[show abstract][hide abstract] ABSTRACT: Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.Molecular Psychiatry advance online publication, 15 January 2013; doi:10.1038/mp.2012.172.
[show abstract][hide abstract] ABSTRACT: Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia.
We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm).
During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures.
This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobia-specific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.
Psychological Medicine 01/2014; · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes. However, little is known about the contribution of genetic variants in genes relevant for the neurosteroidogenesis to anxiety disorders.
We performed an association analysis of single nucleotide polymorphisms (SNPs) in five genes related to the neurosteroidal pathway with emphasis on progesterone and allopregnanolone biosynthesis (steroid-5-alpha-reductase 1A (SRD5A1), aldo-keto reductase family 1 C1-C3 (AKR1C1-AKR1C3) and translocator protein 18 kDA (TSPO) with panic disorder (PD) and dimensional anxiety in two German PD samples (cases N = 522, controls N = 1,115).
Case-control analysis for PD and SNPs in the five selected genes was negative in the combined sample. However, we detected a significant association of anticipatory anxiety with two intronic SNPs (rs3930965, rs41314625) located in the gene AKR1C1 surviving correction for multiple testing in PD patients. Stratification analysis for gender revealed a female-specific effect of the associations of both SNPs.
These results suggest a modulatory effect of AKR1C1 activity on anxiety levels, most likely through changes in progesterone and allopregnanolone levels within and outside the brain. In summary, this is the first evidence for the gender-specific implication of the AKR1C1 gene in the expression of anticipatory anxiety in PD. Further analyses to unravel the functional role of the SNPs detected here and replication analyses are needed to validate our results.
Depression and Anxiety 01/2014; · 4.61 Impact Factor
[show abstract][hide abstract] 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.
Psychological Medicine 01/2014; 44(2):381–394. · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimer's disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE ε4 or ε2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these alleles may only become apparent in later life.
Journal of Alzheimer's disease: JAD 12/2013; · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neuroimaging group analysis are used to relate inter-subject signal differences observed in brain imaging with behavioral or genetic variables and to assess risks factors of brain diseases. The lack of stability and of sensitivity of current voxel-based analysis schemes may however lead to non-reproducible results. We introduce a new approach to overcome the limitations of standard methods, in which active voxels are detected according to a consensus on several random parcellations of the brain images, while a permutation test controls the false positive risk. Both on synthetic and real data, this approach shows higher sensitivity, better accuracy and higher reproducibility than state-of-the-art methods. In a neuroimaging-genetic application, we find that it succeeds in detecting a significant association between a genetic variant next to the COMT gene and the BOLD signal in the left thalamus for a functional Magnetic Resonance Imaging contrast associated with incorrect responses of the subjects from a Stop Signal Task protocol.
[show abstract][hide abstract] ABSTRACT: Objective: The mechanisms of action underlying treatment are inadequately understood. This study examined 5 variables implicated in the treatment of panic disorder with agoraphobia (PD/AG): catastrophic agoraphobic cognitions, anxiety about bodily sensations, agoraphobic avoidance, anxiety sensitivity, and psychological flexibility. The relative importance of these process variables was examined across treatment phases: (a) psychoeducation/interoceptive exposure, (b) in situ exposure, and (c) generalization/follow-up. Method: Data came from a randomized controlled trial of cognitive behavioral therapy for PD/AG (n = 301). Outcomes were the Panic and Agoraphobia Scale (Bandelow, 1995) and functioning as measured in the Clinical Global Impression scale (Guy, 1976). The effect of process variables on subsequent change in outcome variables was calculated using bivariate latent difference score modeling. Results: Change in panic symptomatology was preceded by catastrophic appraisal and agoraphobic avoidance across all phases of treatment, by anxiety sensitivity during generalization/follow-up, and by psychological flexibility during exposure in situ. Change in functioning was preceded by agoraphobic avoidance and psychological flexibility across all phases of treatment, by fear of bodily symptoms during generalization/follow-up, and by anxiety sensitivity during exposure. Conclusions: The effects of process variables on outcomes differ across treatment phases and outcomes (i.e., symptomatology vs. functioning). Agoraphobic avoidance and psychological flexibility should be investigated and therapeutically targeted in addition to cognitive variables. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Journal of Consulting and Clinical Psychology 11/2013; · 4.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neuroticism involves a tendency for enhanced emotional and cognitive processing of negative affective stimuli and a propensity to worry and be anxious. It is known that this trait modulates fear learning and the activation of brain regions involved in it such as the amygdala, hippocampus and prefrontal cortex and their connectivity. Thirty-nine (21 female) 14-year-old healthy adolescents participated in functional magnetic resonance imaging (fMRI) of aversive pavlovian differential delay conditioning. An unpleasant sound served as unconditioned stimulus and pictures of neutral male faces as conditioned stimuli (CS+, followed by the US in 50% of the cases; CS- never followed by the US). During acquisition (CS+/- differentiation), higher levels of neuroticism were associated with a stronger interaction between the right amygdala and the right hippocampus as well as the right amygdala and prefrontal cortical regions, specifically ventromedial prefrontal cortex, dorsolateral prefrontal cortex and anterior cingulate cortex. The association of stronger conditionability of fear and connectivity of brain regions related to consolidation of fear associations and neuroticism points to underlying mechanisms of the enhanced propensity for anxiety disorders in highly neurotic participants. This is especially important in adolescence, a vulnerable time for the onset of mental disorders such as anxiety disorders.Neuropsychopharmacology accepted article preview online, 15 October 2013. doi:10.1038/npp.2013.287.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; · 6.99 Impact Factor
[show abstract][hide abstract] 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.
American Journal of Psychiatry 08/2013; 170(11):1345-1355. · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Since 1999, the German Armed Forces (Bundeswehr) have been conducting 3-weeks preventive treatment programs aimed at psychological resource-strengthening in soldiers returning from deployment.METHODS: Five hundred participants of these programs received the Posttraumatic Stress Scale 10 (PTSS-10) before and after treatment and the rehabilitation assessment questionnaire of the German statutory pension insurance body. Sixty control group subjects received the PTSS-10 twice in an interval of 4-5 months without therapeutic interventions.
Comparison of pre- and post-treatment PTSS-10 results in the covariance analysis showed an effect of the initial PTSS-10-stress-levels and rank category, not of the intervention. On average, the treatment program received 'very good' to 'excellent' overall ratings in the rehabilitation questionnaire. The acceptance of sports and movement therapy was significantly above average, whereas that of individual and group counselling was below.
The results of this pilot study suggest a high acceptance of the post-deployment preventive program. Effectiveness in terms of psychometric improvement cannot be proven at this point.
[show abstract][hide abstract] ABSTRACT: The present study aimed to systematically assess the association of socio-economic characteristics and psychological distress in a disadvantaged urban area of a post-Soviet Republic. Psychological distress was assessed in a random sample of 200 persons, aged 18-57, living in a disadvantaged urban area of Kazakhstan using the General Health Questionnaire with 28 items (GHQ-28). Bivariate and multivariate analyses were used to examine the association of social characteristics and psychological distress. Female gender (P < 0.05), living without a partner (P < 0.01), higher age (P < 0.01), unemployment (P < 0.01), and low perceived income (P < 0.05) were associated with psychological distress in multivariate analyses. Non-Kazakh ethnicity (P < 0.05) was linked with psychological distress in bivariate analyses. The educational level was not significantly associated with psychological distress. Women, aged 38-57, living without partner and with low access to financial resources, were at a very high risk of psychological distress. Possibly due to social drift or status inconsistency, higher educational levels were not associated with lower levels of psychological distress in the disadvantaged area.
Community Mental Health Journal 05/2013; · 1.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: Bipolar disorder is a severe mood disorder, which normally begins during adolescence or early adulthood and has a heritability of up to 80%. The largest genome-wide association analysis of bipolar disorder recently identified a new genome-wide associated variant in OZD4 (rs12576775). The aim of the present study was to further elucidate the role of this risk variant in the disease process using an imaging genetics approach. As increased amygdala and striatal responses during the processing of reward and emotion are characteristic for bipolar disorder patients, it was tested whether the risk variant has an influence on this endophenotype in healthy adolescents. METHODS: We examined the impact of the risk variant rs12576775 on functional magnetic resonance imaging data in an adolescent sample (N = 485). Differential activation between carriers of the risk allele (G-allele) and homozygous A-allele carriers in the amygdala and the striatum during a modification of the monetary incentive delay task (examining reward) and a face task (examining emotion) was analyzed. RESULTS: Carriers of the risk allele showed an increased blood oxygen level-dependent response in the amygdala during reward sensitivity (p = 0.05) and reward expectation (p < 0.05) but not during the face task. No significant group differences were found in the striatum during both reward and emotion processing. CONCLUSION: Our results indicate that the ODZ4 risk variant influences reward processing in the amygdala. Alterations in the processing of emotion may have different underlying mechanisms and need to be further examined.
[show abstract][hide abstract] ABSTRACT: Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.
European Journal of Neuroscience 04/2013; · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: Although homework assignments are an integral component of cognitive-behavioral therapy (CBT) and relate to positive therapy outcomes, it is unclear whether specific homework types and their completion have specific effects on outcome. METHOD: Data from N = 292 patients (75% female, mean age 36 years) with panic disorder and agoraphobia and treated with standardized CBT were analyzed with homework compliance quality and quantity for different types of homework serving as predictors for different outcome variables. RESULTS: Quality ratings of homework completion were stronger outcome predictors than quantitative compliance ratings. Exposure homework was a better outcome predictor than homework relating to psychoeducation and self-monitoring. CONCLUSION: Different aspects of homework compliance and specific homework types might differentially relate to CBT outcome.
Journal of Clinical Psychology 03/2013; · 2.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with depression show an enhanced preoccupation with negative expectations and are often unable to look forward to positive events. Here we studied anticipatory emotional processes in unmedicated depressed patients using functional magnetic resonance imaging. Consistent with a negative processing bias, we hypothesized enhanced responses to negative and attenuated responses to positive expectancy cues in brain areas associated with emotional expectancy. Participants comprised 19 drug-free depressed patients and 19 matched healthy control subjects who viewed affective photographs. Pictures were preceded by an expectancy cue which signaled the emotional valence of the upcoming picture in half of the trials. Depressed patients showed attenuated blood-oxygen-level-dependent responses in the left lateral prefrontal cortex (inferior frontal gyrus, Brodmann area 44) during positive expectancy and-contrary to our hypothesis-in the right lateral orbitofrontal cortex (middle frontal gyrus, Brodmann area 47) during negative expectancy. This attenuation was specific for the anticipation (as opposed to the perception) of emotional pictures and correlated with a clinical measure of depressive symptoms. The observed attenuation suggests emotion-context insensitivity rather than a negative processing bias during anticipatory emotional processes in depression. This hyporeactivity may contribute to clinical features like anergia, apathy, and loss of motivation in the context of both positive and negative incentives.
[show abstract][hide abstract] ABSTRACT: During recent years, a growing interest emerged in using salivary alpha-amylase (sAA) as a non-invasive, surrogate marker for sympathetic activity. Numerous studies applying stress protocols have demonstrated that sAA is highly sensitive to stress-related changes (in healthy subjects). Additionally, it was suggested that sAA might moreover serve as an index for pathological dysregulation of the autonomic nervous system (ANS) in patients showing psychopathology. Since then, a small but growing literature investigated sAA in patients with mental disorders. This review aims to give an overview of preliminary findings in this field of research. The results of n=15 studies are described in detail and implications for further research are discussed. Although the number of studies and the samples examined were rather small, changes in sAA, reflecting adrenergic dysregulation, could be demonstrated in psychopathology, especially in anxiety-related disorders. This field of research is still in its early stages. However, the studies included in this review revealed first evidence that the employment of sAA, as an indicator of ANS dysregulation in mental disorders, is promising.
[show abstract][hide abstract] ABSTRACT: Military duty places high demands on the soldiers' social adaptability and competences. Avoidant personality traits can lead to interpersonal conflicts and at least to mental disorders. 192 German Armed Forces soldiers were treated in a multimodal inpatient psychiatric treatment setting at a Bundeswehr hospital between 2007 and 2010. 129 of these patients received a social skills group training (group training of social competence [GSC]) as part of this setting. A comparison group (n=63) did not participate but got unspecific treatment elements instead. The Symptom Checklist 90-Revised (SCL-90-R) and the Inventory on Competence and Control Beliefs (Fragebogen zu Kompetenz- und Kontrollüberzeugungen [FKK]) were applied. Symptom severity in the SCL-Global Severity Index, sum scale of the SCL-90-R and the four primary scales of the FKK showed significant improvements both immediately after treatment and at follow-up. No significant influence of the form of treatment (with/without GSC), age, gender, diagnosis, and deployments on the treatment result was established in the analysis of covariance. The data suggest that an inpatient psychiatric treatment setting focused on avoidant personality traits has a favorable effect on psychiatric symptom severity in military personnel. Social skills group training as a treatment component does not seem to be significantly superior to the standard setting.
Military medicine 02/2013; 178(2):213-7. · 0.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. METHODS: In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. RESULTS: After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS-) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the "fear network" (amygdalae, insulae, anterior cingulate cortex) across time. CONCLUSIONS: This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional ("fear network") processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.
[show abstract][hide abstract] ABSTRACT: Several epidemiological studies have shown that exercise (EX) and physical activity (PA) can prevent or delay the onset of different mental disorders, and have therapeutic benefits when used as sole or adjunct treatment in mental disorders. This review summarizes studies that used EX interventions in patients with anxiety, affective, eating, and substance use disorders, as well as schizophrenia and dementia/mild cognitive impairment. Despite several decades of clinical evidence with EX interventions, controlled studies are sparse in most disorder groups. Preliminary evidence suggests that PA/EX can induce improvements in physical, subjective and disorder-specific clinical outcomes. Potential mechanisms of action are discussed, as well as implications for psychiatric research and practice.
Journal of preventive medicine and public health = Yebang Ŭihakhoe chi. 01/2013; 46 Suppl 1:S12-21.