Functional fractionation of large-scale brain networks in the human subcortex

Brain network mapping plays a crucial role in advancing our understanding of human brain organization and the neuroanatomic foundations of cognition. Historically, the identification of large-scale brain networks has focused on the cerebral cortex. Some cortical networks have been fractionated into subnetworks, yielding valuable insights into their domain-specific cognitive functions. In contrast, functional mapping of large-scale brain networks within subcortical regions remains an emerging and challenging field, hindered by a low signal-to-noise ratio in subcortical functional MRI data and an inability to distinguish networks with substantial spatiotemporal overlap. In this study, we fractionated and identified fifteen spatially overlapped and temporally correlated subnetworks, which can be categorized into four large-scale brain networks. The subcortical functional connectivity patterns of these subnetworks exhibited distinct, yet overlapping, spatial configurations, with widely connected hub nodes identified in the caudate, putamen, hippocampus, and thalamus. These subnetworks are highly reproducible across healthy human brains and provide normative functional atlases, which we release here as a resource for the academic community. As a proof-of-principle demonstration of how the atlases can be used to elucidate the pathophysiology of neuropsychiatric disorders, we show that the spatial patterns of the subnetworks predict the level of consciousness in patients with severe traumatic brain injury. These observations indicate a highly conserved and spatially overlapped subcortical functional architecture in the human brain, providing opportunities to elucidate pathophysiologic mechanisms and develop new neuromodulatory therapies for a broad spectrum of neuropsychiatric diseases.