Effects of External Stimulation on Psychedelic State Neurodynamics

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results show that while brain entropy increases with LSD under all of the experimental conditions, it exhibits the largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing a video—potentially due to a “competition” between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence of the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.


Supporting Information Text Additional controls on the interaction between drug and condition
In Figure 1 of the main text, we report as the main finding of the paper the result that there exists a negative drug×eyes interaction effect on whole-brain average LZ.To confirm these results we performed a number of additional controls (all agreeing with our conclusions), described here and reported in the tables below: (1) Table S1 presents the results of a LME model in which the condition variable is an integer coding of external stimulation, according to the following order: closed (0), music (1), open (2), and video (3).For the LME, the condition was treated as a continuous variable.This is the model shown in Figure 1b of the main text.
(2) Table S2 shows the result of a two-way ANOVA run on the drug and condition variables, with the condition variable being a four-valued discrete variable.
(3) Table S3 presents the replication of the results in Table 1 of the main text on data under a more conservative filteringa low-pass 4 th -order Butterworth filter with cut-off frequency at 30 Hz.
(4) Table S4 presents the results of a LME model controlling for ordering effects between the stimulus and non-stimulus sessions -i.e.run on a different set of data in which the eyes-closed and eyes-open conditions were recorded after the music and video conditions, respectively.

Sensitivity of correlations to the external condition
Here we provide additional information about the results in Figure 3 of the main text, related to how external stimulation affects correlation (i) between VAS scores and LZ in the considered ROIs, and (ii) between LZ in each pair of ROIs.To study this, we computed the between-subjects correlation between VAS and LZ changes (LZ LSD -LZ PLA ), in each experimental condition (Figure S1).To draw quantitative conclusions, we constructed a multivariate regression model using the correlation coefficients as target variables and stimuli and eye opening as predictors.We constructed two separate models: one using VAS-VAS correlations as target (Table S5), and one using VAS-ROI correlations as target (Table S6).For completeness, we also verified these results percent signal change (i.e.(LZ LSD -LZ PLA )/LZ PLA ), with virtually identical results (Tables S7 and S8).
In order to discard potential ordering effects driving this results, we re-ran these analyses on the same order-flipped data used in item (4) above, with nearly identical results (Figure S2).The numerical results of these models are presented in Tables S9 and S10.

Relation between LZ complexity and alpha power
Decreased power in the alpha band is one of the most systematic spectral effects reported in the M/EEG psychedelics literature (1)(2)(3).This has raised questions regarding to what extent is the LSD-induced increase in LZ merely a reflection of the corresponding alpha power suppression.To touch briefly on this issue, here we show that while alpha suppression shows a behaviour similar to LZ when comparing across gross state changes (Figures S3 and S4), it is substantially less correlated with subjective reports than LZ (Figure S5).More specifically, first Figure S3 presents a comparison between LZ and alpha power for each subject in the placebo session, for each of the four experimental conditions.As expected, alpha power is inversely related to LZ, with richer stimuli inducing stronger suppression.Additionally, Figure S4 shows that when measured with alpha suppression the drug also has an interaction with external stimulation (c.f. Figure 1b in the main text).Quantitatively, LME modelling reveals that both the drug and eye opening have significant negative effects on alpha power, and that they have a significant positive interaction (Table S12).
Finally, we explored the preditive capability of alpha changes in all ROIs to predict VAS ratings (Figure S5).In this case, unlike the above, the results of alpha suppression do not resemble those of LZ: while some relationships survive the multiple-comparisons correction, alpha power seems to be far less capable of predicting subjective reports than LZ (c.f. Figure 4 in the main text).This suggests LZ to be a more sensitive, and therefore more suitable, marker of the psychedelic experience -although a full analysis decomposing the spectral components of the LZ difference is needed to shed more light on the matter (4).

of LME models predicting VAS changes from LZ changes in each ROI. Models for all VAS,ROI pairs were fitted following the procedure in Materials and Methods, and those with
p < 0.05 are shown here.