Effective Connectivity of LSD-induced Ego Dissolution

This preprint (2022) used fMRI to assess whether anticorrelated activity between the default mode network (DMN) and the salience network (SN), which recruits the dorsal attention network (DAN), underlies the peak effects of LSD (n=25). It was found that LSD (100µg) decreased inhibitory effective connectivity from the SN to DMN as well as decreasing inhibitory effective connectivity from DMN to DAN when compared to placebo. These findings suggest anticorrelation between resting networks may be a key neural mechanism of LSD peak experiences.

Abstract

“Classic psychedelic-induced ego dissolution involves a shift in the sense of self and blurring of the boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated with the balance of anticorrelated activity between the default mode network (DMN), which directs attention inwards, and the salience network (SN), which recruits the dorsal attention network (DAN) to direct attention outward. To test whether a change in anticorrelated networks underlies the peak effects of LSD, we applied dynamic causal modelling to infer (directed) effective connectivity of resting-state functional MRI scans from a double-blind, randomised, placebo-controlled cross-over study where 100mg of LSD, or placebo, was administered to 25 healthy adults. Under the peak effects of LSD, the hierarchical organisation of the resting-state brain networks was altered. Inhibitory effective connectivity from the SN to DMN decreased and became excitatory, and inhibitory effective connectivity from DMN to DAN decreased when compared to the placebo. These changes in connectivity reflect diminution of the anticorrelation between the resting state networks which may be a key neural mechanism of LSD-induced ego dissolution. Our findings suggest the hierarchically organised balance of resting-state networks is a central feature in the construct of self.”

Authors: Devon Stoliker, Leonardo Novelli, Franz X. Vollenweider, Gary Egan, Katrin Preller & Adeel Razi

Summary

Psychedelics induce ego dissolution, which is associated with the balance of anticorrelated activity between the default mode network (DMN) and the salience network (SN). We applied dynamic causal modeling to infer effective connectivity of resting state functional MRI scans from a study of 25 healthy adults who were administered 100mg of LSD, or placebo. We found that the anticorrelation between resting state brain networks decreased under the peak effect of LSD.

Classic psychedelics are powerful substances with low toxicity that can temporarily alter brain activity and produce profound changes to consciousness. These changes are thought to involve changes to resting state network activity. Functional magnetic resonance imaging investigations indicate that the brain is functionally integrated into multiple RSNs, with the default mode network (DMN) activating primarily in the absence of immediate external goal-directed attention, and the dorsal attention network (DAN) activating during external-focused task-driven attention.

The DMN-DAN anticorrelation can be hypothesised to be a mechanism maintaining the boundary between the subject (observer) and object (observation) that is altered during experiences of psychedelic ego dissolution. The salience network (SN) is the switching mechanism coordinating the direction of attention between internal and external stimuli. The SN and DAN interact to produce important biopsychological functions, such as detecting bottom-up features in the visual environment and enabling the detection of resources relevant to higher-order goals. The SN is also associated with schizophrenia, psychosis, and internalizing disorders.

The DMN and SN have been investigated in relation to unique senses of self. The DMN has been shown to be involved in the minimal or embodied self, and the SN has been reduced in connectivity under psychedelic-induced ego dissolution. Psychedelics have been reported to reduce symptoms of patients experiencing internalising mental health disorders. This may be because psychedelic-induced free energy increase in networks such as the DMN disinhibits high-order, secondary processes of the ego.

The SN controls the anticorrelation of extrinsic and intrinsic activated brain regions, which is a neural mechanism that underlies ego dissolution. Meditation also resembles a similar trajectory of ego disarmament by seeking cessation of the self. Ayahuasca (oral brew, 2.2 mL/kg body weight, containing 0.8 mg/ml DMT and 0.21 mg/ml harmine) failed to show anticorrelation changes between the DMN and task positive networks, suggesting the value of adopting mechanistic approaches to determine changes in effective connectivity of networks under psychedelics.

The SN is at the apex of the DMN and DAN triple network hierarchy and controls the switching of DAN and DMN activity, suggesting that change to the SN by psychedelics may influence their patterns of anticorrelated activity. The neural mechanisms of ego dissolution were investigated using DCM analysis of LSD effects across placebo, peak effects at 75 minutes and later effects at 300 minutes post LSD administration. Ego dissolution was measured on the five dimensions of altered states of consciousness scale.

Regional functional connectivity changes were observed across groups, with a fading of the pattern of anticorrelation between DMN and DAN and SN from placebo to peak effects of LSD. During the peak effects of LSD, effective connectivity increased from the SN to DMN and from the DMN to DAN, resulting in reduced inhibitory connectivity. This increased connectivity was accompanied by decreased hierarchical connectivity strength of the SN and increased hierarchical connectivity strength of the DMN and DAN from placebo.

LSD changes effective connectivity in several regions, including the dACC, lFEF, lAG, lIPS, and rAI. These changes show larger effect sizes during the peak effects than in the later effects of LSD.

LSD effects are distinguished by changes from placebo that last across time under LSD, including increased DAN to DMN and decreased DMN to SN effective connectivity at 75 minutes, and increased lAG and rIPS self-inhibition, lFEF to mPFC inhibition and lIPS to PCC excitation at 300 minutes.

This investigation seeks to understand how effective connectivity between anticorrelated large-scale brain networks is related to ego dissolution under the peak effects of LSD. It shows that the DMN and DAN show increased hierarchical connectivity strength under the peak effects of LSD.

The decrease in functional anticorrelation between the DMN and DAN and the reduction in inhibition between them suggest that the boundary between the subject and the object is dissolving under LSD. The AG serves multiple functions in the brain, including autobiographical memory and bodily awareness. It also operates complex language functions, such as making meaning out of visually perceived self-related words. The SN was included in the analysis of LSD effects because of its importance in basic conscious-awareness and its role in the breakdown of sub-personal processes underlying the minimal self. The SN’s effective connectivity to the DMN changed from inhibitory to excitatory before returning to inhibitory in the later effects.

LSD increases SN connectivity to the DMN, which may influence the DMN-DAN interactions. This change in SN connectivity to the DMN is accompanied by a change in SN hierarchical connectivity strength, which may liberate the ego from the reality principle. The dACC is a central brain hub involved in cognitive functions, social emotions, performance monitoring, and has been noted in social cognition under psilocybin and ayahuasca. The dACC and lAI inhibition at the peak effects of LSD may indicate the role of SN inhibition that is relevant to ego dissolution and psychedelic assisted therapy.

The connectivity between the DMN and SN is reduced during peak effects, and increases in the later effects. The PCC and dACC are related to the narrative and minimal aspects of self, and the excitation from the dACC to PCC may suggest dACC cognitive control functions influence on self-related functions of PCC. The FEF, IPS, and rIPL were identified as regions involved in visual attention, attentional control, and self-other discrimination. These regions showed a stronger increase in change of effective connectivity under the peak effects of LSD.

Effective connectivity explains the collapse of the hierarchy of the self during peak effects of LSD, and this may relate to the shift in sense of self described under ego dissolution. Identifying the change in network interactions associated with the dichotomy of the subject-object relationship under LSD may provide a better understanding of psychedelic clinical therapy. Our small sample size, processing pipeline and high variance in subjective responses to a standard dose of LSD may bias the results. However, replication of the investigation with alternate classic psychedelic substances, including psilocybin, ayahuasca and mescaline, will be a worthy direction to validate our results.

The selection of regions composing networks of interest and the selection of region centroids can affect the results. This is because there is anatomical variability between participants, variability in the method of determining coordinates and variability in the selection of regions composing networks of interest. Future work should include connectivity dynamics of additional task positive networks anticorrelated to the DMN and under control of the SN, such as the CEN, to provide a more complete account of anticorrelated network changes associated with ego dissolution.

Theoretical challenges include consensus on the nature of ego dissolution within the taxonomy of psychedelic-induced effects, and future directions include integration of psychoanalytic theory and brain connectivity processes.

LSD appears to shift the balance of network activation and diminish the anticorrelation between brain networks responsible for internal and external modes of perception. This may explain the blurring of boundary between subject and object experienced in ego dissolution.

25 healthy subjects were recruited through advertisements at universities in Zurich, Switzerland. They were screened using the Mini-International Neuropsychiatric Interview, the Diagnostic and Statistical Manual of Mental Disorders, fourth edition self-rating questionnaire for Axis-II personality disorders, and the Hopkins Symptom Checklist. Participants were asked to abstain from prescription and illicit drug use, and alcohol use 24 hours prior to testing days. They were also tested for left-handedness, poor knowledge of the German language, cardiovascular disease, history of head injury or neurological disorder, history of alcohol or illicit drug dependence, and pregnancy.

MRI data were acquired on a Philips Achieva 3.0T whole-body scanner using a whole brain gradient-echo planar imaging (EPI) sequence and high-resolution anatomical images were acquired using a standard T1-weighted 3D magnetization prepared rapid-acquisition gradient echo sequence. The resting state networks were identified using Group ICA for fMRI Toolbox (GIFT), and were composed of cardinal regions constituting a core part of DMN (Andrews-Hanna, Reidler, Sepulcre, Poulin, & Buckner, 2010; Dixon et al., 2017).

We used peak RSN activity of clusters within networks to identify cardinal nodes within each intrinsic network, and determined the MNI coordinates of regions of interest using expert visual inspection. A generalized linear model was used to regress 6 head motion parameters, white matter and cerebrospinal fluid signals.

The functional connectivity matrix between regions of the DMN, SN, and DAN was computed for all subjects, and 4 subjects that did not show evidence of the anticorrelation were excluded from further analysis. A fully-connected DCM was specified using 11 ROIs and inverted using spectral DCM. A General Linear Model (GLM) was employed to decompose individual differences in effective connectivity into hypothesised group-average connection strengths plus unexplained noise, and hypotheses were tested within the Parametric Empirical Bayes framework.

The expected network-level effective connectivity and hierarchical organization of the brain were computed using Bayesian model reduction (BMR), and a similar approach was used for analysing hierarchical projections in the monkey brain and prefrontal cortex in humans.