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A review of neuroimaging studies in generalized anxiety disorder: “So where do we stand?”

Journal of Neural Transmission volume 126, pages 1203–1216 (2019)Cite this article

Abstract

Generalized anxiety disorder (GAD) is a prevalent anxiety disorder, but is still poorly recognized in clinical practice. The aim of this review is to provide a coherent understanding of the functional neuroanatomy of GAD; second, to discuss the current theoretical cognitive models surrounding GAD; and finally to discuss the discrepancy between fundamental research and clinical practice and highlight several potential directions for future research in this domain. A systematic review of original papers investigating the neural correlates of DSM-IV and DSM-5 defined GAD samples was undertaken in Ovid literature search, PubMed, Medline, EMbase, PsycINFO, Google Scholar, and TRIP databases. Articles published between 2007 and 2018 were included. First, GAD seems to be characterized by limbic and (pre)frontal abnormalities. More specifically, GAD patients show difficulties in engaging the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) during emotional regulation tasks. Second, the involved brain areas appear to be characterized by heterogeneity possibly due to a variety of experimental designs and test subjects. Third, regarding the discrimination between GAD and other anxiety disorders via fMRI, results appear to be mixed. Studies report both GAD-specific activity and an inability to differentiate between GAD and other anxiety or mood disorders. The usage of different experimental tasks, test subjects, outcome measures and experimental designs limits the possibilities of generalizing results as well as conducting meta-analytical research. Certain theoretical models of GAD describe our understanding of this disorder and form the basis for treatment interventions. However, fMRI research thus far has failed to validate these models. To bridge the gap between fundamental research and clinical practice in GAD, we propose that fMRI researchers make an effort to validate the existing cognitive model of GAD. An alternative approach could be that new models would be based on current neuroimaging research as well as convergent research methods such as Heart Rate Variability (a bottom up approach).

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References

  • American Psychiatric Association (APA) (2013) Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Washington, DC

    Book  Google Scholar 

  • Anderson JR, Carter CS, Fincham JM, Qin Y, Susan M, Ravizza SM, Rosenberg- Lee M (2008) Using fMRI to test models of complex cognition. Cogn Sci 32:1323–1348

    Article  PubMed  Google Scholar 

  • Ball TM, Ramsawh HJ, Campbell-Sills L, Paulus MP, Stein MB (2013) Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders. Psychol Med 43(7):475–1486

    Article  Google Scholar 

  • Ball TM, Stein MB, Ramsawh HJ, Campbell-Sills L, Paulus MP (2014) Single-subject anxiety treatment outcome prediction using functional neuroimaging. Neuropsychopharmacology 39:1254–1261

    Article  PubMed  PubMed Central  Google Scholar 

  • Beesdo K, Hoyer J, Jacobi F, Low NCP, Höfler M, Wittchen H-U (2009) Association between generalized anxiety levels and pain in a community sample: evidence for diagnostic specificity. J Anxiety Disord 23:684–693

    Article  PubMed  Google Scholar 

  • Behar E, Di Marco ID, Hekler EB, Mohlman J, Staples AM (2009) Current theoretical models of generalized anxiety disorder (GAD): conceptual review and treatment implications. J Anxiety Disord 23:1011–1023

    Article  PubMed  Google Scholar 

  • Blair K, Shaywitz J, Smith BW, Rhodes R, Geraci M, Jones M, Pine DS (2008) Response to emotional expressions in generalized SOP and GAD: evidence for separate disorders. Am J Psychiatry 165:1193–1202

    Article  PubMed  PubMed Central  Google Scholar 

  • Blom JD (2017) Psychiatry is warming up to personalized medicine 2.0. Per Med 14(3):185–187

    Article  CAS  PubMed  Google Scholar 

  • Borkovec TD (1994) The nature, functions, and origins of worry. In: Davey G, Tallis F (eds) Worrying: perspectives on theory assessment and treatment. Wiley, Sussex, pp 5–33

    Google Scholar 

  • Borkovec TD, Inz J (1990) The nature of worry in generalized anxiety disorder: a predominance of thought activity. Behav Res Ther 28:153–158

    Article  CAS  PubMed  Google Scholar 

  • Borkovec TD, Alcaine OM, Behar E (2004) Avoidance theory of worry and generalized anxiety disorder. In: Heimberg R, Turk C, Mennin D (eds) Generalized anxiety disorder: advances in research and practice. Guilford Press, New York, pp 77–108

    Google Scholar 

  • Borsboom D (2017) A network theory of mental disorders. World Psychiatry 16:5–13

    Article  PubMed  PubMed Central  Google Scholar 

  • Borst JP, Nijboer M, Taatgen NA, Van Rijn H, Anderson JR (2015) Using data-driven model-brain mappings to constrain formal models of cognition. PLoS One 10(3):e0119673. https://doi.org/10.1371/journal.pone.0119673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bourdy R, Barrot M (2012) A new control center for dopaminergic systems: pulling the VTA by the tail. Trends Neurosci 35(11):681–690

    Article  CAS  PubMed  Google Scholar 

  • Brown TA, Di Nardo PA, Lehman CL, Campbell LA (2001) Reliability of DSM-IV anxiety and mood disorders: implications for classification of emotional disorders. J Abnorm Psychol 110:49–58

    Article  CAS  PubMed  Google Scholar 

  • Buff C, Brinkmann L, Neumeister P, Feldker K, Heitmann C, Gathmann B, Straube T (2016) Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder. NeuroImage Clin 12:698–706

    Article  PubMed  PubMed Central  Google Scholar 

  • Buff C, Brinkmann L, Bruchmann M, Becker MPI, Tupaka S, Herrmann MJ, Straube T (2017) Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder, social cognitive and affective neuroscience. Soc Cogn Affect Neurosci 12(11):1766–1774

    Article  PubMed  PubMed Central  Google Scholar 

  • Cha J, Carlson JM, De Dora DJ, Greenberg T, Proudfit GH, Mujica-Parodi LR (2014a) Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder. J Neurosci 34:5855–5860

    Article  CAS  PubMed  Google Scholar 

  • Cha J, Greenberg T, Carlson JM, DeDora D, Hajcak G, Mujica-Parodi LR (2014b) Circuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorder. J Neurosci 34:4043–4053

    Article  CAS  PubMed  Google Scholar 

  • Chow MSM, Wu SL, Webb SE, Gluskin K, Yew DT (2017) Functional magnetic resonance imaging and the brain: a brief review. World J Radiol 9(1):5–9

    Article  PubMed  PubMed Central  Google Scholar 

  • Cui H, Zhang J, Liu Y, Li H, Zhang L, Hu Q, Northoff G (2016) Differential alterations of resting-state functional connectivity in generalized anxiety disorder and panic disorder. Hum Brain Mapp 37(4):1459–1473

    Article  PubMed  Google Scholar 

  • Damsa C, Kosela M, Moussallya J (2009) Current status of brain imaging in anxiety disorders. Curr Opin Psychiatry 22:96–110

    Article  PubMed  Google Scholar 

  • Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL, Davidson RJ, Kalin NH (2008) A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol Psychiatry 63:858–863

    Article  CAS  PubMed  Google Scholar 

  • Dugas MJ, Freeston MH, Ladouceur R (1997) Intolerance of uncertainty and problem orientation in worry. Cogn Ther Res 21:593–606

    Article  Google Scholar 

  • Eklund A, Nichols TE, Knutsson H (2016) Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1602413113

    Article  PubMed  Google Scholar 

  • Ellard KE, Barlow DH, Whitfield-Gabrieli S, Gabrieli JDE, Deckersback T (2017) Neural correlates of emotion acceptance vs.worry or suppression in generalized anxiety disorder. Soc Cogn Affect Neurosci 12(6):1009–1021

    Article  PubMed  PubMed Central  Google Scholar 

  • Etkin A, Wager TD (2007) Functional neuroimaging of anxiety: a meta-analysis ofEmotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164(10):1476–1488

    Article  PubMed  PubMed Central  Google Scholar 

  • Etkin A, Schatzberg AF (2011) Common abnormalities and disorder specific compensation during implicit regulation of emotional processing in generalized anxiety and major depressive disorders. Am J Psychiatry 168(9):968–978

    Article  PubMed  Google Scholar 

  • Etkin A, Prater KE, Schatzberg AF, Menon V, Greicius MD (2009) Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch Gen Psychiatry 66:1361–1372

    Article  PubMed  Google Scholar 

  • Etkin A, Prater KE, Hoeft F, Menon V, Schatzberg AF (2010) Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. Am J Psychiatry 167:545–554

    Article  PubMed  PubMed Central  Google Scholar 

  • Foa EB, Kozak MJ (1986) Emotional processing of fear: exposure to corrective information. Psychol Bull 99:20–35

    Article  CAS  PubMed  Google Scholar 

  • Fonzo GA, Etkin A (2017) Affective neuroimaging in generalized anxiety disorder: an integrated review. Dialogues Clin Neurosci 19(2):169–179

    PubMed  PubMed Central  Google Scholar 

  • Fonzo GA, Ramsawh HJ, Flagan TM, Sullivan SG, Letamendi A, Simmons AN, Paulus MP, Stein MB (2015) Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders. Br J Psychiatry 206:206–215

    Article  PubMed  PubMed Central  Google Scholar 

  • Friston KJ (2011) Functional and effective connectivity: a review. Brain Connect 1(1):13–36

    Article  PubMed  Google Scholar 

  • Greenberg T, Carlson JM, Cha J, Hajcak G, Mujica-Parodi LR (2012) Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization. Depress Anxiety 30:242–250

    Article  PubMed  Google Scholar 

  • Greenberg T, Carlson JM, Cha J, Hajcak G, Mujica-Parodi LR (2013) Neural reactivity tracks fear generalization gradients. Biol Psychol 92(1):2–8

    Article  PubMed  Google Scholar 

  • Gross JJ (2001) Emotion regulation in adulthood: timing is everything. Curr Dir Psychol Sci 10:214–219

    Article  Google Scholar 

  • Hilbert K, Lueken U, Beesdo-Baum K (2014) Neural structures, functioning and connectivity in generalized anxiety disorder and interaction with neuroendocrine systems: a systematic review. J Affect Disord 158:114–126

    Article  PubMed  Google Scholar 

  • Hölzel BK, Hoge EA, Greve DN, Gard T, Creswell JD, Brown KW, Lazar SW (2013) Neural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness training. NeuroImage Clin 2:448–458

    Article  PubMed  PubMed Central  Google Scholar 

  • Johnsson P (2017) Respiratory sinus arrytmia as a function of state anxiety in healthy individuals. Int J Psychophysiol 63(1):48–54

    Article  Google Scholar 

  • Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU (2012) Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatry 21:169–184

    Article  Google Scholar 

  • Lenk JC, Möbus C, Özyurt J, Thiel CM, Claassen A (2011) From fMRI data to cognitive models: testing the ACT-R brain mapping hypothesis with an ex-post model. Cogn Syst Res 12(3–4):321–335

    Google Scholar 

  • Linehan MM (1993) Cognitive-behavioral treatment of borderline personality disorder. Guilford Press, New York

    Google Scholar 

  • Makovac E, Meeten F, Watson DR, Herman A, Garfinkel SN, Critchley H, Ottaviani C (2016) Alterations in amygdala prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder. Biol Psychiat 80(10):786–795

    Article  PubMed  Google Scholar 

  • Makovac E, Smallwood J, Watson DR, Meeten F, Critchley HD, Ottaviani C (2018) The verbal nature of worry in generalized anxiety: insights from the brain. NeuroImage 17:882–892

    Article  PubMed  Google Scholar 

  • Mennin DS, Heimberg RG, Turk CL, Fresco DM (2002) Applying an emotion regulation framework to integrative approaches to generalized anxiety disorder. Clin Psychol Sci Pract 9:85–90

    Article  Google Scholar 

  • Meyer TJ, Miller ML, Metzger RL, Borkovec TD (1990) Development and validation of the Penn State Worry Questionnaire. Behav Res Ther 28:487–495

    Article  CAS  PubMed  Google Scholar 

  • Mochcovitch MD, Freire RCR, Garcia RF, Nardi AE (2014) A systematic review of fMRI studies in generalized anxiety disorder: evaluating it’s neural and cognitive basis. J Affect Disord 167:336–342

    Article  PubMed  Google Scholar 

  • Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269

    Article  Google Scholar 

  • Moon CM, Jeong GW (2015) Functional neuroanatomy on the working memory under emotional distraction in patients with Functional Connectivity in GAD and PD generalized anxiety disorder. Psychiatry Clin Neurosci 69:609–619

    Article  PubMed  Google Scholar 

  • Moon CM, Jeong GW (2016) Functional and morphological alterations associated with working memory dysfunction in patients with generalized anxiety disorder. Acta Radiol 58:1–9

    Google Scholar 

  • Morcom AM, Fletcher PC (2007) Does the brain have a baseline? Why we should be resisting a rest. NeuroImage 37(4):1073–1082

    Article  PubMed  Google Scholar 

  • Nitschke JB, Sarinopoulos I, Oathes DJ, Johnstone T, Whalen PJ, Davidson RJ, Kalin NH (2009) Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatry 166:302

    Article  PubMed  PubMed Central  Google Scholar 

  • Nutt D, Argyropoulos S, Hood S, Potokar J (2006) Generalized anxiety disorder: a comorbid disease. Eur Neuropharmacoly 16:109–118

    Article  CAS  Google Scholar 

  • Oathes DJ, Patenaude B, Schatzberg AF, Etkin A (2016) Neurobiological signatures of anxiety and depression in resting-state fMRI. Biol Psychiat 77(4):385–393

    Article  Google Scholar 

  • Ottaviani C, Watson DR, Meeten F, Makovac E, Garfinkel SN, Critchley HD (2016) Neurobiological substrates of cognitive rigidity and autonomic inflexibility in generalized anxiety disorder. Biol Psychol 119:31–41

    Article  PubMed  Google Scholar 

  • Palm ME, Elliott R, McKie S, Deakin JF, Anderson IM (2011) Attenuated responses to emotional expressions in women with generalized anxiety disorder. Psychol Med 41(5):1009–1018

    Article  CAS  PubMed  Google Scholar 

  • Park J-I, Kim G-W, Jeong G-W, Ho Chung G, Yang J-C (2016) Brain activation patterns associated with the effects of emotional distracters during working memory maintenance in patients with generalized anxiety disorder. Psychiatry Investig 13:152–156

    Article  PubMed  Google Scholar 

  • Paulesu E, Sambugaro E, Torti T, Danelli L, Ferri F, Scialfa G, Sassaroli S (2010) Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study. Psychol Med 40:117–124

    Article  CAS  PubMed  Google Scholar 

  • Roberge P, Normand-Lauzière F, Raymond L, Luc M, Tanguay-Bernard MM, Duhoux A, Bocti C, Fournier L (2015) Generalized anxiety disorder in primary care: mental health services use and treatment adequacy. BMC Fam Pract 16:146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson OJ, Krimsky M, Lieberman L, Allen P, Vytal K, Grillon C (2014) The dorsal medial prefrontal (anterior cingulate) cortex–amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: an observational study. Lancet Psychiatry 1(4):294–302

    Article  PubMed  PubMed Central  Google Scholar 

  • Roche RAP, Commins S, Dockree PM (2009) Cognitive neuroscience: introduction and historical perspective. In: Roche Richard, Commins Sean (eds) Pioneering studies in cognitive neuroscience. Open University Press, Berkshire, pp 1–18

    Google Scholar 

  • Roemer L, Orsillo SM, Salters-Pedneault K (2008) Efficacy of an acceptance based behavior therapy for generalized anxiety disorder: evaluation in a randomized control trial. J Couns Clin Psychol 76:1083–1089

    Article  Google Scholar 

  • Sato JR, Moll J, Green S, Deakin JFW, Thomaz CE, Zahn R (2015) Machine learning algorithm accurately detects fMRI signature of vulnerability to major depression. Psychiatry Res 233(2):289–291

    Article  PubMed  PubMed Central  Google Scholar 

  • Van den Heuvel MP, Hulshoff-Pol HE (2010) Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur Neuropsychopharmacol 20:519–534

    Article  CAS  PubMed  Google Scholar 

  • Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Wang P (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167:748–751

    Article  Google Scholar 

  • Wang W, Hou J, Qian S, Liu K, Li B, Li M, Sun G (2016) Aberrant regional neural fluctuations and functional connectivity in generalized anxiety disorder revealed by resting-state functional magnetic resonance imaging. Neurosci Lett 624:78–84

    Article  CAS  PubMed  Google Scholar 

  • Wells A (1999) A metacognitive model and therapy for generalized anxiety disorder. Clin Psychol Psychother 6:86–95

    Article  Google Scholar 

  • White SF, Geraci M, Lewis E, Leshin J, Teng C, Averbeck B, Blair KS (2015) Prediction error representation in individuals with generalized anxiety disorder during passive avoidance. Am J Psychiatry 174(2):110–117

    Article  Google Scholar 

  • Xia L, Li S, Wang T, Guo Y, Meng L, Feng Y, Jiang G (2017) Spontaneous alterations of regional brain activity in patients with adult generalized anxiety disorder. Neuropsychiatr Dis Treat 13:1957–1965

    Article  PubMed  PubMed Central  Google Scholar 

  • Yassa MA, Hazlett RL, Stark CEL, Hoehn-Saric R (2012) Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder. J Psychiatr Res 46:1045–1052

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Dr. R. A. J. Smit, PhD for methodological advice.

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Authors and Affiliations

  1. Outpatient Treatment Center GGZ Delfland, Sint Jorisweg 2, 2612 GA, Delft, The Netherlands

    Bastiaan Goossen

  2. Outpatient Treatment Center Indigo, Spijkenisse, The Netherlands

    Jeffrey van der Starre & Colin van der Heiden

  3. Institute of Psychology, Erasmus University Rotterdam, Rotterdam, The Netherlands

    Colin van der Heiden

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  1. Bastiaan Goossen
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  2. Jeffrey van der Starre
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Correspondence to Bastiaan Goossen.

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Goossen, B., van der Starre, J. & van der Heiden, C. A review of neuroimaging studies in generalized anxiety disorder: “So where do we stand?”. J Neural Transm 126, 1203–1216 (2019). https://doi.org/10.1007/s00702-019-02024-w

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