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Deep brain stimulation of habenula reduces depressive symptoms and modulates brain activities in treatment-resistant depression

Nature Mental Health volume 2, pages 1045–1052 (2024)Cite this article

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Abstract

The habenula (Hb) is a phylogenetically old structure connecting forebrain and brainstem monoaminergic nuclei that has been implicated in the pathogenesis of depression. Here, to investigate the clinical efficacy and neural mechanisms of stimulating the Hb for alleviating depression symptoms in humans, we bilaterally implanted electrodes in six patients with treatment-resistant depression and delivered high-frequency stimulation. Compared to baseline, we observed a substantial reduction in Hamilton Depression Rating Scale scores: 62.1% at 1-month, 64.0% at 3-month and 66.2% at 6-month follow-up. Local field potential data showed that acute Hb stimulation increased theta-band power, especially in the right side, which was related to the following clinical remission. Moreover, functional magnetic resonance imaging data showed that acute Hb stimulation enhanced blood oxygen level-dependent responses of the medial orbitofrontal cortex, raphe and substantia nigra, which are important components of the dopaminergic and serotonergic systems. Our findings demonstrated that Hb stimulation can alleviate depressive symptoms and modulate the activity of the medial orbitofrontal cortex, raphe and substantia nigra in treatment-resistant depression patients. This trial was registered under the clinical trial numbers NCT03667872 and ChiCTR2100045363.

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Fig. 1: Equipment and experimental protocol.
Fig. 2: Individualized clinical outcomes.
Fig. 3: The modulation of PSD at the Hb by acute stimulation and its relationship with clinical improvements.
Fig. 4: Acute stimulation induced fALFF changes in key regions of the reward system at month 0.

Data availability

All data generated or analyzed are included in the manuscript and supporting files. Source data are provided with this paper.

Code availability

The publicly available software and code for the analysis has been described in Methods of our manuscript. The code for LFP analysis can be accessed at https://github.com/nercnlab/LFP-analysis/blob/main/Num_LFP%20analysis (ref. 50).

References

  1. Dandekar, M. P. et al. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol. Psychiatry 23, 1094–1112 (2018).

    Article  PubMed  Google Scholar 

  2. Hitti, F. L. et al. Deep brain stimulation is effective for treatment-resistant depression: a meta-analysis and meta-regression. J. Clin. Med. 9, 2796 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Holtzheimer, P. E. et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4, 839–849 (2017).

    Article  PubMed  Google Scholar 

  4. Coenen, V. A. et al. Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial. Neuropsychopharmacology 44, 1224–1232 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bergfeld, I. O. et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 73, 456–464 (2016).

    Article  PubMed  Google Scholar 

  6. Dougherty, D. D. et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol. Psychiatry 78, 240–248 (2015).

    Article  PubMed  Google Scholar 

  7. Voineskos, D., Daskalakis, Z. J. & Blumberger, D. M. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr. Dis. Treat. 16, 221–234 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Abraham, M. E. et al. Investigating deep brain stimulation of the habenula: a review of clinical studies. Neuromodulation 26, 292–301 (2023).

    Article  PubMed  Google Scholar 

  9. Germann, J. et al. Deep brain stimulation of the habenula: systematic review of the literature and clinical trial registries. Front. Psychiatry 12, 730931 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Proulx, C. D., Hikosaka, O. & Malinow, R. Reward processing by the lateral habenula in normal and depressive behaviors. Nat. Neurosci. 17, 1146–1152 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fakhoury, M. The habenula in psychiatric disorders: more than three decades of translational investigation. Neurosci. Biobehav. Rev. 83, 721–735 (2017).

    Article  PubMed  Google Scholar 

  12. Yang, Y. et al. Lateral habenula in the pathophysiology of depression. Curr. Opin. Neurobiol. 48, 90–96 (2018).

    Article  PubMed  Google Scholar 

  13. Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007).

    Article  PubMed  Google Scholar 

  14. Matsumoto, M. & Hikosaka, O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hu, H., Cui, Y. & Yang, Y. Circuits and functions of the lateral habenula in health and in disease. Nat. Rev. Neurosci. 21, 277–295 (2020).

    Article  PubMed  Google Scholar 

  16. Beier, K. T. et al. Circuit architecture of VTA dopamine neurons revealed by systematic input-output mapping. Cell 162, 622–634 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ren, J. et al. Anatomically defined and functionally distinct dorsal raphe serotonin subsystems. Cell 175, 472–487.e20 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cerniauskas, I. et al. Chronic stress induces activity, synaptic, and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors. Neuron 104, 899–915.e8 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Foster, S. et al. Abnormal habenula functional connectivity characterizes treatment-resistant depression. Neuroimage Clin. 34, 102990 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yang, Y. et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554, 317–322 (2018).

    Article  PubMed  Google Scholar 

  21. Morris, J. S. et al. Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion. Neuroimage 10, 163–172 (1999).

    Article  PubMed  Google Scholar 

  22. Schmidt, F. M. et al. Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI. Eur. Arch. Psychiatry Clin. Neurosci. 267, 107–115 (2017).

    Article  PubMed  Google Scholar 

  23. Sartorius, A. et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol. Psychiatry 67, e9–e11 (2010).

    Article  PubMed  Google Scholar 

  24. Zhang, C. et al. Bilateral habenula deep brain stimulation for treatment-resistant depression: clinical findings and electrophysiological features. Transl. Psychiatry 12, 52 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang, Z. et al. Case report: lateral habenula deep brain stimulation for treatment-resistant depression. Front. Psychiatry 11, 616501 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cui, Z. et al. Safety and precision of frontal trajectory of lateral habenula deep brain stimulation surgery in treatment-resistant depression. Front. Neurol 14, 1113545 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    Article  PubMed  Google Scholar 

  28. Fenoy, A. J. et al. A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression. Transl. Psychiatry 8, 111 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhang, Y. et al. Deep brain stimulation in the lateral habenula reverses local neuronal hyperactivity and ameliorates depression-like behaviors in rats. Neurobiol. Dis. 180, 106069 (2023).

    Article  PubMed  Google Scholar 

  30. Amo, R. et al. Identification of the zebrafish ventral habenula as a homolog of the mammalian lateral habenula. J. Neurosci. 30, 1566–1574 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lawson, R. P. et al. The habenula encodes negative motivational value associated with primary punishment in humans. Proc. Natl Acad. Sci. USA 111, 11858–11863 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ahumada-Galleguillos, P. et al. Directional asymmetry in the volume of the human habenula. Brain Struct. Funct. 222, 1087–1092 (2017).

    Article  PubMed  Google Scholar 

  33. Barreiros, A. R. et al. Abnormal habenula functional connectivity characterizes treatment-resistant depression. Neuroimage Clin. 34, 102990 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hu, H. Reward and aversion. Annu. Rev. Neurosci. 39, 297–324 (2016).

    Article  PubMed  Google Scholar 

  35. Lin, S. et al. The ATP level in the medial prefrontal cortex regulates depressive-like behavior via the medial prefrontal cortex–lateral Habenula pathway. Biol. Psychiatry 92, 179–192 (2022).

    Article  PubMed  Google Scholar 

  36. Fan, Z. et al. Neural mechanism underlying depressive-like state associated with social status loss. Cell 186, 560–576.e17 (2023).

    Article  PubMed  Google Scholar 

  37. Li, G. et al. Instantaneous antidepressant effect of lateral habenula deep brain stimulation in rats studied with functional MRI. eLife 12, e84693 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Shen, L. et al. Subthalamic nucleus deep brain stimulation modulates 2 distinct neurocircuits. Ann. Neurol. 88, 1178–1193 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Min, H. K. et al. Deep brain stimulation induces BOLD activation in motor and non-motor networks: an fMRI comparison study of STN and EN/GPi DBS in large animals. Neuroimage 63, 1408–1420 (2012).

    Article  PubMed  Google Scholar 

  40. Horn, A. et al. Lead-DBS v2: towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage 184, 293–316 (2019).

    Article  PubMed  Google Scholar 

  41. Qian, X. et al. A method for removal of deep brain stimulation artifact from local field potentials. IEEE Trans. Neural Syst. Rehabil. Eng. 25, 2217–2226 (2017).

    Article  PubMed  Google Scholar 

  42. Qian, X. et al. Chronically monitoring the deep brain rhythms: from stimulation to recording. Sci. Bull. 61, 1522–1524 (2016).

    Article  Google Scholar 

  43. Ding, J. Q. et al. Role of MRI coils in radio frequency heating of implantable medical devices. Electron. Lett. 54, 682–683 (2018).

    Article  Google Scholar 

  44. Zhang, F. et al. Safety assessment of displacement force, torque and vibration of a deep brain stimulation system under 3T MRI. Int. J. Appl. Electromagnet. Mech. 59, 1081–1086 (2019).

    Article  Google Scholar 

  45. Chen, Y. et al. Neuromodulation effects of deep brain stimulation on beta rhythm: a longitudinal local field potential study. Brain Stimul. 13, 1784–1792 (2020).

    Article  PubMed  Google Scholar 

  46. Wan, S. et al. Evaluation of local B1 field as dosimeter of RF heating for implant in MRI. Electron. Lett. 55, 302–304 (2019).

    Article  Google Scholar 

  47. Qian, X. et al. A platform for long-term monitoring the deep brain rhythms. Exp. Neurol. 294, 68–77 (2017).

    Google Scholar 

  48. Keshtkaran, M. R. & Yang, Z. A fast, robust algorithm for power line interference cancellation in neural recording. J. Neural Eng. 11, 026017 (2014).

    Article  PubMed  Google Scholar 

  49. Zou, Q. H. et al. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF. J. Neurosci. Methods 172, 137–141 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  50. nercnlab / LFP-analysis. GitHub https://github.com/nercnlab/LFP-analysis/blob/main/Num_LFP%20analysis (2024).

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Acknowledgements

We thank Q. Cui and Y. Tian at the National Engineering Research Center of Neuromodulation for assistance in the reconstruction of implanted DBS images. We also thank Beijing PINS Medical Equipment Co., Ltd. for donating the most cutting-edge DBS systems. This work was supported by the Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences (E2CX6515, Z.W.), the National Key Research and Development Program of China (2019YFC0118503, Z.C.), the Shenzhen International Cooperative Research Project (GJHZ20180930110402104, L.L.) and the National Natural Science Foundation of China (82101549, Z.W.).

Author information

Authors and Affiliations

  1. CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Zhiyan Wang, Lei Zhao, Feixue Wang & Yiheng Tu

  2. Department of Psychology, University of Chinese Academy of Sciences, Beijing, China

    Zhiyan Wang, Lei Zhao, Feixue Wang & Yiheng Tu

  3. National Engineering Research Center of Neuromodulation, School of Aerospace Engineering, Tsinghua University, Beijing, China

    Zhiyan Wang, Lingxiao Guan, Chunhua Hu & Luming Li

  4. Department of Neurosurgery, Chinese People’s Liberation Army of China General Hospital, Beijing, China

    Chao Jiang, Jian Wang & Zhiqiang Cui

  5. Peking University Institute of Mental Health, National Health Commission Key Laboratory of Mental Health, Peking University, National Clinical Research Center for Mental Disorders, Peking University Six Hospital, Beijing, China

    Tengteng Fan

  6. Department of Neurosurgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China

    Xiaodong Cai & Chen Yao

  7. Department of Depressive Disorder, Shenzhen Mental Health Center, Shenzhen, China

    Yingli Zhang & Bo Peng

  8. IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China

    Luming Li

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Contributions

Z.W.: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, visualization, writing—original draft, writing—review and editing. C.J.: data curation, investigation, methodology, writing—original draft. L.G.: data curation, investigation, methodology, software, writing—original draft. L.Z.: formal analysis, methodology, software, visualization, writing—original draft. T.F.: conceptualization, data curation, methodology, supervision. J.W.: data curation, methodology. X.C.: data curation, methodology, supervision. Y.Z.: data curation, methodology, supervision. C.Y.: data curation, methodology. B.P.: data curation, methodology. F.W.: visualization. C.H.: funding acquisition, project administration. Z.C.: conceptualization, data curation, funding acquisition, project administration, resources, supervision, writing—review and editing. Y.T.: formal analysis, methodology, visualization, writing—original draft, writing—review and editing. L.L.: conceptualization, funding acquisition, resources, supervision, writing—review and editing.

Corresponding authors

Correspondence to Zhiqiang Cui, Yiheng Tu or Luming Li.

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Nature Mental Health thanks Jürgen Germann and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information.

Supplementary Tables 1–5 and Figs. 1 and 2.

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Source data

Source Data Fig. 2

The HDRS17 and HARS scores of each patient at baseline, 1-, 3- and 6-month follow-up.

Source Data Fig. 3

The statistical source of PSD data in the left and right Hb at month 0.

Source Data Fig. 4

The statistical source of fMRI data in the left and right Hb at month 0.

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Wang, Z., Jiang, C., Guan, L. et al. Deep brain stimulation of habenula reduces depressive symptoms and modulates brain activities in treatment-resistant depression. Nat. Mental Health 2, 1045–1052 (2024). https://doi.org/10.1038/s44220-024-00286-2

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