Mapping Consistent, Reproducible, and Transcriptionally Relevant Connectome Hubs of the Human Brain

Abstract

AbstractMacroscopic functional connectomic analyses have identified sets of densely connected regions in the human brain, known as connectome hubs, which play a vital role in understanding network communication, cognitive processing, and brain disorders. However, anatomical locations of functional connectome hubs are largely inconsistent and less reproducible among extant reports, partly due to inadequate sample size and differences in image processing and network analysis. Moreover, the genetic signatures underlying robust connectome hubs remain unknown. Here, we conduct the first worldwide voxelwise meta-connectomic analysis by pooling resting-state functional MRI data of 5,212 healthy young adults across 61 independent international cohorts with harmonized image processing and network analysis protocols. We identify highly consistent and reproducible functional connectome hubs that are spatially distributed in multiple heteromodal and unimodal regions, with the most robust findings mainly located in lateral parietal regions. These connectome hubs show unique, heterogeneous connectivity profiles and are critical for both intra- and inter-network communications. Using transcriptome data from the Allen Human Brain Atlas and BrainSpan Atlas as well as machine learning approaches, we demonstrate that these hubs are significantly associated with a transcriptomic pattern dominated by genes involved in the neuropeptide signaling pathway, neurodevelopmental processes, and cellular metabolic processes. This pattern represents microstructural and metabolic substrates underlying the development and functioning of brain hubs. Together, these results highlight the robustness of macroscopic connectome hubs of the human brain and their potential cellular and molecular underpinnings and have implications for understanding how brain hubs support the connectome organization in health and disease.SignificanceThe resting human brain includes some densely connected regions, known as functional connectome hubs. However, anatomical locations of these hubs are largely inconsistent and less reproducible among extant reports and the genetic signatures underlying hubs remain unknown. We identify highly consistent and reproducible hubs using a harmonized meta-connectomic analysis. These hubs are primarily located in heteromodal and unimodal regions and show unique, heterogeneous connectivity profiles. These hubs are also significantly associated with a transcriptomic pattern dominated by genes involved in the neuropeptide signaling pathway, neurodevelopmental processes, and cellular metabolic processes. These results highlight macroscopic hubs’ robustness and their potential microstructural and metabolic substrates and have implications for understanding how brain hubs develop and function in health and disease.