Psychedelics disrupt hierarchical cortical propagations in the default mode network of humans and mice
This new study aimed to identify a common circuit-level mechanism by which psychedelics alter brain function. Previous neuroimaging studies showed that psychedelics affect the default mode network (DMN) but produced conflicting findings about whether they increase or decrease hierarchical brain processing. The authors addressed this by developing a new method to track the direction and propagation of neural activity over time, rather than treating brain activity as static.
Key findings
Psychedelics consistently reduced cortical signal propagation
Bottom-up hierarchical signalling was attenuated
The same propagation changes were observed using:
human resting-state fMRI,
mouse calcium imaging,
The effect was associated with subjective psychedelic experiences. Changes in cortical propagation correlated with participants' self-reported psychedelic experiences.
The study provides a new framework for understanding psychedelic brain function - Previous studies typically measured functional connectivity as though brain activity were relatively static.
Significance
Psychedelic substances are increasingly recognized for both their therapeutic potential and risks. Dissensus in how psychedelics impact macroscale brain function is one barrier to understanding risks and benefits at a neurobiological level. Here, we combine four independent datasets to evaluate how psychedelics impact hierarchical processing in an often-implicated cortical network, the default mode network (DMN). Using multiple neuroimaging modalities to track the movement of activity over the cortical surface, we demonstrate that MDMA, psilocybin, and LSD all attenuate hierarchically ascending cortical propagations in the DMN of humans and mice. Effects are not attributable to data quality, functional connectivity, or temporal autocorrelation in signal. Our results suggest that psychedelics attenuate bottom–up processing in the DMN in a generalizable, evolutionarily conserved manner.
Abstract
Psychedelic drugs are poised to become mainstream treatments, yet we lack a circuit-level account of how they reshape brain activity. Emerging evidence suggests that multiple psychedelic compounds modulate activity in the brain’s default mode network (DMN), often interpreted as either increased or decreased bottom–up hierarchical processing. Most imaging studies, however, quantify activity as if it were stationary, remaining agnostic to the ascending or descending movements of activity that defines hierarchical processing. Here, we adapt optical flow analyses to track frame-to-frame trajectories of DMN activity across four independent datasets (humans and mice; methylenedioxymethamphetamine, psilocybin, and lysergic acid diethylamide; nine drug-vs.-control contrasts). In functional magnetic resonance and calcium imaging, all psychedelics attenuate signal flow magnitude and bottom–up directionality within the DMN. Propagation attenuation is not attributable to data quality or previously documented effects of psychedelics and is uniquely associated with self-reported outcomes. This replicable and generalizable attenuation of bottom–up cortical propagations provides fundamental clarification of the effects of psychedelics on macroscale hierarchical processing.
Pines, A. R., Zhang, X., Kochalka, J., Vesuna, S. S., Kauvar, I. V., Rajasekharan, D., Reneau, T. R., Akiki, T. J., Hack, L. M., Siegel, J. S., & Williams, L. M. (2026). Psychedelics disrupt hierarchical cortical propagations in the default mode network of humans and mice. Proceedings of the National Academy of Sciences of the United States of America, 123(24), e2522000123. Read Paper
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