Linking human brain functional connectivity to underlying neurotransmission
. 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).
Authors
- Arjun Sethi (ORCID: https://orcid.org/0000-0001-5352-4164)
- Casey Paquola (ORCID: https://orcid.org/0000-0002-0190-4103)
- Mara Cercignani (ORCID: https://orcid.org/0000-0002-4550-2456)
- Julian Koenig (ORCID: https://orcid.org/0000-0003-1009-9625)
- Abhay Koushik (ORCID: https://orcid.org/0000-0002-7181-3215)
- Štefan Holiga (ORCID: https://orcid.org/0000-0002-6248-2792)
- Anna Forsyth
- Ottavia Dipasquale (ORCID: https://orcid.org/0000-0002-2867-8222)
- Daniel Umbricht
- I Yakushev
- K Patil
- Suresh Muthukumaraswamy (ORCID: https://orcid.org/0000-0001-7042-3920)
- Mitul Mehta
- Leon D. Lotter (ORCID: https://orcid.org/0000-0002-2337-6073)
- Juergen Dukart (ORCID: https://orcid.org/0000-0003-0492-5644)
- Bratislav Misic (ORCID: https://orcid.org/0000-0003-0307-2862)
- Daouia Larabi (ORCID: https://orcid.org/0000-0001-7381-6076)
- Golia Shafiei (ORCID: https://orcid.org/0000-0002-2036-5571)
- Joerg F. Hipp
- Neil Harrison
- Svenja Caspers (ORCID: https://orcid.org/0000-0001-5083-4669)
- Simon B. Eickhoff
Institutions
- Roche (Switzerland) (CH)
- Montreal Neurological Institute and Hospital (CA)
- University of Auckland (NZ)
- University of Groningen (NL)
- Forschungszentrum Jülich (DE)
- King's College London (GB)
- University Hospital of Basel (CH)
- TUM Klinikum (DE)
- Olea Medical (France) (FR)
- Düsseldorf University Hospital (DE)
- Penn Center for AIDS Research (US)
- Max Planck Institute for Human Cognitive and Brain Sciences (DE)
- University Hospital Cologne (DE)
- Heinrich Heine University Düsseldorf (DE)
- Cardiff University (GB)
- University of Pennsylvania (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-05-01
- DOI
- https://doi.org/10.64898/2026.04.28.721294
- Primary Topic
- Functional Brain Connectivity Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00