Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Common and differential connectivity profiles of deep brain stimulation and capsulotomy in refractory obsessive-compulsive disorder

Molecular Psychiatry volume 27, pages 1020–1030 (2022)Cite this article

Subjects

Abstract

Neurosurgical interventions including deep brain stimulation (DBS) and capsulotomy have been demonstrated effective for refractory obsessive-compulsive disorder (OCD), although treatment-shared/-specific network mechanisms remain largely unclear. We retrospectively analyzed resting-state fMRI data from three cohorts: a cross-sectional dataset of 186 subjects (104 OCD and 82 healthy controls), and two longitudinal datasets of refractory patients receiving ventral capsule/ventral striatum DBS (14 OCD) and anterior capsulotomy (27 OCD). We developed a machine learning model predictive of OCD symptoms (indexed by the Yale–Brown Obsessive Compulsive Scale, Y-BOCS) based on functional connectivity profiles and used graphic measures of network communication to characterize treatment-induced profile changes. We applied a linear model on 2 levels treatments (DBS or capsulotomy) and outcome to identify whether pre-surgical network communication was associated with differential treatment outcomes. We identified 54 functional connectivities within fronto-subcortical networks significantly predictive of Y-BOCS score in patients across 3 independent cohorts, and observed a coexisting pattern of downregulated cortico-subcortical and upregulated cortico-cortical network communication commonly shared by DBS and capsulotomy. Furthermore, increased cortico-cortical communication at ventrolateral and centrolateral prefrontal cortices induced by DBS and capsulotomy contributed to improvement of mood and anxiety symptoms, respectively (p < 0.05). Importantly, pretreatment communication of ventrolateral and centrolateral prefrontal cortices were differentially predictive of mood and anxiety improvements by DBS and capsulotomy (effect sizes = 0.45 and 0.41, respectively). These findings unravel treatment-shared and treatment-specific network characteristics induced by DBS and capsulotomy, which may facilitate the search of potential evidence-based markers for optimally selecting among treatment options for a patient.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Connectivity profiles of OCD pathophysiology.
Fig. 2: Connectivity profiles of DBS and capsulotomy treatments.
Fig. 3: Cortico-cortical and cortico-subcortical communication strength altered by DBS and capsulotomy.
Fig. 4: Treatment stratification analysis and summary schematic.

Similar content being viewed by others

References

  1. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46:1006–11.

    Article  CAS  PubMed  Google Scholar 

  2. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–5.

    Article  CAS  PubMed  Google Scholar 

  3. Hamilton M. A rating scale for depression. J Neurol, Neurosurg, Psychiatry. 1960;23:56–62.

    Article  CAS  Google Scholar 

  4. Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci. 2014;15:410–24.

    Article  CAS  PubMed  Google Scholar 

  5. Robbins TW, Vaghi MM, Banca P. Obsessive-Compulsive Disorder: Puzzles and Prospects. Neuron. 2019;102:27–47.

    Article  CAS  PubMed  Google Scholar 

  6. Stein DJ, Costa DLC, Lochner C, Miguel EC, Reddy YCJ, Shavitt RG, et al. Obsessive-compulsive disorder. Nat Rev Dis Prim. 2019;5:52.

    Article  PubMed  Google Scholar 

  7. Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet. 1999;354:1526.

    Article  CAS  PubMed  Google Scholar 

  8. Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D, et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N. Engl J Med. 2008;359:2121–34.

    Article  CAS  PubMed  Google Scholar 

  9. Dougherty DD, Baer L, Cosgrove GR, Cassem EH, Price BH, Nierenberg AA, et al. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry. 2002;159:269–75.

    Article  PubMed  Google Scholar 

  10. Ruck C, Karlsson A, Steele JD, Edman G, Meyerson BA, Ericson K, et al. Capsulotomy for obsessive-compulsive disorder: long-term follow-up of 25 patients. Arch Gen Psychiatry. 2008;65:914–21.

    Article  PubMed  Google Scholar 

  11. Davidson B, Hamani C, Rabin JS, Goubran M, Meng Y, Huang Y, et al. Magnetic resonance-guided focused ultrasound capsulotomy for refractory obsessive compulsive disorder and major depressive disorder: clinical and imaging results from two phase I trials. Mol Psychiatry. 2020;25:1946–57.

    Article  PubMed  Google Scholar 

  12. Goodman WK, Foote KD, Greenberg BD, Ricciuti N, Bauer R, Ward H, et al. Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design. Biol Psychiatry. 2010;67:535–42.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Denys D, Mantione M, Figee M, van den Munckhof P, Koerselman F, Westenberg H, et al. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2010;67:1061–8.

    Article  PubMed  Google Scholar 

  14. Greenberg BD, Gabriels LA, Malone DA Jr, Rezai AR, Friehs GM, Okun MS, et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry. 2010;15:64–79.

    Article  CAS  PubMed  Google Scholar 

  15. Denys D, Graat I, Mocking R, de Koning P, Vulink N, Figee M, et al. Efficacy of Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Refractory Obsessive-Compulsive Disorder: A Clinical Cohort of 70 Patients. Am J Psychiatry. 2020;177:265–71.

    Article  PubMed  Google Scholar 

  16. Lopes AC, Greenberg BD, Canteras MM, Batistuzzo MC, Hoexter MQ, Gentil AF, et al. Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71:1066–76.

    Article  PubMed  Google Scholar 

  17. Rasmussen SA, Noren G, Greenberg BD, Marsland R, McLaughlin NC, Malloy PJ, et al. Gamma Ventral Capsulotomy in Intractable Obsessive-Compulsive Disorder. Biol Psychiatry. 2018;84:355–64.

    Article  PubMed  Google Scholar 

  18. Graat I, Mocking R, Figee M, Vulink N, de Koning P, Ooms P, et al. Long-term Outcome of Deep Brain Stimulation of the Ventral Part of the Anterior Limb of the Internal Capsule in a Cohort of 50 Patients With Treatment-Refractory Obsessive-Compulsive Disorder. Biol Psychiatry. 2021;90:714–20.

    Article  PubMed  Google Scholar 

  19. Voon V, Droux F, Morris L, Chabardes S, Bougerol T, David O, et al. Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity. Brain. 2017;140:442–56.

    Article  PubMed  Google Scholar 

  20. Dougherty DD, Brennan BP, Stewart SE, Wilhelm S, Widge AS, Rauch SL. Neuroscientifically informed formulation and treatment planning for patients with obsessive-compulsive disorder: a review. JAMA Psychiatry. 2018;75:1081–7.

    Article  PubMed  Google Scholar 

  21. Cagnan H, Denison T, McIntyre C, Brown P. Emerging technologies for improved deep brain stimulation. Nat Biotechnol. 2019;37:1024–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kohl S, Schonherr DM, Luigjes J, Denys D, Mueller UJ, Lenartz D, et al. Deep brain stimulation for treatment-refractory obsessive compulsive disorder: a systematic review. BMC Psychiatry. 2014;14:214.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Herrington TM, Cheng JJ, Eskandar EN. Mechanisms of deep brain stimulation. J Neurophysiol. 2016;115:19–38.

    Article  CAS  PubMed  Google Scholar 

  24. Chen X, Zhang C, Li Y, Huang P, Lv Q, Yu W, et al. Functional Connectivity-Based Modelling Simulates Subject-Specific Network Spreading Effects of Focal Brain Stimulation. Neurosci Bull. 2018;34:921–38.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lv Q, Lv Q, Yin D, Zhang C, Sun B, Voon V, et al. Neuroanatomical substrates and predictors of response to capsulotomy in intractable obsessive-compulsive disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6:29–38.

    PubMed  Google Scholar 

  26. Yin D, Zhang C, Lv Q, Chen X, Zeljic K, Gong H, et al. Dissociable frontostriatal connectivity: mechanism and predictor of the clinical efficacy of capsulotomy in obsessive-compulsive disorder. Biol Psychiatry. 2018;84:926–36.

    Article  PubMed  Google Scholar 

  27. Hoexter MQ. Are we ready for individualized target planning of ablative procedures in intractable obsessive-compulsive disorder? Biol Psychiatry. 2018;84:e85–7.

    Article  PubMed  Google Scholar 

  28. Baldermann JC, Melzer C, Zapf A, Kohl S, Timmermann L, Tittgemeyer M, et al. Connectivity profile predictive of effective deep brain stimulation in obsessive-compulsive disorder. Biol Psychiatry. 2019;85:735–43.

    Article  PubMed  Google Scholar 

  29. Li N, Baldermann JC, Kibleur A, Treu S, Akram H, Elias GJB, et al. A unified connectomic target for deep brain stimulation in obsessive-compulsive disorder. Nat Commun. 2020;11:3364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Abi-Dargham A, Horga G. The search for imaging biomarkers in psychiatric disorders. Nat Med. 2016;22:1248–55.

    Article  CAS  PubMed  Google Scholar 

  31. Zhan Y, Wei J, Liang J, Xu X, He R, Robbins TW, et al. Diagnostic classification for human autism and obsessive-compulsive disorder based on machine learning from a primate genetic model. Am J Psychiatry. 2021;178:65–76.

    Article  PubMed  Google Scholar 

  32. Figee M, Luigjes J, Smolders R, Valencia-Alfonso CE, van Wingen G, de Kwaasteniet B, et al. Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder. Nat Neurosci. 2013;16:386–7.

    Article  CAS  PubMed  Google Scholar 

  33. Wang Z, Zeljic K, Jiang Q, Gu Y, Wang W, Wang Z. Dynamic network communication in the human functional connectome predicts perceptual variability in visual illusion. Cereb Cortex. 2018;28:48–62.

    Article  PubMed  Google Scholar 

  34. Lv Q, Yang L, Li G, Wang Z, Shen Z, Yu W, et al. Large-scale persistent network reconfiguration induced by ketamine in anesthetized monkeys: relevance to mood disorders. Biol Psychiatry. 2016;79:765–75.

    Article  CAS  PubMed  Google Scholar 

  35. Lv Q, Wang Z, Zhang C, Fan Q, Zhao Q, Zeljic K, et al. Divergent structural responses to pharmacological interventions in orbitofronto-striato-thalamic and premotor circuits in obsessive-compulsive disorder. EBioMedicine. 2017;22:242–8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhang C, Kim SG, Li J, Zhang Y, Lv Q, Zeljic K, et al. Anterior limb of the internal capsule tractography: relationship with capsulotomy outcomes in obsessive-compulsive disorder. J Neurol Neurosurg Psychiatry. 2021;92:637.

  37. Behzadi Y, Restom K, Liau J, Liu TT. A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. Neuroimage. 2007;37:90–101.

    Article  PubMed  Google Scholar 

  38. Bezgin G, Vakorin VA, van Opstal AJ, McIntosh AR, Bakker R. Hundreds of brain maps in one atlas: registering coordinate-independent primate neuro-anatomical data to a standard brain. Neuroimage. 2012;62:67–76.

    Article  PubMed  Google Scholar 

  39. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002;33:341–55.

    Article  CAS  PubMed  Google Scholar 

  40. Zalesky A, Fornito A, Bullmore ET. Network-based statistic: identifying differences in brain networks. Neuroimage. 2010;53:1197–207.

    Article  PubMed  Google Scholar 

  41. Moody TD, Morfini F, Cheng G, Sheen C, Tadayonnejad R, Reggente N, et al. Mechanisms of cognitive-behavioral therapy for obsessive-compulsive disorder involve robust and extensive increases in brain network connectivity. Transl Psychiatry. 2017;7:e1230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee JJ, Kim HJ, Ceko M, Park BY, Lee SA, Park H, et al. A neuroimaging biomarker for sustained experimental and clinical pain. Nat Med. 2021;27:174–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, et al. Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. 2013;70:821–9.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Norman LJ, Mannella KA, Yang H, Angstadt M, Abelson JL, Himle JA, et al. Treatment-Specific Associations Between Brain Activation and Symptom Reduction in OCD Following CBT: A Randomized fMRI Trial. Am J Psychiatry. 2021;178:39–47.

    Article  PubMed  Google Scholar 

  45. Cho S, Hachmann JT, Balzekas I, In MH, Andres-Beck LG, Lee KH, et al. Resting-state functional connectivity modulates the BOLD activation induced by nucleus accumbens stimulation in the swine brain. Brain Behav. 2019;9:e01431.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lozano AM, Lipsman N, Bergman H, Brown P, Chabardes S, Chang JW, et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol. 2019;15:148–60.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Alstott J, Breakspear M, Hagmann P, Cammoun L, Sporns O. Modeling the impact of lesions in the human brain. Plos Comput Biol. 2009;5:e1000408.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Horn A, Wenzel G, Irmen F, Huebl J, Li N, Neumann WJ, et al. Deep brain stimulation induced normalization of the human functional connectome in Parkinson’s disease. Brain. 2019;142:3129–43.

    Article  PubMed  Google Scholar 

  49. Kahan J, Urner M, Moran R, Flandin G, Marreiros A, Mancini L, et al. Resting state functional MRI in Parkinson’s disease: the impact of deep brain stimulation on ‘effective’ connectivity. Brain. 2014;137:1130–44.

    Article  PubMed  PubMed Central  Google Scholar 

  50. O’Reilly JX, Croxson PL, Jbabdi S, Sallet J, Noonan MP, Mars RB, et al. Causal effect of disconnection lesions on interhemispheric functional connectivity in rhesus monkeys. Proc Natl Acad Sci USA. 2013;110:13982–7.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Roland JL, Snyder AZ, Hacker CD, Mitra A, Shimony JS, Limbrick DD, et al. On the role of the corpus callosum in interhemispheric functional connectivity in humans. Proc Natl Acad Sci USA. 2017;114:13278–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. van den Heuvel MP, Sporns O. A cross-disorder connectome landscape of brain dysconnectivity. Nat Rev Neurosci. 2019;20:435–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Joglekar MR, Mejias JF, Yang GR, Wang XJ. Inter-areal balanced amplification enhances signal propagation in a large-scale circuit model of the primate cortex. Neuron. 2018;98:222–34.

    Article  CAS  PubMed  Google Scholar 

  54. Misic B, Betzel RF, Nematzadeh A, Goni J, Griffa A, Hagmann P, et al. Cooperative and competitive spreading dynamics on the human connectome. Neuron. 2015;86:1518–29.

    Article  CAS  PubMed  Google Scholar 

  55. Tyagi H, Apergis-Schoute AM, Akram H, Foltynie T, Limousin P, Drummond LM, et al. A randomized trial directly comparing ventral capsule and anteromedial subthalamic nucleus stimulation in obsessive-compulsive disorder: clinical and imaging evidence for dissociable effects. Biol psychiatry. 2019;85:726–34.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Malone DA Jr., Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65:267–75.

    Article  PubMed  Google Scholar 

  57. Fridgeirsson EA, Figee M, Luigjes J, van den Munckhof P, Schuurman PR, van Wingen G, et al. Deep brain stimulation modulates directional limbic connectivity in obsessive-compulsive disorder. Brain. 2020;143:1603–12.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Schoene-Bake JC, Parpaley Y, Weber B, Panksepp J, Hurwitz TA, Coenen VA. Tractographic analysis of historical lesion surgery for depression. Neuropsychopharmacology. 2010;35:2553–63.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Irmen F, Horn A, Mosley P, Perry A, Petry-Schmelzer JN, Dafsari HS, et al. Left prefrontal connectivity links subthalamic stimulation with depressive symptoms. Ann Neurol. 2020;87:962–75.

    Article  PubMed  Google Scholar 

  60. Cocchi L, Zalesky A, Nott Z, Whybird G, Fitzgerald PB, Breakspear M. Transcranial magnetic stimulation in obsessive-compulsive disorder: a focus on network mechanisms and state dependence. NeuroImage Clin. 2018;19:661–74.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Siddiqi SH, Taylor SF, Cooke D, Pascual-Leone A, George MS, Fox MD. Distinct symptom-specific treatment targets for circuit-based neuromodulation. Am J Psychiatry. 2020;177:435–46.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Yan Y, Dahmani L, Ren J, Shen L, Peng X, Wang R, et al. Reconstructing lost BOLD signal in individual participants using deep machine learning. Nat Commun. 2020;11:5046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We specially thank Jinqiang Peng for his support to the management of our database and computation resources, where all the imaging and clinical data were harmonized and analyzed. This work was supported by the Key-Area Research and Development Program of Guangdong Province (2019B030335001), National Key R&D Program of China (No. 2017YFC1310400; No. 2018YFC1313803), Strategic Priority Research Program of Chinese Academy of Science (No. XDB32000000), grants from National Natural Science Foundation (81527901, 31771174), and Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX05).

Author information

Author notes

  1. These authors contributed equally: Xiaoyu Chen, Zhen Wang.

Authors and Affiliations

  1. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, China

    Xiaoyu Chen

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

    Xiaoyu Chen

  3. Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Zhen Wang & Qiming Lv

  4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China

    Zhen Wang & Qiming Lv

  5. School of Psychological and Cognitive Sciences; Beijing Key Laboratory of Behavior and Mental Health; IDG/McGovern Institute for Brain Research; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

    Qian Lv & Zheng Wang

  6. Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands

    Guido van Wingen, Egill Axfjord Fridgeirsson & Damiaan Denys

  7. Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands

    Guido van Wingen, Egill Axfjord Fridgeirsson & Damiaan Denys

  8. The Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

    Damiaan Denys

  9. Department of Psychology, Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

    Valerie Voon

Authors
  1. Xiaoyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiming Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guido van Wingen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Egill Axfjord Fridgeirsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Damiaan Denys
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Valerie Voon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XC, ZW (Zhen Wang), DD, VV, and ZW (Zheng Wang) contributed to the conception and design of the study. XC, QL (Qian Lv), QL (Qiming Lv), GvW, EAF, DD, and VV contributed to acquisition, post-processing and analysis of the data. XC and ZW (Zhen Wang) analyzed all or parts of the data. XC and ZW (Zheng Wang) drafted the text and prepared the figures with the help of VV. ZW (Zheng Wang) obtained the funding and supervised the study. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Zheng Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Wang, Z., Lv, Q. et al. Common and differential connectivity profiles of deep brain stimulation and capsulotomy in refractory obsessive-compulsive disorder. Mol Psychiatry 27, 1020–1030 (2022). https://doi.org/10.1038/s41380-021-01358-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01358-w

This article is cited by

Search

Advanced search

Quick links