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Articles   |    
Neural Substrates of Treatment Response to Cognitive-Behavioral Therapy in Panic Disorder With Agoraphobia
Ulrike Lueken, Ph.D.; Benjamin Straube, Ph.D.; Carsten Konrad, M.D.; Hans-Ulrich Wittchen, Ph.D.; Andreas Ströhle, M.D.; André Wittmann, Dipl.-Psych.; Bettina Pfleiderer, M.D., Ph.D.; Christina Uhlmann, Ph.D.; Volker Arolt, M.D.; Andreas Jansen, M.D.; Tilo Kircher, M.D.
Am J Psychiatry 2013;170:1345-1355. doi:10.1176/appi.ajp.2013.12111484
View Author and Article Information

Profs. Jansen and Kircher contributed equally to this article as senior authors.

Dr. Konrad has received fees for educational programs from Aristo Pharma GmbH, Esparma GmbH, Lilly Deutschland GmbH, MagVenture GmbH, and Servier Deutschland GmbH. Dr. Wittchen has received research grants and travel funds from and served on the advisory boards of Lundbeck, Novartis, Pfizer, and Servier. Prof. Ströhle has received research grants from the European Commission (FP6), the German Federal Ministry of Education and Research, and Lundbeck, and he has received speaking honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lundbeck, Pfizer, UCB, and Wyeth. Prof. Ströhle has received research funding from the German Federal Ministry of Education and Research, the European Commission (FP6), and Lundbeck; he has received speaker's honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lundbeck, Pfizer, Wyeth, and UCB; and he has received educational grants from the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds, and the Eli Lilly International Foundation. Prof. Arolt has participated in CME activities for or served on the advisory boards of AstraZeneca, Eli Lilly, Janssen-Organon, Lundbeck, Pfizer, Servier, and Wyeth. Prof. Kircher has received fees for educational programs from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, and Servier; he has also received travel sponsorship from Servier, speaking honoraria from Janssen-Cilag, and research grant support from Lundbeck and Pfizer. All other authors report no financial relationships with commercial interests.

Supported in part by the German multicenter trial Mechanisms of Action in CBT (MAC). The MAC study is funded by the German Federal Ministry of Education and Research (project number, 01GV0615; neuroimaging study: project number, 01GV0611) as part of the Federal Ministry of Education and Research Psychotherapy Research Funding Initiative.

Controlled-trials.com identifier: ISRCTN80046034.

From the Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität, Dresden, Germany; the Department of Psychology, Neuroimaging Center, Technische Universität; the Department of Psychiatry and Psychotherapy, Philipp University of Marburg, Marburg, Germany; the Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité University of Berlin; and the Departments of Clinical Radiology and Psychiatry and Psychotherapy, University of Münster, Münster, Germany.

Presented in part at the 24th Congress of the European College of Neuropsychopharmacology, Paris, Sept. 3–7, 2011; the 25th Congress of the European College of Neuropsychopharmacology, Vienna, Oct. 13–17, 2012; and the Annual Meeting of the International Society of Neuroimaging in Psychiatry, Heidelberg, Germany, Sept. 7–10, 2011.

Address correspondence to Dr. Lueken (lueken@psychologie.tu-dresden.de).

Copyright © 2013 by the American Psychiatric Association

Received November 28, 2012; Revised February 27, 2013; Accepted April 05, 2013.

Abstract

Objective  Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia.

Method  Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rating Scale scores.

Results  At baseline, nonresponders exhibited enhanced activation in the right pregenual anterior cingulate cortex, the hippocampus, and the amygdala in response to a safety signal. While this activation pattern partly resolved in nonresponders after CBT, successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies. Treatment response was associated with an inhibitory functional coupling between the anterior cingulate cortex and the amygdala that did not change over time.

Conclusions  This study identified brain activation patterns associated with treatment response in patients with panic disorder with agoraphobia. Altered safety signal processing and anterior cingulate cortex-amygdala coupling may indicate individual differences among these patients that determine the effectiveness of exposure-based CBT and associated neuroplastic changes. Findings point to brain networks by which successful CBT in this patient population is mediated.

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FIGURE 1. Differences in Functional Brain Activation During the Fear-Conditioning Task in Responders (N=25) and Nonresponders (N=24) Before Cognitive-Behavioral Therapya

a In panel A, differences are as indicated by the interaction effect of group-by-CS (conditioned stimulus) during the extinction phase (error bars indicate the standard error of the mean). Estimated beta values from the pregenual anterior cingulate cortex (ACC), amygdala, and hippocampus cluster show that the effect is driven by enhanced activation toward the CS– (conditioned stimulus not followed by the unconditioned stimulus, safety signal) during the extinction phase in nonresponders but not in responders. In panel B, group differences in functional connectivity between the ACC and the amygdala are shown. Connectivity was analyzed across the entire time course of the conditioning paradigm. The activation cluster of the ACC served as the seed region. Results are presented using a region-of-interest approach for the amygdala (p<0.05, family-wise-error corrected). Responders and nonresponders differed in functional connectivity between these two regions, with responders showing a negative coupling between the ACC and the amygdala (error bars indicate the standard error of the means). Panel C presents classification accuracy for treatment response, using neural activation in the ACC in response to the CS– (extinction phase) as a predictor. ROC=receiver operating characteristics; AUC=area under the curve; L=left; R=right.

*p<0.05. **p<0.01. ***p<0.001.

FIGURE 2. Treatment-Related Changes in Clinical and Neural Data (Extinction Phase) From Baseline to Posttreatment Assessmenta

a The graphs in panel A compare measures of clinical improvement for responders (N=24) and nonresponders (N=18). CGI=Clinical Global Impressions Scale; SIGH-A=Structured Interview Guide for the Hamilton Anxiety Rating Scale; PAS=Panic and Agoraphobia Scale; ASI=Anxiety Sensitivity Index. In panel B, neuroplastic changes, as indicated by the interaction effect of group by time from baseline (t1) to posttreatment assessment (t2), are presented. Post hoc tests show that this effect is driven by increased activation in the right hippocampus in responders but decreased activation in the anterior cingulate cortex in nonresponders. In panel C, neuroplastic changes, as indicated by the interaction of group-by-time-by-CS (conditioned stimulus), are shown. This effect is driven by a reduction of activation in the right hippocampus in response to the CS– (conditioned stimulus not followed by the unconditioned stimulus, safety signal) from t1 to t2 in nonresponders. Error bars indicate the standard error of the mean.

*p<0.05. **p<0.01. ***p<0.001.

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TABLE 1.Demographic and Clinical Characteristics of Patients With Panic Disorder With Agoraphobiaa
Table Footer Note

a CBT=cognitive-behavioral therapy; CGI=Clinical Global Impressions Scale; SIGH-A=Structured Interview Guide for the Hamilton Anxiety Rating Scale; BDI-II=Beck Depression Inventory–II.

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b Data represent the number of patients at baseline.

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c Data indicate depressive disorders encompassing major depression and dysthymia.

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d Data missing for one patient.

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TABLE 2.Brain Activation Clusters During Fear Conditioning and Extinction Characterizing Treatment Response at Baseline and Neuroplastic Changes Before and After Cognitive-Behavioral Therapy in Patients With Panic Disorder With Agoraphobiaa
Table Footer Note

a MNI=Montreal Neurological Institute; CS+=conditioned stimulus associated with the unconditioned stimulus (unpaired); CS–=conditioned stimulus not associated with the unconditioned stimulus.

Table Footer Note

b A significance threshold was set at a p value <0.005 (uncorrected), with a minimum cluster size of 142 contiguous voxels, to correct for multiple comparisons at a p value <0.05.

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c No differential activation was observed.

Table Footer Note

d Data represent the cluster encompassing the anterior cingulate, medial and superior orbitofrontal gyri, and middle, superior, and superior medial frontal gyri, with the peak voxel deviating 2.83 mm from the anterior cingulate gyrus.

Table Footer Note

e Data represent the cluster encompassing the hippocampus, inferior and middle temporal gyri, fusiform gyrus, insula, and putamen, with the peak voxel deviating 3.46 mm from the hippocampus.

Table Footer Note

f Data represent the region-of-interest analysis of the amygdala (p<0.05, family-wise-error corrected; inclusive of masking at <0.005 by the respective F contrast for post hoc t contrasts).

Table Footer Note

g Data represent the cluster encompassing the precuneus, cerebellum, and lingual gyrus, with the peak voxel deviating 2.00 mm from the precuneus.

Table Footer Note

h Data represent the cluster encompassing the anterior cingulate gyrus and middle, superior, and superior medial frontal gyri, with the peak voxel deviating 3.46 mm from the anterior cingulate gyrus.

Table Footer Note

i Data represent the cluster encompassing the precuneus, calcarine gyrus, and hippocampus, with the peak voxel deviating 2.83 mm from the precuneus.

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TABLE 3.Group Differences at Baseline (N=49) and After Cognitive-Behavioral Therapy (CBT) (N=42) in Functional Connectivity Using the Anterior Cingulate Gyrus as a Seed Regiona
Table Footer Note

a MNI=Montreal Neurological Institute. Statistical significance for the whole-brain analysis was set at a p value <0.005 (uncorrected).

Table Footer Note

b Data represent the region-of-interest analysis in the left amygdala (p=0.003; family-wise-error corrected; cluster extent, two voxels).

Table Footer Note

c Statistical significance for the region-of-interest analysis was set at a p value <0.05 (family-wise-error corrected).

Table Footer Note

d No differential activation was observed.

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