Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

Girn, Manesh; Roseman, Leor; Bernhardt, Boris C.; Smallwood, Jonathan; Carhart‐Harris, Robin; Spreng, R. Nathan

doi:10.1101/2020.05.01.072314

Cited by 31 publications

(46 citation statements)

References 84 publications

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“…Our analysis of transition probabilities supported this hypothesis (Figure 4a, i, diagonal). The increased persistence of states (SOM-) dominated by somatomotor/salience (bottom-up) activity and correspondingly, the decreased persistence of states (FPN+) dominated by frontoparietal (top-down) activity seen under LSD fits with a flattening of the functional hierarchy proposed by REBUS 2,37 .…”

Section: Lsd Modulates Brain Dynamics By Increasing Occupancy In Bottom-up Somatomotor-dominated Brain-statesmentioning

confidence: 60%

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

Singleton

Luppi

Carhart-Harris

et al. 2021

Preprint

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Psychedelics like lysergic acid diethylamide (LSD) offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. The RElaxed Beliefs Under Psychedelics (REBUS) model postulates that 5-HT2a receptor agonism allows the brain to explore its dynamic landscape more readily, as suggested by more diverse (entropic) brain activity. Formally, this effect is theorized to correspond to a reduction in the energy required to transition between different brain-states, i.e. a ″flattening of the energy landscape.″ However, this hypothesis remains thus far untested. Here, we leverage network control theory to map the brain′s energy landscape, by quantifying the energy required to transition between recurrent brain states. In accordance with the REBUS model, we show that LSD reduces the energy required for brain-state transitions, and, furthermore, that this reduction in energy correlates with more frequent state transitions and increased entropy of brain-state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors, we demonstrate the specific role of this receptor in flattening the brain′s energy landscape. Also, in accordance with REBUS, we show that the occupancy of bottom-up states is increased by LSD. In addition to validating fundamental predictions of the REBUS model of psychedelic action, this work highlights the potential of receptor-informed network control theory to provide mechanistic insights into pharmacological modulation of brain dynamics.

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Section: Lsd Modulates Brain Dynamics By Increasing Occupancy In Bottom-up Somatomotor-dominated Brain-statesmentioning

confidence: 60%

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

Singleton

Luppi

Carhart-Harris

et al. 2021

Preprint

Self Cite

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“…Furthermore autism also has been found to relate to differences in this multimodal network hierarchy 82 . The relationship between hierarchical organization in the brain and criticality (including critical slowing) was the focus of a recent major review on the acute and potential therapeutic action of psychedelics 32 – and flattened functional hierarchy in the brain has recently been observed in formal ‘gradient-based’ analyses applied to the present dataset 83 .…”

Section: Discussionmentioning

confidence: 94%

Increased sensitivity to strong perturbations in a whole-brain model of LSD

Jobst

Atasoy

Ponce‐Alvarez

et al. 2021

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Lysergic acid diethylamide (LSD) is a potent psychedelic drug, which has seen a revival in clinical and pharmacological research within recent years. Human neuroimaging studies have shown fundamental changes in brain-wide functional connectivity and an expansion of dynamical brain states, thus raising the question about a mechanistic explanation of the dynamics underlying these alterations. Here, we applied a novel perturbational approach based on a whole-brain computational model, which opens up the possibility to externally perturb different brain regions in silico and investigate differences in dynamical stability of different brain states, i.e. the dynamical response of a certain brain region to an external perturbation. After adjusting the whole-brain model parameters to reflect the dynamics of functional magnetic resonance imaging (fMRI) BOLD signals recorded under the influence of LSD or placebo, perturbations of different brain areas were simulated by either promoting or disrupting synchronization in the regarding brain region. After perturbation offset, we quantified the recovery characteristics of the brain area to its basal dynamical state with the Perturbational Integration Latency Index (PILI) and used this measure to distinguish between the two brain states. We found significant changes in dynamical complexity with consistently higher PILI values after LSD intake on a global level, which indicates a shift of the brain’s global working point further away from a stable equilibrium as compared to normal conditions. On a local level, we found that the largest differences were measured within the limbic network, the visual network and the default mode network. Additionally, we found a higher variability of PILI values across different brain regions after LSD intake, indicating higher response diversity under LSD after an external perturbation. Our results provide important new insights into the brain-wide dynamical changes underlying the psychedelic state - here provoked by LSD intake - and underline possible future clinical applications of psychedelic drugs in particular psychiatric disorders.HighlightsNovel offline perturbational method applied on functional magnetic resonance imaging (fMRI) data under the effect of lysergic acid diethylamide (LSD)Shift of brain’s global working point to more complex dynamics after LSD intakeConsistently longer recovery time after model perturbation under LSD influenceStrongest effects in resting state networks relevant for psychedelic experienceHigher response diversity across brain regions under LSD influence after an external in silico perturbation

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“…in the so-called ‘REBUS’ model). This model, which is receiving growing empirical support ( Alamia et al, 2020 ; Girn et al, 2020 ), argues that the de-weighting (decreased ‘precision’) of internal predictive models (‘prior probability distributions’) under psychedelics opens a window for their subsequent revision ( Carhart-Harris and Friston, 2019 ). Consistently, it can be hypothesized here that in individuals undergoing intense PiMSs, the brain inhabits a mode of functioning that is conducive to the modulation or recalibration of internal predictive models, including how they are weighted.…”

Section: The Adaptive Function Of Pivotal Mental Statesmentioning

confidence: 99%

Pivotal mental states

2020

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This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.

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Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

Cited by 31 publications

References 84 publications

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

Increased sensitivity to strong perturbations in a whole-brain model of LSD

Pivotal mental states

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