Identifying generalized anxiety disorder using resting state habenular circuitry

  • Zijuan Ma
  • Yuan Zhong
  • Christina S. Hines
  • Yun Wu
  • Yuting Li
  • Manlong Pang
  • Jian Li
  • Chiyue Wang
  • Peter T. Fox
  • Ning Zhang
  • Chun WangEmail author


Studies identify the habenula as a key subcortical component in anxiety, with a role in predicting error coding within the evaluative system. However, no clinical reports of generalized anxiety disorder (GAD) describe resting state functional connectivity of habenular circuits. We hypothesized that resting-state functional connectivities of habenula would show differences in neuroanatomical correlates of the evaluative system (prefrontal cortex, habenula) of patients with GAD. We obtained 22 patients with GAD and 21 HCs, matched for gender, age, and years of education. Resting-state functional connectivity of the habenula was assessed using a seed-based template imposed on whole brain MRI, which provided an objective and semi-automated segmentation algorithm in MNI space. Patients with GAD demonstrated enhanced connectivities in the bilateral premotor cortex, right ventrolateral prefrontal cortex, medial frontal cortex, as well as the left orbitofrontal cortex, and reduced connectivities in the left posterior cingulate cortex, and right pulvinar. Moreover, striking differences of abnormal connectivities between groups were observed via analysis of receiver operating characteristic curves (ROC) of statistically significant. These results including ROC curves suggest the potential importance of the habenula in evaluating and deciding to personally relevant reward-related information.


Generalized anxiety disorder Habenula Resting-state functional connectivity Reward circuit Evaluation system 



generalized anxiety disorder


health controls


ventral tegmental area


Diagnostic and Statistical Manual of Mental Disorders


Mini-International Neuropsychiatric Interview


Hamilton Anxiety Rating Scale


echo planar imaging


field of view


repetition time


echo time


flip angle


Digital Imaging and Communications in Medicine


Montreal Neurological Institute


full width at half maximum


Statistical Package for the Social Sciences21


receiver operating characteristic


areas under curves


premotor cortex


ventrolateral prefrontal cortex


medial frontal cortex


orbitofrontal cortex


posterior cingulate cortex



This work was supported by the Nanjing Brain Hospital Affiliated to Nanjing Medical University. Also, the protocol for the research project has been approved by a suitably constituted Ethics Committee of the Nanjing Brain Hospital Affiliated to Nanjing Medical University. All co-authors listed have approved the manuscript that is enclosed and there is no financial interest to report. The views expressed in this paper are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.


This study was funded by National Natural Science Foundation of China (Grant 81571344, 81201064, 81871344); Natural Science Foundation of Jiangsu Province (Grant BK20161109); the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (Grant 18KJB190003); key research and development program (Social Development) project of Jiangsu province (Grant BE20156092015).

Compliance with ethical standards

Conflict of interest

Author Yuan Zhong has received research grants from National Natural Science Foundation of China (Grant 81871344) and Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (Grant 18KJB190003). Author Chun Wang has received has received research grants from National Natural Science Foundation of China (Grant 81571344, 81201064) and Natural Science Foundation of Jiangsu Province (Grant BK20161109). Author Ning Zhang has received has received research grants from key research and development program (Social Development). project of Jiangsu province (Grant BE20156092015).

Author Zijuan Ma, Yuan Zhong, Christina S. Hines, Yun Wu, Yuting Li, Manlong Pang, Jian Li, Chiyue Wang, Peter T. Fox, Ning Zhang, Chun Wang declares that he/she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2019_55_MOESM1_ESM.docx (62 kb)
ESM 1 (DOCX 61 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Nanjing Brain Hospital Affiliated to Nanjing Medical UniversityNanjingChina
  2. 2.Functional Brain Imaging Institute of Nanjing Medical UniversityNanjingChina
  3. 3.School of PsychologyNanjing Normal UniversityNanjingChina
  4. 4.South Texas Veterans Healthcare SystemUniversity of Texas Health San AntonioSan AntonioUSA
  5. 5.Research Imaging InstituteUniversity of Texas Health San AntonioSan AntonioUSA

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