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Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

ABSTRACT: Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.

SUBMITTER: Hollandt M

PROVIDER: S-EPMC7174283 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

Hollandt Maike M Wroblewski Adrian A Yang Yunbo Y Ridderbusch Isabelle C IC Kircher Tilo T Hamm Alfons O AO Straube Benjamin B Richter Jan J

Translational psychiatry 20200421 1

Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment proced ...[more]

PMID: 32317621

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Project description:Far too much biomedical research is wasted and ends in the so called "Valley of Death": the gap that exists between biomedical research and its clinical application. While the translational process requires collaboration between many disciplines, current translational medicine focuses on single disciplines. Therefore, educational pathways that integrate clinical and research skills in interdisciplinary and interprofessional contexts are needed. The Eureka institute (http://www.eurekainstitute.org/) was founded to address these issues. The institute organizes an annual 1-week international certificate course to educate professionals in the domains of translational medicine. Study design: This study set out to investigate the impact of the Eureka certificate course on the alumni, focusing on their ability to engage in translational activities and thus become more proficient translational professionals. An explanatory, mixed-methods study was executed. Data collection: A questionnaire was distributed to collect quantitative data on the number of alumni who were able to apply what they learned during the Eureka course and engage in translational activities. Questionnaire data were also used to inform the semi-structured interviews that were conducted subsequently. Results: Fifty-one percent of the alumni reported that participating in the Eureka course played a role in their decision to change to a different job or in the way they were accomplishing their everyday work. Ten conditions for change that either hampered or supported the Eureka alumni's engagement in translational research activities were identified. Further, the learning outcomes of the Eureka course that impacted the alumni's professional activities were explored using Personal Professional Theory (PPT). The insight that alumni gained in the full translational spectrum and stakeholders involved stimulated reflection on their own role within that pathway. Further, according to the alumni, the course provided them with the skills and confidence to pursue a career as translational professional. These learning outcomes, in combination with conditions that supported alumni's engagement in translational activities, such as supportive professional partners, opportunities to network or collaborate, and a translational work environment, contributed to the large number of alumni that were able to engage in translational activities.

Project description:The fear conditioning and extinction neurocircuitry has been extensively studied in healthy and clinical populations, with a particular focus on posttraumatic stress disorder. Despite significant overlap of symptoms between posttraumatic stress disorder and anxiety disorders, the latter has received less attention. Given that dysregulated fear levels characterize anxiety disorders, examining the neural correlates of fear and extinction learning may shed light on the pathogenesis of underlying anxiety disorders.To investigate the psychophysiological and neural correlates of fear conditioning and extinction recall in anxiety disorders and to document how these features differ as a function of multiple diagnoses or anxiety severity.This investigation was a cross-sectional, case-control, functional magnetic resonance imaging study at an academic medical center. Participants were healthy controls and individuals with at least 1 of the following anxiety disorders: generalized anxiety disorder, social anxiety disorder, specific phobia, and panic disorder. The study dates were between March 2013 and May 2015.Two-day fear conditioning and extinction paradigm.Skin conductance responses, blood oxygenation level-dependent responses, trait anxiety scores from the State Trait Anxiety Inventory-Trait Form, and functional connectivity.This study included 21 healthy controls (10 women) and 61 individuals with anxiety disorders (36 women). P values reported for the neuroimaging results are all familywise error corrected. Skin conductance responses during extinction recall did not differ between individuals with anxiety disorders and healthy controls (?p2?=?0.001, P?=?.79), where ?p2 is partial eta squared. The anxiety group had lower activation of the ventromedial prefrontal cortex (vmPFC) during extinction recall (?p2?=?0.178, P?=?.02). A similar hypoactive pattern was found during early conditioning (?p2?=?0.106, P?=?.009). The vmPFC hypoactivation was associated with anxiety symptom severity (r?=?-0.420, P?=?.01 for conditioning and r?=?-0.464, P?=?.004 for extinction recall) and the number of co-occuring anxiety disorders diagnosed (?p2?=?0.137, P?=?.009 for conditioning and ?p2?=?0.227, P?=?.004 for extinction recall). Psychophysiological interaction analyses revealed that the fear network connectivity differed between healthy controls and the anxiety group during fear learning (?p2 range between 0.088 and 0.176 and P range between 0.02 and 0.003) and extinction recall (?p2 range between 0.111 and 0.235 and P range between 0.02 and 0.002).Despite no skin conductance response group differences during extinction recall, brain activation patterns between anxious and healthy individuals differed. These findings encourage future studies to examine the conditions longitudinally and in the context of treatment trials to improve and guide therapeutics via advanced neurobiological understanding of each disorder.

Project description:Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain.

Project description:ImportanceThe Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested.ObjectiveTo use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders.Design, setting, and participantsThis cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019.ExposuresA 2-day threat conditioning and extinction protocol.Main outcomes and measuresSkin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning.ResultsThis cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (?p2?=?0.15; P?=?.004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, ?p2?=?0.21; P?=?.01 and in functional magnetic resonance imaging results, ?p2?=?0.12; P?=?.02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (?p2 values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches.Conclusions and relevanceThe data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms.

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Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

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Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

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