Mechanisms of cognitive-behavioral therapy for obsessive-compulsive disorder involve robust and extensive increases in brain network connectivity

T D Moody, F Morfini, G Cheng, C Sheen, R Tadayonnejad, N Reggente, J O'Neill, J D Feusner, T D Moody, F Morfini, G Cheng, C Sheen, R Tadayonnejad, N Reggente, J O'Neill, J D Feusner

Abstract

Cognitive-behavioral therapy (CBT) is effective for obsessive compulsive disorder (OCD); however, little is understood about its mechanisms related to brain network connectivity. We examined connectivity changes from resting-state functional magnetic resonance imaging data pre-to-post-CBT in 43 OCD participants, randomized to receive either 4 weeks of intensive CBT or 4 weeks waitlist followed by 4 weeks of CBT, and 24 healthy controls before and after 4 weeks of no treatment. Network-based-statistic analysis revealed large-magnitude increases in OCD connectivity in eight networks. Strongest increases involved connectivity between the cerebellum and caudate/putamen, and between the cerebellum and dorsolateral/ventrolateral prefrontal cortices. Connectivity increases were associated with increased resistance to compulsions. Mechanisms of CBT may involve enhanced cross-network integration, both within and outside of classical cortico-striatal-thalamo-cortical regions; those involving cerebellar to striatal and prefrontal regions may reflect acquisition of new non-compulsive goal-directed behaviors and thought patterns. Our findings have implications for identifying targets for enhancing treatment efficacy and monitoring treatment progress.

Trial registration: ClinicalTrials.gov NCT01368510.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart for NBS analysis of whole-brain resting-state fMRI. (1) Resting state data were acquired, preprocessed to remove motion artifact, and normalized to the MNI template; (2) On the MNI template, 160 functional nodes were defined; (3) Time series within each node were extracted; (4) Functional connectivity was calculated for each pair of nodes for each participant; (5) 160 × 160 connectivity matrices (full-correlations) were computed; (6) Network-based statistic (NBS) method was used to identify connectivity differences between groups and before and after CBT; (7) Linear regressions compared connectivity strength and OCD symptoms. rsfMRI, resting state functional MRI.
Figure 2
Figure 2
Obsessive compulsive disorder (OCD) networks showing significantly stronger connectivity pre- to post-CBT. L, left; R, right; L.Crus I, L. cerebellum crus I; L.frPole, L. frontal pole; L.ICC, L. intracalcarine cortex; L.Insula, L. posterior insula; L.Lingual, L. lingual gyrus; L.LOC, L. superior lateral occipital; L.parOper, L. parietal operculum; L.PCC, L. posterior cingulate; L.pCun, L. precuneus; L.Put, L. putamen; L.spLobule, L. superior parietal lobule; L.Thal, L. thalamus, caudate; L.V, L. cerebellum V; L.VI, L. cerebellum VI; R.Crus I, R. cerebellum crus I; R.DAC, R. dorsal anterior cingulate; R.frPole, R. frontal pole; R.ICC, R. intracalcarine cortex; R.IFG, R. inferior frontal gyrus, precentral gyrus; R.MFG, R. middle frontal gyrus; R.pCun, R. precuneus; R.STG, R. superior temporal gyrus; R.Thal, R. thalamus. Network-based statistic (NBS) analysis identified eight networks using a t-threshold=6 and P-value <0.01. See Table 2 for list of connections and t-statistics.
Figure 3
Figure 3
Associations between functional connectivity and obsessive compulsive disorder (OCD) symptom severity. (a) Correlation across OCD participants (blue circles) between pre-to-post-CBT change in OCD symptom severity (YBOCS Item 9 sub-score, resistance to compulsions) and pre-to-post-CBT change in functional connectivity between right frontal pole and left parietal operculum (inset right; 10-mm nodes centered at MNI coordinates (6, 64, 3) and (–41, −37, 16); r=0.51, P<0.001). Increased connectivity between this node pair may reflect improved resistance to OCD compulsions induced by CBT. (b) Pre-CBT there was a significant negative correlation between OCD symptom severity (YBOCS scores) and connection strength between left and right insula (inset right). (Nodes centered at (38, 21, −1) and (−36, 18, 2); r=−0.35, P=0.02). Lower pretreatment connectivity between this node pair is associated with worse symptoms. CBT, cognitive-behavioral therapy.

References

    1. American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th edn, American Psychiatric Association: Washington, DC, USA, 2013.
    1. Markarian Y, Larson MJ, Aldea MA, Baldwin SA, Good D, Berkeljon A et al. Multiple pathways to functional impairment in obsessive-compulsive disorder. Clin Psychol Rev. 2010; 30: 78–88.
    1. Eddy KT, Dutra L, Bradley R, Westen D. A multidimensional meta-analysis of psychotherapy and pharmacotherapy for obsessive-compulsive disorder. Clin Psychol Rev. 2004; 24: 1011–1030.
    1. Rosa-Alcazar AI, Sanchez-Meca J, Gomez-Conesa A, Marin-Martinez F. Psychological treatment of obsessive-compulsive disorder: a meta-analysis. Clin Psychol Rev. 2008; 28: 1310–1325.
    1. Rosa-Alcazar AI, Sanchez-Meca J, Rosa-Alcazar A, Iniesta-Sepulveda M, Olivares-Rodriguez J, Parada-Navas JL. Psychological treatment of obsessive-compulsive disorder in children and adolescents: a meta-analysis. Span J Psychol. 2015; 18: E20.
    1. Bystritsky A, Munford PR, Rosen RM, Martin KM, Vapnik T, Gorbis EE et al. A preliminary study of partial hospital management of severe obsessive-compulsive disorder. Psychiatr Serv. 1996; 47: 170–174.
    1. Calvocoressi L, McDougle CI, Wasylink S, Goodman WK, Trufan SJ, Price LH. Inpatient treatment of patients with severe obsessive-compulsive disorder. Hosp Community Psychiatry. 1993; 44: 1150–1154.
    1. Maia TV, Cooney RE, Peterson BS. The neural bases of obsessive-compulsive disorder in children and adults. Dev Psychopathol. 2008; 20: 1251–1283.
    1. 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: 525–549.
    1. Anticevic A, Hu S, Zhang S, Savic A, Billingslea E, Wasylink S et al. Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder. Biol Psychiatry. 2014; 75: 595–605.
    1. 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: 1039–1047.
    1. Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci. 2012; 16: 43–51.
    1. 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: e36356.
    1. Zhang T, Wang J, Yang Y, Wu Q, Li B, Chen L et al. Abnormal small-world architecture of top-down control networks in obsessive-compulsive disorder. J Psychiatry Neurosci. 2011; 36: 23–31.
    1. Shin DJ, Jung WH, He Y, Wang J, Shim G, Byun MS et al. The effects of pharmacological treatment on functional brain connectome in obsessive-compulsive disorder. Biological Psychiatry. 2014; 75: 606–614.
    1. Feusner JD, Moody T, Lai TM, Sheen C, Khalsa S, Brown J et al. Brain connectivity and prediction of relapse after cognitive-behavioral therapy in obsessive-compulsive disorder. Front Psychiatry 2015; 6: 74.
    1. Zalesky A, Fornito A, Bullmore ET. Network-based statistic: identifying differences in brain networks. Neuroimage 2010; 53: 1197–1207.
    1. Goldin PR, Ziv M, Jazaieri H, Hahn K, Heimberg R, Gross JJ. Impact of cognitive behavioral therapy for social anxiety disorder on the neural dynamics of cognitive reappraisal of negative self-beliefs: randomized clinical trial. JAMA Psychiatry 2013; 70: 1048–1056.
    1. Mansson KN, Carlbring P, Frick A, Engman J, Olsson CJ, Bodlund O et al. Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder. Psychiatry Res. 2013; 214: 229–237.
    1. Månsson KNT, Frick A, Boraxbekk CJ, Marquand AF, Williams SCR, Carlbring P et al. Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning. Translational Psychiatry 2015; 5: e530.
    1. Mason L, Peters ER, Dima D, Williams SC, Kumari V. Cognitive Behavioral Therapy Normalizes Functional Connectivity for Social Threat in Psychosis. Schizophr Bull. 2016; 42: 684–692.
    1. Simmons AN, Norman SB, Spadoni AD, Strigo IA. Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder. Psychother Psychosom. 2013; 82: 382–389.
    1. Straube B, Lueken U, Jansen A, Konrad C, Gloster AT, Gerlach AL et al. Neural correlates of procedural variants in cognitive-behavioral therapy: a randomized, controlled multicenter FMRI study. Psychother Psychosom. 2014; 83: 222–233.
    1. Lazaro L, Calvo A, Ortiz AG, Ortiz AE, Morer A, Moreno E et al. Microstructural brain abnormalities and symptom dimensions in child and adolescent patients with obsessive-compulsive disorder: a diffusion tensor imaging study. Depression and anxiety 2014; 31: 1007–1017.
    1. Wen SL, Cheng MF, Cheng MH, Yue JH, Li JF, Xie LJ. Neurocognitive dysfunction and regional cerebral blood flow in medically naive patients with obsessive-compulsive disorder. Developmental neuropsychology 2014; 39: 37–50.
    1. Tian L, Meng C, Jiang Y, Tang Q, Wang S, Xie X et al. Abnormal functional connectivity of brain network hubs associated with symptom severity in treatment-naive patients with obsessive–compulsive disorder: A resting-state functional MRI study. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2016; 66: 104–111.
    1. Hou J-M, Zhao M, Zhang W, Song L-H, Wu W-J, Wang J et al. Resting-state functional connectivity abnormalities in patients with obsessive–compulsive disorder and their healthy first-degree relatives. Journal of Psychiatry & Neuroscience : JPN 2014; 39: 304–311.
    1. Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, Lopez-Sola M, Hernandez-Ribas R et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch Gen Psychiatry. 2009; 66: 1189–1200.
    1. Sakai Y, Narumoto J, Nishida S, Nakamae T, Yamada K, Nishimura T et al. Corticostriatal functional connectivity in non-medicated patients with obsessive-compulsive disorder. Eur Psychiatry. 2011; 26: 463–469.
    1. DiNardo PA, Brown TA, Barlow DH. Anxiety Disorders Interview Schedule for DSM-IV: Lifetime version. Graywind: Albany, 1994.
    1. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al. The Yale-Brown Obsessive Compulsive Scale.1. Development, Use, and Reliability. Arch Gen Psychiatry. 1989; 46: 1006–1011.
    1. Wechsler D. Wechsler Abbreviated Scale of Intelligence (WASI). Psychological Corporation: San Antonio, 1999.
    1. Pocock SJ. Interim analyses for randomized clinical trials: the group sequential approach. Biometrics 1982; 38: 153–162.
    1. Smoak C, Lin J-S. A SAS program to perform adaptive randomization. Statistics, Data Analysis, and Data Mining. Chiron Corporation: Emeryville, CA, 2006.
    1. 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: 485–496.
    1. Hamilton M. The assessment of anxiety states by rating. The British journal of medical psychology 1959; 32: 50–55.
    1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979; 134: 382–389.
    1. Endicott J, Spitzer RL, Fleiss JL, Cohen J. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry. 1976; 33: 766–771.
    1. Kozak MJ, Foa EB. Mastery of obsessive-compulsive disorder: a cognitive-behavioral approach client workbook. Oxford University Press: New York, 1997.
    1. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage 2012; 59: 2142–2154.
    1. Dosenbach NU, Nardos B, Cohen AL, Fair DA, Power JD, Church JA et al. Prediction of individual brain maturity using fMRI. Science 2010; 329: 1358–1361.
    1. Nabeyama M, Nakagawa A, Yoshiura T, Nakao T, Nakatani E, Togao O et al. Functional MRI study of brain activation alterations in patients with obsessive-compulsive disorder after symptom improvement. Psychiatry Res. 2008; 163: 236–247.
    1. Vaghi MM, Vértes 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. Biological Psychiatry 2017; 81: 708–717.
    1. Milad MR, Furtak SC, Greenberg JL, Keshaviah A, Im JJ, Falkenstein MJ et al. Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit. JAMA Psychiatry 2013; 70: 608–618, quiz 554.
    1. Ping L, Su-Fang L, Hai-Ying H, Zhang-Ye D, Jia L, Zhi-Hua G et al. Abnormal Spontaneous Neural Activity in Obsessive-Compulsive Disorder: A Resting-State Functional Magnetic Resonance Imaging Study. PLoS ONE 2013; 8: e67262.
    1. Wang X, Cao Q, Wang J, Wu Z, Wang P, Sun L et al. The effects of cognitive-behavioral therapy on intrinsic functional brain networks in adults with attention-deficit/hyperactivity disorder. Behaviour Research and Therapy. 2016; 76: 32–39.
    1. Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 2009; 44: 489–501.
    1. Zou QH, Zhu CZ, Yang Y, Zuo XN, Long XY, Cao QJ et al. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF. J Neurosci Methods. 2008; 172: 137–141.
    1. Zuo XN, Di Martino A, Kelly C, Shehzad ZE, Gee DG, Klein DF et al. The oscillating brain: complex and reliable. Neuroimage 2010; 49: 1432–1445.
    1. Shpaner M, Kelly C, Lieberman G, Perelman H, Davis M, Keefe FJ et al. Unlearning chronic pain: A randomized controlled trial to investigate changes in intrinsic brain connectivity following Cognitive Behavioral Therapy. NeuroImage: Clinical 2014; 5: 365–376.
    1. 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.
    1. Manni E, Petrosini L. A century of cerebellar somatotopy: a debated representation. Nat Rev Neurosci. 2004; 5: 241–249.
    1. Burguiere E, Arabo A, Jarlier F, De Zeeuw CI, Rondi-Reig L. Role of the cerebellar cortex in conditioned goal-directed behavior. J Neurosci. 2010; 30: 13265–13271.
    1. Burguiere E, Arleo A, Hojjati M, Elgersma Y, De Zeeuw CI, Berthoz A et al. Spatial navigation impairment in mice lacking cerebellar LTD: a motor adaptation deficit? Nat Neurosci. 2005; 8: 1292–1294.
    1. Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp. 1996; 4: 174–198.
    1. Sacchetti B, Scelfo B, Strata P. Cerebellum and emotional behavior. Neuroscience 2009; 162: 756–762.
    1. Saxena S, Gorbis E, O'Neill J, Baker SK, Mandelkern MA, Maidment KM et al. Rapid effects of brief intensive cognitive-behavioral therapy on brain glucose metabolism in obsessive-compulsive disorder. Mol Psychiatry. 2008; 14: 197–205.
    1. Armstrong CC, Moody TD, Feusner JD, McCracken JT, Chang S, Levitt JG et al. Graph-theoretical analysis of resting-state fMRI in pediatric obsessive-compulsive disorder. J Affect Disord. 2016; 193: 175–184.
    1. Meunier D, Ersche KD, Craig KJ, Fornito A, Merlo-Pich E, Fineberg NA et al. Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder. Neuroimage 2012; 59: 1461–1468.
    1. Lindsay M, Crino R, Andrews G. Controlled trial of exposure and response prevention in obsessive-compulsive disorder. The British Journal of Psychiatry 1997; 171: 135–139.
    1. Nakatani E, Nakagawa A, Nakao T, Yoshizato C, Nabeyama M, Kudo A et al. A randomized controlled trial of Japanese patients with obsessive-compulsive disorder—effectiveness of behavior therapy and fluvoxamine. Psychother Psychosom. 2005; 74: 269–276.
    1. Zhu Y, Fan Q, Zhang H, Qiu J, Tan L, Xiao Z et al. Altered intrinsic insular activity predicts symptom severity in unmedicated obsessive-compulsive disorder patients: a resting state functional magnetic resonance imaging study. BMC psychiatry 2016; 16: 104.
    1. Beucke JC, Sepulcre J, Talukdar T et al. Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder. JAMA Psychiatry 2013; 70: 619–629.
    1. Lochner C, Stein DJ. Heterogeneity of obsessive-compulsive disorder: a literature review. Harvard review of psychiatry 2003; 11: 113–132.
    1. Dosenbach NU, Fair DA, Miezin FM, Cohen AL, Wenger KK, Dosenbach RA et al. Distinct brain networks for adaptive and stable task control in humans. Proc Natl Acad Sci U S A. 2007; 104: 11073–11078.
    1. van Velzen LS, de Wit SJ, Curcic-Blake B, Cath DC, de Vries FE, Veltman DJ et al. Altered Inhibition-Related Frontolimbic Connectivity in Obsessive-Compulsive Disorder. Hum Brain Mapp. 2015; 36: 4064–4075.
    1. Gottlich M, Kramer UM, Kordon A, Hohagen F, Zurowski B. Resting-state connectivity of the amygdala predicts response to cognitive behavioral therapy in obsessive compulsive disorder. Biol Psychol. 2015; 111: 100–109.

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