Linking hubness, embryonic neurogenesis, transcriptomics and diseases in human brain networks
Ibai Diez*1,2, Fernando Garcia-Moreno*3,4,5, Nayara Carral-Sainz6, Sebastiano Stramaglia7, Alicia Nieto-Reyes8, Mauro D’Amato5,9,10, Jesús Maria Cortes5,11,12,Paolo Bonifazi5,11,13
1Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
2Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
3Achucarro Basque Center for Neuroscience, Scientific Park of the University of the Basque Country (UPV/EHU), Leioa, Spain.
4Department of Neuroscience, Faculty of Medicine and Odontology, UPV/EHU, Barrio Sarriena s/n, Leioa, Bizkaia, Spain.
5IKERBASQUE: The Basque Foundation for Science, Bilbao, Spain.
6Departamento de Ciencias de la Tierra y Física de la Materia Condensada, Facultad de Ciencias, Universidad de Cantabria, Santander, Spain.
7Dipartimento Interateneo di Fisica, Università degli Studi di Bari Aldo Moro, and INFN, Sezione di Bari, Italy.
8Departamento de Matemáticas, Estadística y Computación, Facultad de Ciencias, Universidad de Cantabria, Santander, Spain.
9Department of Medicine and Surgery, LUM University, Casamassima, Italy.
10Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
11Computational Neuroimaging Lab, Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain.
12Department of Cell Biology and Histology, University of the Basque Country (UPV/EHU), Leioa, Spain.
13Department of Physics, University of Bologna, Italy.
* These authors contributed equally to this work; Corresponding author:paol.bonifazi@gmail.com
Intro. The human brain is organized across multiple spatial scales, where micro-scale circuits integrate into macro-scale networks via long-range connections. Understanding the connectivity rules shaping networks is key to deciphering brain function and the effects of neurological damage. Previous studies have explored brain network maturation, but a link between adult connectivity and the sequential evolutionarily preserved neurogenesis remains unestablished. Inspired by the preferential attachment model in network science shaped by the “rich gets richer” principle 1, this study2hypothesizes that brain network topology follows an "older gets richer" principle, where earlier-developed circuits play central roles in adult connectivity. Our hypothesis extrapolates on the macro-scale level previous evidence that hippocampal hubs are early born GABAergic neurons3-5.
Methods. Brain circuits were categorized by their First neurogenic Time (FirsT), determined from developmental neuromeres. Eighteen macro-circuits (MACs) were identified based on available neurodevelopmental data. Structural and functional brain networks were reconstructed using 7-Tesla dMRI and resting-state fMRI from 184 subjects. Connectivity metrics were assessed at high (2,566 ROIs) and low (18 MACs) resolutions. Eigenvector centrality was calculated for each ROI and MAC, with correlations between FirsT and connectivity patterns. Brain transcriptomic data were mapped to connectivity metrics, and enrichment analysis identified associated biological processes and disease relevance.
Results. Significant correlations between structural connectivity and FirsT supported the "older gets richer" principle, with early-born circuits exhibiting higher structural hubness. In contrast, functional centrality was positively correlated with FirsT, highlighting late-maturing circuits' functional prominence. Connectivity strength was stronger among circuits with similar neurogenic timing, supporting a "preferential age attachment" mechanism. Gene expression analysis revealed correlations with FirsT and connectivity metrics, with enriched pathways linked to neurodevelopment, synaptic function, and neuropsychiatric disorders. Disease-associated genes (e.g., APOE for Alzheimer’s, SCN1A for epilepsy) showed significant enrichment at correlation extremes, suggesting differential genetic influences on brain network organization and pathology susceptibility.
Discussion. The study examines adult brain networks reconstructed from MRI to analyze how early neurogenesis affects structural and functional connectivity. Structural findings confirm that older brain regions act as stronger hubs ("older gets richer"). Functional and structural networks follow a "preferential age attachment" rule, linking neurogenesis timing to network topology. Genetic analysis ties neurodevelopmental disorders to network centrality, highlighting disease-linked transcriptional alterations.
Acknowledgements
We thank M De Pittá, D Papo, D Marinazzo, A Mazzoni, Y Ben-Ari for comments. Funds: ANR by MCIN/AEI/10.13039/501100011033 and “ERDF”; PB by Ikerbasque, the Ministerio Economia, Industria y Competitividad (MICINN, Spain) and Maratoia EITB (grant PID2021-127163NB-I00 and BIO22/ALZ/010/BCB);FGMby Ikerbasque, MICINN(grant PID2021-125156NB-I00) andBasque Gov (grant PIBA_2022_1_0027).
References
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