N,N-dimethyltryptamine effects on connectome harmonics, subjective experience and comparative psychedelic experiences

Understanding how subjective experience emerges from the interplay between brain structure and function is a central aim of contemporary neuroscience. Psychedelic compounds provide a tractable means to probe this relationship because their action on neurotransmitter systems produces widespread changes in brain activity that propagate across the structural connectome, the brain's network of white-matter pathways. The authors adopt connectome harmonic decomposition (CHD), a mathematical framework that represents cortical activity as contributions from intrinsic spatial modes of the structural connectome (connectome harmonics), analogous to how the Fourier transform decomposes signals into temporal frequencies. Low-frequency connectome harmonics capture coarse-grained, global patterns of activity tied closely to large-scale structural topology, whereas high-frequency harmonics index finer-grained, more localised deviations from that topology. Vohryzek and colleagues set out to characterise how intravenous N,N-dimethyltryptamine (DMT), a potent serotonergic psychedelic with a rapid onset and short duration, alters the brain's connectome harmonic landscape. Based on prior CHD studies of LSD, psilocybin and ketamine, they hypothesised that DMT would reduce the contribution of low-frequency harmonics and increase high-frequency contributions, and that it would broaden the repertoire of harmonics (increase repertoire entropy). The brief and predictable time-course of intravenous DMT also enabled the investigators to test whether CHD-derived measures (energy spectrum difference and repertoire entropy) track subjective intensity ratings in a time-resolved, within-session manner, rather than only in time-averaged recordings.

The DMT dataset was acquired in a single-blind, counterbalanced, placebo-controlled design. Twenty-five participants were recruited and underwent physical and psychiatric screening; exclusion criteria included age under 18, no prior psychedelic experience, personal or family history of psychotic disorders, excessive alcohol use, and phobia of blood or needles. After screening and attrition related to completion and motion, 17 participants remained for the principal analyses (7 female, mean age reported as 33.5 years, SD = 7.9). For the time-resolved analyses a further three participants were excluded for motion, leaving 14; the extracted text makes clear these participant counts but indicates some procedural detail and full participant characterisation are reported elsewhere or in supplementary material. Each subject completed two scanning visits two weeks apart, each with two sessions. In the main session a 28-minute functional MRI run included an intravenous bolus (60 s) of either DMT or saline placebo administered at the start of minute 8; allocation was 50/50 DMT/placebo across sessions. Subjects lay with eyes closed and wore an eyemask. One session included minute-by-minute subjective intensity ratings, enabling time-resolved behavioural measures. Simultaneous EEG was recorded during scanning but the primary analyses reported here used fMRI-derived CHD measures. fMRI data were collected at 3T (T2*-weighted EPI, TR = 2000 ms, TE = 30 ms, acquisition time ≈ 28.06 min, voxel size 3 × 3 × 3 mm, 35 slices). Pre-processing followed a pipeline previously used in LSD research and included despiking, slice-timing correction, motion correction, brain extraction, rigid and non-linear registration to MNI space, motion-scrubbing, spatial smoothing (6 mm FWHM), band-pass filtering (0.01–0.08 Hz), detrending, and regression of nine nuisance regressors (three translations, three rotations and three anatomical signals). Connectome harmonics were derived from group-averaged structural connectomes built from independent Human Connectome Project (HCP) diffusion data. The main analyses used a connectome constructed from ten HCP participants (surface reconstruction with FreeSurfer, registration to a 10,242-vertex per hemisphere template, deterministic tractography), consistent with prior CHD work; robustness checks re-ran analyses using a larger 985-subject HCP connectome. The investigators note that CHD assumes the fundamental harmonic bases are consistent across individuals; supplementary analyses also tested a degree-preserving randomised connectome as a control. Analytically, the researchers decomposed cortical fMRI signals into connectome harmonics and computed an energy spectrum across harmonics. They binned harmonics into logarithmically spaced bins (canonical analysis used 15 bins; sensitivity checks used 25 bins) and evaluated changes in bin-wise energy between pre- and post-injection periods and between DMT and placebo. Multivariate patterns distinguishing conditions were extracted using Partial Least Squares Discriminant Analysis (PLS-DA) to produce multivariate signatures (MVS). Repertoire diversity was quantified as CH repertoire entropy derived from the normalised harmonic power spectrum. Time-resolved correlations between CH measures (entropy and energy-spectrum projections onto MVS) and minute-by-minute subjective intensity ratings were calculated at the individual and group levels. Cross-modal comparisons included correlating fMRI-derived CH entropy with EEG Lempel–Ziv (LZ) complexity measures. Statistical testing reported paired t-tests, Bonferroni correction for multiple bins where stated, and group-level t-tests of individual correlation coefficients.

Describing the DMT-induced state in terms of connectome harmonics, the investigators report a systematic redistribution of harmonic energy from low to high spatial frequencies. When the harmonic spectrum was binned into 15 logarithmically spaced bins, a range of low-frequency bins (reported as k ∈ [1,…,10^2]) showed significant suppression under DMT relative to pre-DMT (p < 0.01, Bonferroni-corrected paired t-test), whereas a range of high-frequency bins (k ∈ [10^3,…,10^4]) showed significant increases (p < 0.01, Bonferroni-corrected paired t-test). No significant pre/post changes were found in the placebo condition. Comparing the DMT-induced energy difference to the placebo difference at the subject level produced the same pattern: suppressed lower-harmonics (p < 0.05, Bonferroni-corrected) and increased higher-harmonics (p < 0.01, Bonferroni-corrected), with non-significant effects at intermediate bins. These energy-distribution changes were robust to the choice of structural connectome: results were replicated when using the 985-subject HCP connectome. A degree-preserving randomisation of the connectome failed to reproduce the low-frequency energy loss, supporting the importance of the actual white-matter topology. Using PLS-DA to summarise multivariate connectome harmonic patterns, the DMT-versus-placebo multivariate signature aligned strongly and positively with previously reported psychedelic signatures for LSD (LSD vs placebo; p < 0.00001) and ketamine (ketamine vs placebo; p < 0.00001). Conversely, the DMT signature was the opposite of signatures distinguishing wakefulness from propofol anaesthesia (awake vs propofol; p < 0.00001) and of fMRI-responsive versus unresponsive disorders-of-consciousness patients (DOC fMRI+ vs fMRI-; p < 0.00001). These relationships also held when analyses used the larger HCP-derived connectome. Connectome-harmonic repertoire entropy increased under DMT. Specific comparisons reported: pre/post DMT p = 0.0001 (increase), pre/post placebo p = 0.9278 (no change), pre placebo/post DMT p = 0.0003, post placebo/post DMT p < 0.0001. The difference in pre–post DMT versus pre–post placebo was significant (p < 0.00001). These entropy results were consistent when the larger HCP connectome was used. Time-resolved analyses linked neural CH measures to subjective experience. Individual-level correlations between CH repertoire entropy timecourses and minute-by-minute intensity ratings were significant in roughly half of participants; the distribution of individual correlation coefficients was significantly greater than zero at the group level (t-test p = 0.00002). For the energy-spectrum difference signature (the PLS-DA projection reflecting the psychedelic pattern), five individuals showed significant within-subject correlations with intensity ratings, and the group-level test of those correlations was significant (t-test p = 0.013). The investigators also report that EEG Lempel–Ziv (LZ) complexity correlated with CH repertoire entropy at the group level for DMT (Spearman correlations reported as p < 0.001 and p < 0.0001 for relevant contrasts), whereas no such correlation was observed for placebo. At the subject level, however, CH repertoire entropy did not significantly correlate with self-reported ‘‘richness of the experience’’, unlike earlier reports linking richness to LZ complexity. Sensitivity analyses showed the main findings generalised to a 25-bin decomposition. The randomised-connectome control failed to reproduce the low-frequency suppression and did not capture the DMT relationships with ketamine or disorders of consciousness, supporting the specificity of the CHD results to true structural connectome topology.

Vohryzek and colleagues interpret their findings as evidence that intravenous DMT substantially reshapes the brain's connectome harmonic landscape in a manner consistent with other psychedelics. The principal neural signatures observed were a suppression of low-frequency (coarse-grained) connectome harmonics together with an increase in high-frequency (fine-grained) harmonics, and a concurrent increase in the entropy of the connectome-harmonic repertoire. The investigators note these changes are analogous to prior CHD findings in psilocybin, LSD and ketamine, and that multivariate harmonic signatures distinguishing DMT from placebo align positively with psychedelic signatures and oppose signatures of reduced consciousness such as propofol anaesthesia and certain disorders of consciousness. Crucially, the researchers highlight the time-resolved coupling between CHD measures and subjective intensity: both repertoire entropy and the energy-spectrum difference tracked minute-by-minute intensity ratings within individuals and at the group level, indicating a close temporal relationship between the connectome-harmonic reorganisation and the phenomenology of the DMT experience. A cross-modal relationship was also observed between fMRI-derived CH repertoire entropy and EEG Lempel–Ziv complexity, suggesting that CHD captures aspects of neural complexity that relate to established electrophysiological measures. The discussion situates CHD among other structure–function approaches, noting that connectome harmonics extend spherical-harmonic-like representations by embedding both local grey-matter geometry and long-range white-matter connectivity. The failure of randomised connectome bases to reproduce the effects is emphasised as evidence for the role of real long-range connectivity in shaping psychedelic states. The authors also relate their findings to the entropic brain hypothesis, arguing that increased repertoire entropy aligns with the idea that psychedelics increase the richness or diversity of spontaneous brain dynamics. Limitations acknowledged in the extracted text include the single-blind design and a modest final sample size (17 participants for main analyses and 14 for time-resolved analyses), arising from dropouts and motion-related exclusions, which the investigators concede reduces statistical power. The authors recommend future studies incorporate additional control conditions that manipulate arousal (for example stimulants such as modafinil or caffeine) to dissociate arousal-related effects from psychedelic-specific signatures; they note an existing example where methylphenidate controlled for arousal but did not reproduce psychedelic functional changes. Despite the sample-size limitation, the researchers argue that the observed effects are robust and reproducible across connectome choices and multiple analytical checks.