Psilocybin shapes the slow, global propagation of brain activity over the cortical layout of 5HT2a receptors

Previous studies had shown that serotonergic psychedelics can produce marked changes in whole-brain functional connectivity on fMRI, including increased global connectivity and a reduction in the distinction between unimodal and transmodal cortex, but the neural phenomena underlying these patterns remained unclear. The introduction also notes that slow travelling waves of brain activity propagate across the cortex along the unimodal-to-transmodal principal gradient, and that this propagation can be influenced by arousal and neuromodulatory tone. However, less work had linked psychedelic-related functional connectivity findings to these slower spatio-temporal events, or examined how cortical 5HT2a receptor distribution might shape them. V. and colleagues set out to test whether psilocybin alters the propagation of slow travelling waves over the cortical principal gradient, whether these propagation changes could help explain the commonly reported connectivity effects of psychedelics, and whether the spatial distribution of 5HT2a receptors contributes to any observed effects. They also explored whether travelling wave characteristics were associated with subjective psychedelic experience. The study used open data from the Psilocybin Precision Functional Mapping study to connect macroscopic brain dynamics, cortical receptor architecture, and psychedelic state effects.

The researchers analysed open data from the Psilocybin Precision Functional Mapping study, which used a randomised cross-over design in seven healthy volunteers. Participants underwent several baseline scanning sessions and two drug sessions, with psilocybin and methylphenidate assigned as the two within-subject drug conditions. For the current analysis, the researchers used the first three baseline sessions when available, together with the methylphenidate control session and the psilocybin session; four participants also had a second set of baseline and psilocybin sessions at least 6 months later. In the psilocybin condition, fMRI was acquired 60-180 minutes after 25 mg of psilocybin, and each session included resting-state and task scans. The extracted text is not fully consistent on scan duration, but it reports two 15-minute resting-state scans and two task scans of about 6 minutes 50 seconds each. The sample’s mean age was 34.1 years, and 3 of the 7 participants were female. MRI data were collected on a 3T Siemens Prisma scanner using multi-echo echo-planar imaging. Preprocessing followed a standard pipeline with slice timing and realignment, plus extensive noise and movement correction, and the data were filtered between 0.009 and 0.08 Hz. Subjective psychedelic effects were assessed with the 30-item Mystical Experience Questionnaire (MEQ30). Ethical approval and informed consent were reported. Travelling waves were identified from time-delay profiles around global signal peaks. The researchers first detected intervals around peaks, then measured the temporal delay between each voxel’s peak and the global signal peak to build a delay profile. A principal gradient of cortical organisation was derived from baseline sessions using singular value decomposition, and cortical voxels were ordered along this gradient and binned into 70 bins. The coefficient relating bin position to peak timing was used to determine propagation direction: positive values indicated bottom-up waves and negative values top-down waves. Wave speed was estimated from this coefficient, geodesic distance, number of bins and TR. Significant propagation events were identified using a threshold based on control directions. To examine functional connectivity, the researchers computed the principal gradient from Schaefer atlas-based connectivity matrices using diffusion embedding, and calculated total functional connectivity (FCTOT) as the average of all upper-triangle correlations. To study receptor-related effects, they analysed cortical 5HT2a receptor maps from PET data reported by Hansen and colleagues, averaged across three maps, and compared receptor expression with wave propagation energy along the gradient. Statistical analyses used linear mixed models with treatment and task condition as within-subject effects and participant as a random effect, whereas wave counts were compared with ANOVA. Linear models also tested whether wave measures predicted FCTOT or gradient score differences.

The psilocybin condition was associated with more travelling waves than baseline or methylphenidate, with a significant treatment effect (F(2,62) = 34.09, p < 0.001). The proportion of bottom-up versus top-down waves did not differ across conditions (F(2,45) = 0.82, p = 0.446). In contrast, wave speed was significantly higher under psilocybin than under baseline and methylphenidate (rmANOVA treatment effect F(2,90) = 28.84, p < 0.001; baseline vs psilocybin and psilocybin vs methylphenidate both p < 0.001, while baseline vs methylphenidate was not significant, p = 0.182). The researchers replicated two previously reported functional connectivity findings: psilocybin was associated with a narrower principal gradient range and a smaller gradient score difference (rmANOVA F(1,42) = 16.30, p < 0.001; baseline vs psilocybin p = 0.004; psilocybin vs methylphenidate p = 0.039; baseline vs methylphenidate p = 0.266). Total functional connectivity was also greater under psilocybin, and the distance between psilocybin and baseline connectivity matrices was larger than the distance between methylphenidate and baseline matrices (T(20) = 4.23, p < 0.001). These gradient and total connectivity findings were reportedly replicated using a different cortical parcellation. Across all conditions, faster wave speed was significantly associated with a narrower gradient score difference (F(1,26) = 19.08, p < 0.001). The researchers report that speed was a better predictor than treatment itself, whereas the number of waves and the bottom-up/top-down ratio were not significantly related to gradient score difference. This suggests that the connectivity changes were linked more closely to propagation speed than to wave count or direction. When wave energy was examined along the principal gradient, it was not uniform: energy decreased after an initial segment and then increased towards the end. Psilocybin increased wave energy in the initial segment, with a stronger effect for bottom-up waves than for top-down waves. The distribution of 5HT2a receptor expression also varied along the principal gradient, with a transition from higher to lower expression aligning with the part of the wave where energy changed. Finally, higher MEQ30 scores, indicating a stronger psychedelic experience, were associated with faster wave speed at the individual level (F(1,8) = 6.31, p = 0.03). MEQ30 scores were not related to wave count or the bottom-up/top-down ratio.

The authors interpret their findings as evidence that psilocybin alters slow, global travelling waves of cortical activity and that these changes may help explain prominent functional connectivity effects previously reported under psychedelics. In their view, the faster propagation observed under psilocybin is closely linked to the contraction of the principal gradient and increased total functional connectivity, suggesting that some connectivity-based measures may reflect properties of large-scale propagation rather than independent phenomena. They also argue that the non-uniform pattern of wave energy along the principal gradient, together with the spatial variation in 5HT2a receptor expression, supports the idea that receptor distribution shapes how psilocybin modulates global brain dynamics. The discussion places the results in relation to earlier psychedelic research and to the REBUS model, which proposes reduced top-down control and increased bottom-up sensory flow. The authors say their results are consistent with broader claims from previous fMRI and EEG studies about increased global connectivity, reduced network segregation, altered gradients and higher entropy under psychedelics. They also relate the findings to work on infra-slow activity, brain harmonics and travelling waves in other altered states, including deep sleep and ketamine. Several limitations and uncertainties are acknowledged. The sample was small, although the authors note that this was partly offset by repeated scans per person. They caution that the brain-behaviour association with MEQ30 should be interpreted carefully. They also note that BOLD-based results may be influenced by neurovascular coupling, and that non-neuronal sources can affect infra-slow fMRI analyses, even though other multimodal studies support a neuronal interpretation of travelling waves. The authors suggest that future studies should examine other psychedelics and patient populations. In terms of implications, the authors propose that neuromodulators may exert their whole-brain effects by modifying slow propagation across the cortical landscape, and that one possible mechanism for therapeutic action is facilitation of plasticity across brain systems through faster propagation. They conclude that analysing spatio-temporal brain patterns may help connect macroscopic fMRI signatures with underlying neural processes and clarify how neuromodulatory systems shape brain function.