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.

Defining brain-based OCD patient profiles using task-based fMRI and unsupervised machine learning

Abstract

While much research has highlighted phenotypic heterogeneity in obsessive compulsive disorder (OCD), less work has focused on heterogeneity in neural activity. Conventional neuroimaging approaches rely on group averages that assume homogenous patient populations. If subgroups are present, these approaches can increase variability and can lead to discrepancies in the literature. They can also obscure differences between various subgroups. To address this issue, we used unsupervised machine learning to identify subgroup clusters of patients with OCD who were assessed by task-based fMRI. We predominantly focused on activation of cognitive control and performance monitoring neurocircuits, including three large-scale brain networks that have been implicated in OCD (the frontoparietal network, cingulo-opercular network, and default mode network). Participants were patients with OCD (n = 128) that included both adults (ages 24–45) and adolescents (ages 12–17), as well as unaffected controls (n = 64). Neural assessments included tests of cognitive interference and error processing. We found three patient clusters, reflecting a “normative” cluster that shared a brain activation pattern with unaffected controls (65.9% of clinical participants), as well as an “interference hyperactivity” cluster (15.2% of clinical participants) and an “error hyperactivity” cluster (18.9% of clinical participants). We also related these clusters to demographic and clinical correlates. After post-hoc correction for false discovery rates, the interference hyperactivity cluster showed significantly longer reaction times than the other patient clusters, but no other between-cluster differences in covariates were detected. These findings increase precision in patient characterization, reframe prior neurobehavioral research in OCD, and provide a starting point for neuroimaging-guided treatment selection.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Neural activation patterns are depicted for a number of OCD-relevant brain areas in study participants.
Fig. 2: Yale-brown obsessive compulsive scale (Y-BOCS) scores at pre- and post-treatment for each patient cluster.

References

  1. Angst J, Gamma A, Endrass J, Hantouche E, Goodwin R, Ajdacic V, et al. Obsessive-compulsive syndromes and disorders: Significance of comorbidity with bipolar and anxiety syndromes. Eur Arch Psychiatry Clin Neurosci. 2005;255:65–71.

    PubMed  Article  Google Scholar 

  2. Kessler RC, Berglund P, Demler O, Jin R, 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.

    PubMed  Article  Google Scholar 

  3. Watson D, Stasik SM. Dispositional basis of anxiety disorders. In: Emmelkamp P, Ehring T, editors. The Wiley handbook of anxiety disorders. Chichester, UK: John Wiley & Sons; 2014. 201–12.

  4. Conceição do Rosário M, Batistutto M, Ferrao Y. Symptom heterogeneity in OCD: A dimensional approach. In: Pittenger C, editor. Obsessive-compulsive disorder phenomenology, pathophysiology, and treatment. New York: Oxford University Press; 2017. 75–92.

  5. Larson MJ, Clawson A. A critical review of neuropsychological functioning and heterogeneity in individuals with obsessive-compulsive disorder. In: McKay D, Storch EA, Abramowitz JS, editors. The Wiley handbook of obsessive compulsive disorders. Chichester, UK: John Wiley & Sons; 2017. 155–75.

  6. Williams LM. Precision psychiatry: A neural circuit taxonomy for depression and anxiety. Lancet Psychiatry. 2016;3:472–80.

    PubMed  PubMed Central  Article  Google Scholar 

  7. Menon V. Large-scale brain networks and psychopathology: A unifying triple network model. Trends Cogn Sci. 2011;15:483–506.

    PubMed  Article  Google Scholar 

  8. Downar J, Blumberger DM, Daskalakis ZJ. The neural crossroads of psychiatric illness: An emerging target for brain stimulation. Trends Cogn Sci. 2016;20:107–20.

    PubMed  Article  Google Scholar 

  9. Dosenbach NUF, Visscher KM, Palmer ED, Miezin FM, Wenger KK, Kang HC, et al. A core system for the implementation of task sets. Neuron 2006;50:799–812.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Sridharan D, Levitin DJ, Menon V. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci USA. 2008;105:12569–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Fitzgerald KD, Taylor SF. Error-processing abnormalities in pediatric anxiety and obsessive compulsive disorders. CNS Spectr. 2015;20:346–54.

    PubMed  PubMed Central  Article  Google Scholar 

  12. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann NY Acad Sci. 2008;1124:1–38.

    PubMed  Article  Google Scholar 

  13. Fitzgerald KD, Stern ER, Angstadt M, Nicholson-Muth KC, Maynor MR, Welsh RC, et al. Altered function and connectivity of the medial frontal cortex in pediatric obsessive-compulsive disorder. Biol Psychiatry. 2010;68:1039–47.

    PubMed  PubMed Central  Article  Google Scholar 

  14. Becker HC, Norman LJ, Yang H, Monk CS, Phan KL, Taylor SF, et al. Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety. Psychol Med. 16 August 2021. https://doi.org/10.1017/S0033291721003044.

  15. Stern ER, Welsh RC, Fitzgerald KD, Gehring WJ, Lister JJ, Himle JA, et al. Hyperactive error responses and altered connectivity in ventromedial and frontoinsular cortices in obsessive-compulsive disorder. Biol Psychiatry. 2011;69:583–91.

    PubMed  Article  Google Scholar 

  16. Stern ER, Fitzgerald KD, Welsh RC, Abelson JL, Taylor SF. Resting-state functional connectivity between fronto-parietal and default mode networks in obsessive-compulsive disorder. PLoS ONE. 2012;7:1–9.

    Google Scholar 

  17. Gürsel DA, Avram M, Sorg C, Brandl F, Koch K. Frontoparietal areas link impairments of large-scale intrinsic brain networks with aberrant fronto-striatal interactions in OCD: A meta-analysis of resting-state functional connectivity. Neurosci Biobehav Rev. 2018;87:151–60.

    PubMed  Article  Google Scholar 

  18. Posner J, Song I, Lee S, Rodriguez CI, Moore H, Marsh R, et al. Increased functional connectivity between the default mode and salience networks in unmedicated adults with obsessive-compulsive disorder. Hum Brain Mapp. 2017;38:678–87.

    PubMed  Article  Google Scholar 

  19. de Wit SJ, de Vries FE, van der Werf YD, Cath DC, Heslenfeld DJ, Veltman EM, et al. Presupplementary motor area hyperactivity during response inhibition: A candidate endophenotype of obsessive-compulsive disorder. Am J Psychiatry. 2012;169:1100–8.

    PubMed  Article  Google Scholar 

  20. Rubia K, Cubillo A, Woolley J, Brammer MJ, Smith A. Disorder-specific dysfunctions in patients with attention-deficit/hyperactivity disorder compared to patients with obsessive-compulsive disorder during interference inhibition and attention allocation. Hum Brain Mapp. 2011;32:601–11.

    PubMed  Article  Google Scholar 

  21. Roth RM, Saykin AJ, Flashman LA, Pixley HS, West JD, Mamourian AC. Event-related functional magnetic resonance imaging of response inhibition in obsessive-compulsive disorder. Biol Psychiatry. 2007;62:901–09.

    PubMed  Article  Google Scholar 

  22. Kang DH, Jang JH, Han JY, Kim JH, Jung WH, Choi JS, et al. Neural correlates of altered response inhibition and dysfunctional connectivity at rest in obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2013;40:340–46.

    PubMed  Article  Google Scholar 

  23. Botvinick MM, Cohen JD, Carter CS. Conflict monitoring and anterior cingulate cortex: An update. Trends Cogn Sci. 2004;8:539–46.

    PubMed  Article  Google Scholar 

  24. Cole MW, Schneider W. The cognitive control network: Integrated cortical regions with dissociable functions. Neuroimage. 2007;37:343–60.

    PubMed  Article  Google Scholar 

  25. Fitzgerald KD, Liu Y, Johnson TD, Moser JS, Marsh R, Hanna GL, et al. Development of posterior medial frontal cortex function in pediatric obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2018;57:397–406.

    PubMed  PubMed Central  Article  Google Scholar 

  26. Ursu S, Stenger VA, Shear MK, Jones MR, Carter CS. Overactive action monitoring in obsessive-compulsive disorder: Evidence from functional magnetic resonance imaging. Psychol Sci. 2003;14:347–53.

    PubMed  Article  Google Scholar 

  27. Yücel M, Harrison BJ, Wood SJ, Fornito A, Wellard RM, Pujol J, et al. Functional and biochemical alterations of the medial frontal cortex in obsessive-compulsive disorder. Arch Gen Psychiatry. 2007;64:946–55.

    PubMed  Article  Google Scholar 

  28. Maltby N, Tolin DF, Worhunsky P, O’Keefe TM, Kiehl KA. Dysfunctional action monitoring hyperactivates frontal-striatal circuits in obsessive-compulsive disorder: An event-related fMRI study. Neuroimage. 2005;24:495–503.

    PubMed  Article  Google Scholar 

  29. Gehring WJ, Himle J, Nisenson LG. Action-monitoring dysfunction in obsessive-compulsive disorder. Psychol Sci. 2000;11:1–6.

    CAS  PubMed  Article  Google Scholar 

  30. Bellato A, Norman L, Idrees I, Ogawa CY, Waitt A, Zuccolo PF, et al. A systematic review and meta-analysis of altered electrophysiological markers of performance monitoring in obsessive-compulsive disorder (OCD), Gilles de la Tourette syndrome (GTS), attention-deficit/hyperactivity disorder (ADHD) and autism. Neurosci Biobehav Rev. 2021;131:964–87.

    CAS  PubMed  Article  Google Scholar 

  31. Fitzgerald KD, Welsh RC, Gehring WJ, Abelson JL, Himle JA, Liberzon I, et al. Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. Biol Psychiatry. 2005;57:287–94.

    PubMed  Article  Google Scholar 

  32. Huyser C, Veltman DJ, Wolters LH, De Haan E, Boer F. Developmental aspects of error and high-conflict-related brain activity in pediatric obsessive-compulsive disorder: A fMRI study with a Flanker task before and after CBT. J Child Psychol Psychiatry. 2011;52:1251–60.

    PubMed  Article  Google Scholar 

  33. Lillevik Thorsen A, de Wit SJ, Hagland P, Ousdal OT, Hansen B, Hagen K, et al. Stable inhibition-related inferior frontal hypoactivation and fronto-limbic hyperconnectivity in obsessive-compulsive disorder after concentrated exposure therapy. Neuroimage Clin. 2020;28:1–8.

    Article  Google Scholar 

  34. Norman LJ, Taylor SF, Liu Y, Radua J, Chye Y, De Wit SJ, et al. Error processing and inhibitory control in obsessive-compulsive disorder: A meta-analysis using statistical parametric maps. Biol Psychiatry. 2019;85:713–25.

    PubMed  Article  Google Scholar 

  35. Battista C, Evans TM, Ngoon TJ, Chen T, Chen L, Kochalka J, et al. Mechanisms of interactive specialization and emergence of functional brain circuits supporting cognitive development in children. NPJ Sci Learn. 2018;3:1–11.

    PubMed  PubMed Central  Article  Google Scholar 

  36. Henderson NC, Louis TA, Wang C, Varadhan R. Bayesian analysis of heterogeneous treatment effects for patient-centered outcomes research. Health Serv Outcomes Res Methodol. 2016;16:213–33.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Taylor SF, Martis B, Fitzgerald KD, Welsh RC, Abelson JL, Liberzon I, et al. Medial frontal cortex activity and loss-related responses to errors. J Neurosci. 2006;26:4063–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 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.

    PubMed  Article  Google Scholar 

  39. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID), clinician version: User’s guide. Washington, DC: American Psychiatric Publishing; 1996.

  40. Hein D, Matzner F, First M, Spitzer R, Williams J, Gibbon M. Structured Clinical Interview for DSM-IV Childhood Diagnoses, KID-SCID. New York: Columbia University Department of Psychiatry; 1998.

  41. 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.

    CAS  PubMed  Article  Google Scholar 

  42. Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK, et al. Children’s Yale-Brown Obsessive Compulsive Scale: Reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36:844–52.

    CAS  PubMed  Article  Google Scholar 

  43. Foa EB, Huppert JD, Leiberg S, Langner R, Kichic R, Hajcak G, et al. The obsessive-compulsive inventory: Development and validation of a short version. Psychol Assess. 2002;14:485–96.

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  45. Hall RC. Global assessment of functioning: A modified scale. Psychosomatics 1995;36:267–75.

    CAS  PubMed  Article  Google Scholar 

  46. Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, et al. A children’s global assessment scale (CGAS). Arch Gen Psychiatry. 1983;40:1228–31.

    CAS  PubMed  Article  Google Scholar 

  47. Wechsler D. Wechsler Abbreviated Scale of Intelligence - Second Edition. Pearson: San Antonio, TX; 2011.

  48. Boedhoe PS, Schmaal L, Abe Y, Ameis SH, Arnold PD, Batistuzzo MC, et al. Distinct subcortical volume alterations in pediatric and adult OCD: A worldwide meta- and mega-analysis. Am J Psychiatry. 2017;174:60–69.

    PubMed  Article  Google Scholar 

  49. Kwak S, Kim M, Kim T, Kwak Y, Oh S, Lho SK, et al. Defining data-driven subgroups of obsessive-compulsive disorder with different treatment responses based on resting-state functional connectivity. Transl Psychiatry. 2020;10:1–11.

    Article  Google Scholar 

  50. Muthén LK, Muthén BO Mplus user’s guide. 8th edn. Los Angeles, CA: Muthén & Muthén; 2017

  51. Masyn KE Latent class analysis and finite mixture modeling. In: Little TD, editor. The Oxford handbook of quantitative methods. New York: Oxford University Press; 2013. 551–611.

  52. Benjamini Y, Hochberg Y. Controlling the false discovery rate: A practical and powerful appraoch to multiple testing. J R Stat Soc Ser B-Methodol. 1995;57:289–300.

    Google Scholar 

  53. Bakk Z, Vermunt JK. Robustness of stepwise latent class modeling with continuous distal outcomes. Struct Equ Modeling. 2016;23:20–31.

    Article  Google Scholar 

  54. Kass RE, Raftery AE. Bayes factors. J Am Stat Assoc. 1995;90:773–95.

    Article  Google Scholar 

  55. Carp J, Kim K, Taylor SF, Fitzgerald KD, Weissman DH. Conditional differences in mean reaction time explain effects of response congruency, but not accuracy, on posterior medial frontal cortex activity. Front Hum Neurosci. 2010;4:1–9.

    Article  Google Scholar 

  56. Fitzgerald KD, Perkins SC, Angstadt M, Johnson T, Stern ER, Welsh RC, et al. The development of performance-monitoring function in the posterior medial frontal cortex. Neuroimage. 2010;49:3463–73.

    PubMed  Article  Google Scholar 

  57. Davies PL, Segalowitz SJ, Gavin WJ. Development of error‐monitoring event‐related potentials in adolescents. Ann NY Acad Sci. 2004;1021:324–28.

    PubMed  Article  Google Scholar 

  58. Casey BJ, Jones RM, Hare TA. The adolescent brain. Ann NY Acad Sci. 2008;1124:111–26.

    CAS  PubMed  Article  Google Scholar 

  59. Rubia K, Smith AB, Taylor E, Brammer M. Linear age-correlated functional development of right inferior fronto-striato-cerebellar networks during response inhibition and anterior cingulate during error-related processes. Hum Brain Mapp. 2007;28:1163–77.

    PubMed  PubMed Central  Article  Google Scholar 

  60. Taylor S. Early versus late onset obsessive-compulsive disorder: Evidence for distinct subtypes. Clin Psychol Rev. 2011;31:1083–100.

    PubMed  Article  Google Scholar 

Download references

Funding

This research was supported by National Institute of Mental Health grants R01MH102242-01A1 and R01MH102242-05S1 to KDF and SFT as well as R01MH107419 to KDF. SFT has received contract research support from Boehringer-Ingelheim. The authors report no competing financial interests in relation to the work described.

Author information

Authors and Affiliations

Authors

Contributions

ASD: Manuscript writing, data analysis. KDF: Study design and execution, manuscript writing. LJN: Study execution, manuscript writing, data analysis. SRB: Manuscript writing. KAM: Study execution, manuscript writing. JAH: Study execution, manuscript editing. SFT: Study design and execution, manuscript writing. All authors have reviewed and approved the final version of this manuscript.

Corresponding author

Correspondence to Alessandro S. De Nadai.

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

Verify currency and authenticity via CrossMark

Cite this article

De Nadai, A.S., Fitzgerald, K.D., Norman, L.J. et al. Defining brain-based OCD patient profiles using task-based fMRI and unsupervised machine learning. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01353-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-022-01353-x

Search

Quick links