Neurobiology of Pediatric Anxiety Disorders

  • Amanda E. Guyer
  • Carrie L. Masten
  • Daniel S. Pine
Part of the Current Clinical Psychiatry book series (CCPSY)


Anxiety during childhood and adolescence is a highly prevalent problem that contributes to long-term dysfunction in adulthood. This chapter highlights research on the neurobiology of pediatric anxiety disorders aimed at understanding how anxiety takes hold in the brain and the mechanisms that fuel its developmental course. We present an overview of anatomical and functional brain-based differences in children and adolescents with and without anxiety disorders. With regard to work focused on brain function in pediatric anxiety, we discuss four key psychological processes that are highly relevant to clinical characteristics in anxiety: attention orienting, threat learning, social–emotional information processing, and reward processing. We also review recent work that delineates connections between and within neural regions that appear to be distinctly modulated by anxiety both in response to specific tasks and while at rest. We close the chapter with a summary of emerging work on neurobiological response to treatments for anxiety in children and adolescents, followed by conclusions and future directions for this course of work.


Anxiety Adolescence Childhood Neuroimaging Brain structure Brain function Neural connectivity 



Support for this work was provided by the National Institute of Mental Health Intramural Research Program and National Institutes of Health Career Development Award K99/R900 MH080076 to A.E.G. The authors wish to thank Jennifer Buser and Sarah Ruiz for assistance with literature reviews and table and figure creation.


  1. 1.
    Pine DS, Cohen P, Gurley D, Brook J, Ma Y. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry. 1998;55(1):56–64.PubMedCrossRefGoogle Scholar
  2. 2.
    Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A. Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry. 2003;60(8):837–44. Epub 2003/08/13.PubMedCrossRefGoogle Scholar
  3. 3.
    Pine DS. Research review: a neuroscience framework for pediatric anxiety disorders. J Child Psychol Psychiatry. 2007;48(7):631–48.PubMedCrossRefGoogle Scholar
  4. 4.
    Pine DS, Guyer AE, Leibenluft E. Functional magnetic resonance imaging and pediatric anxiety. J Am Acad Child Adolesc Psychiatry. 2008;47(11):1217–21. Epub 2008/10/22.PubMedCrossRefGoogle Scholar
  5. 5.
    Mana S, Paillere Martinot ML, Martinot JL. Brain imaging findings in children and adolescents with mental disorders: a cross-sectional review. Eur Psychiatry. 2010;25(6):345–54. Epub 2010/07/14.PubMedCrossRefGoogle Scholar
  6. 6.
    LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155–84. Epub 2000/06/09.PubMedCrossRefGoogle Scholar
  7. 7.
    Adolphs R, Tranel D, Damasio H, Damasio AR. Fear and the human amygdala. J Neurosci. 1995;15(9):5879–91.PubMedGoogle Scholar
  8. 8.
    Amaral DG. The amygdala, social behavior, and danger detection. Ann N Y Acad Sci. 2003;1000:337–47.PubMedCrossRefGoogle Scholar
  9. 9.
    Monk CS. The development of emotion-related neural circuitry in health and psychopathology. Dev Psychopathol. 2008;20(4):1231–50. Epub 2008/10/08.PubMedCrossRefGoogle Scholar
  10. 10.
    Yang TT, Menon V, Eliez S, Blasey C, White CD, Reid AJ, et al. Amygdalar activation associated with positive and negative facial expressions. Neuroreport. 2002;13(14):1737–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, et al. A differential neural response in the human amygdala to fearful and happy facial expressions. Nature. 1996;383(6603):812–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, et al. Response and habituation of the human amygdala during visual processing of facial expression. Neuron. 1996;17(5):875–87.PubMedCrossRefGoogle Scholar
  13. 13.
    Nelson EE, Guyer AE. The development of the ventral prefrontal cortex and social flexibility. Dev Cogn Neurosci. 2011;1(3):233–45. Epub 2011/08/02.PubMedCrossRefGoogle Scholar
  14. 14.
    Kalin NH, Shelton SE, Davidson RJ, Kelley AE. The primate amygdala mediates acute fear but not the behavioral and physiological components of anxious temperament. J Neurosci. 2001;21(6):2067–74. Epub 2001/03/14.PubMedGoogle Scholar
  15. 15.
    Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry. 2001;6(1):13–34.PubMedCrossRefGoogle Scholar
  16. 16.
    Adolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR. A mechanism for impaired fear recognition after amygdala damage. Nature. 2005;433(7021):68–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Adolphs R, Tranel D, Hamann S, Young AW, Calder AJ, Phelps EA, et al. Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia. 1999;37(10):1111–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Nelson EE, Leibenluft E, McClure EB, Pine DS. The social re-orientation of adolescence: a neuroscience perspective on the process and its relation to psychopathology. Psychol Med. 2005;35:163–74.PubMedCrossRefGoogle Scholar
  19. 19.
    Tottenham N, Sheridan MA. A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. Front Hum Neurosci. 2009;3:68. Epub 2010/02/18.Google Scholar
  20. 20.
    Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev. 2006;30(6):718–29.PubMedCrossRefGoogle Scholar
  21. 21.
    Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci. 2003;6(3):309–15.PubMedCrossRefGoogle Scholar
  22. 22.
    Casey BJ, Giedd JN, Thomas KM. Structural and functional brain development and its relation to cognitive development. Biol Psychol. 2000;54(1–3):241–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Paus T. Mapping brain maturation and cognitive development during adolescence. Trends Cogn Sci. 2005;9(2):60–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Forbes EE, Phillips ML, Silk JS, Ryan ND, Dahl RE. Neural systems of threat processing in adolescents: role of pubertal maturation and relation to measures of negative affect. Dev Neuropsychol. 2011;36(4):429–52. Epub 2011/04/26.PubMedCrossRefGoogle Scholar
  25. 25.
    Amaral DG. The primate amygdala and the neurobiology of social behavior: implications for understanding social anxiety. Biol Psychiatry. 2002;51(1):11–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Payne C, Machado CJ, Bliwise NG, Bachevalier J. Maturation of the hippocampal formation and amygdala in Macaca mulatta: a volumetric magnetic resonance imaging study. Hippocampus. 2010;20(8):922–35. Epub 2009/09/10.PubMedCrossRefGoogle Scholar
  27. 27.
    Prather MD, Lavenex P, Mauldin-Jourdain ML, Mason WA, Capitanio JP, Mendoza SP, et al. Increased social fear and decreased fear of objects in monkeys with neonatal amygdala lesions. Neuroscience. 2001;106(4):653–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Giedd JN, Snell JW, Lange N, Rajapakse JC, Casey BJ, Kozuch PL, et al. Quantitative magnetic resonance imaging of human brain development: ages 4–18. Cereb Cortex. 1996;6(4):551–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, et al. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci. 2004;24(28):6392–401.PubMedCrossRefGoogle Scholar
  30. 30.
    Mosconi MW, Cody-Hazlett H, Poe MD, Gerig G, Gimpel-Smith R, Piven J. Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism. Arch Gen Psychiatry. 2009;66(5):509–16. Epub 2009/05/06.PubMedCrossRefGoogle Scholar
  31. 31.
    Cunningham MG, Bhattacharyya S, Benes FM. Amygdalo-cortical sprouting continues into early adulthood: implications for the development of normal and abnormal function during adolescence. J Comp Neurol. 2002;453(2):116–30.PubMedCrossRefGoogle Scholar
  32. 32.
    De Bellis MD, Casey BJ, Dahl RE, Birmaher B, Williamson DE, Thomas KM, et al. A pilot study of amygdala volumes in pediatric generalized anxiety disorder. Biol Psychiatry. 2000;48(1):51–7. Epub 2000/07/29.PubMedCrossRefGoogle Scholar
  33. 33.
    Milham MP, Nugent AC, Drevets WC, Dickstein DP, Leibenluft E, Ernst M, et al. Selective reduction in amygdala volume in pediatric anxiety disorders: a voxel-based morphometry investigation. Biol Psychiatry. 2005;57(9):961–6.PubMedCrossRefGoogle Scholar
  34. 34.
    De Bellis MD, Keshavan MS, Frustaci K, Shifflett H, Iyengar S, Beers SR, et al. Superior temporal gyrus volumes in maltreated children and adolescents with PTSD. Biol Psychiatry. 2002;51(7):544–52.PubMedCrossRefGoogle Scholar
  35. 35.
    Monk CS, Nelson EE, McClure EB, Mogg K, Bradley BP, Leibenluft E, et al. Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder. Am J Psychiatry. 2006;163(6):1091–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro HM, et al. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Arch Gen Psychiatry. 2008;65(5):568–76. Epub 2008/05/07.PubMedCrossRefGoogle Scholar
  37. 37.
    Telzer EH, Mogg K, Bradley BP, Mai X, Ernst M, Pine DS, et al. Relationship between trait anxiety, prefrontal cortex, and attention bias to angry faces in children and adolescents. Biol Psychol. 2008;79(2):216–22. Epub 2008/07/05.PubMedCrossRefGoogle Scholar
  38. 38.
    Thomas KM, Drevets WC, Dahl RE, Ryan ND, Birmaher B, Eccard CH, et al. Amygdala response to fearful faces in anxious and depressed children. Arch Gen Psychiatry. 2001;58(11):1057–63.PubMedCrossRefGoogle Scholar
  39. 39.
    Killgore WD, Yurgelun-Todd DA. Social anxiety predicts amygdala activation in adolescents viewing fearful faces. Neuroreport. 2005;16(15):1671–5. Epub 2005/09/29.PubMedCrossRefGoogle Scholar
  40. 40.
    McClure EB, Monk CS, Nelson EE, Parrish JM, Adler A, Blair RJ, et al. Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Arch Gen Psychiatry. 2007;64(1):97–106. Epub 2007/01/03.PubMedCrossRefGoogle Scholar
  41. 41.
    Perez-Edgar K, Roberson-Nay R, Hardin MG, Poeth K, Guyer AE, Nelson EE, et al. Attention alters neural responses to evocative faces in behaviorally inhibited adolescents. NeuroImage. 2007;35(4):1538–46. Epub 2007/03/23.PubMedCrossRefGoogle Scholar
  42. 42.
    Beesdo K, Lau JY, Guyer AE, McClure-Tone EB, Monk CS, Nelson EE, et al. Common and distinct amygdala-function perturbations in depressed vs anxious adolescents. Arch Gen Psychiatry. 2009;66(3):275–85. Epub 2009/03/04.PubMedCrossRefGoogle Scholar
  43. 43.
    Lau JY, Goldman D, Buzas B, Fromm SJ, Guyer AE, Hodgkinson C, et al. Amygdala function and 5-HTT gene variants in adolescent anxiety and major depressive disorder. Biol Psychiatry. 2009;65(4):349–55. Epub 2008/10/28.PubMedCrossRefGoogle Scholar
  44. 44.
    Blair KS, Geraci M, Korelitz K, Otero M, Towbin K, Ernst M, et al. The Pathology of social phobia is independent of developmental changes in face processing. Am J Psychiatry. 2011;168(11):1202–9. Epub 2011/06/03.Google Scholar
  45. 45.
    Guyer AE, Lau JY, McClure-Tone EB, Parrish J, Shiffrin ND, Reynolds RC, et al. Amygdala and ventrolateral prefrontal cortex function during anticipated peer evaluation in pediatric social anxiety. Arch Gen Psychiatry. 2008;65(11):1303–12. Epub 2008/11/05.PubMedCrossRefGoogle Scholar
  46. 46.
    Lau JY, Guyer AE, Tone EB, Jenness J, Parrish J, Pine DS, et al. Neural responses to peer rejection in anxious adolescents: contributions from the amygdala-hippocampal complex. Int J Behav Dev. 2011;36(1):36–44. Epub 17 June 2011.Google Scholar
  47. 47.
    McClure-Tone EB, Nawa NE, Nelson EE, Detloff AM, Fromm SJ, Pine DS, et al. Preliminary findings: neural responses to feedback regarding betrayal and cooperation in adolescent anxiety disorders. Dev Neuropsychol. 2011;36(4):453–72. Epub 2011/04/26.PubMedCrossRefGoogle Scholar
  48. 48.
    Guyer AE, Nelson EE, Perez-Edgar K, Hardin MG, Roberson-Nay R, Monk CS, et al. Striatal functional alteration in adolescents characterized by early childhood behavioral inhibition. J Neurosci. 2006;26(24):6399–405. Epub 2006/06/16.PubMedCrossRefGoogle Scholar
  49. 49.
    Krain AL, Gotimer K, Hefton S, Ernst M, Castellanos FX, Pine DS, et al. A functional magnetic resonance imaging investigation of uncertainty in adolescents with anxiety disorders. Biol Psychiatry. 2008;63(6):563–8. Epub 2007/08/28.PubMedCrossRefGoogle Scholar
  50. 50.
    Bar-Haim Y, Fox NA, Benson B, Guyer AE, Williams A, Nelson EE, et al. Neural correlates of reward processing in adolescents with a history of inhibited temperament. Psychol Sci. 2009;20(8):1009–18. Epub 2009/07/15.PubMedCrossRefGoogle Scholar
  51. 51.
    Helfinstein SM, Benson B, Perez-Edgar K, Bar-Haim Y, Detloff A, Pine DS, et al. Striatal responses to negative monetary outcomes differ between temperamentally inhibited and non-inhibited adolescents. Neuropsychologia. 2011;49(3):479–85. Epub 2010/12/21.PubMedCrossRefGoogle Scholar
  52. 52.
    Guyer AE, Choate VR, Detloff A, Benson B, Nelson EE, Perez-Edgar K, et al. Striatal functional alteration during incentive anticipation in pediatric anxiety disorders. Am J Psychiatry. 2012;169(2):205–12. Epub 2012/03/17.PubMedCrossRefGoogle Scholar
  53. 53.
    Bar-Haim Y, Lamy D, Pergamin L. Bakermans-Kranenburg MJ, van IMH. Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol Bull. 2007;133(1):1–24. Epub 2007/01/05.PubMedCrossRefGoogle Scholar
  54. 54.
    Mogg K, Bradley BP. A cognitive-motivational analysis of anxiety. Behav Res Ther. 1998;36(9):809–48.PubMedCrossRefGoogle Scholar
  55. 55.
    Puliafico AC, Kendall PC. Threat-related attentional bias in anxious youth: a review. Clin Child Fam Psychol Rev. 2006;9(3–4):162–80. Epub 2006/10/21.PubMedCrossRefGoogle Scholar
  56. 56.
    Bar-Haim Y, Morag I, Glickman S. Training anxious children to disengage attention from threat: a randomized controlled trial. J Child Psychol Psychiatry. 2011;52(8):861–9. Epub 2011/01/22.PubMedCrossRefGoogle Scholar
  57. 57.
    Eldar S, Apter A, Lotan D, Edgar KP, Naim R, Fox NA, et al. Attention bias modification treatment for pediatric anxiety disorders: a randomized controlled trial. Am J Psychiatry. 2012;169(2):213–20. Epub 2012/03/17.PubMedCrossRefGoogle Scholar
  58. 58.
    Field AP, Lester KJ. Is there room for ‘development’ in developmental models of information processing biases to threat in children and adolescents? Clin Child Fam Psychol Rev. 2010;13(4):315–32. Epub 2010/09/03.PubMedCrossRefGoogle Scholar
  59. 59.
    Lindstrom KM, Guyer AE, Mogg K, Bradley BP, Fox NA, Ernst M, et al. Normative data on development of neural and behavioral mechanisms underlying attention orienting toward social-emotional stimuli: an exploratory study. Brain Res. 2009;1292:61–70. Epub 2009/07/28.PubMedCrossRefGoogle Scholar
  60. 60.
    Roy AK, Vasa RA, Bruck M, Mogg K, Bradley BP, Sweeney M, et al. Attention bias toward threat in pediatric anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2008;47(10):1189–96. Epub 2008/08/14.PubMedCrossRefGoogle Scholar
  61. 61.
    Ladouceur CD, Silk JS, Dahl RE, Ostapenko L, Kronhaus DM, Phillips ML. Fearful faces influence attentional control processes in anxious youth and adults. Emotion. 2009;9(6):855–64. Epub 2009/12/17.PubMedCrossRefGoogle Scholar
  62. 62.
    Perez-Edgar K, Bar-Haim Y, McDermott JM, Chronis-Tuscano A, Pine DS, Fox NA. Attention biases to threat and behavioral inhibition in early childhood shape adolescent social withdrawal. Emotion. 2010;10(3):349–57. Epub 2010/06/03.PubMedCrossRefGoogle Scholar
  63. 63.
    Wald I, Lubin G, Holoshitz Y, Muller D, Fruchter E, Pine DS, et al. Battlefield-like stress following simulated combat and suppression of attention bias to threat. Psychol Med. 2011;41(4):699–707. Epub 2010/11/27.PubMedCrossRefGoogle Scholar
  64. 64.
    Bar-Haim Y, Holoshitz Y, Eldar S, Frenkel TI, Muller D, Charney DS, et al. Life-threatening danger and suppression of attention bias to threat. Am J Psychiatry. 2010;167(6):694–8. Epub 2010/04/17.PubMedCrossRefGoogle Scholar
  65. 65.
    Lindstrom KM, Mandell DJ, Musa GJ, Britton JC, Sankin LS, Mogg K, et al. Attention orientation in parents exposed to the 9/11 terrorist attacks and their children. Psychiatry Res. 2011;187(1–2):261–6. Epub 2010/10/26.PubMedCrossRefGoogle Scholar
  66. 66.
    Sen S, Burmeister M, Ghosh D. Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet. 2004;127B(1):85–9. Epub 2004/04/27.PubMedCrossRefGoogle Scholar
  67. 67.
    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274(5292):1527–31. Epub 1996/11/29.PubMedCrossRefGoogle Scholar
  68. 68.
    Thomason ME, Henry ML, Paul Hamilton J, Joormann J, Pine DS, Ernst M, et al. Neural and behavioral responses to threatening emotion faces in children as a function of the short allele of the serotonin transporter gene. Biol Psychol. 2010;85(1):38–44. Epub 2010/05/25.PubMedCrossRefGoogle Scholar
  69. 69.
    Pine DS. Integrating research on development and fear learning: a vision for clinical neuroscience? Depress Anxiety. 2009;26(9):775–9. Epub 2009/09/05.PubMedCrossRefGoogle Scholar
  70. 70.
    Lau JY, Lissek S, Nelson EE, Lee Y, Roberson-Nay R, Poeth K, et al. Fear conditioning in adolescents with anxiety disorders: results from a novel experimental paradigm. J Am Acad Child Adolesc Psychiatry. 2008;47(1):94–102. Epub 2008/01/05.PubMedCrossRefGoogle Scholar
  71. 71.
    Britton JC, Lissek S, Grillon C, Norcross MA, Pine DS. Development of anxiety: the role of threat appraisal and fear learning. Depress Anxiety. 2011;28(1):5–17. Epub 2010/08/25.PubMedCrossRefGoogle Scholar
  72. 72.
    Lissek S, Powers AS, McClure EB, Phelps EA, Woldehawariat G, Grillon C, et al. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav Res Ther. 2005;43(11):1391–424. Epub 2005/05/12.PubMedCrossRefGoogle Scholar
  73. 73.
    Dunsmoor JE, Mitroff SR, LaBar KS. Generalization of conditioned fear along a dimension of increasing fear intensity. Learn Mem. 2009;16(7):460–9. Epub 2009/06/26.PubMedCrossRefGoogle Scholar
  74. 74.
    Lissek S, Rabin SJ, McDowell DJ, Dvir S, Bradford DE, Geraci M, et al. Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behav Res Ther. 2009;47(2):111–8. Epub 2008/11/26.PubMedCrossRefGoogle Scholar
  75. 75.
    Craske MG, Waters AM, Lindsey Bergman R, Naliboff B, Lipp OV, Negoro H, et al. Is aversive learning a marker of risk for anxiety disorders in children? Behav Res Ther. 2008;46(8):954–67. Epub 2008/06/10.PubMedCrossRefGoogle Scholar
  76. 76.
    Liberman LC, Lipp OV, Spence SH, March S. Evidence for retarded extinction of aversive learning in anxious children. Behav Res Ther. 2006;44(10):1491–502. Epub 2005/12/20.PubMedCrossRefGoogle Scholar
  77. 77.
    Waters AM, Henry J, Neumann DL. Aversive Pavlovian conditioning in childhood anxiety disorders: impaired response inhibition and resistance to extinction. J Abnorm Psychol. 2009;118(2):311–21. Epub 2009/05/06.PubMedCrossRefGoogle Scholar
  78. 78.
    Lau JY, Britton JC, Nelson EE, Angold A, Ernst M, Goldwin M, et al. Distinct neural signatures of threat learning in adolescents and adults. Proc Natl Acad Sci U S A. 2011;108(11):4500–5. Epub 2011/03/04.PubMedCrossRefGoogle Scholar
  79. 79.
    Giedd JN, Rapoport JL. Structural MRI of pediatric brain development: what have we learned and where are we going? Neuron. 2010;67(5):728–34. Epub 2010/09/10.PubMedCrossRefGoogle Scholar
  80. 80.
    Adolphs R, Baron-Cohen S, Tranel D. Impaired recognition of social emotions following amygdala damage. J Cogn Neurosci. 2002;14(8):1264–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Guyer AE, Monk CS, McClure-Tone EB, Nelson EE, Roberson-Nay R, Adler AD, et al. A developmental examination of amygdala response to facial expressions. J Cogn Neurosci. 2008;20(9):1565–82. Epub 2008/03/19.PubMedCrossRefGoogle Scholar
  82. 82.
    Beesdo K, Bittner A, Pine DS, Stein MB, Hofler M, Lieb R, et al. Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life. Arch Gen Psychiatry. 2007;64(8):903–12. Epub 2007/08/08.PubMedCrossRefGoogle Scholar
  83. 83.
    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(6):593–602.PubMedCrossRefGoogle Scholar
  84. 84.
    Munafo MR, Brown SM, Hariri AR. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry. 2008;63(9):852–7. Epub 2007/10/24.PubMedCrossRefGoogle Scholar
  85. 85.
    Lau JY, Goldman D, Buzas B, Hodgkinson C, Leibenluft E, Nelson E, et al. BDNF gene polymorphism (Val66Met) predicts amygdala and anterior hippocampus responses to emotional faces in anxious and depressed adolescents. NeuroImage. 2010;53(3):952–61. Epub 2009/11/26.PubMedCrossRefGoogle Scholar
  86. 86.
    Guyer AE, McClure-Tone EB, Shiffrin ND, Pine DS, Nelson EE. Probing the neural correlates of anticipated peer evaluation in adolescence. Child Development. 2009;80(4):1000–15. Epub 2009/07/28.PubMedCrossRefGoogle Scholar
  87. 87.
    Guyer AE, Choate VR, Pine DS, Nelson EE. Neural circuitry underlying affective response to peer feedback in adolescence. Soc Cogn Affect Neurosci. 2012;7(1):81–92. Epub 2011/08/11.Google Scholar
  88. 88.
    Davidson RJ. Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry. 2002;51(1):68–80. Epub 2002/01/22.PubMedCrossRefGoogle Scholar
  89. 89.
    Jackson DC, Mueller CJ, Dolski I, Dalton KM, Nitschke JB, Urry HL, et al. Now you feel it, now you don’t: frontal brain electrical asymmetry and individual differences in emotion regulation. Psychol Sci. 2003;14(6):612–7. Epub 2003/11/25.PubMedCrossRefGoogle Scholar
  90. 90.
    Ernst M, Fudge JL. A developmental neurobiological model of motivated behavior: anatomy, connectivity and ontogeny of the triadic nodes. Neurosci Biobehav Rev. 2009;33(3):367–82. Epub 2008/11/26.PubMedCrossRefGoogle Scholar
  91. 91.
    Amaral DG, Bauman MD, Capitanio JP, Lavenex P, Mason WA, Mauldin-Jourdain ML, et al. The amygdala: is it an essential component of the neural network for social cognition? Neuropsychologia. 2003;41(4):517–22.PubMedCrossRefGoogle Scholar
  92. 92.
    Bauman MD, Lavenex P, Mason WA, Capitanio JP, Amaral DG. The development of social behavior following neonatal amygdala lesions in rhesus monkeys. J Cogn Neurosci. 2004;16(8):1388–411.PubMedCrossRefGoogle Scholar
  93. 93.
    Schultz W. Behavioral theories and the neurophysiology of reward. Ann Rev Psychol. 2006;57:87–115. Epub 2005/12/02.CrossRefGoogle Scholar
  94. 94.
    Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5(6):483–94.PubMedCrossRefGoogle Scholar
  95. 95.
    Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311(5762):864–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24(2):97–129.PubMedCrossRefGoogle Scholar
  97. 97.
    Nestler EJ. Common molecular and cellular substrates of addiction and memory. Neurobiol Learn Mem. 2002;78(3):637–47.PubMedCrossRefGoogle Scholar
  98. 98.
    Hardin MG, Mandell D, Mueller SC, Dahl RE, Pine DS, Ernst M. Inhibitory control in anxious and healthy adolescents is modulated by incentive and incidental affective stimuli. J Child Psychol Psychiatry. 2009;50(12):1550–8. Epub 2009/07/04.PubMedCrossRefGoogle Scholar
  99. 99.
    Schlund MW, Siegle GJ, Ladouceur CD, Silk JS, Cataldo MF, Forbes EE, et al. Nothing to fear? Neural systems supporting avoidance behavior in healthy youths. NeuroImage. 2010;52(2):710–9. Epub 2010/05/01.PubMedCrossRefGoogle Scholar
  100. 100.
    Perez-Edgar K, Fox NA. Temperament and anxiety disorders. Child Adolesc Psychiatr Clinics North America. 2005;14(4):681–706.CrossRefGoogle Scholar
  101. 101.
    Chronis-Tuscano A, Degnan KA, Pine DS, Perez-Edgar K, Henderson HA, Diaz Y, et al. Stable early maternal report of behavioral inhibition predicts lifetime social anxiety disorder in adolescence. J Am Acad Child Adolesc Psychiatry. 2009;48(9):928–35. Epub 2009/07/25.PubMedCrossRefGoogle Scholar
  102. 102.
    Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL. Inhibited and uninhibited infants “grown up”: Adult amygdalar response to novelty. Science. 2003;300(5627):1952–3.PubMedCrossRefGoogle Scholar
  103. 103.
    Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, et al. Effect of social status on striatal dopamine D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse. 1998;29(1):80–3.PubMedCrossRefGoogle Scholar
  104. 104.
    Liebowitz MR, Campeas R, Hollander E. MAOIs: impact on social behavior. Psychiatry Res. 1987;22(1):89–90.PubMedCrossRefGoogle Scholar
  105. 105.
    Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M. Low dopamine D(2) receptor binding potential in social phobia. Am J Psychiatry. 2000;157(3):457–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Tiihonen J, Kuikka J, Bergstrom K, Lepola U, Koponen H, Leinonen E. Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry. 1997;154(2):239–42.PubMedGoogle Scholar
  107. 107.
    Lorberbaum JP, Kose S, Johnson MR, Arana GW, Sullivan LK, Hamner MB, et al. Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport. 2004;15(18):2701–5. Epub 2004/12/15.PubMedGoogle Scholar
  108. 108.
    Lee S, Ruiz S, Caria A, Veit R, Birbaumer N, Sitaram R. Detection of cerebral reorganization induced by real-time fMRI feedback training of insula activation: a multivariate investigation. Neurorehabil Neural Repair. 2011;25(3):259–67. Epub 2011/03/02.PubMedCrossRefGoogle Scholar
  109. 109.
    Basten U, Stelzel C, Fiebach CJ. Trait anxiety modulates the neural efficiency of inhibitory control. J Cogn Neurosci. 2011;23(10):3132–45. Epub 2011/03/12.Google Scholar
  110. 110.
    Zhao XH, Wang PJ, Li CB, Xi Q, Shao ZH, Hu ZH. Anxiety disease: decreased of functional connectivity in left superior temporal gyrus (GTs) and right GTs. Zhonghua Yi Xue Za Zhi. 2008;88(23):1603–6. Epub 2008/11/28.PubMedGoogle Scholar
  111. 111.
    Kim MJ, Loucks RA, Palmer AL, Brown AC, Solomon KM, Marchante AN, et al. The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav Brain Res. 2011;223(2):403–10. Epub 2011/05/04.Google Scholar
  112. 112.
    Etkin A. Functional neuroanatomy of anxiety: a neural circuit perspective. Curr Top Behav Neurosci. 2010;2:251–77. Epub 2011/02/11.PubMedCrossRefGoogle Scholar
  113. 113.
    Marchand WR. Cortico-basal ganglia circuitry: a review of key research and implications for functional connectivity studies of mood and anxiety disorders. Brain Struct Funct. 2010;215(2):73–96. Epub 2010/10/13.PubMedCrossRefGoogle Scholar
  114. 114.
    Goldin PR, Manber-Ball T, Werner K, Heimberg R, Gross JJ. Neural mechanisms of cognitive reappraisal of negative self-beliefs in social anxiety disorder. Biol Psychiatry. 2009;66(12):1091–9. Epub 2009/09/01.PubMedCrossRefGoogle Scholar
  115. 115.
    Etkin A, Prater KE, Hoeft F, Menon V, Schatzberg AF. Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. Am J Psychiatry. 2010;167(5):545–54. Epub 2010/02/04.PubMedCrossRefGoogle Scholar
  116. 116.
    Fox MD, Greicius M. Clinical applications of resting state functional connectivity. Front Syst Neurosci. 2010;4:19. Epub 2010/07/02.PubMedGoogle Scholar
  117. 117.
    Zhang D, Raichle ME. Disease and the brain’s dark energy. Nat Rev Neurol. 2010;6(1):15–28. Epub 2010/01/09.PubMedCrossRefGoogle Scholar
  118. 118.
    Greicius M. Resting-state functional connectivity in neuropsychiatric disorders. Curr Opin Neurol. 2008;21(4):424–30. Epub 2008/07/09.PubMedCrossRefGoogle Scholar
  119. 119.
    Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, et al. Toward discovery science of human brain function. Proc Natl Acad Sci U S A. 2010;107(10):4734–9. Epub 2010/02/24.PubMedCrossRefGoogle Scholar
  120. 120.
    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(3):881–9. Epub 2011/03/02.PubMedCrossRefGoogle Scholar
  121. 121.
    Liao W, Qiu C, Gentili C, Walter M, Pan Z, Ding J, et al. Altered effective connectivity network of the amygdala in social anxiety disorder: a resting-state FMRI study. PLoS One. 2010;5(12):e15238. Epub 2011/01/05.PubMedCrossRefGoogle Scholar
  122. 122.
    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(4):1549–58. Epub 2010/05/18.PubMedCrossRefGoogle Scholar
  123. 123.
    Liao W, Xu Q, Mantini D, Ding J, Machado-de-Sousa JP, Hallak JE, et al. Altered gray matter morphometry and resting-state functional and structural connectivity in social anxiety disorder. Brain Res. 2011;1388:167–77. Epub 2011/03/16.PubMedCrossRefGoogle Scholar
  124. 124.
    Ding J, Chen H, Qiu C, Liao W, Warwick JM, Duan X, et al. Disrupted functional connectivity in social anxiety disorder: a resting-state fMRI study. Magn Reson Imaging. 2011;29(5):701–11. Epub 2011/05/03.PubMedCrossRefGoogle Scholar
  125. 125.
    Etkin A, Prater KE, Schatzberg AF, Menon V, Greicius MD. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch Gen Psychiatry. 2009;66(12):1361–72. Epub 2009/12/10.PubMedCrossRefGoogle Scholar
  126. 126.
    Kim MJ, Gee DG, Loucks RA, Davis FC, Whalen PJ. Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest. Cereb Cortex. 2010;21(7):1667–73. Epub 2010/12/04.Google Scholar
  127. 127.
    Paulesu E, Sambugaro E, Torti T, Danelli L, Ferri F, Scialfa G, et al. Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study. Psychol Med. 2010;40(1):117–24. Epub 2009/05/08.PubMedCrossRefGoogle Scholar
  128. 128.
    Knyazev GG. Motivation, emotion, and their inhibitory control mirrored in brain oscillations. Neurosci Biobehav Rev. 2007;31(3):377–95. Epub 2006/12/06.PubMedCrossRefGoogle Scholar
  129. 129.
    Putman P, van Peer J, Maimari I, van der Werff S. EEG theta/beta ratio in relation to fear-modulated response-inhibition, attentional control, and affective traits. Biol Psychol. 2010;83(2):73–8. Epub 2009/11/10.PubMedCrossRefGoogle Scholar
  130. 130.
    Putman P. Resting state EEG delta-beta coherence in relation to anxiety, behavioral inhibition, and selective attentional processing of threatening stimuli. Int J Psychophysiol. 2011;80(1):63–8. Epub 2011/02/01.PubMedCrossRefGoogle Scholar
  131. 131.
    Beidel DC, Turner SM, Morris TL. Behavioral treatment of childhood social phobia. J Consult Clin Psychol. 2000;68(6):1072–80. Epub 2001/01/06.PubMedCrossRefGoogle Scholar
  132. 132.
    Kendall PC. Treating anxiety disorders in children: results of a randomized clinical trial. J Consult Clin Psychol. 1994;62(1):100–10. Epub 1994/02/01.PubMedCrossRefGoogle Scholar
  133. 133.
    Kendall PC, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M. Therapy for youths with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol. 1997;65(3):366–80. Epub 1997/06/01.PubMedCrossRefGoogle Scholar
  134. 134.
    Rapee RM, Kennedy S, Ingram M, Edwards S, Sweeney L. Prevention and early intervention of anxiety disorders in inhibited preschool children. J Consult Clin Psychol. 2005;73(3):488–97. Epub 2005/06/29.PubMedCrossRefGoogle Scholar
  135. 135.
    Rupp G. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med. 2001;344(17):1279–85.CrossRefGoogle Scholar
  136. 136.
    Wagner KD, Berard R, Stein MB, Wetherhold E, Carpenter DJ, Perera P, et al. A multicenter, randomized, double-blind, placebo-controlled trial of paroxetine in children and adolescents with social anxiety disorder. Arch Gen Psychiatry. 2004;61(11):1153–62. Epub 2004/11/03.PubMedCrossRefGoogle Scholar
  137. 137.
    Clark DB, Birmaher B, Axelson D, Monk K, Kalas C, Ehmann M, et al. Fluoxetine for the treatment of childhood anxiety disorders: open-label, long-term extension to a controlled trial. J Am Acad Child Adolesc Psychiatry. 2005;44(12):1263–70. Epub 2005/11/18.Google Scholar
  138. 138.
    Birmaher B, Axelson DA, Monk K, Kalas C, Clark DB, Ehmann M, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003;42(4):415–23. Epub 2003/03/22.PubMedCrossRefGoogle Scholar
  139. 139.
    McClure EB, Adler A, Monk CS, Cameron J, Smith S, Nelson EE, et al. fMRI predictors of treatment outcome in pediatric anxiety disorders. Psychopharmacology (Berl). 2007;191(1):97–105. Epub 2006/09/15.CrossRefPubMedGoogle Scholar
  140. 140.
    Maslowsky J, Mogg K, Bradley BP, McClure-Tone E, Ernst M, Pine DS, et al. A preliminary investigation of neural correlates of treatment in adolescents with generalized anxiety disorder. J Child Adolesc Psychopharmacol. 2010;20(2):105–11. Epub 2010/04/27.PubMedCrossRefGoogle Scholar
  141. 141.
    Forbes EE, Olino TM, Ryan ND, Birmaher B, Axelson D, Moyles DL, et al. Reward-related brain function as a predictor of treatment response in adolescents with major depressive disorder. Cogn Affect Behav Neurosci. 2010;10(1):107–18. Epub 2010/03/18.PubMedCrossRefGoogle Scholar
  142. 142.
    Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW. Longitudinal mapping of cortical thickness and brain growth in normal children. J Neurosci. 2004;24(38):8223–31. Epub 2004/09/24.PubMedCrossRefGoogle Scholar
  143. 143.
    Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, et al. Brain development during childhood and adolescence: A longitudinal MRI study. Nat Neurosci. 1999;2(10):861–3.PubMedCrossRefGoogle Scholar
  144. 144.
    Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004;101(21):8174–9. Epub 2004/05/19.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Amanda E. Guyer
    • 1
  • Carrie L. Masten
    • 2
  • Daniel S. Pine
    • 3
  1. 1.Department of Human Ecology and Center for Mind and BrainUniversity of CaliforniaDavisUSA
  2. 2.Department of Psychology and Human DevelopmentPeabody College, Vanderbilt UniversityNashvilleUSA
  3. 3.Section on Development and Affective NeuroscienceNational Institute of Mental HealthBethesdaUSA

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