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

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.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

Prefrontal contributions to the stability and variability of thought and conscious experience

“…4), consistent with experimental findings of psychedelically-induced reductions to brainwide top-down signaling [73], directed information flow [60,74], and hierarchical information flow [29,30]. Such alterations to hierarchical information flow may play a role in creating the increased variability or diversity of brain activity that is observed during psychedelic states [75][76][77][78][79][80], given that bottom-up information flow is no longer as constrained by top-down sources. In other words, a diversity of information that is usually compressed out of conscious awareness is now available to register more fully within it.…”

“…For instance, highly entropic brain states are hypothesised to reflect informationally rich experiential states. Psychedelic states are one such kind, featuring an increased diversity and flexibility of subjective experience [65,96] as well as highly entropic underlying neural activity [75][76][77][78][79][80]. In contrast, other conscious states feature a relatively diminished richness and flexibility of subjective experience, along with highly predictable brain dynamics (i.e., low entropy).…”

“…Moreover, we hold that the functions of any one brain region only emerge in relation to its interactions with other areas of the brain. This perspective has become prevalent in the field of cognitive neuroscience over the past decade, with work increasingly focusing on major scale brain networks [2,3], brain activity configuration states [99,107,108], and whole-brain information dynamics [75][76][77][78]97]. However, we also hold that it is important to recognize how individual regions play relatively distinct and important roles in cognition.…”

“…In particular, the field of psychedelics research could benefit from a more specific discrimination between different brain networks and regions. Neuroscientific work on psychedelics often makes use of whole-brain measurements [29,30,61,73,75,77,99,339]. These approaches have and will continue to be highly beneficial for understanding the effects of psychedelics on global brain measures, but may obscure the more specialized contributions made by specific brain regions and networks to psychological phenomena.…”

Pattern Breaking: A Complex Systems Approach to Psychedelic Medicine

“…Applied to the brain, an increase in entropy may indicate that neuronal circuits are exploring a wider array of patterns of activity, with potential departures from normal repertoire of states. The principle that brain entropy increases under psychedelics has been supported by a large number of empirical findings (Toker et al 2022;Savino and Nichols, 2021;Jobst et al 2021;Luppi et al, 2021;Herzog et al, 2020;Timmermann et al, 2019;Lyons and Carhart-Harris, 2018;Liechti, 2017;Schartner et al 2017;Viol et al, 2017;Lebedev et al, 2016;Alonso et al 2015) and moreover, the principle that brain entropy tracks a principal dimension of conscious experience, is increasingly well supported -now well beyond just research with psychedelics (Keshmiri, 2020;Carhart-Harris, 2018;John, 2002). When we look at the brain as a hierarchical prediction engine -e.g., as one does under the so-called 'Free Energy Principle' (FEP) (Friston, 2010;Parr, Pezzulo and Friston, 2022), an increase in the entropy of spontaneous brain activity can be related to a decrease in the precision weighting -or the stability or reliability -of prior assumptions.…”