Observational study finds an exploratory link between spectral slope and TMS complexity fails blind preregistered replication, highlighting methodological risks in complexity metrics.
Simulation work (companion papers) indicates that perturbational complexity — the quantity behind the clinically validated PCI family of consciousness measures — reflects the reproducible dimensionality of a system's causal response, maximal at the edge of chaos on its stable side, with excitation/inhibition balance controlling the distance to that edge. This predicts that, across awake humans, individuals whose spontaneous cortical dynamics sit closer to the edge should produce longer-lasting and more complex evoked responses. We tested this in the open TMS-EEG dataset of Biabani et al. (three samples: n = 29, 94, 12; 62 channels; prefrontal, premotor and parietal stimulation), using the pre-stimulus spectral slope (3–40 Hz, alpha excluded) — an established proxy of E/I ratio — as the distance-to-edge variable, and standard PCIst of the evoked response as the complexity readout. A flatter resting slope predicted higher evoked PCIst in the discovery sample (Spearman ρ = +0.42, p = 0.024, n = 29) and replicated in the independent large sample (ρ = +0.47, p < 10⁻⁴, n = 94); the third sample (n = 12) was uninformative (ρ = +0.03, wide CI), as expected at that size. Three controls address the main artifact routes: the slope did not predict a matched pre-stimulus null PCIst (ρ = −0.14/−0.20, n.s. — ruling out generic data-quality coupling); the association survived partialing out baseline RMS, a proxy for trial count (partial ρ = +0.33, p = 0.0012); and a mechanistic intermediate emerged — flatter slopes predicted longer-persisting evoked responses (ρ = +0.34, p = 0.0008), and response persistence predicted complexity (ρ = +0.32, p = 0.0017; ρ = +0.71, p < 10⁻⁴ in the discovery sample) — the critical-slowing signature expected if flatter spectra index proximity to instability. Secondarily, in the sample with realistic sham (sensory-matched control stimulation, no noise masking), sham evoked PCIst was statistically indistinguishable from real TMS (median 41.4 vs 42.8, paired p = 0.09, n = 48 site×subjects), quantifying at the level of the index itself how much of "perturbational" complexity sensory co-stimulation can carry without masking. We then performed the definitive test: a blind, preregistered confirmation on an independent trial-level dataset (ds008037, same laboratory, CC0; 30 subjects; analysis plan, windows, thresholds and direction frozen before download; pilot subject excluded; trial counts equalized at 60; debiased PCIst-XV as readout). The association did not confirm: Spearman ρ = +0.031, one-sided p = 0.43 — a clean null at ~80% power for the exploratory effect size, with the trial-rejection confound check clean. The exploratory association — replicated across two samples, surviving three artifact controls, p < 10⁻⁴ — did not survive the one test that could not flatter it. The confirmatory design changed three things at once (true resting-state slope instead of averaged-baseline slope; debiased instead of standard estimator; new sample), and a labeled post-hoc decomposition measuring all four variable combinations in the same subjects is reported to localize the broken link — including the possibility, consistent with our companion paper, that the selection bias of the standard estimator participated in manufacturing the original association. We publish the full arc as a case study in why internal controls and replication, without blind preregistered confirmation, are not enough. The realistic-sham finding (sensory-only stimulation reproducing most of the perturbational complexity value without masking) is independent of the failed association and stands.
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Nicolás Federico Galindez (2026) studied this question.
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