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:10.1016/j.neuroimage.2022.119220

Cited by 56 publications

(67 citation statements)

References 80 publications

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“…A flatter energy landscape corresponds to lower barriers to transition between different states of brain activity. This is theorized to correspond to a flattening of the functional hierarchy as well 60 , i.e. a relaxation of the weighting of high-level priors - thought to be a pivotal component of psychedelics’ therapeutic mechanism 3 .…”

Section: Discussionmentioning

confidence: 99%

“…We wanted to test the hypothesis that the true scenario would be the opposite -namely, that a flatter control energy landscape would in fact correspond to an increase in the diversity of brain dynamics. Numerous studies have linked changes in the entropy of neuroimaging signals to the psychedelic state 5,[55][56][57][58][59] and the ability for these compounds to increase neural entropy via 5-HT2a agonism is thought to be a key process in the breakdown of the functional hierarchy of the brain and a central component of REBUS 3,4,60 . To test this hypothesis, we used Lempel-Ziv compressibility to compute the entropy rate of the temporal sequence of brain meta-states (MS-1 and MS-2).…”

Section: Increased Flattening Of the Control Energy Landscape Is Asso...mentioning

confidence: 99%

“…Although small sample size is common in neuroimaging studies of psychedelics and other states of altered consciousness due to the inherent difficulties of collecting such data, future replications with larger samples would be appropriate. We also acknowledge that these datasets have been studied extensively before [6][7][8][9]35,36,59,60,[67][68][69][70][71] and replications in different datasets will be warranted to ensure the generalizability of these results. Although the LSD dataset is more suitable for obtaining robust measurements of brain dynamics using the methods presented here, primarily because of the longer scans, and, in addition, the larger sample size, we still found that psilocybin modified the brain's energy landscape and dynamics in a similar fashion to LSD.…”

Section: Limitations and Future Workmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Increased Flattening Of the Control Energy Landscape Is Asso...mentioning

confidence: 99%

Section: Limitations and Future Workmentioning

confidence: 99%

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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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show abstract

“…We wanted to test the hypothesis that the true scenario would be the opposite-namely, that a flatter control energy landscape would in fact correspond to an increase in the diversity of brain dynamics. Numerous studies have linked changes in the entropy of neuroimaging signals to the psychedelic state 5,[53][54][55][56][57] and the ability for these compounds to increase neural entropy via 5-HT2a agonism is thought to be a key process in the breakdown of the functional hierarchy of the brain and a central component of REBUS 3,4,58 . To test this hypothesis, we used Lempel-Ziv compressibility to compute the entropy rate of the temporal sequence of brain meta-states (MS-1 and MS-2).…”

Section: Network Control Theory Reveals Psychedelic-induced Flattenin...mentioning

confidence: 99%

Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape

et al. 2022

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Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control 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 (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics.

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“…This year, Girn published an analysis of existing fMRI data that supports the model. He found that LSD and psilocybin compress the usual hierarchy of connectivity between sensory and association networks 6 . "These sensory areas -and their bare, concrete processing of the external world -become less separate from the processes conceivably related to our abstract thinking and beliefs," The thalamus is a brain area that processes and filters sensory information en route to the cortex.…”

Section: Integration and Disintegrationmentioning

confidence: 99%

Your brain on psychedelics

Drew

2022

Nature

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Classic psychedelic drugs, such as LSD and psilocybin, disrupt neural activity by diffusing through the brain and activating a serotonin Your brain on psychedelicsMindaltering drugs are shaking up medicine -but how they actually work remains a mystery. A flurry of imaging studies could clarify the picture. By Liam Drew Brain imaging is an important tool as researchers try to understand the effects of psychedelic drugs.

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

Cited by 56 publications

References 80 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

Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape

Your brain on psychedelics

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