TMS-EEG and resting-state EEG applied to Altered States of Consciousness: Oscillations, Complexity, and Phenomenology

Altered states of consciousness (ASCs) produced by serotonergic psychedelics such as psilocybin involve profound changes in mood, perception, self-awareness and sensory-emotional processing. Earlier research has shown that spontaneous electroencephalographic (EEG) signal diversity is elevated during these drug-induced ASCs compared with typical wakefulness and dreaming; however, it is unclear whether that increased diversity reflects richer causal interactions across brain regions or instead arises from more unstructured or chaotic neuronal activity. Measuring the brain's response to direct perturbations with Transcranial Magnetic Stimulation (TMS) and analysing the ensuing EEG response provides a way to probe causal interactions and integration, quantified here by the Perturbational Complexity Index (PCI), as distinct from spontaneous measures such as Lempel-Ziv complexity (LZc). Ort and colleagues set out to test whether the dissociation previously observed between spontaneous EEG diversity and perturbational complexity during sub‑anesthetic ketamine also holds for a classical 5-HT2A agonist, psilocybin. Using a placebo-randomized, double-blind within-subject design, they compared spontaneous EEG and TMS-evoked EEG measures across key cortical sites and related neurophysiological changes to participants' reported phenomenology, aiming to distinguish chaotic ongoing activity from alterations in the underlying causal interactions that support consciousness.

The study used a within-subject, placebo-controlled double-blind design with N = 22 healthy participants, each completing two recording days separated by two weeks. On each day participants received either an oral moderate dose of psilocybin (mean 225 µg/kg) or placebo, with spontaneous EEG recorded about 60 minutes after ingestion and TMS-EEG sessions following in randomized order. Three cortical targets along the rostro-caudal axis were stimulated: premotor cortex (PM, BA 6), primary motor cortex (M1, BA 4) and primary somatosensory cortex (S1, BA 1–3). Each TMS-EEG session delivered 200 pulses per stimulation site with jittered inter-stimulus intervals (~2000–2500 ms), and stimulation parameters were adjusted using neuro-navigation and an operational EEG amplitude criterion (peak‑to‑peak ~10 μV within 20 trials). EEG and TMS-EEG data were preprocessed with standard pipelines: TMS artifacts were removed by signal mirroring and filtering, detrending and independent component analysis (ICA) were applied, data were downsampled to 1000 Hz and re-referenced to the channel average. Resting EEG epochs were 10 s long after artifact rejection. Key quantitative measures were PCI (source‑level perturbational complexity computed following Casali et al., 2013), PCI‑ST (a faster sensor-level state-transition variant), and LZc (Lempel‑Ziv complexity of concatenated binary sequences from resting EEG). Single-channel LZ (LZs) and a phase-shuffled normalisation (LZsN / LZcN) were used to probe the influence of oscillatory structure. Spectral analyses included global mean field power (GMFP) to summarise TMS-evoked global reactivity, event-related spectral perturbation (ERSP) for time-frequency TMS responses (Morlet wavelets, mean gERSP averaged across channels), and power spectral density (PSD) for resting-state band powers. The primary TMS-related spectral window of interest was empirically chosen as 10–25 Hz within 20–200 ms post-stimulus. Subjective experience was measured after recordings using the 11‑Dimensional Altered States of Consciousness (11D‑ASC) questionnaire. Statistical testing used t-tests, repeated-measures ANOVA and correlation analyses, with variables checked for normality by the Kolmogorov–Smirnov test and multiple-comparison corrections applied where relevant.

All participants completed both drug conditions (N = 22). PCI values computed at the source level were similar on and off psilocybin across stimulation sites: pairwise tests and ANOVA on PCI changes (psilocybin minus placebo) found no significant differences (one-way ANOVA: SS = 0.003, df = 2, MS = 0.002, F = 0.31, Prob>F = 0.73). Time-resolved PCI(t) grew at comparable rates under placebo and psilocybin, and PCI-ST at the sensor level likewise showed no significant drug effect. In contrast, spontaneous EEG LZc was significantly increased by psilocybin in the eyes-closed condition (P < 10-3) but not in eyes open. Under placebo, eye closure reduced LZc (P < 10-4), an effect absent after psilocybin. Single-channel LZs analyses, corrected for false discovery rate, identified significant LZs increases at posterior‑occipital and medial‑frontal electrodes during eyes closed (and to a lesser extent eyes open). Normalising LZs by phase-shuffling (LZsN) reduced the number and strength of affected channels, indicating a contribution of periodic signals to LZ metrics. TMS-evoked activity showed region-specific spectral changes: although total GMFP between 50–200 ms post‑stimulation did not differ significantly between drug conditions at any site, global ERSP analysis revealed increased TMS-related spectral power in the 10–25 Hz band during 20–200 ms post-stimulus under psilocybin. The increase reached statistical significance for M1 stimulation. Resting-state PSD analyses showed significant reductions in theta (4–8 Hz) and alpha (8–12 Hz) band power under psilocybin for both eyes-open and eyes-closed recordings. Subjectively, psilocybin produced robust phenomenological changes: 10 of 11 11D‑ASC subscales increased significantly (elementary and complex imagery, audio-visual synesthesia, disembodiment, changed meaning of percepts, cognitive impairment, unity, insightfulness, blissfulness and spiritual experience); only Anxiety was not significantly altered after correction for multiple comparisons. Neurophenomenological associations were strongest between relative changes in TMS-evoked 10–25 Hz ERSP power and subjective ratings: relative change in ERSP power after PM stimulation correlated strongly and negatively with Blissfulness (R = −0.924, P < 10-6) and with Unity (N = 17, R = −0.7, P = 0.001). Changes in spontaneous or evoked complexity measures showed no Pearson correlations ≥ 0.5 with 11D‑ASC scores.

Ort and colleagues interpret their findings as demonstrating a dissociation between spontaneous signal diversity and perturbational complexity during psilocybin-induced ASCs. Specifically, increased LZc at rest alongside stable PCI suggests that psilocybin makes ongoing brain activity more temporally differentiated or noisy while leaving the brain's capacity for integrated causal interactions intact; PCI here is taken as an index more directly tied to causal integration. The result replicates findings previously reported for sub‑anesthetic ketamine, implying that increased spontaneous diversity with preserved PCI may be a reproducible feature across pharmacologically distinct ASCs. The authors relate increased LZc to reductions in oscillatory synchrony, particularly alpha-band power: during placebo, eye closure typically increases alpha and reduces LZc, whereas psilocybin reduces alpha power and abolishes that LZc decrease. Phase-shuffle normalisation attenuated LZ effects, supporting the idea that diminished periodicity contributes to higher LZc. Despite lower spontaneous alpha, the TMS perturbation could still elicit enhanced oscillatory entrainment in similar frequency ranges, which may explain why evoked spectral power in the 10–25 Hz band increased even though resting rhythmicity decreased. This distinction illustrates the orthogonality between observational (resting EEG) and perturbational (TMS-EEG) approaches: spontaneous measures may not predict evoked dynamics, and a combined approach yields complementary insights. Regionally, psilocybin-modulated TMS-evoked 10–25 Hz activity in frontal areas correlated with phenomenological measures, notably Blissfulness and Unity, suggesting that frontal cortex dynamics may be particularly relevant to certain aspects of the psychedelic experience. The authors discuss a mechanistic account drawing on the "glutamatergic overspill" hypothesis—both ketamine and serotonergic hallucinogens might increase glutamatergic drive in medial prefrontal cortex (mPFC) circuits via effects on Layer 1 and Layer 5 pyramidal neurons and thalamocortical afferents—potentially lowering firing thresholds and increasing spontaneous firing. They note, however, that translating rodent circuit findings to human phenomenology remains uncertain. Finally, the investigators propose that PCI remains a reliable marker of whether awareness is present but is not specific to particular phenomenological contents. They advocate for multimodal perturbational and observational paradigms to capture the multidimensional, dynamic nature of ASCs and to better link regional neurophysiology with subjective experience.