Background: Cognitive behavioral therapy (CBT) is an effective treatment for panic disorder with agoraphobia (PD/AG). It is unknown, how variants of CBT differentially modulate brain networks involved in PD/AG. This study was aimed to evaluate the effects of therapist-guided (T+) versus self-guided (T-) exposure on the neural correlates of fear conditioning in PD/AG. Method: In a randomized, controlled multicenter clinical trial in medication-free patients with PD/AG who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before (t1) and after CBT (t2). Quality-controlled fMRI data from 42 patients and 42 healthy subjects (HS) were obtained. Patients were randomized to two variants of CBT (T+, n = 22, and T-, n = 20). Results: The interaction of diagnosis (PD/AG, HS), treatment group (T+, T-), time point (t1, t2) and stimulus type (conditioned stimulus: yes, no) revealed activation in the left hippocampus and the occipitotemporal cortex. The T+ group demonstrated increased activation of the hippocampus at t2 (t2 > t1), which was positively correlated with treatment outcome, and a decreased connectivity between the left inferior frontal gyrus and the left hippocampus across time (t1 > t2). Conclusion: After T+ exposure, contingency-encoding processes related to the posterior hippocampus are augmented and more decoupled from processes of the left inferior frontal gyrus, previously shown to be dysfunctionally activated in PD/AG. Linking single procedural variants to neural substrates offers the potential to inform about the optimization of targeted psychotherapeutic interventions.

Keywords:
Panic disorder, Agoraphobia, Cognitive-behavioral therapy, Hippocampus, Functional magnetic resonance imaging, Fear conditioning, Functional connectivity
1.
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 B: Effect of cognitive-behavioral therapy on neural correlates of fear conditioning in panic disorder. Biol Psychiatry 2013;73:93-101.
2.
Prasko J, Horacek J, Zalesky R, Kopecek M, Novak T, Paskova B, Skrdlantova L, Belohlavek O, Hoschl C: The change of regional brain metabolism (18FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antidepressants. Neuroendocrinol Lett 2004;25:340-348.
3.
Sakai Y, Kumano H, Nishikawa M, Sakano Y, Kaiya H, Imabayashi E, Ohnishi T, Matsuda H, Yasuda A, Sato A, Diksic M, Kuboki T: Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive-behavioral therapy. Neuroimage 2006;33:218-226.
4.
Kumari V, Peters ER, Fannon D, Antonova E, Premkumar P, Anilkumar AP, Williams SC, Kuipers E: Dorsolateral prefrontal cortex activity predicts responsiveness to cognitive-behavioral therapy in schizophrenia. Biol Psychiatry 2009;66:594-602.
5.
Fu CH, Williams SC, Cleare AJ, Scott J, Mitterschiffthaler MT, Walsh ND, Donaldson C, Suckling J, Andrew C, Steiner H, Murray RM: Neural responses to sad facial expressions in major depression following cognitive behavioral therapy. Biol Psychiatry 2008;64:505-512.
6.
Wittchen HU, Jacobi F: Size and burden of mental disorders in Europe - a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005;15:357-376.
7.
Katon WJ: Clinical practice. Panic disorder. N Engl J Med 2006;354:2360-2367.
8.
Bouton ME, Mineka S, Barlow DH: A modern learning theory perspective on the etiology of panic disorder. Psychol Rev 2001;108:4-32.
9.
Lissek S, Powers AS, McClure EB, Phelps EA, Woldehawariat G, Grillon C, Pine DS: Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav Res Ther 2005;43:1391-1424.
10.
Grillon C, Lissek S, McDowell D, Levenson J, Pine DS: Reduction of trace but not delay eyeblink conditioning in panic disorder. Am J Psychiatry 2007;164:283-289.
11.
Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS, Grillon C: Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatry 2010;167:47-55.
12.
Acheson DT, Forsyth JP, Moses E: Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability. Behav Ther 2012;43:174-189.
13.
De Cort K, Griez E, Büchler M, Schruers K: The role of ‘interoceptive' fear conditioning in the development of panic disorder. Behav Ther 2012;43:203-215.
14.
Lissek S: Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of pavlovian fear-learning: the case for conditioned overgeneralization. Depress Anxiety 2012;29:257-263.
15.
Lissek S, Rabin SJ, McDowell DJ, Dvir S, Bradford DE, Geraci M, Pine DS, Grillon C: Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behav Res Ther 2009;47:111-118.
16.
Michael T, Blechert J, Vriends N, Margraf J, Wilhelm FH: Fear conditioning in panic disorder: enhanced resistance to extinction. J Abnorm Psychol 2007;116:612-617.
17.
Lueken U, Straube B, Reinhardt I, Maslowski NI, Wittchen HU, Ströhle A, Wittmann A, Pfleiderer B, Konrad C, Ewert A, Uhlmann C, Arolt V, Jansen A, Kircher T: Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia. Psychol Med 2014;44:381-394.
18.
McHugh RK, Smits JA, Otto MW: Empirically supported treatments for panic disorder. Psychiatr Clin North Am 2009;32:593-610.
19.
Sanchez-Meca J, Rosa-Alcazar AI, Marin-Martinez F, Gomez-Conesa A: Psychological treatment of panic disorder with or without agoraphobia: a meta-analysis. Clin Psychol Rev 2010;30:37-50.
20.
Beck AT, Emery G: Anxiety Disorders and Phobias: A Cognitive Perspective. New York, Basic Books, 1985.
21.
Clark DM: A cognitive approach to panic. Behav Res Ther 1986;24:461-470.
22.
Fava GA, Rafanelli C, Tossani E, Grandi S: Agoraphobia is a disease: a tribute to Sir Martin Roth. Psychother Psychosom 2008;77:133-138.
23.
Wolpe J, Rowan VC: Panic disorder - a product of classical conditioning. Behav Res Ther 1988;26:441-450.
24.
Moscovitch DA, Antony MM, Swinson RP: Exposure-based treatments for anxiety disorders: theory and process; in Antony MM, Stein MB (ed): Oxford Handbook of Anxiety and Related Disorders. Oxford, Oxford University Press, 2009.
25.
Gloster AT, Wittchen HU, Einsle F, Lang T, Helbig-Lang S, Fydrich T, Fehm L, Hamm AO, Richter J, Alpers GW, Gerlach AL, Ströhle A, Kircher T, Deckert J, Zwanzger P, Höfler M, Arolt V: Psychological treatment for panic disorder with agoraphobia: a randomized controlled trial to examine the role of therapist-guided exposure in situ in CBT. J Consult Clin Psychol 2011;79:406-420.
26.
Craske MG, Kircanski K, Zelikowsky M, Mystkowski J, Chowdhury N, Baker A: Optimizing inhibitory learning during exposure therapy. Behav Res Ther 2008;46:5-27.
27.
Craske MG, Wolitzky-Taylor KB, Mineka S, Zinbarg R, Waters AM, Vrshek-Schallhorn S, Epstein A, Naliboff B, Ornitz E: Elevated responding to safe conditions as a specific risk factor for anxiety versus depressive disorders: evidence from a longitudinal investigation. J Abnorm Psychol 2012;121:315-324.
28.
Gorman JM, Kent JM, Sullivan GM, Coplan JD: Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000;157:493-505.
29.
De Carvalho MR, Dias GP, Cosci F, de-Melo-Neto VL, Bevilaqua MC, Gardino PF, Nardi AE: Current findings of fMRI in panic disorder: contributions for the fear neurocircuitry and CBT effects. Expert Rev Neurother 2010;10:291-303.
30.
Lueken U, Straube B, Konrad C, Wittchen HU, Ströhle A, Wittmann A, Pfleiderer B, Uhlmann C, Arolt V, Jansen A, Kircher T: Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia. Am J Psychiatry 2013;170:1345-1355.
31.
Farmer GE, Thompson LT: Learning-dependent plasticity of hippocampal CA1 pyramidal neuron postburst afterhyperpolarizations and increased excitability after inhibitory avoidance learning depend upon basolateral amygdala inputs. Hippocampus 2012;22:1703-1719.
32.
McHugh SB, Marques-Smith A, Li J, Rawlins JN, Lowry J, Conway M, Gilmour G, Tricklebank M, Bannerman DM: Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during pavlovian fear conditioning in behaving rats. Eur J Neurosci 2013;37:498-507.
33.
Liu CC, Crone NE, Franaszczuk PJ, Cheng DT, Schretlen DS, Lenz FA: Fear conditioning is associated with dynamic directed functional interactions between and within the human amygdala, hippocampus, and frontal lobe. Neuroscience 2011;189:359-369.
34.
Lang S, Kroll A, Lipinski SJ, Wessa M, Ridder S, Christmann C, Schad LR, Flor H: Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex. Eur J Neurosci 2009;29:823-832.
35.
Sehlmeyer C, Schöning S, Zwitserlood P, Pfleiderer B, Kircher T, Arolt V, Konrad C: Human fear conditioning and extinction in neuroimaging: a systematic review. PLoS One 2009;4:e5865.
36.
Reinhardt I, Jansen A, Kellermann T, Schüppen A, Kohn N, Gerlach AL, Kircher T: Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders. Eur Arch Psychiatry Clin Neurosci 2010;260:443-453.
37.
Hofmann SG: Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clin Psychol Rev 2008;28:199-210.
38.
Etkin A, Wager TD: Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007;164:1476-1488.
39.
Shin LM, Liberzon I: The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 2010;35:169-191.
40.
Tuescher O, Protopopescu X, Pan H, Cloitre M, Butler T, Goldstein M, Root JC, Engelien A, Furman D, Silverman M, Yang Y, Gorman J, LeDoux J, Silbersweig D, Stern E: Differential activity of subgenual cingulate and brainstem in panic disorder and PTSD. J Anxiety Disord 2011;25:251-257.
41.
Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR: Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 1995;269:1115-1118.
42.
LaBar KS, Cabeza R: Cognitive neuroscience of emotional memory. Nat Rev Neurosci 2006;7:54-64.
43.
Hamm AO, Weike AI: The neuropsychology of fear learning and fear regulation. Int J Psychophysiol 2005;57:5-14.
44.
Van Well S, Visser RM, Scholte HS, Kindt M: Neural substrates of individual differences in human fear learning: evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data. Cogn Affect Behav Neurosci 2012;12:499-512.
45.
Roffman JL, Marci CD, Glick DM, Dougherty DD, Rauch SL: Neuroimaging and the functional neuroanatomy of psychotherapy. Psychol Med 2005;35:1385-1398.
46.
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;36:626-644.
47.
Porto PR, 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;21:114-125.
48.
Beutel ME, Stark R, Pan H, Silbersweig D, Dietrich S: Changes of brain activation pre-post short-term psychodynamic inpatient psychotherapy: an fMRI study of panic disorder patients. Psychiatry Res 2010;184:96-104.
49.
Bouton ME, Westbrook RF, Corcoran KA, Maren S: Contextual and temporal modulation of extinction: behavioral and biological mechanisms. Biol Psychiatry 2006;60:352-360.
50.
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: Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia. Eur Arch Psychiatry Clin Neurosci 2009;259:155-166.
51.
Arolt V, Zwanzger P, Strohle A, Hamm A, Gerlach A, Kircher T, Deckert J: The research network panic-net: improving the treatment of panic disorder - from a better understanding of fear circuit mechanisms to more effective psychological treatment and routine care (in German). Psychother Psychosom Med Psychol 2009;59:124-131.
52.
Oldfield RC: The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;9:97-113.
53.
Cammin-Nowak S, Helbig-Lang S, Lang T, Gloster AT, Fehm L, Gerlach AL, Ströhle A, Deckert J, Kircher T, Hamm AO, Alpers GW, Arolt V, Wittchen HU: Specificity of homework compliance effects on treatment outcome in CBT: evidence from a controlled trial on panic disorder and agoraphobia. J Clin Psychol 2013;69:616-629.
54.
Friedman L, Glover GH, Krenz D, Magnotta V, Birn F: Reducing inter-scanner variability of activation in a multicenter fMRI study: role of smoothness equalization. Neuroimage 2006;32:1656-1668.
55.
Stocker T, Schneider F, Klein M, Habel U, Kellermann T, Zilles K, Shah NJ: Automated quality assurance routines for fMRI data applied to a multicenter study. Hum Brain Mapp 2005;25:237-246.
56.
Friedman L, Glover GH: Reducing interscanner variability of activation in a multicenter fMRI study: controlling for signal-to-fluctuation-noise-ratio (SFNR) differences. Neuroimage 2006;33:471-481.
57.
Büchel C, Morris J, Dolan RJ, Friston KJ: Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 1998;20:947-957.
58.
Slotnick SD, Moo LR, Segal JB, Hart J Jr: Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. Brain Res Cogn Brain Res 2003;17:75-82.
59.
Reif A, Richter J, Straube B, Höfler M, Lueken U, Gloster AT, Weber H, Domschke K, Fehm L, Ströhle A, Jansen A, Gerlach A, Pyka M, Reinhardt I, Konrad C, Wittmann A, Pfleiderer B, Alpers GW, Pauli P, Lang T, Arolt V, Wittchen HU, Hamm A, Kircher T, Deckert J: MAOA and mechanisms of panic disorder revisited: From bench to molecular psychotherapy. Mol Psychiatry 2014;19:122-128.
60.
Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K: A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 2005;25:1325-1335.
61.
Amunts K, Kedo O, Kindler M, Pieperhoff P, Mohlberg H, Shah NJ, Habel U, Schneider F, Zilles K: Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anat Embryol (Berl) 2005;210:343-352.
62.
Chen J, Shi S: A review of neuroimaging studies of anxiety disorders in China. Neuropsychiatr Dis Treat 2011;7:241-249.
63.
Pantazatos SP, Talati A, Schneier FR, Hirsch J: Reduced anterior temporal and hippocampal functional connectivity during face processing discriminates individuals with social anxiety disorder from healthy controls and panic disorder, and increases following treatment. Neuropsychopharmacology 2014;39:425-434.
64.
Pejic T, Hermann A, Vaitl D, Stark R: Social anxiety modulates amygdala activation during social conditioning. Soc Cogn Affect Neurosci 2013;8:267-276.
65.
Pohlack ST, Nees F, Liebscher C, Cacciaglia R, Diener SJ, Ridder S, Woermann FG, Flor H: Hippocampal but not amygdalar volume affects contextual fear conditioning in humans. Hum Brain Mapp 2012;33:478-488.
66.
Alvarez RP, Biggs A, Chen G, Pine DS, Grillon C: Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J Neurosci 2008;28:6211-6219.
67.
Maren S: Pavlovian fear conditioning as a behavioral assay for hippocampus and amygdala function: cautions and caveats. Eur J Neurosci 2008;28:1661-1666.
68.
Marschner A, Kalisch R, Vervliet B, Vansteenwegen D, Büchel C: Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning. J Neurosci 2008;28:9030-9036.
69.
Vythilingam M, Lawley M, Collin C, Bonne O, Agarwal R, Hadd K, Charney DS, Grillon C: Hydrocortisone impairs hippocampal-dependent trace eyeblink conditioning in post-traumatic stress disorder. Neuropsychopharmacology 2006;31:182-188.
70.
Cisler JM, Steele JS, Lenow JK, Smitherman S, Everett B, Messias E, Kilts CD: Functional reorganization of neural networks during repeated exposure to the traumatic memory in posttraumatic stress disorder: an exploratory fMRI study. J Psychiatr Res 2014;48:47-55.
71.
Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H: Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 2004;61:34-41.
72.
Felmingham K, Kemp A, Williams L, Das P, Hughes G, Peduto A, Bryant R: Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder. Psychol Sci 2007;18:127-129.
73.
Dickie EW, Brunet A, Akerib V, Armony JL: Neural correlates of recovery from post-traumatic stress disorder: a longitudinal fMRI investigation of memory encoding. Neuropsychologia 2011;49:1771-1778.
74.
Holschneider DP, Yang J, Sadler TR, Nguyen PT, Givrad TK, Maarek JM: Mapping cerebral blood flow changes during auditory-cued conditioned fear in the nontethered, nonrestrained rat. Neuroimage 2006;29:1344-1358.
75.
Selden NR, Everitt BJ, Jarrard LE, Robbins TW: Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience 1991;42:335-350.
76.
Daumas S, Halley H, Francés B, Lassalle JM: Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions. Learn Mem 2005;12:375-382.
77.
Phillips RG, LeDoux JE: Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992;106:274-285.
78.
Hasler G, Fromm S, Alvarez RP, Luckenbaugh DA, Drevets WC, Grillon C: Cerebral blood flow in immediate and sustained anxiety. J Neurosci 2007;27:6313-6319.
79.
Powers MB, Smits JAJ, Telch MJ: Disentangling the effects of safety-behavior utilization and safety-behavior availability during exposure-based treatment: a placebo-controlled trial. J Consult Clin Psychol 2004;72:448-454.
80.
Gloster AT, Klotsche J, Gerlach AL, Hamm A, Ströhle A, Gauggle S, Kircher T, Alpers G, Deckert J, Wittchen H-U: Timing matters: mediators of outcomes in cognitive behavioral therapy for panic disorder with agoraphobia depend on the stage of treatment. J Consult Clin Psychol 2014;82:141-153.
81.
Motanis H, Maroun M: Exposure to a novel context following contextual fear conditioning enhances the induction of hippocampal long-term potentiation. Eur J Neurosci 2010;32:840-846.
82.
Hu YS, Long N, Pigino G, Brady ST, Lazarov O: Molecular mechanisms of environmental enrichment: impairments in AKT/GSK3β, neurotrophin-3 and CREB signaling. PLoS One 2013;8:e64460.
83.
Leger M, Quiedeville A, Paizanis E, Natkunarajah S, Freret T, Boulouard M, Schumann-Bard P: Environmental enrichment enhances episodic-like memory in association with a modified neuronal activation profile in adult mice. PLoS One 2012;7:e48043.
84.
Gogolla N, Galimberti I, Deguchi Y, Caroni P: Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus. Neuron 2009;62:510-525.
85.
Galimberti I, Gogolla N, Alberi S, Santos AF, Muller D, Caroni P: Long-term rearrangements of hippocampal mossy fiber terminal connectivity in the adult regulated by experience. Neuron 2006;50:749-763.
86.
Friston K: Ten ironic rules for non-statistical reviewers. Neuroimage 2012;61:1300-1310.
87.
Tomba E: Nowhere patients. Psychother Psychosom 2012;81:69-72.
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