Navigating the chaos of psychedelic fMRI brain-entropy via multi-metric evaluations of acute psilocybin effects

Abstract

Investigations into the acute effects of psychedelics on brain imaging have emphasised increased 'brain entropy' as a potential neural correlate. To date, 12 previous studies have reported brain entropy effects, each reporting a single and unique metric, none of which have been examined in an independent cohort. Here we evaluated acute psilocybin effects on these 12 brain entropy metrics in an independent cohort of 28 healthy participants. Following a single psilocybin dose, participants completed pre/post resting-state BOLD fMRI scans (28 pre-drug, 93 post-drug scans during the acute drug effects). Each scan was accompanied by a plasma sample to quantify plasma drug levels and estimate brain serotonin 2A receptor occupancy, as well as a rating of subjective drug intensity. We assessed relations between brain entropy and these measures with linear mixed-effects models. There was a significantly positive association for Shannon entropy of path-length and instantaneous correlation distributions and divergent associations of network-wise sample entropy at varying time-scales. We did not observe significant psilocybin effects for seven of 12 brain-entropy metrics. Whole-brain entropy metrics showed limited correlations between each other. Our observations suggest a nuanced acute effect of psychedelics on brain entropy, underscoring the need for reproducing effects. The variable effects and limited inter-metric correlation undermines the generalisability of 'brain entropy' as a singular construct. Future studies in clinical cohorts are crucial to elucidate the link between these metrics and therapeutic effects of psychedelics.

LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics

“…L. Carhart-Harris et al, 2012, 2016). (In fact, a study on a new dataset found that psilocybin did not have a significant effect on seven of the 12 entropy measures in the literature (McCulloch et al, 2023)).…”

“…Virtually all of them demonstrated that psychedelics increase entropy, though they do not use consistent techniques and are mostly secondary analyses of the same two datasets (R. L. Carhart-Harris et al, 2012, 2016. (In fact, a study on a new dataset found that psilocybin did not have a significant effect on seven of the 12 entropy measures in the literature (McCulloch et al, 2023)).…”

Altered structural connectivity and functional brain dynamics in individuals with heavy alcohol use

“…Brain entropy, here assessed as meta-state complexity, has been shown to index different levels of consciousness as well as various brain disorders, and higher brain entropy is believed to be related to increased information processing in the brain [25, 28, 37]. Brain entropy is impacted by the acute and/or chronic administration of various substances including alcohol [43], caffeine [44], nicotine [45], cocaine [46], as well as the classic psychedelics LSD, psilocybin, and DMT [37, 47–49]. Sevel et al [43] found that the acute administration of alcohol in healthy drinkers decreases brain entropy, a result that matches the sub-acute effects observed here in chronic heavy users of alcohol.…”

“…We calculated the meta-state complexity (MSC) of each individual’s k -means partition as previously described [24, 36]. In short, each individual’s partition was binarized based on assignment to either of the pairs of anticorrelated states (VIS-/+ or DMN-/+) to construct the meta-state time-series (Figure 3a).…”

Breathwork-Induced Psychedelic Experiences Modulate Neural Dynamics

“…1It is of note that this association may be most robust within high temporal resolution neuroimaging modalities, such as EEG and MEG. A recent study has found conflicting results when investigating the relationship between neural complexity and psychedelics using fMRI (McCulloch et al, 2023). …”