[Show abstract][Hide abstract] ABSTRACT: Adaption to changing environments is evolutionarily advantageous. Studies that link genetic and phenotypic expression of flexible adjustment to one's context are largely lacking. In this study, we tested the importance of psychological flexibility, or goal-related context sensitivity, in an interaction between psychotherapy outcome for panic disorder with agoraphobia (PD/AG) and a genetic polymorphism. Given the established role of the 5HTT-LPR polymorphism in behavioral flexibility, we tested whether this polymorphism (short group vs. long group) impacted therapy response as a function of various endophenotypes (i.e., psychological flexibility, panic, agoraphobic avoidance, and anxiety sensitivity). Patients with PD/AG were recruited from a large multicenter randomized controlled clinical trial on cognitive-behavioral therapy. Pre- to post-treatment changes by 5HTT polymorphism were analyzed. 5HTT polymorphism status differentiated pre- to post-treatment changes in the endophenotype psychological flexibility (effect size difference d = 0.4, p < 0.05), but none of the specific symptom-related endophenotypes consistently for both the intent-to-treat sample (n = 228) and the treatment completers (n = 194). Based on the consistency of these findings with existing theory on behavioral flexibility, the specificity of the results across phenotypes, and the consistency of results across analyses (i.e., completer and intent to treat), we conclude that 5HTT polymorphism and the endophenotype psychological flexibility are important variables for the treatment of PD/AG. The endophenotype psychological flexibility may help bridge genetic and psychological literatures. Despite the limitation of the post hoc nature of these analyses, further study is clearly warranted.
European Archives of Psychiatry and Clinical Neuroscience 01/2015; · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Previous studies of the dimensional structure of panic attack symptoms have mostly identified a respiratory and a vestibular/mixed somatic dimension. Evidence for additional dimensions such as a cardiac dimension and the allocation of several of the panic attack symptom criteria is less consistent. Clarifying the dimensional structure of the panic attack symptoms should help to specify the relationship of potential risk factors like anxiety sensitivity and fear of suffocation to the experience of panic attacks and the development of panic disorder. Method. In an outpatient multicentre study 350 panic patients with agoraphobia rated the intensity of each of the ten DSM-IV bodily symptoms during a typical panic attack. The factor structure of these data was investigated with nonlinear confirmatory factor analysis (CFA). The identified bodily symptom dimensions were related to panic cognitions, anxiety sensitivity and fear of suffocation by means of nonlinear structural equation modelling (SEM). Results. CFA indicated a respiratory, a vestibular/mixed somatic and a cardiac dimension of the bodily symptom criteria. These three factors were differentially associated with specific panic cognitions, different anxiety sensitivity facets and suffocation fear. Conclusions. Taking into account the dimensional structure of panic attack symptoms may help to increase the specificity of the associations between the experience of panic attack symptoms and various panic related constructs.
Psychological Medicine 12/2014; · 5.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: In cognitive behavioural therapy of phobic anxiety, in vivo exposure is considered as an effective treatment strategy. Apparently, it involves the experience of stress and anxiety in patients. Given the therapist's role during exposure sessions, it is conceivable that the performance is also accompanied with the experience of stress in therapists, especially when unversed in conducting psychotherapy. Studies confirmed that cognitive behavioural therapists tend to avoid therapist-guided in vivo exposure. The objective of this study was the simultaneous investigation of therapist's and patient's stress response during in vivo exposure. Therefore, 23 agoraphobic patients and their 23 treating therapists in training provided five saliva samples during an in vivo exposure and five samples during an ordinary therapy session. Before and during exposure session, subjective evaluations of stress and anxiety were assessed. Results suggested that therapists reported similar levels of perceived stress as patients before exposure. Both groups displayed significantly elevated salivary cortisol (sC) levels during exposure compared to the control session and a trend for alterations in salivary alpha-amylase (sAA) activity was found. Therapists reached peak concentrations of sC before start of the intervention followed by a decline during exposure, while patients displayed peak levels of cortisol secretion after 60 min of exposure.
In vivo exposure seems to be a demanding intervention not only for the patient, but also for therapists in training. However, it was also demonstrated that physiological and subjective stress rather decrease during the intervention and that both groups rated exposure to be substantially successful. Based on the presented results, another potential factor contributing to the under-usage of exposure treatment is conceivable and needs to be addressed in future research.
[Show abstract][Hide abstract] ABSTRACT: Current data point to an alteration of both the hypothalamo-pituitary-adrenal (HPA)-system and the peripheral transmission of catecholamines in anxiety disorders. There is also some evidence for the effect of several components of cognitive-behavioural interventions such as coping and control and for an effect of exercise training on the neuroendocrine stress response in healthy subjects as well as patients suffering from distinct (mental) disorders. This double-blind, controlled study investigated the effect of cognitive-behavioural therapy (CBT) in combination with either high-level endurance training or low-level exercise on salivary cortisol (sC) and on levels of salivary alpha-amylase (sAA) in patients suffering from panic disorder (PD) with and without agoraphobia. In comparison to the low-level exercise condition, there were significantly lower sC-levels in the experimental group performing high-level endurance training at a 7-month follow-up. In contrast, there were no group differences in sAA levels during the study period.
In this trial, we found evidence for a decelerated effect of endurance-training on HPA-system’s functioning in PD. Further studies addressing the alteration of sAA levels in this population might investigate physical exercise different in intensity and duration.
Journal of Psychiatric Research 11/2014; · 4.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ADHD is associated with decreased ventral-striatal (VS) responsiveness during reward anticipation. However, previous research mostly focused on adults with heterogeneous ADHD subtype and divers drug treatment status while studies in children with ADHD are sparse. Moreover, it remains unclear to what degree ADHD is characterized by a delay of normal brain structure or function maturation. We therefore attempt to determine whether results from structural and functional magnetic resonance imaging are associated with childhood and adult ADHD-CT.
Social Cognitive and Affective Neuroscience 10/2014; · 5.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The potentially detrimental effects of safety behaviors during exposure therapy are still subject to debate. Empirical findings are inconsistent, and few studies have investigated effects of idiosyncratic safety behavior manifestations during exposure or in everyday life.
These limitations might be due to a lack of appropriate measures that address individual safety behaviors. We examined psychometric properties and predictive value of the Texas Safety Maneuver Scale (TSMS), a questionnaire specifically targeting safety behaviors in panic disorder and agoraphobia. Effects of safety behavior use, both during everyday life and during therapy, were examined using data from a multicenter RCT of N = 268 patients that aimed at evaluating efficacy and mechanism of action of two variants of an exposure-based therapy. The TSMS total score demonstrated good internal consistency (α = .89), and it showed significant correlations with selected measures of baseline anxiety and impairment. The proposed factor structure could not be replicated. Frequent safety behavior use at baseline was associated with actual safety behavior during exposure exercises. Pronounced in-situ safety behavior, but not baseline safety behavior was associated to detrimental treatment outcome. The results underline the relevance of a rigorous safety behavior assessment in therapy. The actual relationship between safety behavior use and treatment outcome is yet to determine.
Journal of Anxiety Disorders 10/2014; · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Variation in the 5'-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ≥50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.
Journal of Neural Transmission 09/2014; · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.Molecular Psychiatry advance online publication, 16 September 2014; doi:10.1038/mp.2014.99.
[Show abstract][Hide abstract] ABSTRACT: Generalized anxiety disorder (GAD) is a prevalent mental condition with substantial impact on psychosocial functioning and quality of life. There is also an increased risk of comorbidity with several other mental and somatic diseases. Clinical symptomatology is characterized by excessive and uncontrollable worrying about distinct issues of daily living which is frequently associated with somatic symptoms of stress and anxiety. Neurobiological and psychological research provide evidence for alterations in (para) limbic areas, a disturbed monoaminergic transmission as well as for dysfunctional learning in the pathogenesis of GAD. Therefore, second generation antidepressants, such as selective serotonin reuptake inhibitors (SSRI), selective serotonin-norepinephrine reuptake inhibitors (SSNRI), the calcium channel modulator pregabalin and cognitive behavioral therapy (CBT) are the first choice treatment options. Depending on symptom severity, patient preference and availability, both medication and CBT can be applied as monotherapy or in combination.
[Show abstract][Hide abstract] ABSTRACT: Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40-50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R2 = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R2 = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.
[Show abstract][Hide abstract] ABSTRACT: A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.
[Show abstract][Hide abstract] ABSTRACT: The study describes prescription patterns of psychotropic medications for patients treated for psychosis in psychiatric hospitals of Uganda. A cross-sectional quantitative survey of age, sex, diagnoses, and psychotropic medication of 682 psychiatric inpatients of the 2 national referral hospitals in Uganda was conducted on 1 day in March 2012. The percentage of patients treated with the same substance within the diagnostic categories schizophrenia, bipolar affective disorder, unspecified psychosis, and depressive disorder was calculated. Close to 90% of the patients with conditions diagnosed with any psychotic disorder were treated with first-generation antipsychotic drugs (eg, chlorpromazine, haloperidol, trifluoperazine, and depot fluphenazine). Carbamazepine in combination with first-generation antipsychotics was prescribed frequently (45%) for the treatment of bipolar affective disorder. The use of second-generation antipsychotics, lithium, and valproic acid was exceptional. Patients with depression usually received a combination (63%) of first-generation antipsychotics and antidepressants (fluoxetine or amitriptyline). Benzodiazepines were only infrequently used for patients diagnosed with psychoses. First-generation antipsychotics, antidepressants, and carbamazepine were the most frequently used medications for treatment of psychosis in Uganda. Although lithium and valproic acid were on the essential drug list in Uganda, their use was still infrequent. There is a need to ensure the practical availability of the drugs listed on the essential drug list and to support the implementation of their use in clinical practice.
Journal of Clinical Psychopharmacology 06/2014; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Individuals with alcohol-dependent parents show an elevated risk of developing alcohol-related problems themselves. Modulations of the mesolimbic reward circuit have been postulated as a pre-existing marker of alcoholism. We tested whether a positive family history of alcoholism is correlated with ventral striatum functionality during a reward task. All participants performed a modified version of the monetary incentive delay task while their brain responses were measured with functional magnetic resonance imaging. We compared 206 healthy adolescents (aged 13-15) who had any first- or second-degree relative with alcoholism to 206 matched controls with no biological relative with alcoholism. Reward anticipation as well as feedback of win recruited the ventral striatum in all participants, but adolescents with a positive family history of alcoholism did not differ from their matched peers. Also we did not find any correlation between family history density and reward anticipation or feedback of win. This finding of no differences did not change when we analyzed a subsample of 77 adolescents with at least one parent with alcohol use disorder and their matched controls. Because this result is in line with another study reporting no differences between children with alcohol-dependent parents and controls at young age, but contrasts with studies of older individuals, one might conclude that at younger age the effect of family history has not yet exerted its influence on the still developing mesolimbic reward circuit.
[Show abstract][Hide abstract] ABSTRACT: Motivation is important for learning and cognition. While dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic datasets - IMAGEN (n=1080, age 13-15 years) and BrainChild (n~300, age 6-27) - we investigated whether rs1800497 is associated with WM. In the IMAGEN-dataset, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, while the GG homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission.Neuropsychopharmacology accepted article peview online, 09 April 2014; doi:10.1038/npp.2014.83.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2014; · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Playing video games is a common recreational activity of adolescents. Recent research associated frequent video game playing with improvements in cognitive functions. Improvements in cognition have been related to grey matter changes in prefrontal cortex. However, a fine-grained analysis of human brain structure in relation to video gaming is lacking. In magnetic resonance imaging scans of 152 14-year old adolescents, FreeSurfer was used to estimate cortical thickness. Cortical thickness across the whole cortical surface was correlated with self-reported duration of video gaming (hours per week). A robust positive association between cortical thickness and video gaming duration was observed in left dorsolateral prefrontal cortex (DLPFC) and left frontal eye fields (FEFs). No regions showed cortical thinning in association with video gaming frequency. DLPFC is the core correlate of executive control and strategic planning which in turn are essential cognitive domains for successful video gaming. The FEFs are a key region involved in visuo-motor integration important for programming and execution of eye movements and allocation of visuo-spatial attention, processes engaged extensively in video games. The results may represent the biological basis of previously reported cognitive improvements due to video game play. Whether or not these results represent a-priori characteristics or consequences of video gaming should be studied in future longitudinal investigations.
PLoS ONE 03/2014; 9(3):e91506. · 3.53 Impact Factor