Neural Substrates of Treatment Response to Cognitive-Behavioral Therapy in Panic Disorder With Agoraphobia

Lueken, Ulrike; Straube, Benjamin; Konrad, Carsten; Wittchen, Hans‐Ulrich; Ströhle, Andreas; Wittmann, André; Pfleiderer, Bettina; Uhlmann, Christina; Arolt, Volker; Jansen, Andreas; Kircher, Tilo

doi:10.1176/appi.ajp.2013.12111484

Cited by 118 publications

(99 citation statements)

References 33 publications

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“…These data indicate that different top down and bottom-up processes during fear conditioning 55 are affected by genetically driven CRHR1 expression differences in patients with PD/AG. Especially the generalization of fear and dysfunctional safety signal processing has been considered to be a relevant pathological mechanisms of PD/AG 68 and has been shown to be associated to treatment response 54 . Altogether, these data indicate that variation in CHRH1 genotypes and subsequent expressional changes might contribute to the development of sustained fear due to impaired safety signaling processing and increased amygdala reactivity towards neural stimuli.…”

Section: Discussionmentioning

confidence: 99%

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Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

et al. 2015

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Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here, we aimed to evaluate CRHR1 as a candidate molecule in panic disorder (PD).Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (p rs17689918 =1.3*10 -4 ; p rs17689966 =0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala.Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) allele of rs17689918 led to less flight behavior during fear provoking situations, but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus, reduced CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

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Section: Discussionmentioning

confidence: 99%

“…A Monte Carlo simulation was conducted to establish an appropriate voxel contiguity threshold 53 . Thus, for all analyses voxels with a significance level of p < 0.005 uncorrected belonging to clusters with at least 142 voxels are reported (see also 51,52,54,55 ). Whole-brain analysis was carried out first.…”

Section: Functional Mrimentioning

confidence: 99%

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

et al. 2015

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“…Particularly in PD, two resting positron emission tomography studies demonstrated change in glucose utilization in distributed regions of predominantly the medial and lateral frontal and temporal cortices in CBT groups of 6 [2] and 11 patients [3]. Besides our own [1,30], the only other fMRI study [48] used an emotional linguistic go/nogo design in 9 patients with PD following short-term psychodynamic inpatient treatment (4 weeks), after treatment symptoms had improved, and frontolimbic activation patterns had been normalized. Despite the small sample sizes and only partially overlapping results, these studies indicate that different forms of psychotherapy can influence processes in the brain in patients with PD.…”

Section: Introductionmentioning

confidence: 90%

“…Thus, the advantage of going with the patient out into the field during exposure might be mediated by different encoding or learning strategies, possibly also leading to a better cognitive awareness of contingencies for external and internal events. The investigation of the neural correlates of learning mechanisms such as exteroceptive fear conditioning in PD/AG can help to understand CBT-related changes on the brain level [1,28,29,30]. …”

Section: Introductionmentioning

confidence: 99%

“…The results suggest aberrant top-down and bottom-up processes during fear conditioning in PD/AG [17]. Whereas the left inferior frontal gyrus during differential conditioning seemed to be generally involved in the psychopathology and treatment of PD/AG [1], successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies [30]. However, despite this evidence about treatment effects on fear conditioning, the effects of different single variants of CBT on neural correlates have not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Neural Correlates of Procedural Variants in Cognitive-Behavioral Therapy: A Randomized, Controlled Multicenter fMRI Study

Straube¹,

Lueken²,

Jansen³

et al. 2014

Psychother Psychosom

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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.

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Predicting Treatment Response to Cognitive Behavioral Therapy in Panic Disorder With Agoraphobia by Integrating Local Neural Information

et al. 2015

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IMPORTANCE Although neuroimaging research has made substantial progress in identifying the large-scale neural substrate of anxiety disorders, its value for clinical application lags behind expectations. Machine-learning approaches have predictive potential for individual-patient prognostic purposes and might thus aid translational efforts in psychiatric research. OBJECTIVE To predict treatment response to cognitive behavioral therapy (CBT) on an individual-patient level based on functional magnetic resonance imaging data in patients with panic disorder with agoraphobia (PD/AG). DESIGN, SETTING, AND PARTICIPANTS We included 49 patients free of medication for at least 4 weeks and with a primary diagnosis of PD/AG in a longitudinal study performed at 8 clinical research institutes and outpatient centers across Germany. The functional magnetic resonance imaging study was conducted between July 2007 and March 2010. INTERVENTIONS Twelve CBT sessions conducted 2 times a week focusing on behavioral exposure. MAIN OUTCOMES AND MEASURES Treatment response was defined as exceeding a 50% reduction in Hamilton Anxiety Rating Scale scores. Blood oxygenation level-dependent signal was measured during a differential fear-conditioning task. Regional and whole-brain gaussian process classifiers using a nested leave-one-out cross-validation were used to predict the treatment response from data acquired before CBT. RESULTS Although no single brain region was predictive of treatment response, integrating regional classifiers based on data from the acquisition and the extinction phases of the fear-conditioning task for the whole brain yielded good predictive performance (accuracy, 82%; sensitivity, 92%; specificity, 72%; P < .001). Data from the acquisition phase enabled 73% correct individual-patient classifications (sensitivity, 80%; specificity, 67%; P < .001), whereas data from the extinction phase led to an accuracy of 74% (sensitivity, 64%; specificity, 83%; P < .001). Conservative reanalyses under consideration of potential confounders yielded nominally lower but comparable accuracy rates (acquisition phase, 70%; extinction phase, 71%; combined, 79%). CONCLUSIONS AND RELEVANCE Predicting treatment response to CBT based on functional neuroimaging data in PD/AG is possible with high accuracy on an individual-patient level. This novel machine-learning approach brings personalized medicine within reach, directly supporting clinical decisions for the selection of treatment options, thus helping to improve response rates.

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Neural Substrates of Treatment Response to Cognitive-Behavioral Therapy in Panic Disorder With Agoraphobia

Cited by 118 publications

References 33 publications

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

Neural Correlates of Procedural Variants in Cognitive-Behavioral Therapy: A Randomized, Controlled Multicenter fMRI Study

Predicting Treatment Response to Cognitive Behavioral Therapy in Panic Disorder With Agoraphobia by Integrating Local Neural Information

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