Lotter, L. D.; Shafiei, G.; Larabi, D.; Koushik, A.; Dipasquale, O.; Mehta, M.; Cercignani, M.; Sethi, A.; Harrison, N.; Holiga, S.; Umbricht, D.; Yakushev, I.; Muthukumaraswamy, S.; Forsyth, A.; Hipp, J. F.; Misic, B.; Caspers, S.; Koenig, J.; Patil, K. R.; Paquola, C.; Eickhoff, S. B.; Dukart, J.

The human brain is organized into interacting functional systems. Their underlying neurobiological mechanisms remain difficult to study in vivo1,2. Here, we adopt a topological framework to quantify the association between neurobiology and brain functional connectivity derived from both resting-state functional magnetic resonance imaging (rsfMRI) and magnetic encephalography (MEG). Across six healthy adult cohorts (n = 19-112), regional variation in rsfMRI connectivity robustly aligns with the distribution of neurotransmitter receptors and transporters. We find that low-frequency functional synchronization measured by rsfMRI is predominantly modulated by decreased regional availability of multiple receptors and transporters. These patterns are present in every single subject, replicate across all cohorts, and are mirrored in MEG, where high-frequency synchronization increases with availability of the same receptors and transporters. Most prominently, we observe noradrenergic modulation of functional connectivity in a sensorimotor-posterior-insular network that is consistently detected across individuals and is linked to autonomic arousal. In pharmacological and clinical samples, the associations are sensitive to manipulation of the respective neurotransmitter systems and are altered in patients with early psychosis, aligning with clinical symptomatology. These findings provide biological insight into typical and atypical functional organization of the human brain using a framework linking underlying neurobiology to the functional connectome (NEOFC).