The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

This study further analyzed fMRI data (BOLD signals) using dynamic causal modeling and found that psilocybin decreased top-down connectivity from the amygdala to visual cortex.

Abstract

“Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin’s effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.”

Authors: Rainer Kraehenmann, André Schmidt, Karl Friston, Katrin H. Preller, Erich Seifritz & Franz X. Vollenweider

Notes

This paper is included in our ‘Top 12 Articles on Psychedelics and Serotonin (5HT) Receptors‘

This study builds further on/uses the fMRI data from Kraehenmann and colleagues (2014).

Summary

1. Introduction

Serotonin (5-HT) is an important neurotransmitter within neural networks related to emotion processing. Psilocybin reduces amygdala activation in response to threat-related visual stimuli and increases PFC connectivity.

Processing of threat-related visual stimuli may be modulated via feedback connections from the amygdala to the visual cortex, and via inhibitory feedback connections from the prefrontal cortex to the amygdala. These connections may also contribute to the effects of psilocybin on threat processing.

We used dynamic causal modeling and Bayesian model selection to infer hidden mechanisms at the neuronal level from functional magnetic resonance imaging data. We found that changes in bottom-up and top-down connections contributed to the psilocybin-induced reduction of AMG and V1 activation in response to threat-related visual stimuli.

2.1. Subjects

25 healthy, right-handed subjects with normal or corrected-to-normal vision were recruited through advertisements placed in local universities. They were screened for DSM-IV mental and personality disorders and were exempt from pregnancy, left-handedness, poor knowledge of the German language, and drug abuse.

2.2. Experimental design

The study design was randomized, double-blind, placebo-controlled, cross-over and consisted of two separate imaging sessions at least 14 days apart. Psilocybin was administered in gelatin capsules and subjects’ mood state was assessed before and 210 min after each drug treatment.

2.3. fMRI paradigm: amygdala reactivity task

The International Affective Picture System (IAPS) was used to create stimulus sets for the amygdala reactivity task. The IAPS consisted of 48 different pictures, 24 of which were categorized as threat and 24 as neutral.

Subjects were asked to select one of two pictures that matched the target picture in an emotional picture discrimination task and a shape discrimination task. Both tasks were shown as alternating 24-s blocks without intermittent pauses.

2.4. fMRI image acquisition and data analysis

Data analysis was performed with SPM12b on a 3 T scanner, using a general linear model, convolved with a canonical hemodynamic response function, and a 128 s highpass filter. Subject-specific condition effects for threat minus shapes were computed using t-contrasts.

2.5. Dynamic causal modeling (DCM)

The current DCM analyses are based on the GLM analyses of the fMRI data described above. The modeled neuronal dynamic is mapped to the measured BOLD signal using a hemodynamic forward model.

2.5.1. Regions of interest and time series extraction

We selected three regions of interest within a right-hemispheric network implicated in visual threat processing, and performed a directed connectivity map (DCM) analysis to determine whether the decrease of right amygdala activation in response to threat was mediated by top-down connectivity changes from the right prefrontal cortex or bottom-up connectivity changes from the right visual cortex.

The rV1, rAMG and rLPFC were identified based on the contrast of threat pictures minus shapes.

We extracted regional time series from each subject and session and summarized them with the first eigenvariate of voxels above a subject-specific F threshold of p b 0.01 (uncorrected) within the anatomical areas. We could not extract an rLPFC time series in two subjects due to lack of individual activations fulfilling both the above functional and anatomical criteria.

2.5.2. DCM model space

We specified a three-area base model with bidirectional endogenous connections between V1 and AMG and between AMG and LPFC, and varied the basic model to provide alternative models of the modulatory effect.

2.5.3. Model inference

We used random-effects Bayesian model summing (BMS) in DCM12 to determine the most plausible of the three model variants for each drug separately, and then used random-effects Bayesian model averaging (BMA) to compute subject specific connectivity estimates across all three models separately for psilocybin and placebo.

2.5.4. Parameter inference

Psilocybin affected endogenous connections and their modulation by threat stimuli. A paired t test was used to compare direct inputs into V1 across both treatments.

3.2. Parameter inference

To compare connectivity across drug treatments, endogenous parameters, threat induced modulations, and direct inputs from the BMA were averaged over the three models for each treatment. The effective connectivity can be interpreted as a rate constant.

There was no main effect of psilocybin on modulatory coupling parameters, but a significant main effect of connection type, and a significant drug by connection type interaction.

Parameter estimates were obtained from Bayesian Model Averaging for placebo and psilocybin treatments, with significant differences between treatments marked by an asterisk.

4. Discussion

In this study, we used DCM to analyze fMRI data from a previous psilocybin study. We found that psilocybin reduced the modulatory effect of threat on the top-down connection from the amygdala to visual regions.

BMS found that the full model, which characterized by bidirectional modulatory effects of threat on visual – limbic – prefrontal connectivity, outperformed both the bottom-up and the top-down model, and that this model contained reciprocal connections between V1 and AMG and between AMG andLPFC.

Psilocybin reduced the modulatory effect of visual threat on the top-down connection from the amygdala to V1, an important mechanism underlying visual threat processing. This effect may be amplified in psychopathological conditions such as anxiety disorders or depression. Psilocybin may attenuate top-down threat signaling from the amygdala to visual cortex, which may explain the decrease of behavioral and electrophysiological responses in the visual cortex to threat stimuli during psilocybin administration and the shift away from negative towards positive valence during emotion processing.

Serotonergic stimulation of LPFC may increase inhibitory top-down connectivity from LPFC to AMG during threat processing, but psilocybin did not appear to increase top-down connectivity.

Two reasons might account for the reduced top-down modulation of the amygdala by psilocybin in the current analysis: (1) a reduced top-down connectivity with the visual cortex, (2) a reduced load on the LPFC to regulate the amygdala, (3) a reduced top-down modulation of the amygdala by other prefrontal cortical regions. Sladky et al. (2015) found that the OFC downregulates amygdala activation, and that this effect was significantly increased by the antidepressant (S)-citalopram. However, given that our task did not explicitly require subjects to evaluate or regulate their emotional responses, top-down effects from other prefrontal regions are unlikely. Psilocybin and (S)-citalopram both normalize amygdala hyper-reactivity to threat-related stimuli, but psilocybin regulates emotion processing and mood by acting on network interactions.

4.1. Limitations and future directions

The present study used a fairly simplistic neuronal network to model threat related effective connectivity, and only considered right-hemispheric networks in our DCM analyses. Therefore, top-down connectivity from the left LPFC to the right AMG might have been missed.

4.2. Conclusion

The study suggests that a decrease of top-down connectivity from the AMG to the visual cortex underlies the psilocybin effect on visual threat processing, which may have important therapeutic implications for mood and anxiety disorders.

Disclosure and conflict of interest

This work was supported by grants from the Swiss Neuromatrix Foundation and the Heffter Research Institute, and by the Swiss National Science Foundation.