Abstract
Neuroimaging has shown promise as a tool to predict likelihood of treatment response in adult anxiety disorders, with potential implications for clinical decision-making. Despite the relatively high prevalence and emergence of anxiety disorders in youth, very little work has evaluated neural predictors of response to treatment. The goal of the current study was to examine brain function during emotional face processing as a predictor of response to treatment in children and adolescents (age 7–19 years; N=41) with generalized, social, and/or separation anxiety disorder. Prior to beginning treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline or cognitive behavior therapy (CBT), participants completed an emotional faces matching task during functional magnetic resonance imaging (fMRI). Whole brain responses to threatening (ie, angry and fearful) and happy faces were examined as predictors of change in anxiety severity following treatment. Greater activation in inferior and superior frontal gyri, including dorsolateral prefrontal cortex and ventrolateral prefrontal cortex, as well as precentral/postcentral gyri during processing of threatening faces predicted greater response to CBT and SSRI treatment. For processing of happy faces, activation in postcentral gyrus was a significant predictor of treatment response. Post-hoc analyses indicated that effects were not significantly moderated by type of treatment. Findings suggest that greater activation in prefrontal regions involved in appraising and regulating responses to social signals of threat predict better response to SSRI and CBT treatment in anxious youth and that neuroimaging may be a useful tool for predicting how youth will respond to treatment.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ball TM, Stein MB, Paulus MP (2014a). Toward the application of functional neuroimaging to individualized treatment for anxiety and depression. Depress Anxiety 31: 920–933.
Ball TM, Stein MB, Ramsawh HJ, Campbell-Sills L, Paulus MP (2014b). Single-subject anxiety treatment outcome prediction using functional neuroimaging. Neuropsychopharmacology 39: 1254–1261.
Barbey AK, Koenigs M, Grafman J (2013). Dorsolateral prefrontal contributions to human working memory. Cortex 49: 1195–1205.
Brett M, Anton J-L, Valabregue R, Poline J-B (2002). Region of interest analysis using an SPM toolbox. Presented at the 8th International Conference on Funcational Mapping of the Human Brain; 2–6 June 2002; Sendai, Japan. Available on CD-ROM in NeuroImage, Vol 16, No 2.
Buhle JT, Silvers JA, Wager TD, Lopez R, Onyemekwu C, Kober H et al (2014). Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cereb Cortex 24: 2981–2990.
Caporino NE, Brodman DM, Kendall PC, Albano AM, Sherrill J, Piacentini J et al (2013). Defining treatment response and remission in child anxiety: signal detection analysis using the pediatric anxiety rating scale. J Am Acad Child Adolesc Psychiatry 52: 57–67.
Compton SN, Walkup JT, Albano AM, Piacentini JC, Birmaher B, Sherrill JT et al (2010). Child/Adolescent Anxiety Multimodal Study (CAMS): rationale, design, and methods. Child Adolesc Psychiatry Ment Health 4: 1.
Copeland WE, Angold A, Shanahan L, Costello EJ (2014). Longitudinal patterns of anxiety from childhood to adulthood: the Great Smoky Mountains Study. J Am Acad Child Adolesc Psychiatry 53: 21–33.
Costello EJ, Egger HK, Angold A (2005). The developmental epidemiology of anxiety disorders: phenomenology, prevalence, and comorbidity. Child Adolesc Psychiatr Clin N Am 14: 631–648.
Cox RW (1996). AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29: 162–173.
Doehrmann O, Ghosh SS, Polli FE, Reynolds GO, Horn F, Keshavan A et al (2013). Predicting treatment response in social anxiety disorder from functional magnetic resonance imaging. JAMA Psychiatry 70: 87–97.
Frank DW, Dewitt M, Hudgens-Haney M, Schaeffer DJ, Ball BH, Schwarz NF et al (2014). Emotion regulation: quantitative meta-analysis of functional activation and deactivation. Neurosci Biobehav Rev 45: 202–211.
Fu CHY, Steiner H, Costafreda SG (2013). Predictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies. Neurobiol Dis 52: 75–83.
Gabrieli JDE, Ghosh SS, Whitfield-gabrieli S (2015). Prediction as a humanitarian and pragmatic contribution from human cognitive neuroscience. Neuron 85: 11–26.
Goldin PR, McRae K, Ramel W, Gross JJ (2008). The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry 63: 577–586.
Grubbs FE (1969). Procedures for detecting outlying observations in samples. Technometrics 11: 1–21.
Gyurak A, Gross JJ, Etkin A (2011). Explicit and implicit emotion regulation: a dual-process framework. Cogn Emot 25: 400–412.
Hariri AR, Tessitore A, Mattay VS, Fera F, Weinberger DR (2002). The amygdala response to emotional stimuli: a comparison of faces and scenes. Neuroimage 17: 317–323.
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P et al (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36: 980–988.
Kendall PC, Choudhury S, Hudson J, Webb A (2002) The C.A.T. Project Workbook. Worbook Publishing: Ardmore, PA, USA.
Kendall PC, Hedtke K (2006) Coping Cat Workbook, 2nd edn. Worbook Publishing: Ardmore, PA, USA.
Killgore WDS, Yurgelun-Todd DA (2005). Social anxiety predicts amygdala activation in adolescents viewing fearful faces. Neuroreport 16: 1671–1675.
Klumpp H, Fitzgerald DA, Phan KL (2013). Neural predictors and mechanisms of cognitive behavioral therapy on threat processing in social anxiety disorder. Prog Neuropsychopharmacol Biol Psychiatry 45: 83–91.
Kober H, Barrett LF, Joseph J, Bliss-Moreau E, Lindquist K, Wager TD (2008). Functional grouping and cortical-subcortical interactions in emotion: a meta-analysis of neuroimaging studies. Neuroimage 42: 998–1031.
Kohn N, Eickhoff SB, Scheller M, Laird AR, Fox PT, Habel U (2014). Neural network of cognitive emotion regulation - an ALE meta-analysis and MACM analysis. Neuroimage 87: 345–355.
Kujawa A, MacNamara A, Fitzgerald KD, Monk CS, Phan KL (2015). Enhanced neural reactivity to threatening faces in anxious youth: evidence from event-related potentials. J Abnorm Child Psychol 43: 1493–1501.
Maslowsky J, Mogg K, Bradley BP, McClure-Tone E, Ernst M, Pine DS et al (2010). A preliminary investigation of neural correlates of treatment in adolescents with generalized anxiety disorder. J Child Adolesc Psychopharmacol 20: 105–111.
McClure EB, Adler A, Monk CS, Cameron J, Smith S, Nelson EE et al (2007a). fMRI predictors of treatment outcome in pediatric anxiety disorders. Psychopharmacology (Berl) 191: 97–105.
McClure EB, Monk CS, Nelson EE, Parrish JM, Adler A, Blair RJR et al (2007b). Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Arch Gen Psychiatry 64: 97–106.
Merikangas KR, He J-P, Burstein M, Swanson SA, Avenevoli S, Cui L et al (2010). Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication—Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry 49: 980–989.
Mohatt J, Bennett SM, Walkup JT (2014). Treatment of separation, generalized, and social anxiety disorders in youths. Am J Psychiatry 171: 741–748.
Monk CS (2008). The development of emotion-related neural circuitry in health and psychopathology. Dev Psychopathol 20: 1231–1250.
Monk CS, Nelson EE, McClure EB, Mogg K, Bradley BP, Leibenluft E et al (2006). Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder. Am J Psychiatry 163: 1091–1097.
Nitschke JB, Sarinopoulos I, Oathes DJ, Johnstone T, Whalen PJ, Davidson RJ et al (2009). Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of reatment response. Am J Psychiatry 166: 302–310.
Ochsner KN, Gross JJ (2005). The cognitive control of emotion. Trends Cogn Sci 9: 242–249.
Phan KL, Coccaro EF, Angstadt M, Kreger KJ, Mayberg HS, Liberzon I et al (2013). Corticolimbic brain reactivity to social signals of threat before and after sertraline treatment in generalized social phobia. Biol Psychiatry 73: 329–336.
Phillips ML, Drevets WC, Rauch SL, Lane R (2003). Neurobiology of emotion perception. I: The neural basis of normal emotion perception. Biol Psychiatry 54: 504–514.
Plichta MM, Schwarz AJ, Grimm O, Morgen K, Mier D, Haddad L et al (2012). Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery. Neuroimage 60: 1746–1758.
Research Units of Pediatric Psychopharmacology Anxiety Study Group (2002). The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties. J Am Acad Child Adolesc Psychiatry 41: 1061–1069.
Tanji J, Hoshi E (2008). Role of the lateral prefrontal cortex in executive behavioral control. Physiol Rev 88: 37–57.
Thomas KM, Drevets WC, Dahl RE, Ryan ND, Birmaher B, Eccard CH et al (2001). Amygdala response to fearful faces in anxious and depressed children. Arch Gen Psychiatry 58: 1057–1063.
van den Bulk B, Koolschijn PCMP, Meens PHF, van Lang NDJ, van der Wee NJA, Rombouts SARB et al (2013). How stable is activation in the amygdala and prefrontal cortex in adolescence? A study of emotional face processing across three measurements. Dev Cogn Neurosci 4: 65–76.
Verduin TL, Kendall PC (2003). Differential occurence of comorbidity within childhood anxiety disorders. J Clin Child Adolesc Psychol 32: 290–295.
Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT et al (2008). Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med 359: 2753–2766.
Walter B, Blecker C, Kirsch P, Sammer G, Schienle A, Stark R et al (2003). MARINA: an easy to use tool for the creation of MAsks for Region of INterest Analyses. Presented at the 9th International Conference on Functional Mapping of the Human Brain; 19–22 June 2003; New York, NY, USA. Available on CD-Rom in NeuroImage, Vol. 19, No. 2.
Weems CF, Silverman WK (2013) Anxiety disorders. In: Beauchaine T, Hinshaw S (eds). Child and Adolescent Psychopathology. John Wiley: Hoboken, NJ, USA, pp 513–541.
Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL et al (2008). A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol Psychiatry 63: 858–863.
Whitfield-Gabrieli S, Ghosh SS, Nieto-Castanon A, Saygin Z, Doehrmann O, Chai XJ et al (2015). Brain connectomics predict response to treatment in social anxiety disorder. Mol Psychiatry (e-pub ahead of print).
Woodward LJ, Fergusson DM (2001). Life course outcomes of young people with anxiety disorders in adolescence. J Am Acad Child Adolesc Psychiatry 40: 1086–1093.
Acknowledgements
This work was supported by the National Institute of Mental Health Grant R01-MH086517 to CSM and KLP. AK is supported by the National Institute of Mental Health Grant T32-MH067631 to Mark Rasenick.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kujawa, A., Swain, J., Hanna, G. et al. Prefrontal Reactivity to Social Signals of Threat as a Predictor of Treatment Response in Anxious Youth. Neuropsychopharmacol 41, 1983–1990 (2016). https://doi.org/10.1038/npp.2015.368
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2015.368
This article is cited by
-
Quantitative electroencephalographic biomarker of pharmacological treatment response in patients with anxiety disorder: a retrospective study
Scientific Reports (2023)
-
Regional cerebral blood flow as predictor of response to occipital nerve block in cluster headache
The Journal of Headache and Pain (2021)
-
Nucleus accumbens volume as a predictor of anxiety symptom improvement following CBT and SSRI treatment in two independent samples
Neuropsychopharmacology (2020)
-
Cortical Thickness and Subcortical Gray Matter Volume in Pediatric Anxiety Disorders
Neuropsychopharmacology (2017)
