Hostname: page-component-78c5997874-g7gxr Total loading time: 0 Render date: 2024-11-10T19:36:47.417Z Has data issue: false hasContentIssue false
  • English
  • Français

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia

Published online by Cambridge University Press:  23 April 2013

U. Lueken ,
B. Straube ,
I. Reinhardt ,
N. I. Maslowski ,
H.-U. Wittchen ,
A. Ströhle ,
A. Wittmann ,
B. Pfleiderer ,
C. Konrad  and
A. Ewert
...Show all authors
U. Lueken
Affiliation:
Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Germany
B. Straube
Affiliation:
Department of Psychiatry and Psychotherapy, Philipps University Marburg, Germany
I. Reinhardt
Affiliation:
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany
N. I. Maslowski
Affiliation:
Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Germany
H.-U. Wittchen
Affiliation:
Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Germany
A. Ströhle
Affiliation:
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Germany
A. Wittmann
Affiliation:
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Germany
B. Pfleiderer
Affiliation:
Department of Clinical Radiology, University of Münster, Germany
C. Konrad
Affiliation:
Department of Psychiatry and Psychotherapy, Philipps University Marburg, Germany
A. Ewert
Affiliation:
Department of Clinical Radiology, University of Münster, Germany
C. Uhlmann
Affiliation:
Department of Psychiatry and Psychotherapy, University of Münster, Germany
V. Arolt
Affiliation:
Department of Psychiatry and Psychotherapy, University of Münster, Germany
A. Jansen
Affiliation:
Department of Psychiatry and Psychotherapy, Philipps University Marburg, Germany
T. Kircher*
Affiliation:
Department of Psychiatry and Psychotherapy, Philipps University Marburg, Germany
*
* Address for correspondence: Prof. Dr. T. Kircher, Department of Psychiatry and Psychotherapy, Philipps University Marburg, Rudolf-Bultmann-Straße 8, D-35039 Marburg, Germany. (Email: kircher@med.uni-marburg.de)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients.

Method

The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls.

Results

Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation.

Conclusions

The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Keywords

Agoraphobiadefensive reactionfear conditioningfMRIfrontal cortexmidbrainpanic disorder
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 2 , January 2014 , pp. 381 - 394
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Amaral, DG, Price, JC, Pitkänen, A, Carmichael, ST (1992). Anatomical organization of the primate amygdaloid complex. In The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (ed. Aggleton, J. P.), pp. 1–66. Wiley-Liss: New York.Google Scholar
An, X, Bandler, R, Ongur, D, Price, JL (1998). Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys. Journal of Comparative Neurology 401, 455–479.3.0.CO;2-6>CrossRefGoogle ScholarPubMed
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision (DSM-IV-TR). American Psychiatric Association: Washington, DC.Google Scholar
Aron, AR, Fletcher, PC, Bullmore, ET, Sahakian, BJ, Robbins, TW (2003). Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nature Neuroscience 6, 115–116.CrossRefGoogle ScholarPubMed
Beck, AT, Steer, RA, Brown, GK (1996). Beck Depression Inventory, Second Edition. The Psychological Corporation: San Antonio, TX.Google Scholar
Bernstein, A, Zvolensky, MJ, Marshall, EC, Schmidt, NB (2009). Laboratory test of a novel structural model of anxiety sensitivity and panic vulnerability. Behavior Therapy 40, 171–180.CrossRefGoogle ScholarPubMed
Boshuisen, ML Ter Horst, GJ, Paans, AMJ, Reinders, AATS, Den Boer, JA (2002). rCBF differences between panic disorder patients and control subjects during anticipatory anxiety and rest. Biological Psychiatry 52, 126–135.CrossRefGoogle ScholarPubMed
Bouton, ME, Mineka, S, Barlow, DH (2001). A modern learning theory perspective on the etiology of panic disorder. Psychological Review 108, 4–32.CrossRefGoogle ScholarPubMed
Bradley, MM, Lang, PJ (1994). Measuring emotion: the Self-Assessment Manikin and the Semantic Differential. Journal of Behavior Therapy and Experimental Psychiatry 25, 49–59.CrossRefGoogle ScholarPubMed
Brandao, ML, Zanoveli, JM, Ruiz-Martinez, RC, Oliveira, LC, Landeira-Fernandez, J (2008). Different patterns of freezing behavior organized in the periaqueductal gray of rats: association with different types of anxiety. Behavioural Brain Research 188, 1–13.CrossRefGoogle ScholarPubMed
Dresler, T, Guhn, A, Tupak, SV, Ehlis, AC, Herrmann, MJ, Fallgatter, AJ, Deckert, J, Domschke, K (2012). Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder. Journal of Neural Transmission 120, 3–29.CrossRefGoogle ScholarPubMed
Etkin, A, Wager, TD (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. American Journal of Psychiatry 164, 1476–1488.CrossRefGoogle ScholarPubMed
Friedman, L, Glover, GH, Krenz, D, Magnotta, V (2006). Reducing inter-scanner variability of activation in a multicenter fMRI study: role of smoothness equalization. NeuroImage 32, 1656–1668.CrossRefGoogle Scholar
Fujiwara, A, Yoshida, T, Otsuka, T, Hayano, F, Asami, T, Narita, H, Nakamura, M, Inoue, T, Hirayasu, Y (2011). Midbrain volume increase in patients with panic disorder. Psychiatry and Clinical Neurosciences 65, 365–373.CrossRefGoogle ScholarPubMed
Gloster, AT, Wittchen, HU, Einsle, F, Hofler, M, Lang, T, Helbig-Lang, S, Fydrich, T, Fehm, L, Hamm, AO, Richter, J, Alpers, GW, Gerlach, AL, Strohle, A, Kircher, T, Deckert, J, Zwanzger, P, Arolt, V (2009). Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia. European Archives of Psychiatry and Clinical Neuroscience 259 (Suppl. 2), S155–S166.CrossRefGoogle ScholarPubMed
Gorman, JM, Kent, JM, Sullivan, GM, Coplan, JD (2000). Neuroanatomical hypothesis of panic disorder, revised. American Journal of Psychiatry 157, 493–505.CrossRefGoogle ScholarPubMed
Graeff, FG, Del Ben, CM (2008). Neurobiology of panic disorder: from animal models to brain neuroimaging. Neuroscience and Biobehavioral Reviews 32, 1326–1335.CrossRefGoogle ScholarPubMed
Guy, W (1976). ECDEU Assessment Manual for Psychopharmacology. U.S. National Institute of Health, Psychopharmacology Research Branch: Rockville, MD.Google Scholar
Kircher, T, Arolt, V, Jansen, A, Pyka, M, Reinhardt, I, Kellermann, T, Konrad, C, Lueken, U, Gloster, AT, Gerlach, AL, Ströhle, A, Wittmann, A, Pfleiderer, B, Wittchen, HU, Straube, T (2013). Effect of cognitive behavioural therapy on neural correlates of fear conditioning in panic disorder. Biological Psychiatry 73, 93–101.CrossRefGoogle ScholarPubMed
LeDoux, JE, Iwata, J, Cicchetti, P, Reis, DJ (1988). Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. Journal of Neuroscience 8, 2517–2529.CrossRefGoogle ScholarPubMed
Lenartowicz, A, Verbruggen, F, Logan, GD, Poldrack, RA (2011). Inhibition-related activation in the right inferior frontal gyrus in the absence of inhibitory cues. Journal of Cognitive Neuroscience 23, 3388–3399.CrossRefGoogle ScholarPubMed
Lissek, S (2012). Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for conditioned overgeneralization. Depression and Anxiety 29, 257–263.CrossRefGoogle ScholarPubMed
Lissek, S, Powers, AS, McClure, EB, Phelps, EA, Woldehawariat, G, Grillon, C, Pine, DS (2005). Classical fear conditioning in the anxiety disorders: a meta-analysis. Behaviour Research and Therapy 43, 1391–1424.CrossRefGoogle ScholarPubMed
Lissek, S, Rabin, SJ, McDowell, DJ, Dvir, S, Bradford, DE, Geraci, M, Pine, DS, Grillon, C (2009). Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behaviour Research and Therapy 47, 111–118.CrossRefGoogle ScholarPubMed
Lovick, TA (2000). Panic disorder – a malfunction of multiple transmitter control systems within the midbrain periaqueductal gray matter? Neuroscientist 6, 48–59.CrossRefGoogle Scholar
Lueken, U, Muehlhan, M, Wittchen, HU, Kellermann, T, Reinhardt, I, Konrad, C, Lang, T, Wittmann, A, Strohle, A, Gerlach, AL, Ewert, A, Kircher, T (2011). (Don't) panic in the scanner! How panic patients with agoraphobia experience a functional magnetic resonance imaging session. European Neuropsychopharmacology 21, 516–525.CrossRefGoogle ScholarPubMed
McNaughton, N, Corr, PJ (2004). A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neuroscience and Biobehavioral Reviews 28, 285–305.CrossRefGoogle ScholarPubMed
Michael, T, Blechert, J, Vriends, N, Margraf, J, Wilhelm, FH (2007). Fear conditioning in panic disorder: enhanced resistance to extinction. Journal of Abnormal Psychology 116, 612–617.CrossRefGoogle ScholarPubMed
Mobbs, D, Marchant, JL, Hassabis, D, Seymour, B, Tan, G, Gray, M, Petrovic, P, Dolan, RJ, Frith, CD (2009). From threat to fear: the neural organization of defensive fear systems in humans. Journal of Neuroscience 29, 12236–12243.CrossRefGoogle ScholarPubMed
Mobbs, D, Petrovic, P, Marchant, JL, Hassabis, D, Weiskopf, N, Seymour, B, Dolan, RJ, Frith, CD (2007). When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 317, 1079–1083.CrossRefGoogle ScholarPubMed
Nichols, T, Brett, M, Andersson, J, Wager, T, Poline, JB (2005). Valid conjunction inference with the minimum statistic. NeuroImage 25, 653–660.CrossRefGoogle ScholarPubMed
Oldfield, RC (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97–113.CrossRefGoogle ScholarPubMed
Ottaviani, C, Cevolani, D, Nucifora, V, Borlimi, R, Agati, R, Leonardi, M, De Plato, G, Brighetti, G (2012). Amygdala responses to masked and low spatial frequency fearful faces: a preliminary fMRI study in panic disorder. Psychiatry Research 203, 159–165.CrossRefGoogle ScholarPubMed
Protopopescu, X, Pan, H, Tuescher, O, Cloitre, M, Goldstein, M, Engelien, A, Yang, YH, Gorman, J, LeDoux, J, Stern, E, Silbersweig, D (2006). Increased brainstem volume in panic disorder: a voxel-based morphometric study. Neuroreport 17, 361–363.CrossRefGoogle ScholarPubMed
Reinhardt, I, Jansen, A, Kellermann, T, Schuppen, A, Kohn, N, Gerlach, AL, Kircher, T (2010). Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders. European Archives of Psychiatry and Clinical Neuroscience 260, 443–453.CrossRefGoogle ScholarPubMed
Reiss, S, Peterson, RA, Gursky, DM, McNally, RJ (1986). Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behaviour Research and Therapy 24, 1–8.CrossRefGoogle ScholarPubMed
Schmidt, NB, Zvolensky, MJ, Maner, JK (2006). Anxiety sensitivity: prospective prediction of panic attacks and Axis I pathology. Journal of Psychiatric Research 40, 691–699.CrossRefGoogle ScholarPubMed
Sehlmeyer, C, Schoning, S, Zwitserlood, P, Pfleiderer, B, Kircher, T, Arolt, V, Konrad, C (2009). Human fear conditioning and extinction in neuroimaging: a systematic review. Plos One 4, e5865.CrossRefGoogle ScholarPubMed
Shear, MK, Vander Bilt, J, Rucci, P, Endicott, J, Lydiard, B, Otto, MW, Pollack, MH, Chandler, L, Williams, J, Ali, A, Frank, DM (2001). Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH-A). Depression and Anxiety 13, 166–178.CrossRefGoogle ScholarPubMed
Shin, LM, Liberzon, I (2010). The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191.CrossRefGoogle ScholarPubMed
Slotnick, SD, Moo, LR, Segal, JB, Hart, J Jr. (2003). Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. Brain Research. Cognitive Brain Research 17, 75–82.CrossRefGoogle ScholarPubMed
Slotnick, SD, Schacter, DL (2004). A sensory signature that distinguishes true from false memories. Nature Neuroscience 7, 664–672.CrossRefGoogle ScholarPubMed
Swick, D, Ashley, V, Turken, U (2008). Left inferior frontal gyrus is critical for response inhibition. BMC Neuroscience 9, 102.CrossRefGoogle ScholarPubMed
Tuescher, O, Protopopescu, X, Pan, H, Cloitre, M, Butler, T, Goldstein, M, Root, JC, Engelien, A, Furman, D, Silverman, M, Yang, YH, Gorman, J, LeDoux, J, Silbersweig, D, Stern, E (2011). Differential activity of subgenual cingulate and brainstem in panic disorder and PTSD. Journal of Anxiety Disorders 25, 251–257.CrossRefGoogle ScholarPubMed
Uchida, RR, Del Ben, CM, Busatto, GF, Duran, FLS, Guimaraes, FS, Crippa, JAS, Araujo, D, Santos, AC, Graeff, FG (2008). Regional gray matter abnormalities in panic disorder: a voxel-based morphometry study. Psychiatry Research 163, 21–29.CrossRefGoogle ScholarPubMed
Wilensky, AE, Schafe, GE, Kristensen, MP, LeDoux, JE (2006). Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. Journal of Neuroscience 26, 12387–12396.CrossRefGoogle ScholarPubMed
Wittchen, HU, Jacobi, F, Rehm, J, Gustavsson, A, Svensson, M, Jonsson, B, Olesen, J, Allgulander, C, Alonso, J, Faravelli, C, Fratiglioni, L, Jennum, P, Lieb, R, Maercker, A, van Os, J, Preisig, M, Salvador-Carulla, L, Simon, R, Steinhausen, HC (2011). The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology 21, 655–679.CrossRefGoogle ScholarPubMed
Wittchen, HU, Pfister, H (1997). DIA-X Interview. Swets & Zeitlinger: Frankfurt.Google Scholar