[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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.

  • Original Article
  • Published:

Brain connectomics predict response to treatment in social anxiety disorder

Molecular Psychiatry volume 21, pages 680–685 (2016)Cite this article

Subjects

Abstract

We asked whether brain connectomics can predict response to treatment for a neuropsychiatric disorder better than conventional clinical measures. Pre-treatment resting-state brain functional connectivity and diffusion-weighted structural connectivity were measured in 38 patients with social anxiety disorder (SAD) to predict subsequent treatment response to cognitive behavioral therapy (CBT). We used a priori bilateral anatomical amygdala seed-driven resting connectivity and probabilistic tractography of the right inferior longitudinal fasciculus together with a data-driven multivoxel pattern analysis of whole-brain resting-state connectivity before treatment to predict improvement in social anxiety after CBT. Each connectomic measure improved the prediction of individuals’ treatment outcomes significantly better than a clinical measure of initial severity, and combining the multimodal connectomics yielded a fivefold improvement in predicting treatment response. Generalization of the findings was supported by leave-one-out cross-validation. After dividing patients into better or worse responders, logistic regression of connectomic predictors and initial severity combined with leave-one-out cross-validation yielded a categorical prediction of clinical improvement with 81% accuracy, 84% sensitivity and 78% specificity. Connectomics of the human brain, measured by widely available imaging methods, may provide brain-based biomarkers (neuromarkers) supporting precision medicine that better guide patients with neuropsychiatric diseases to optimal available treatments, and thus translate basic neuroimaging into medical practice.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE . Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593–602.

    Article  PubMed  Google Scholar 

  2. Katzelnick DJ, Kobak KA, DeLeire T, Henk HJ, Greist JH, Davidson JR et al. Impact of generalized social anxiety disorder in managed care. Am J Psychiatry 2001; 158: 1999–2007.

    Article  CAS  PubMed  Google Scholar 

  3. Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC . Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry 1996; 53: 159–168.

    Article  CAS  PubMed  Google Scholar 

  4. Stein MB, Kean YM . Disability and quality of life in social phobia: epidemiologic findings. Am J Psychiatry 2000; 157: 1606–1613.

    Article  CAS  PubMed  Google Scholar 

  5. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM . Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen Psychiatry 1992; 49: 282–288.

    Article  CAS  PubMed  Google Scholar 

  6. Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA et al. Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry 1998; 55: 1133–1141.

    Article  CAS  PubMed  Google Scholar 

  7. Davidson JRT, Foa EB, Huppert JD, Keefe FJ, Franklin ME, Compton JS et al. Fluoxetine, comprehensive cognitive behavioral therapy, and placeboin generalized social phobia. Arch Gen Psychiatry 2004; 61: 1005–1013.

    Article  CAS  PubMed  Google Scholar 

  8. Blanco C, Heimberg RG, Schneier FR, Fresco DM, Chen H, Turk CL et al. A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder. Arch Gen Psychiatry 2010; 67: 286–295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Biswal B, Yetkin FZ, Haughton VM, Hyde JS . Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 1995; 34: 537–541.

    Article  CAS  PubMed  Google Scholar 

  10. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME . The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 2005; 102: 9673–9678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liao W, Chen H, Feng Y, Mantini D, Gentili C, Pan Z et al. Selective aberrant functional connectivity of resting state networks in social anxiety disorder. Neuroimage 2010; 52: 1549–1558.

    Article  PubMed  Google Scholar 

  12. Hahn A, Stein P, Windischberger C, Weissenbacher A, Spindelegger C, Moser E et al. Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder. Neuroimage 2011; 56: 881–889.

    Article  PubMed  Google Scholar 

  13. Arnold Anteraper S, Triantafyllou C, Sawyer AT, Hofmann SG, Gabrieli JD, Whitfield-Gabrieli S . Hyper-connectivity of subcortical resting-state networks in social anxiety disorder. Brain Connect 2014; 4: 81–90.

    Article  PubMed  Google Scholar 

  14. Liao W, Xu Q, Mantini D, Ding J, Machado-de-Sousa JP, Hallak JEC et al. Altered gray matter morphometry and resting-state functional and structural connectivity in social anxiety disorder. Brain Res 2011; 1388: 167–177.

    Article  CAS  PubMed  Google Scholar 

  15. Phan KL, Orlichenko A, Boyd E, Angstadt M, Coccaro EF, Liberzon I et al. Preliminary evidence of white matter abnormality in the uncinate fasciculus in generalized social anxiety disorder. Biol Psychiatry 2009; 66: 691–694.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Baur V, Hänggi J, Rufer M, Delsignore A, Jäncke L, Herwig U et al. White matter alterations in social anxiety disorder. J Psychiatr Res 2011; 45: 1366–1372.

    Article  PubMed  Google Scholar 

  17. Klumpp H, Keutmann MK, Fitzgerald DA, Shankman SA, Phan KL . Resting state amygdala-prefrontal connectivity predicts symptom change after cognitive behavioral therapy in generalized social anxiety disorder. Biol Mood Anxiety Disord 2014; 4: 14.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vul E, Harris C, Winkielman P, Pashler H . Puzzlingly high correlations in fMRI studies of emotion, personality, and social cognition. Perspect Psychol Sci 2009; 4: 274–290.

    Article  PubMed  Google Scholar 

  19. Baur V, Brühl AB, Herwig U, Eberle T, Rufer M, Delsignore A et al. Evidence of frontotemporal structural hypoconnectivity in social anxiety disorder: a quantitative fiber tractography study. Hum Brain Mapp 2013; 34: 437–446.

    Article  PubMed  Google Scholar 

  20. Hofmann SG, Otto MW . Cognitive-behavior therapy of social anxiety disorder: Evidence-based and disorder specific treatment techniques. Routledge/Taylor and Francis: New York, NY, 2008.

    Book  Google Scholar 

  21. Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR et al. Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med 1999; 29: 199–212.

    Article  CAS  PubMed  Google Scholar 

  22. Freitas-Ferrari MC, Hallak JEC, Trzesniak C, Filho AS, Machado-de-Sousa JP, Chagas MHN et al. Neuroimaging in social anxiety disorder: a systematic review of the literature. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 565–580.

    Article  PubMed  Google Scholar 

  23. Doehrmann O, Ghosh SS, Polli FE, Reynolds GO, Horn F, Keshavan A et al. Predicting treatment response in social anxiety disorder from functional magnetic resonance imaging. JAMA Psychiatry 2013; 70: 87–97.

    Article  PubMed  Google Scholar 

  24. Catani M, Jones DK, Donato R, Ffytche DH . Occipito‐temporal connections in the human brain. Brain 2003; 126: 2093–2107.

    Article  PubMed  Google Scholar 

  25. Theil H . Economic forecasts and policy. 2nd ed.. North-Holland Publishing Company: Amsterdam, 1961.

    Google Scholar 

  26. American National Adult Reading Test (ANART). In: Encyclopedia of Clinical Neuropsychology. Springer: New York, 2011 p 131–131.

  27. First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Patient Edition With Psychotic Screen (SCID-I/P W/PSY SCREEN). Biometrics Research, New York State Psychiatric Institute: New York, 1997.

    Google Scholar 

  28. DiNardo PA, Brown TA, Barlow DH . Anxiety Disorders Interview Schedule for DSMIV: Lifetime Version (ADIS-IV-L). Psychological Corp: San Antonio, TX, 1994.

  29. Turner SM, Beidel DC, Dancu CV, Stanley MA . An empirically derived inventory to measure social fears and anxiety: The Social Phobia and Anxiety Inventory. Psycholgical Assessment 1989; 1: 35.

    Article  Google Scholar 

  30. Spielberger CD . STAI manual for the State-trait anxiety inventory. Self-Evaluation Questionnaire. Consulting Psychologists Press: Palo Alto, CA, 1983.

    Google Scholar 

  31. Rodrigues H, Figueira I, Lopes A, Gonçalves R, Mendlowicz MV, Coutinho ESF et al. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis. PLoS One 2014; 9: e93519.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hofmann SG, Smits JAJ, Rosenfield D, Simon N, Otto MW, Meuret AE et al. D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. Am J Psychiatry 2013; 170: 751–758.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Whitfield-Gabrieli S, Nieto-Castanon A . Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2012; 2: 125–141.

    Article  PubMed  Google Scholar 

  34. Yendiki A, Panneck P, Srinivasan P, Stevens A, Zöllei L, Augustinack J et al. Automated probabilistic reconstruction of white-matter pathways in health and disease using an atlas of the underlying anatomy. Front Neuroinform 2011; 5: 23.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shehzad Z, Kelly AMC, Reiss PT, Gee DG, Gotimer K, Uddin LQ et al. The resting brain: unconstrained yet reliable. Cereb Cortex 2009; 19: 2209–2229.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gabrieli JDE, Ghosh SS, Whitfield-Gabrieli S . Prediction as a Humanitarian and Pragmatic Contribution from Human Cognitive Neuroscience. Neuron 2015; 85: 11–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fu CHY, Steiner H, Costafreda SG . Predictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies. Neurobiol Dis 2013; 52: 75–83.

    Article  CAS  PubMed  Google Scholar 

  38. Chen C-H, Ridler K, Suckling J, Williams S, Fu CHY, Merlo-Pich E et al. Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment. Biol Psychiatry 2007; 62: 407–414.

    Article  CAS  PubMed  Google Scholar 

  39. Siegle GJ, Carter CS, Thase ME . Use of FMRI to predict recovery from unipolar depression with cognitive behavior therapy. Am J Psychiatry 2006; 163: 735–738.

    Article  PubMed  Google Scholar 

  40. Kumari V, Peters ER, Fannon D, Antonova E, Premkumar P, Anilkumar AP et al. Dorsolateral prefrontal cortex activity predicts responsiveness to cognitive–behavioral therapy in schizophrenia. Biol Psychiatry 2009; 66: 594–602.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fullana MA, Cardoner N, Alonso P, Subirà M, López-Solà C, Pujol J et al. Brain regions related to fear extinction in obsessive-compulsive disorder and its relation to exposure therapy outcome: a morphometric study. Psychol Med 2014; 44: 845–856.

    Article  CAS  PubMed  Google Scholar 

  42. Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL et al. A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol Psychiatry 2008; 63: 858–863.

    Article  CAS  PubMed  Google Scholar 

  43. Noël X, Sferrazza R, Van der Linden M Contribution of frontal cerebral blood flow measured by 99mTc-Bicisate SPECT and executive function deficits to predicting treatment outcome in alcohol-dependent …. Alcohol [Internet] 2002. Available from: http://alcalc.oxfordjournals.org/content/37/4/347.short.

  44. Molfese VJ, Molfese DL, Modgline AA . Newborn and preschool predictors of second-grade reading scores: an evaluation of categorical and continuous scores. J Learn Disabil 2001; 34: 545–554.

    Article  CAS  PubMed  Google Scholar 

  45. Gruber E, DiClemente RJ, Anderson MM, Lodico M . Early drinking onset and its association with alcohol use and problem behavior in late adolescence. Prev Med 1996; 25: 293–300.

    Article  CAS  PubMed  Google Scholar 

  46. Grant BF, Dawson DA . Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse 1997; 9: 103–110.

    Article  CAS  PubMed  Google Scholar 

  47. Yokum S, Ng J, Stice E . Attentional bias to food images associated with elevated weight and future weight gain: an fMRI study. Obesity 2011; 19: 1775–1783.

    Article  PubMed  Google Scholar 

  48. 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: 821–829.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Paulus MP, Tapert SF, Schuckit MA . Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse. Arch Gen Psychiatry 2005; 62: 761–768.

    Article  PubMed  Google Scholar 

  50. Lueken U, Straube B, Konrad C, Witchen HU, Strohle A, Wittmann A et al. Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia. Am J Psychiatry 2013; 170: 1345–1355.

    Article  PubMed  Google Scholar 

  51. Ball TM, Stein MB, Paulus MP . Toward the application of functional neuroimaging to individualized treatment for anxiety and depression. Depress Anxiety 2014; 31: 920–933.

    Article  PubMed  Google Scholar 

  52. Hoeft F, McCandliss BD, Black JM, Gantman A, Zakerani N, Hulme C et al. Neural systems predicting long-term outcome in dyslexia. Proc Natl Acad Sci USA 2011; 108: 361–366.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded in part by NIH grants R01MH078308 and R01MH075889 from the National Institute of Mental Health and the Poitras Center for Affective Disorders Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Author information

Authors and Affiliations

  1. Poitras Center for Affective Disorders Research, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    S Whitfield-Gabrieli, S S Ghosh, A Nieto-Castanon, O Doehrmann, X J Chai, G O Reynolds & J D E Gabrieli

  2. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    S Whitfield-Gabrieli, A Nieto-Castanon, Z Saygin, X J Chai & J D E Gabrieli

  3. Department of Otology and Laryngoloy, Harvard Medical School, Boston, MA, USA

    S S Ghosh

  4. Department of Speech, Language and Hearing Sciences, Boston University, Boston, MA, USA

    A Nieto-Castanon

  5. Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA

    S G Hofmann

  6. Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA

    M H Pollack

Authors
  1. S Whitfield-Gabrieli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S S Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Nieto-Castanon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z Saygin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O Doehrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X J Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G O Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S G Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M H Pollack
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J D E Gabrieli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Whitfield-Gabrieli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Whitfield-Gabrieli, S., Ghosh, S., Nieto-Castanon, A. et al. Brain connectomics predict response to treatment in social anxiety disorder. Mol Psychiatry 21, 680–685 (2016). https://doi.org/10.1038/mp.2015.109

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.109

Search

Advanced search

Quick links