Structure-function tethering of human locus coeruleus connectivity reveals a noradrenergic cortical hierarchy

The locus coeruleus (LC) is the primary source of cerebral norepinephrine and plays a broad role in cognition. Here, we show the macroscale organization of human LC connectivity using 7 T diffusion and resting-state functional magnetic resonance imaging (MRI). Structural and functional connectivity exhibit a dominant rostral-caudal gradient, with structure-function tethering lowest in the intermediate LC and increasing toward its rostral and caudal portions.

In the neocortex, this pattern is expressed as steeply increasing tethering from the central sulcus toward anterior and posterior regions. Allen Mouse Brain Connectivity Atlas tracing further reveals preferential LC projections to somatomotor cortex. The cortical expression of LC structure-function tethering exhibits a network-level hierarchy and aligns with a behavioral axis.

Additionally, this cortical expression shows significant spatial covariance with norepinephrine transporter concentration, fiber length, and gray matter volume. Together, these findings provide MRI-based evidence for a hierarchical macroscale organization of human LC connectivity linking structural and functional architecture to cortical and behavioral variation. This work was supported by the Brain Science and Brain-like Intelligence Technology—National Science and Technology Major Project (No. 2025ZD0215700), the Brain Science and Brain-like Intelligence Technology—National Science and Technology Major Project (No. 2022ZD0208500), the National Natural Science Foundation of China (NSFC; Nos. 62401456 to Y.L., 12305051 to N.Y., and 62601635 to L.F.), and the Shaanxi Provincial Key Research and Development Program, China (No. 2026CY-YBXM-884).

These authors contributed equally: Qian Zhu, Liming Fan. Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Health and Rehabilitation Science, School of Life Science and Technology, Xi’an Jiaotong University, Key Laboratory of Neuro-informatics & Rehabilitation Engineering of Ministry of Civil Affairs, Xi’an, Shaanxi, 710049, China Qian Zhu, Liming Fan, Yutong Wu, Simeng An, Ying Li, Hong Wang, Youjun Li & Zi-Gang Huang Research Center for Brain-inspired Intelligence, Xi’an Jiaotong University, Xi’an, Shaanxi, 710049, China Qian Zhu, Liming Fan, Yutong Wu, Simeng An, Ying Li, Youjun Li & Zi-Gang Huang Department of Medical Imaging, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710049, China Shaanxi University Key Laboratory of Photonic Power Devices and Discharge Regulation & School of Optoelectronic Science and Intelligent Instrumentation, Xi’an University of Technology, Xi’an, Shaanxi, 710048, China Correspondence to Youjun Li or Zi-Gang Huang. The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.