighted fMRI eyes-closed resting-state scans were acquired for each condition. Thirty-five oblique axial slices were acquired in an interleaved fashion, each 3.4 mm thick with zero slice gap.

BOLD Preprocessing

The following preprocessing stages were performed: removal of the first three volumes, despiking, slice time correction, motion correction, brain extraction, rigid body registration, scrubbing, and replacement of scrubbed volumes with the mean of the surrounding volumes. Additional preprocessing steps included band-pass filtering, linear and quadratic detrending, and regressing out 9 nuisance regressors. Local white matter regression was used to deal with motion-related artifacts.

Retinotopic Localizer

Subjects were presented with a video that alternated between vertical and horizontal polar angles. The retinotopic localizer was performed after the resting-state scans to avoid a possible effect of the retinotopic localizer on the resting-state scans.

V1–V3 Retinotopic Coordination

The results below were averaged across the two resting-state scans (both LSD and placebo had two resting-state scans within each session). Retinotopic coordination was calculated as the difference between two retinotopic patches.

Subjective Ratings

The mean between-condition difference in within-scanner VAS ratings of visual hallucinations/imagery was 9.73 6 6.43 and 7.37 6 6.87 for simple and complex hallucinations, respectively.

Retinotopic Localizer

The surface average of the retinotopic activation is presented in Figure 2. The average was calculated by sampling each subject’s morphed sphere onto Freesurfer’s average surface.

V1–V3 Retinotopic Coordination

Mean values for retinotopic coordination were significantly greater under LSD than under placebo, and this difference was also significant for the right and left hemispheres separately. This difference did not correlate with increased head motion or rating scales of psychedelic imagery.

DISCUSSION

This study found that LSD modulated RSFC within the visual cortex, and that this modulation was consistent with the intrinsic retinotopic architecture.

Interpretation of the present results regarding psychedelic imagery may be informed by more general research on visual imagery, and by the debates regarding the role of lower level visual areas in psychedelic imagery.

Early electrophysiological studies involving psychedelics reported altered activity in the retina, LGN, and visual cortex. This study directly addresses how activity within low-level aspects of the visual system is altered under a psychedelic, and found that increased retinotopic coordination between V1 and V3 under LSD did not correlate with ratings of visual hallucinations.

Subjective intensity of psychedelic visions did not correlate with retinotopic coordination. It is possible that higher levels of head motion interfered with accurate measurements of retinotopic coordination, or that the increased retinotopic coordination observed under LSD was an epiphenomenon of a more general increase in “activity” within the relevant brain regions.

Another potential limitation is that there was a difference in the level of arousal between the two conditions. However, this did not correlate significantly with increased retinotopic coordination, so it seems unlikely that this explanation for the present data applies.

This study had several limitations, such as a small sample size and a high level of head motion. However, the results showed that retinotopic coordination was related to visual processing in 9 out of 10 subjects.

CONCLUSION

This study suggests that the visual cortex processes spatially localized visual information under the influence of LSD, but further work is required to determine the specific regional source/s of psychedelic imagery.