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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
ORIGINAL RESEARCH

Abstract

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.

Keywords

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

Abbreviations

GAD

generalized anxiety disorder

HCs

health controls

VTA

ventral tegmental area

DSM-5TM

Diagnostic and Statistical Manual of Mental Disorders

MINI

Mini-International Neuropsychiatric Interview

HAMA

Hamilton Anxiety Rating Scale

EPI

echo planar imaging

FOV

field of view

TR

repetition time

TE

echo time

FA

flip angle

DICOM

Digital Imaging and Communications in Medicine

MNI

Montreal Neurological Institute

FWHM

full width at half maximum

SPSS21

Statistical Package for the Social Sciences21

ROC

receiver operating characteristic

AUC

areas under curves

PMC

premotor cortex

vlPFC

ventrolateral prefrontal cortex

MFC

medial frontal cortex

OFC

orbitofrontal cortex

PCC

posterior cingulate cortex

Notes

Acknowledgements

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.

Funding

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)

References

  1. Aizawa, H., Amo, R., & Okamoto, H. (2011). Phylogeny and ontogeny of the habenular structure. Frontiers in Neuroscience, 5, 138.  https://doi.org/10.3389/fnins.2011.00138.CrossRefGoogle Scholar
  2. APA, A. P. A. (2013). Diagnostic and statistical manual of mental disorders (Fifth ed.). American Psychiatric Publishing, p. 189.Google Scholar
  3. Arend, I., Rafal, R., & Ward, R. (2008). Spatial and temporal deficits are regionally dissociable in patients with pulvinar lesions. Brain, 131(8), 2140–2152.  https://doi.org/10.1093/brain/awn135.CrossRefGoogle Scholar
  4. Ball, T. M., Ramsawh, H. J., Campbell-Sills, L., Paulus, M. P., & Stein, M. B. (2013). Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders. Psychological Medicine, 43(7), 1475–1486.  https://doi.org/10.1017/s0033291712002383.CrossRefGoogle Scholar
  5. Benarroch, E. E. (2015). Habenula: Recently recognized functions and potential clinical relevance. Neurology, 85(11), 992–1000.  https://doi.org/10.1212/wnl.0000000000001937.CrossRefGoogle Scholar
  6. Calhoon, G. G., & Tye, K. M. (2015). Resolving the neural circuits of anxiety. Nature Neuroscience, 18(10), 1394–1404.  https://doi.org/10.1038/nn.4101.CrossRefGoogle Scholar
  7. Chan, J., Ni, Y., Zhang, P., Zhang, J., & Chen, Y. (2017). D1-like dopamine receptor dysfunction in the lateral habenula nucleus increased anxiety-like behavior in rat. Neuroscience, 340, 542–550.  https://doi.org/10.1016/j.neuroscience.2016.11.005.CrossRefGoogle Scholar
  8. Danielmeier, C., Eichele, T., Forstmann, B. U., Tittgemeyer, M., & Ullsperger, M. (2011). Posterior medial frontal cortex activity predicts post-error adaptations in task-related visual and motor areas. The Journal of Neuroscience, 31(5), 1780–1789.  https://doi.org/10.1523/jneurosci.4299-10.2011.CrossRefGoogle Scholar
  9. Di Bono, M. G., Priftis, K., & Umiltà, C. (2017). Bridging the gap between brain activity and cognition: Beyond the different tales of fMRI data analysis. [Opinion]. Frontiers in Neuroscience, 11(31).  https://doi.org/10.3389/fnins.2017.00031.
  10. Diekhof, E. K., & Gruber, O. (2010). When desire collides with reason: Functional interactions between anteroventral prefrontal cortex and nucleus accumbens underlie the human ability to resist impulsive desires. The Journal of Neuroscience, 30(4), 1488–1493.  https://doi.org/10.1523/JNEUROSCI.4690-09.2010.CrossRefGoogle Scholar
  11. Drabant, E. M., Kuo, J. R., Ramel, W., Blechert, J., Edge, M. D., Cooper, J. R., et al. (2011). Experiential, autonomic, and neural responses during threat anticipation vary as a function of threat intensity and neuroticism. Neuroimage, 55(1), 401–410.  https://doi.org/10.1016/j.neuroimage.2010.11.040.CrossRefGoogle Scholar
  12. Ely, B. A., Xu, J., Goodman, W. K., Lapidus, K. A., Gabbay, V., & Stern, E. R. (2016). Resting-state functional connectivity of the human habenula in healthy individuals: Associations with subclinical depression. Human Brain Mapping, 37(7), 2369–2384.  https://doi.org/10.1002/hbm.23179.CrossRefGoogle Scholar
  13. Erpelding, N., Sava, S., Simons, L. E., Lebel, A., Serrano, P., Becerra, L., & Borsook, D. (2014). Habenula functional resting-state connectivity in pediatric CRPS. Journal of Neurophysiology, 111(2), 239–247.  https://doi.org/10.1152/jn.00405.2013.CrossRefGoogle Scholar
  14. Fan, L., Li, H., Zhuo, J., Zhang, Y., Wang, J., Chen, L., et al. (2016). The human Brainnetome atlas: A new brain atlas based on connectional architecture. Cerebral Cortex, 26(8), 3508–3526.  https://doi.org/10.1093/cercor/bhw157.CrossRefGoogle Scholar
  15. Fiorillo, C. D. (2013). Two dimensions of value: Dopamine neurons represent reward but not aversiveness. Science, 341(6145), 546–549.  https://doi.org/10.1126/science.1238699.CrossRefGoogle Scholar
  16. Guo, X., Meng, Z., Huang, G., Fan, J., Zhou, W., Ling, W., et al. (2016). Meta-analysis of the prevalence of anxiety disorders in mainland China from 2000 to 2015. Scientific Reports, 6, 28033.  https://doi.org/10.1038/srep28033.CrossRefGoogle Scholar
  17. Herkenham, M., & Nauta, W. J. (1977). Afferent connections of the habenular nuclei in the rat. A horseradish peroxidase study, with a note on the fiber-of-passage problem. The Journal of Comparative Neurology, 173(1), 123–146.  https://doi.org/10.1002/cne.901730107.CrossRefGoogle Scholar
  18. Hetu, S., Luo, Y., Saez, I., D'Ardenne, K., Lohrenz, T., & Montague, P. R. (2016). Asymmetry in functional connectivity of the human habenula revealed by high-resolution cardiac-gated resting state imaging. Human Brain Mapping, 37(7), 2602–2615.  https://doi.org/10.1002/hbm.23194.CrossRefGoogle Scholar
  19. Hikosaka, O. (2010). The habenula: From stress evasion to value-based decision-making. Nature Reviews. Neuroscience, 11(7), 503–513.  https://doi.org/10.1038/nrn2866.CrossRefGoogle Scholar
  20. Hoffman, D. L., Dukes, E. M., & Wittchen, H.-U. (2008). Human and economic burden of generalized anxiety disorder. Depression and Anxiety, 25(1), 72–90.  https://doi.org/10.1002/da.20257.CrossRefGoogle Scholar
  21. Hong, S., Jhou, T. C., Smith, M., Saleem, K. S., & Hikosaka, O. (2011). Negative reward signals from the lateral Habenula to dopamine neurons are mediated by Rostromedial tegmental nucleus in primates. Journal of Neuroscience, 31(32), 11457–11471.  https://doi.org/10.1523/jneurosci.1384-11.2011.CrossRefGoogle Scholar
  22. Jacinto, L. R., Mata, R., Novais, A., Marques, F., & Sousa, N. (2017). The habenula as a critical node in chronic stress-related anxiety. Experimental Neurology, 289, 46–54.CrossRefGoogle Scholar
  23. Kang, S., Li, J., Bekker, A., & Ye, J. H. (2018). Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats. Neuropharmacology, 129, 47–56.  https://doi.org/10.1016/j.neuropharm.2017.11.013.CrossRefGoogle Scholar
  24. Kelley, W. M., Macrae, C. N., Wyland, C. L., Caglar, S., Inati, S., & Heatherton, T. F. (2002). Finding the self? An event-related fMRI study. Journal of Cognitive Neuroscience, 14(5), 785–794.  https://doi.org/10.1162/08989290260138672.CrossRefGoogle Scholar
  25. Kim, J. W., Naidich, T. P., Joseph, J., Nair, D., Glasser, M. F., O'Halloran, R., ... Xu, J. (2018). Reproducibility of myelin content-based human habenula segmentation at 3 Tesla. doi:  https://doi.org/10.1002/hbm.24060.
  26. Kringelbach, M. L. (2005). The human orbitofrontal cortex: Linking reward to hedonic experience. Nature Reviews Neuroscience, 6, 691.  https://doi.org/10.1038/nrn1747.CrossRefGoogle Scholar
  27. Levy, B. J., & Wagner, A. D. (2011). Cognitive control and right ventrolateral prefrontal cortex: Reflexive reorienting, motor inhibition, and action updating. Annals of the New York Academy of Sciences, 1224(1), 40–62.  https://doi.org/10.1111/j.1749-6632.2011.05958.x.CrossRefGoogle Scholar
  28. Makovac, E., Meeten, F., Watson, D. R., Herman, A., Garfinkel, S. N., H, D. C., & Ottaviani, C. (2016). Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder. Biological Psychiatry, 80(10), 786–795.  https://doi.org/10.1016/j.biopsych.2015.10.013.CrossRefGoogle Scholar
  29. Maner, J. K., Richey, J. A., Cromer, K., Mallott, M., Lejuez, C. W., Joiner, T. E., & Schmidt, N. B. (2007). Dispositional anxiety and risk-avoidant decision-making. Personality and Individual Differences, 42(4), 665–675.  https://doi.org/10.1016/j.paid.2006.08.016.CrossRefGoogle Scholar
  30. Markovic, V., Agosta, F., Canu, E., Inuggi, A., Petrovic, I., Stankovic, I., et al. (2017). Role of habenula and amygdala dysfunction in Parkinson disease patients with punding. Neurology, 88(23), 2207–2215.  https://doi.org/10.1212/wnl.0000000000004012.CrossRefGoogle Scholar
  31. Mathuru, A. S., & Jesuthasan, S. (2013). The medial habenula as a regulator of anxiety in adult zebrafish. Front Neural Circuits, 7, 99.  https://doi.org/10.3389/fncir.2013.00099.CrossRefGoogle Scholar
  32. Matsumoto, M., & Hikosaka, O. (2009). Representation of negative motivational value in the primate lateral habenula. Nature Neuroscience, 12(1), 77–84.  https://doi.org/10.1038/nn.2233.CrossRefGoogle Scholar
  33. Menon, V. (2011). Large-scale brain networks and psychopathology: A unifying triple network model. Trends in Cognitive Sciences, 15(10), 483–506.  https://doi.org/10.1016/j.tics.2011.08.003.CrossRefGoogle Scholar
  34. Miu, A. C., Heilman, R. M., & Houser, D. (2008). Anxiety impairs decision-making: Psychophysiological evidence from an Iowa gambling task. Biological Psychology, 77(3), 353–358.  https://doi.org/10.1016/j.biopsycho.2007.11.010.CrossRefGoogle Scholar
  35. Moon, C. M., Kim, G. W., & Jeong, G. W. (2014). Whole-brain gray matter volume abnormalities in patients with generalized anxiety disorder: Voxel-based morphometry. Neuroreport, 25(3), 184–189.  https://doi.org/10.1097/wnr.0000000000000100.CrossRefGoogle Scholar
  36. Peterson, D. A., Lotz, D. T., Halgren, E., Sejnowski, T. J., & Poizner, H. (2011). Choice modulates the neural dynamics of prediction error processing during rewarded learning. Neuroimage, 54(2), 1385–1394.  https://doi.org/10.1016/j.neuroimage.2010.09.051.CrossRefGoogle Scholar
  37. Pobbe, R. L., & Zangrossi, H., Jr. (2008). Involvement of the lateral habenula in the regulation of generalized anxiety- and panic-related defensive responses in rats. Life Sciences, 82(25–26), 1256–1261.  https://doi.org/10.1016/j.lfs.2008.04.012.CrossRefGoogle Scholar
  38. Proulx, C. D., Hikosaka, O., & Malinow, R. (2014). Reward processing by the lateral habenula in normal and depressive behaviors. Nature Neuroscience, 17(9), 1146–1152.  https://doi.org/10.1038/nn.3779.CrossRefGoogle Scholar
  39. Qiao, J., Li, A., Cao, C., Wang, Z., Sun, J., & Xu, G. (2017). Aberrant functional network connectivity as a biomarker of generalized anxiety disorder. Frontiers in Human Neuroscience, 11, 626.  https://doi.org/10.3389/fnhum.2017.00626.CrossRefGoogle Scholar
  40. Raichle, M. E. (2015). The brain's default mode network. Annual Review of Neuroscience, 38, 433–447.  https://doi.org/10.1146/annurev-neuro-071013-014030.CrossRefGoogle Scholar
  41. Ridderinkhof, K. R., Nieuwenhuis, S., & Braver, T. S. (2007). Medial frontal cortex function: An introduction and overview. Cognitive, Affective, & Behavioral Neuroscience, 7(4), 261–265.CrossRefGoogle Scholar
  42. Song, X. W., Dong, Z. Y., Long, X. Y., Li, S. F., Zuo, X. N., Zhu, C. Z., et al. (2011). REST: A toolkit for resting-state functional magnetic resonance imaging data processing. PLoS One, 6(9), e25031.  https://doi.org/10.1371/journal.pone.0025031.CrossRefGoogle Scholar
  43. Stephenson-Jones, M., Floros, O., Robertson, B., & Grillner, S. (2012). Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems. Proceedings of the National Academy of Sciences of the United States of America, 109(3), E164–E173.  https://doi.org/10.1073/pnas.1119348109.CrossRefGoogle Scholar
  44. Strawn, J. R., Wehry, A. M., Chu, W. J., Adler, C. M., Eliassen, J. C., Cerullo, M. A., et al. (2013). Neuroanatomic abnormalities in adolescents with generalized anxiety disorder: A voxel-based morphometry study. Depression and Anxiety, 30(9), 842–848.  https://doi.org/10.1002/da.22089.CrossRefGoogle Scholar
  45. Strotmann, B., Kogler, C., Bazin, P. L., Weiss, M., Villringer, A., & Turner, R. (2013). Mapping of the internal structure of human habenula with ex vivo MRI at 7T. Frontiers in Human Neuroscience, 7, 878.CrossRefGoogle Scholar
  46. Strotmann, B., Heidemann, R. M., Anwander, A., Weiss, M., Trampel, R., Villringer, A., & Turner, R. (2014). High-resolution MRI and diffusion-weighted imaging of the human habenula at 7 tesla. Journal of Magnetic Resonance Imaging, 39(4), 1018–1026.  https://doi.org/10.1002/jmri.24252.CrossRefGoogle Scholar
  47. Torrisi, S., Nord, C. L., Balderston, N. L., Roiser, J. P., Grillon, C., & Ernst, M. (2017). Resting state connectivity of the human habenula at ultra-high field. Neuroimage, 147, 872–879.  https://doi.org/10.1016/j.neuroimage.2016.10.034.CrossRefGoogle Scholar
  48. Ullsperger, M., Danielmeier, C., & Jocham, G. (2014). Neurophysiology of performance monitoring and adaptive behavior. Physiological Reviews, 94(1), 35–79.  https://doi.org/10.1152/physrev.00041.2012.CrossRefGoogle Scholar
  49. Wang, W., Hou, J., Qian, S., Liu, K., Li, B., Li, M., . . . Sun, G. (2016). Aberrant regional neural fluctuations and functional connectivity in generalized anxiety disorder revealed by resting-state functional magnetic resonance imaging. Neuroscience Letters, 624, 78–84. doi:  https://doi.org/10.1016/j.neulet.2016.05.005.CrossRefGoogle Scholar
  50. Wikenheiser, A. M., & Schoenbaum, G. (2016). Over the river, through the woods: Cognitive maps in the hippocampus and orbitofrontal cortex. Nature Reviews. Neuroscience, 17(8), 513–523.  https://doi.org/10.1038/nrn.2016.56.CrossRefGoogle Scholar
  51. Yang, Y., & Raine, A. (2009). Prefrontal structural and functional brain imaging findings in antisocial, violent, and psychopathic individuals: A meta-analysis. Psychiatry Research, 174(2), 81–88.  https://doi.org/10.1016/j.pscychresns.2009.03.012.CrossRefGoogle Scholar

Copyright information

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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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