Neuroimaging and Anxiety: the Neural Substrates of Pathological and Non-pathological Anxiety

Current Psychiatry Reports

Volumn 17, Issue 6, 2015, Pages

  Taylor, James M ^a   Whalen, Paul J ^a  

^a Lamont Doherty Earth Observatory   (United States)

Author keywords

Amygdala; Anterior cingulate cortex; Anxiety; Insula; Neuroimaging; Prefrontal cortex

Indexed keywords

AMYGDALOID NUCLEUS; ANTERIOR CINGULATE; ANXIETY DISORDER; BRAIN REGION; FUNCTIONAL MAGNETIC RESONANCE IMAGING; HUMAN; INSULA; NEUROIMAGING; NEUROPATHOLOGY; NONHUMAN; POSTTRAUMATIC STRESS DISORDER; REVIEW; SOCIAL PHOBIA; VENTROMEDIAL PREFRONTAL CORTEX; AMYGDALA; ANXIETY; BRAIN; BRAIN CORTEX; CINGULATE GYRUS; PATHOLOGY; PREFRONTAL CORTEX; PROCEDURES;

AMYGDALA; ANXIETY; ANXIETY DISORDERS; BRAIN; CEREBRAL CORTEX; GYRUS CINGULI; HUMANS; NEUROIMAGING; PREFRONTAL CORTEX;

EID: 84929104241     PISSN: 15233812     EISSN: 15351645     Source Type: Journal    
DOI: 10.1007/s11920-015-0586-9     Document Type: Review

References (93)

1. Damsa C, Kosel M, Moussally J. Current status of brain imaging in anxiety disorders. Curr Opin Psychiatry. 2008;22(1):96–110. doi:10.1097/YCO.0b013e328319bd10.
2. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–27. doi:10.1001/archpsyc.62.6.617.
3. Comer JS, Blanco C, Hasin DS, Liu SM, Grant BF, Turner JB, et al. Health-related quality of life across the anxiety disorders. J Clin Psychiatry. 2011. doi:10.4088/JCP.09m05094blu.
4. Rauch SL. Neuorimaging and the neurobiology of anxiety disorders. In: Handbook of affective sciences. Oxford: University Press; 2003. p. 963–75.
5. 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. doi:10.1016/j.biopsych.2007.08.019.
6. Shin LM, Rauch SL, Pitman RK, Whalen PJ. The human amygdala in anxiety disorders. In: Whalen PJ, Phelps EA, editors. The human amygdala. New York: Guilford Press; 2009. p. 321–43. A comprehensive review of the findings and approaches that comprises the field of neuroimaging the anxiety disorders.
7. American Psychiatric Association. DSM 5. American Psychiatric Association; 2013.
8. 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. doi:10.1016/j.bbr.2011.04.025.
9. Rauch SL, Shin LM, Wright CI. Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci. 2003;985(1):389–410. doi:10.1111/j.1749-6632.2003.tb07096.x.
10. Whalen PJ, Davis FC, Oler JA, Kim H, Kim MJ, Neta M. Human amygdala responses to facial expressions of emotion. In: Whalen PJ, Phelps EA, editors. The human amygdala. New York: Guilford Press; 2009. p. 265–88.
11. Paulus MP. The role of neuroimaging for the diagnosis and treatment of anxiety disorders. Depress Anxiety. 2008;25(4):348–56. doi:10.1002/da.20499. Where the current review focuses on the paradigms that helped identify relevant brain circuitry, Paulus offers a view based on outcomes.
12. LeDoux J. The emotional brain: the mysterious underpinnings of emotional life. New York: Simon & Schuster Paperbacks; 1996.
13. Whalen PJ. Fear, vigilance, and ambiguity: initial neuroimaging studies of the human amygdala. Curr Dir Psychol Sci. 1998;7(6):177–88. doi:10.2307/20182537?ref=no-x-route:70ee559cf7b83a6038ec85d41c596aa2.
14. Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA. Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J Neurosci. 1998;18(1):411–8.
15. Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, et al. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry. 2000;47(9):769–76. doi:10.1016/S0006-3223(00)00828-3.
16. Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992;15:353–75.
17. Kapp BS, Whalen PJ, Supple WF, Pascor JP. Amygdaloid contributions to conditioned arousal and sensory information processing. In: Aggleton JP, editor. The amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. New York: Wiley-Liss; 1992. p. 229–54.
18. LeDoux JE. The amygdala and emotion: a view through fear. In: Aggleton JP, editor. The amygdala: a function analysis. 2nd ed. New York: Oxford University Press; 2000. p. 289–310.
19. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol. 2012. doi:10.1146/annurev.psych.121208.131631. A review of the regions and networks involved in fear extinction that makes a compelling case that findings from animal literature can be translated to neuroimaging work in humans.
20. Morgan MA, Romanski LM, LeDoux JE. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett. 1993;163(1):109–13. doi:10.1016/0304-3940(93)90241-C.
21. Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci. 2000;20(16):6225–31.
22. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004. doi:10.1016/j.neuron.2004.08.042.
23. Bouton ME. Learning and behavior: a contemporary synthesis. Massachusettes: Sinauer Associates, Inc. Publishers; 2007.
24. Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002. doi:10.1038/nature01144.
25. Dunsmoor JE, Campese VD, Ceceli AO, LeDoux JE, Phelps EA. Novelty-facilitated extinction: providing a novel outcome in place of an expected threat diminishes recovery of defensive responses. Biol Psychiatry. 2014. This paper examines extinction in both a human and animal model and offers interesting implications for what these findings may mean for the use of extinction in clinical settings.
26. Barrett J, Armony JL. Influence of trait anxiety on brain activity during the acquisition and extinction of aversive conditioning. Psychol Med. 2008;39(02):255. doi:10.1017/S0033291708003516.
27. Sarinopoulos I, Grupe DW, Mackiewicz KL, Herrington JD, Lor M, Steege EE, et al. Uncertainty during anticipation modulates neural responses to aversion in human insula and amygdala. Cereb Cortex. 2010. doi:10.1093/cercor/bhp155.
28. Buckner RL, Hanna JA, Schacter DL. The brain’s default network. Ann N Y Acad Sci. 2008. doi:10.1196/annals.1440.011.
29. Kelley WM, Macrae CN, Wyland CL, Caglar S, Inati S, Heatherton TF. Finding the self? An event-related fMRI study. J Cogn Neurosci. 2002;14(5):785–94. doi:10.1162/08989290260138672.
30. Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry. 2001;6:13–34.
31. Knight DC, Nguyen HT, Bandettini PA. The role of the human amygdala in the production of conditioned fear responses. NeuroImage. 2005. doi:10.1016/j.neuroimage.2005.03.020.
32. LeDoux JE, Schiller D. The human amygdala: insights from other animals. In: Whalen PJ, Phelps EA, editors. The human amygdala. New York: Guilford Press; 2009. p. 43–60.
33. Freese JL, Amaral DG. Neuroanatomy of the primate amygdala. In: Whalen PJ, Phelps EA, editors. The human amygdala. New York: Guilford Press; 2009. p. 3–42.
34. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169–91. doi:10.1038/npp.2009.83. Explains the roots of anxiety research, i.e. the study of fear while also discussing those circuits commonly implicated in stress and anxiety disorders.
35. Hariri AR, Drabant EM, Munoz KE. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry. 2005;62:146–52. doi:10.1016/S0006-3223(02)01543-3.
36. Furmark T, Tillfors M, Garpenstrand H, Marteinsdottir I, Långström B, Oreland L, et al. Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neurosci Lett. 2004;362(3):189–92. doi:10.1016/j.neulet.2004.02.070.
37. Drabant EM, Ramel W, Edge MD, Hyde LW, Kuo JR, Goldin PR, et al. Neural mechanisms underlying 5-HTTLPR-related sensitivity to acute stress. Am J Psychiatry. 2012;169(4). doi:10.1176/appi.ajp.2011.10111699. Highlights the extent to which advances in using genetics to understand individual differences in behaviors and responses to stress continue to better inform our understanding of how different disorders may manifest.
38. Fouche J-P, van Der Wee NJA, Roelofs K, Stein DJ. Recent advances in the brain imaging of social anxiety disorder. Hum Psychopharmacol Clin Exp. 2012;28(1):102–5. doi:10.1002/hup.2281.
39. Stein MB, Goldin PR, Sareen J, Zorrilla LTE, Brown GG. Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry. 2002;59(11):1027–34. doi:10.1001/archpsyc.59.11.1027.
40. Lang PJ, Bradley MM, Cuthbert BN. International affective picture system (IAPS): technical manual and affective ratings. Gainesville: NIMH Center for the Study of Emotion and Attention, University of Florida; 1997.
41. Shah SG, Klumpp H, Angstadt M, Nathan PJ, Phan KL. Amygdala and insula response to emotional images in patients with generalized social anxiety disorder. J Psychiatry Neurosci. 2009;34(4):296-302
42. Blair K, Shaywitz J, Smith B, Rhodes R, Geraci M, Jones M, et al. Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders. Am J Psychiatry. 2008;165:1193-202.
43. Evans KC, Wright CI, Wedig MM, Gold AL, Pollack MH, Rauch SL. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depress Anxiety. 2008;25(6):496–505. doi:10.1002/da.20347.
44. 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.
45. Schienle A, Schäfer A, Walter B, Stark R, Vaitl D. Brain activation of spider phobics towards disorder-relevant, generally disgust- and fear-inducing pictures. Neurosci Lett. 2005;388(1):1–6. doi:10.1016/j.neulet.2005.06.025.
46. Armony JL, Corbo V, Clément MH, Brunet A. Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am J Psychiatr. 2005;162(10):1961–3.
47. Beesdo K, Lau JYF, 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. doi:10.1001/archgenpsychiatry.2008.545.
48. Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro HMC, 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. doi:10.1001/archpsyc.65.5.568.
49. Tottenham N, Hare TA, Casey BJ. A developmental perspective on human amygdala function. In: Whalen PJ, Phelps EA, editors. The human amygdala. New York: Guilford Press; 2009. p. 107–17.
50. Casey BJ, Ruberry EJ, Libby V, Glatt CE, Hare T, Soliman F, et al. Transitional and translational studies of risk for anxiety. Depress Anxiety. 2011;28(1):18–28. doi:10.1002/da.20783. Examines early markers that can serve as risk factors for anxiety and highlights the importance of brain region and network development.
51. Stein M, Simmons A, Feinstein J, Paulus M. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatr. 2007;164(2):318–27. doi:10.1176/appi.ajp.164.2.318.
52. Etkin A, Klemenhagen KC, Dudman JT, Rogan MT, Hen R, Kandel ER, et al. Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces. Neuron. 2004;44(6):1043–55.
53. Bishop SJ, Duncan J, Lawrence AD. State anxiety modulation of the amygdala response to unattended threat-related stimuli. J Neurosci. 2004;24(46):10364–8.
54. Ghashghaei HT, Hilgetag CC, Barbas H. Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage. 2007;34(3):905–23.
55. Pitman RK. Post-traumatic stress disorder, conditioning, and network theory. Psychiatr Ann. 1988;18:182–9.
56. Orr SP, Metzger LJ, Lasko NB, Macklin ML, Peri T, Pitman RK. De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. J Abnorm Psychol. 2000;109(2):290.
57. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 2009. doi:10.1016/j.biopsych.2009.06.026.
58. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am J Psychiatr. 1999;156(4):575–84.
59. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry. 2004;61(2):168–76. doi:10.1001/archpsyc.61.2.168.
60. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry. 2005;62(3):273–81. doi:10.1001/archpsyc.62.3.273.
61. Milad MR, Rauch SL, Pitman RK, Quirk GJ. Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol. 2006. doi:10.1016/j.biopsycho.2006.01.008.
62. Myers-Schulz B, Koenigs M. Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. Mol Psychiatry. 2012;17(2):132–41. doi:10.1038/mp.2011.88.
63. 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. doi:10.1001/archgenpsychiatry.2009.104.
64. 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. doi:10.1016/j.mri.2011.02.013.
65. Qiu C, Liao W, Ding J, Feng Y, Zhu C, Nie X, et al. Regional homogeneity changes in social anxiety disorder: a resting-state fMRI study. Psychiatry Res Neuroimaging. 2011;194(1):47–53. doi:10.1016/j.pscychresns.2011.01.010.
66. Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Psychiatr Clin N Am. 2009. doi:10.1016/j.psc.2009.05.004.
67. Schienle A, Ebner F, Schäfer A. Localized gray matter volume abnormalities in generalized anxiety disorder. Eur Arch Psychiatry Clin Neurosci. 2011;261(4):303–7. doi:10.1007/s00406-010-0147-5.
68. 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. doi:10.1017/S0033291709005649.
69. Quidé Y, Witteveen AB, El-Hage W, Veltman DJ, Olff M. Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review. Neurosci Biobehav Rev. 2012;36(1):626–44. doi:10.1016/j.neubiorev.2011.09.004.
70. Porto P, Oliveira L, Mari J, Volchan E, Figueira I, Ventura P. Does cognitive behavioral therapy change the brain? A systematic review of neuroimaging in anxiety disorders. J Neuropsychiatry Clin Neurosci. 2009;21:114-25.
71. Gross JJ. The emerging field of emotion regulation: an integrative review. Rev Gen Psychol. 1998;2(3):271–99. doi:10.1037/1089-2680.2.3.271.
72. Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005. doi:10.1016/j.tics.2005.03.010.
73. Quirk GJ, Beer JS. Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Curr Opin Neurobiol. 2006. doi:10.1016/j.conb.2006.07.004.
74. 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. 2011;21(7):1667–73. doi:10.1093/cercor/bhq237. Describes differences in resting functional connectivity between prefrontal cortex and amygdala based on individual differences in self-reported anxiety levels.
75. Linnman C, Zeidan MA, Furtak SC, Pitman RK, Quirk GJ, Milad MR. Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit. Am J Psychiatr. 2012;169(4):415–23.
76. Kim MJ, Whalen PJ. The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J Neurosci. 2009;29(37):11614–8. doi:10.1523/JNEUROSCI.2335-09.2009.
77. Bishop SJ. Trait anxiety and impoverished prefrontal control of attention. Nat Neurosci. 2009;12(1):92–8. doi:10.1038/nn.2242.
78. Amir N, Klumpp H, Elias J, Bedwell JS, Yanasak N, Miller LS. Increased activation of the anterior cingulate cortex during processing of disgust faces in individuals with social phobia. Biol Psychiatry. 2005. doi:10.1016/j.biopsych.2005.01.044.
79. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000. doi:10.2307/1694556?ref=no-x-route:777b52a786100de0d844c4a2e8e385f7.
80. Nitschke J, Sarinopoulos I, Oathes D, Johnstone T, Whalen P, Davidson R, et al. Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatr. 2009;166(3):302–10. doi:10.1176/appi.ajp.2008.07101682.
81. Jappe L, Klimes-Dougan B, Cullen KR. Brain imaging and the prediction of treatment outcomes in mood and anxiety disorders. In: Functional brain mapping and the endeavor to understand the working brain. 2013, 279-300. doi:10.5772/55446.
82. Etkin A, Egner T, Peraza DM, Kandel ER, Hirsch J. Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala. Neuron. 2006;51(6):871–82. doi:10.1016/j.neuron.2006.07.029.
83. van Tol MJ, van Der Wee NJA, van den Heuvel OA, Nielen MMA, Demenescu LR, Aleman A, et al. Regional brain volume in depression and anxiety disorders. Arch Gen Psychiatry. 2010;67(10):1002–11. doi:10.1001/archgenpsychiatry.2010.121.
84. Zhang L, Zhang Y, Li L, Li Z, Li W, Ma N, et al. Different white matter abnormalities between the first-episode, treatment-naive patients with posttraumatic stress disorder and generalized anxiety disorder without comorbid conditions. J Affect Disord. 2011;133(1–2):294–9. doi:10.1016/j.jad.2011.03.040.
85. Etkin A, Wager T. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88.
86. Blair KS, Geraci M, Smith BW, Hollon N, DeVido J, Otero M, et al. Reduced dorsal anterior cingulate cortical activity during emotional regulation and top-down attentional control in generalized social phobia, generalized anxiety disorder, and comorbid generalized social phobia/generalized anxiety disorder. Biol Psychiatry. 2012. doi:10.1016/j.biopsych.2012.04.013.
87. Klumpp H, Post D, Angstadt M, Fitzgerald DA, Phan KL. Anterior cingulate cortex and insula response during indirect and direct processing of emotional faces in generalized social anxiety disorder. Biol Mood Anxiety Disord. 2013;3(1):7. doi:10.1186/2045-5380-3-7. Highlights the influence of attention and the ability to shift focus from social stimuli in the behavioral and neural manifestation of gSAD.
88. Simmons A, Matthews SC, Paulus MP, Stein MB. Intolerance of uncertainty correlates with insula activation during affective ambiguity. Neurosci Lett. 2008;430(2):92–7. doi:10.1016/j.neulet.2007.10.030.
89. Engel K, Bandelow B, Gruber O, Wedekind D. Neuroimaging in anxiety disorders. J Neural Transm. 2009;116(6):703–16. doi:10.1007/s00702-008-0077-9.
90. Craig AD. How do you feel—now? The anterior insula and human awareness. Nat Rev Neurosci. 2009;10(1):59–70. doi:10.1038/nrn2555.
91. van Tol MJ, Demenescu LR, van der Wee N, Kortekaas R, Nielen MMA, Den Boer JA, et al. Functional magnetic resonance imaging correlates of emotional word encoding and recognition in depression and anxiety disorders. Biol Psychiatry. 2012. doi:10.1016/j.biopsych.2011.11.016.
92. 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. doi:10.1016/j.neuroimage.2010.05.010.
93. Critchley HD, Mathias CJ, Dolan RJ. Fear conditioning in humans: the influence of awareness and autonomic arousal on functional neuroanatomy. Neuron. 2002;33(4):653–63. doi:10.1016/S0896-6273(02)00588-3.