The blueprint of human functional architecture shifts from cognition to anatomy during perturbations of consciousness
Andrea I. Luppi, Dragana Manasova, Justine Y. Hansen, Zhen-Qi Liu, Asa Farahani, Yonatan Sanz Perl, Jakub Vohryzek, Daniel Golkowski, Andreas Ranft, Rüdiger Ilg, Denis Jordan, Vincent Bonhomme, Audrey Vanhaudenhuyse, Athena Demertzi, Oceane Jaquet, Mohamed Ali Bahri, Naji L. N. Alnagger, Paolo Cardone, Lorina Naci, Adrian M. Owen, John D. Pickard, Guy B. Williams, Judith Allanson, Enrico Amico, Danilo Bzdok, Jacobo D. Sitt, David K. Menon, Emmanuel A. Stamatakis, Bratislav Misic
bioRxiv Preprint Server June 7, 2026 preprint DOI: 10.64898/2026.06.07.730661 via bioRxiv
Summary
Functional connectivity in the awake human brain is shaped primarily by cognitive co-activation—the tendency of brain regions to work together during mental tasks—more than by structural or molecular constraints. This predominance is systematically lost across five datasets involving pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anesthesia with sevoflurane, propofol, or ketamine), when cognition is disconnected from the environment or abolished. During such states, the predictors of functional architecture shift away from cognitive co-activation and toward anatomical and molecular constraints.
Study at a glance
| Characteristics | Observational study |
|---|---|
| Key finding | Cognitive co-activation is the dominant predictor of inter-regional fMRI synchrony in the awake human brain, but this predominance is systematically obliterated during pharmacological and pathological perturbations of consciousness. |
Abstract
Consciousness and cognition arise from the ongoing interactions between brain regions. Synchronous fluctuations of fMRI signals may indicate that two brain regions perform similar cognitive functions, but neural interactions are also constrained by anatomical connectivity and regions’ molecular, cytoarchitectonic, and metabolic profiles. Here we disentangle the respective contributions of ongoing cognition and multimodal neurobiological constraints in shaping functional connectivity. We jointly contextualise haemodynamic FC against eight distinct multimodal representations of the human connectome: (i) structural connectivity from diffusion tractography; (ii) spatial embedding; (iii) similarity of transcriptional profiles from gene expression; (iv) similarity of receptor profiles from Positron Emission Tomography; (v) laminar profile similarity from histology; (vi) correlated electrophysiological activity from magnetoencephalography; (vii) correlated metabolic activity from PET glucose uptake; (viii) coordinated activation across 123 cognitive operations from the NeuroSynth meta-analytic engine. We demonstrate that cognitive co-activation is the dominant predictor of inter-regional fMRI synchrony in the awake human brain, even when quantified using intracranial electrical stimulation. Crucially, this predominance of cognitive co-activation for shaping functional connectivity is systematically obliterated across five datasets of pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anaesthesia with sevoflurane, propofol, or ketamine) when cognition is disconnected from the environment or altogether abolished. Altogether, we show that multimodal predictors of functional architecture shift away from cognitive co-activation and toward anatomicalmolecular constraints during pharmacological and pathological perturbations of consciousness.