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

In this neuroimaging study (n=14) data from participants who were given 75μg of intravenous LSD or placebo and brain activity was assessed using fMRI and a novel whole-brain computer model (in silico) approach. The largest deviations from normal brain function were found in the limbic network, the visual network and the default mode network (DMN). It was found that the computer model used allows for the exploration of changes in brain dynamics that can be challenging to observe via experiments in living subjects (in vivo).

Abstract

“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.”

Authors: Beatrice M. Jobst, Selena Atasoy, Adrián Ponce-Alvarez, Ana Sanjuán, Leor Roseman, Mendel Kaelen, Robin Carhart-Harris, Morten L. Kringelbach & Gustavo Deco

Notes

Author Highlights

  • Novel 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 intake
  • Consistently longer recovery time after model perturbation under LSD influence
  • Strongest effects in resting state networks relevant for psychedelic experience
  • Higher response diversity across brain regions under LSD influence after an external in silico perturbation

Despite a large amount of research, the exact mechanisms through which psychedelics exert their effects on the brain remain unknown. Understanding these mechanisms is imperative to realizing the therapeutic potential of psychedelic’s and make these drugs accessible to people with mental disorders. Neuroimaging studies are helping to illuminate these mechanisms of action and therefore, it is important we continue to explore all possible techniques.

In the present study, researchers investigated the effects of LSD on the brain using data from 14 healthy participants using fMRI (from Carhart-Harris et al., 2016) and a novel silico perturbation approach. In general, silico models are logical extensions of controlled experiments in living participants or cells (in vivo) that are created by a computer that models the pharmacological process.

The main findings

  • LSD intake led to a shift of the brains global working point further away from a stable equilibrium when compared to normal conditions.
  • The largest deviations from normal brain function were found in the limbic system, the visual system and the default mode network (DMN).
  • The novel perturbation approach allowed researchers to better understand how the changes in brain function induced by LSD interact with the connectome (a complete map of structural connectivity in the brain) to produce different network dynamics.
  • The model may be useful for futures research as it allows for the exploration of characteristic changes in whole-brain dynamics in ways that are extremely challenging to do via in vivo experiments.

The authors acknowledge that limitations exist surrounding their novel technique. Mainly, the model assumes that all brain regions have the same intrinsic dynamics and it has a limited frequency range. Nonetheless, the present study has enriched our understanding as to how psychedelics may exert their effect on the brain all while providing a novel technique that may be useful for future research.

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