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Magnetic resonance-guided focused ultrasound capsulotomy for refractory obsessive compulsive disorder and major depressive disorder: clinical and imaging results from two phase I trials

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Abstract

Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. We examined the safety profile, clinical response, and imaging correlates of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive compulsive disorder (OCD, N = 6) and major depressive disorder (MDD, n = 6). There were no serious adverse events. Nonserious adverse events included headaches and pin-site swelling in 7/12 patients. The response rate was 4/6 and 2/6 in the OCD and MDD cohorts respectively. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome was used, revealing tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. Positron emission tomography (PET) analysis (nine subjects) revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months post treatment, as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis (12 subjects) revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe, well tolerated, and according to these initial results, may be an important treatment option for patients with refractory OCD and MDD. MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for the prediction of outcome.

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Fig. 1: A structural analysis of lesions, tracts, and tract endpoints.
Fig. 2: PET analysis.
Fig. 3: Functional connectivity analysis.

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References

  1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–27.

    PubMed  PubMed Central  Google Scholar 

  2. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15:53–63.

    CAS  PubMed  Google Scholar 

  3. Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC. Prevalence of depression in the community from 30 countries between 1994 and 2014. Sci Rep. 2018;8:2861.

    PubMed  PubMed Central  Google Scholar 

  4. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    PubMed  Google Scholar 

  5. Hirschtritt ME, Bloch MH, Mathews CA. Obsessive-Compulsive Disorder: Advances in Diagnosis and Treatment. JAMA 2017;317:1358–67.

    PubMed  Google Scholar 

  6. Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv. 2014;65:977–87.

    PubMed  Google Scholar 

  7. Torres AR, Ramos-Cerqueira AT, Ferrao YA, Fontenelle LF, do Rosario MC, Miguel EC. Suicidality in obsessive-compulsive disorder: prevalence and relation to symptom dimensions and comorbid conditions. J Clin Psychiatry. 2011;72:17–26.

    PubMed  Google Scholar 

  8. Pepper J, Zrinzo L, Hariz M. Anterior capsulotomy for obsessive-compulsive disorder: a review of old and new literature. J Neurosurg. 2019:1–10.

  9. 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.

    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.

    PubMed  Google Scholar 

  11. Christmas D, Eljamel MS, Butler S, Hazari H, MacVicar R, Steele JD, et al. Long term outcome of thermal anterior capsulotomy for chronic, treatment refractory depression. J Neurol Neurosurg Psychiatry. 2011;82:594–600.

    PubMed  Google Scholar 

  12. Subramanian L, Bracht T, Jenkins P, Choppin S, Linden DE, Phillips G, et al. Clinical improvements following bilateral anterior capsulotomy in treatment-resistant depression. Psychol Med. 2017;47:1097–106.

    CAS  PubMed  Google Scholar 

  13. Pepper J, Hariz M, Zrinzo L. Deep brain stimulation versus anterior capsulotomy for obsessive-compulsive disorder: a review of the literature. J Neurosurg. 2015;122:1028–37.

    PubMed  Google Scholar 

  14. 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.

    PubMed  Google Scholar 

  15. Widge AS, Malone DA Jr., Dougherty DD. Closing the loop on deep brain stimulation for treatment-resistant depression. Front Neurosci. 2018;12:175.

    PubMed  PubMed Central  Google Scholar 

  16. Arya S, Filkowski MM, Nanda P, Sheth SA. Deep brain stimulation for obsessive-compulsive disorder. Bull Menninger Clin. 2019;83:84–96.

    PubMed  Google Scholar 

  17. Davidson B, Meng Y, Giacobbe P, Hamani C, Lipsman N. Magnetic resonance-guided focused ultrasound for psychiatric disorders. Clin Pharmacol Ther. 2019;106:720–2.

    PubMed  Google Scholar 

  18. Krishna V, Sammartino F, Rezai A. A review of the current therapies, challenges, and future directions of transcranial focused ultrasound technology: advances in diagnosis and treatment. JAMA Neurol. 2018;75:246–54.

    PubMed  Google Scholar 

  19. Kim M, Kim CH, Jung HH, Kim SJ, Chang JW. Treatment of major depressive disorder via magnetic resonance-guided focused ultrasound surgery. Biol Psychiatry. 2018;83:e17–8.

    PubMed  Google Scholar 

  20. Kim SJ, Roh D, Jung HH, Chang WS, Kim CH, Chang JW. A study of novel bilateral thermal capsulotomy with focused ultrasound for treatment-refractory obsessive-compulsive disorder: 2-year follow-up. J Psychiatry Neurosci. 2018;43:327–37.

    PubMed  PubMed Central  Google Scholar 

  21. Ravikumar VK, Parker JJ, Hornbeck TS, Santini VE, Pauly KB, Wintermark M, et al. Cost-effectiveness of focused ultrasound, radiosurgery, and DBS for essential tremor. Mov Disord. 2017;32:1165–73.

    PubMed  Google Scholar 

  22. Li C, Gajic-Veljanoski O, Schaink AK, Higgins C, Fasano A, Sikich N, et al. Cost-effectiveness of magnetic resonance-guided focused ultrasound for essential tremor. Mov Disord. 2019;34:735–43.

    PubMed  Google Scholar 

  23. Mindus P, Rasmussen SA, Lindquist C. Neurosurgical treatment for refractory obsessive-compulsive disorder: implications for understanding frontal lobe function. J Neuropsychiatry Clin Neurosci. 1994;6:467–77.

    CAS  PubMed  Google Scholar 

  24. Talairach JHH, David M. Lobotomie préfrontale limitée par électrocoagulation des fibres thalamo-frontales à leur émergence du bras antérieur de la capsule interne. Rev Neurol. 1949;83:59.

    Google Scholar 

  25. Su L, Cai Y, Xu Y, Dutt A, Shi S, Bramon E. Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies. BMC Psychiatry. 2014;14:321.

    PubMed  PubMed Central  Google Scholar 

  26. Macpherson T, Hikida T. Role of basal ganglia neurocircuitry in the pathology of psychiatric disorders. Psychiatry Clin Neurosci. 2019;73:289–301.

    PubMed  Google Scholar 

  27. Kopell BH, Greenberg BD. Anatomy and physiology of the basal ganglia: implications for DBS in psychiatry. Neurosci Biobehav Rev. 2008;32:408–22.

    PubMed  Google Scholar 

  28. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14 Suppl 1:S1. https://doi.org/10.1186/1471-244X-14-S1-S1.

    Article  PubMed  Google Scholar 

  29. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, et al. The yale-brown obsessive compulsive scale. II. validity. Arch Gen Psychiatry. 1989;46:1012–6.

    CAS  PubMed  Google Scholar 

  30. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278–96.

    CAS  PubMed  Google Scholar 

  31. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of life enjoyment and satisfaction questionnaire: a new measure. Psychopharmacol Bull. 1993;29:321–6.

    CAS  PubMed  Google Scholar 

  32. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.

    CAS  PubMed  Google Scholar 

  33. Beck AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psychol. 1984;40:1365–7.

    CAS  PubMed  Google Scholar 

  34. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–77.

    PubMed  PubMed Central  Google Scholar 

  35. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35.

    CAS  PubMed  Google Scholar 

  36. Wechsler D. Wechsler test of adult reading: WTAR. San Antonio, TX: the Psychological Corporation; 2001.

  37. Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test-Second Edition (CVLT-II). San Antonio, TX: Psychological Corporation; 2000.

  38. Benedict RHB, Schretlen D, Groninger L, Dobraski M, Shpritz B. Revision of the Brief Visuospatial Memory Test: Studies of normal performance, reliability, and validity. Psychological Assess. 1996;8:145–53.

    Google Scholar 

  39. Fine EM, Delis DC. Delis–Kaplan executive functioning system. In: Kreutzer JS, DeLuca J, Caplan B, editors. Encyclopedia of clinical neuropsychology. New York, NY: Springer; 2011. p. 796–801.

  40. Smith A. Symbol digit modalities test: manual. Los Angeles: Western Psychological Services; 1982.

  41. Stout JC, Ready RE, Grace J, Malloy PF, Paulsen JS. Factor analysis of the frontal systems behavior scale (FrSBe). Assessment. 2003;10:79–85.

    PubMed  Google Scholar 

  42. Jung HH, Kim SJ, Roh D, Chang JG, Chang WS, Kweon EJ, et al. Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study. Mol Psychiatry. 2015;20:1205–11.

    CAS  PubMed  Google Scholar 

  43. Miguel EC, Lopes AC, McLaughlin NCR, Noren G, Gentil AF, Hamani C, et al. Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder. Mol Psychiatry. 2019;24:218–40.

    PubMed  Google Scholar 

  44. Lipsman N, Mainprize TG, Schwartz ML, Hynynen K, Lozano AM. Intracranial applications of magnetic resonance-guided focused ultrasound. Neurotherapeutics. 2014;11:593–605.

    PubMed  PubMed Central  Google Scholar 

  45. Chang WS, Jung HH, Zadicario E, Rachmilevitch I, Tlusty T, Vitek S, et al. Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull. J Neurosurg. 2016;124:411–6.

    PubMed  Google Scholar 

  46. Avants BB, Tustison NJ, Song G, Cook PA, Klein A, Gee JC. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage. 2011;54:2033–44.

    PubMed  Google Scholar 

  47. Yeh FC, Tseng WY. NTU-90: a high angular resolution brain atlas constructed by q-space diffeomorphic reconstruction. Neuroimage. 2011;58:91–9.

    PubMed  Google Scholar 

  48. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968–80.

    PubMed  Google Scholar 

  49. Greve DN, Svarer C, Fisher PM, Feng L, Hansen AE, Baare W, et al. Cortical surface-based analysis reduces bias and variance in kinetic modeling of brain PET data. Neuroimage. 2014;92:225–36.

    PubMed  Google Scholar 

  50. Greve DN, Salat DH, Bowen SL, Izquierdo-Garcia D, Schultz AP, Catana C, et al. Different partial volume correction methods lead to different conclusions: an (18)F-FDG-PET study of aging. Neuroimage. 2016;132:334–43.

    PubMed  Google Scholar 

  51. Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect. 2012;2:125–41.

    PubMed  Google Scholar 

  52. 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.

    PubMed  Google Scholar 

  53. Ruck C, Edman G, Asberg M, Svanborg P. Long-term changes in self-reported personality following capsulotomy in anxiety patients. Nordic J Psychiatry. 2006;60:486–91.

    Google Scholar 

  54. Kumar KK, Bhati MT, Ravikumar VK, Ghanouni P, Stein SC, Halpern CH. MR-guided focused ultrasound versus radiofrequency capsulotomy for treatment-refractory obsessive-compulsive disorder: a cost-effectiveness threshold analysis. Front Neurosci. 2019;13:66.

    PubMed  PubMed Central  Google Scholar 

  55. Hurwitz TA, Honey CR, Allen J, Gosselin C, Hewko R, Martzke J, et al. Bilateral anterior capsulotomy for intractable depression. J Neuropsychiatry Clin Neurosci. 2012;24:176–82.

    PubMed  Google Scholar 

  56. Zhan S, Liu W, Li D, Pan S, Pan Y, Li Y, et al. Long-term follow-up of bilateral anterior capsulotomy in patients with refractory obsessive-compulsive disorder. Clin Neurol Neurosurg. 2014;119:91–5.

    PubMed  Google Scholar 

  57. Liu K, Zhang H, Liu C, Guan Y, Lang L, Cheng Y, et al. Stereotactic treatment of refractory obsessive compulsive disorder by bilateral capsulotomy with 3 years follow-up. J Clin Neurosci. 2008;15:622–9.

    PubMed  Google Scholar 

  58. Suetens K, Nuttin B, Gabriels L, Van Laere K. Differences in metabolic network modulation between capsulotomy and deep-brain stimulation for refractory obsessive-compulsive disorder. J Nucl Med. 2014;55:951–9.

    PubMed  Google Scholar 

  59. Riestra AR, Aguilar J, Zambito G, Galindo y Villa G, Barrios F, Garcia C, et al. Unilateral right anterior capsulotomy for refractory major depression with comorbid obsessive-compulsive disorder. Neurocase. 2011;17:491–500.

    PubMed  Google Scholar 

  60. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev. 2008;32:525–49.

    PubMed  Google Scholar 

  61. Saxena S, Brody AL, Ho ML, Zohrabi N, Maidment KM, Baxter LR Jr. Differential brain metabolic predictors of response to paroxetine in obsessive-compulsive disorder versus major depression. Am J Psychiatry. 2003;160:522–32.

    PubMed  Google Scholar 

  62. Vaghi MM, Vertes PE, Kitzbichler MG, Apergis-Schoute AM, van der Flier FE, Fineberg NA, et al. Specific frontostriatal circuits for impaired cognitive flexibility and goal-directed planning in obsessive-compulsive disorder: evidence from resting-state functional connectivity. Biol Psychiatry. 2017;81:708–17.

    PubMed  PubMed Central  Google Scholar 

  63. Quevedo K, Ng R, Scott H, Kodavaganti S, Smyda G, Diwadkar V, et al. Ventral striatum functional connectivity during rewards and losses and symptomatology in depressed patients. Biol Psychol. 2017;123:62–73.

    PubMed  Google Scholar 

  64. Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61:34–41.

    PubMed  Google Scholar 

  65. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675–82.

    CAS  PubMed  Google Scholar 

  66. Dunlop BW, Mayberg HS. Neuroimaging-based biomarkers for treatment selection in major depressive disorder. Dialogues Clin Neurosci. 2014;16:479–90.

    PubMed  PubMed Central  Google Scholar 

  67. Wang Q, Tian S, Tang H, Liu X, Yan R, Hua L, et al. Identification of major depressive disorder and prediction of treatment response using functional connectivity between the prefrontal cortices and subgenual anterior cingulate: A real-world study. J Affect Disord. 2019;252:365–72.

    PubMed  Google Scholar 

  68. Sun H, Jiang R, Qi S, Narr KL, Wade BS, Upston J, et al. Preliminary prediction of individual response to electroconvulsive therapy using whole-brain functional magnetic resonance imaging data. Neuroimage Clin. 2019:102080.

  69. Boutet A, Gwun D, Gramer R, Ranjan M, Elias GJB, Tilden D, et al. The relevance of skull density ratio in selecting candidates for transcranial MR-guided focused ultrasound. J Neurosurg. 2019:1–7.

  70. Hughes A, Huang Y, Schwartz ML, Hynynen K. The reduction in treatment efficiency at high acoustic powers during MR-guided transcranial focused ultrasound thalamotomy for essential tremor. Med Phys. 2018;45:2925–36.

    PubMed  Google Scholar 

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Funding

This study was funded by the Focused Ultrasound Foundation, the Harquail Centre for Neuromodulation, and philanthropic support to the Sunnybrook Foundation.

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Authors and Affiliations

  1. Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

    Benjamin Davidson, Clement Hamani, Ying Meng & Nir Lipsman

  2. Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada

    Benjamin Davidson, Clement Hamani, Jennifer S. Rabin, Maged Goubran, Ying Meng, Anusha Baskaran, Sachie Sharma, Miracle Ozzoude, Margaret Anne Richter, Anthony Levitt, Peter Giacobbe, Kullervo Hynynen & Nir Lipsman

  3. Sunnybrook Research Institute, Toronto, ON, Canada

    Benjamin Davidson, Clement Hamani, Jennifer S. Rabin, Maged Goubran, Ying Meng, Yuexi Huang, Anusha Baskaran, Sachie Sharma, Miracle Ozzoude, Margaret Anne Richter, Anthony Levitt, Peter Giacobbe, Kullervo Hynynen & Nir Lipsman

  4. Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada

    Jennifer S. Rabin

  5. Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada

    Maged Goubran & Kullervo Hynynen

  6. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Maged Goubran & Kullervo Hynynen

  7. Frederick W. Thompson Anxiety Disorders Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

    Margaret Anne Richter

  8. Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Margaret Anne Richter, Anthony Levitt & Peter Giacobbe

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  1. Benjamin Davidson
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Davidson, B., Hamani, C., Rabin, J.S. 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 25, 1946–1957 (2020). https://doi.org/10.1038/s41380-020-0737-1

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