The role of intolerance of uncertainty in the acquisition and extinction of reward

Individuals, who score high in self-reported intolerance of uncertainty (IU), tend to find uncertainty anxiety-provoking. IU has been reliably associated with disrupted threat extinction. However, it is unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a Pavlovian reward conditioning task with acquisition and extinction training phases (n = 58). In the Pavlovian reward conditioning task, we recorded liking ratings, skin conductance response (SCR), and corrugator supercilii activity (i.e., brow muscle indicative or negative and positive affect) to learned reward (CS+) and neutral (CS−) cues. Typical patterns of reward acquisition and extinction training were observed for liking ratings. There was evidence for conditioning in SCR during the extinction training phase but not the acquisition training phase. However, no evidence of conditioning in either the acquisition or extinction training phase was observed for the corrugator supercilii. IU was not related to any measures during the acquisition or extinction training phases. Taken together, these results suggest that the current Pavlovian reward conditioning task was not sufficient for eliciting a reliable conditioned reward response, and therefore, further research with optimized reward conditioning designs are required to test whether IU-related deficits occur during the extinction of reward

The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder

<p>Abstract</p> <p>Background</p> <p>Cognitive behavioral therapy (CBT) represents a learning process leading to symptom relief and resulting in long-term changes in behavior. CBT for panic disorder is based on exposure and exposure-based processes can be studied in the laboratory as extinction of experimentally acquired fear responses. We have recently demonstrated that the ability to extinguish learned fear responses is associated with a functional genetic polymorphism (COMTval158met) in the <it>COMT </it>gene and this study was aimed at transferring the experimental results on the COMTval158met polymorphism on extinction into a clinical setting.</p> <p>Methods</p> <p>We tested a possible effect of the COMTval158met polymorphism on the efficacy of CBT, in particular exposure-based treatment modules, in a sample of 69 panic disorder patients.</p> <p>Results</p> <p>We present evidence that panic patients with the COMTval158met met/met genotype may profit less from (exposure-based) CBT treatment methods as compared to patients carrying at least one val-allele. No association was found with the 5-HTTLPR/rs25531 genotypes which is presented as additional material.</p> <p>Conclusions</p> <p>We were thus able to transfer findings on the effect of the COMTval158met polymorphism from an experimental extinction study obtained using healthy subjects to a clinical setting. Furthermore patients carrying a COMT val-allele tend to report more anxiety and more depression symptoms as compared to those with the met/met genotype. Limitations of the study as well as possible clinical implications are discussed.</p> <p>Trial registration</p> <p>Clinical Trial Registry name: Internet-Versus Group-Administered Cognitive Behavior Therapy for Panic Disorder (IP2). Registration Identification number: NCT00845260, <url>http://www.clinicaltrials.gov/ct2/show/NCT00845260</url></p

Navigating the manyverse of skin conductance response quantification approaches - A direct comparison of trough-to-peak, baseline correction, and model-based approaches in Ledalab and PsPM

Raw data are typically required to be processed to be ready for statistical analyses, and processing pipelines are often characterized by substantial heterogeneity. Here, we applied seven different approaches (trough-to-peak scoring by two different raters, script-based baseline correction, Ledalab as well as four different models implemented in the software PsPM) to two fear conditioning data sets. Selection of the approaches included was guided by a systematic literature search by using fear conditioning research as a case example. Our approach can be viewed as a set of robustness analyses (i.e., same data subjected to different processing pipelines) aiming to investigate if and to what extent these different quantification approaches yield comparable results given the same data. To our knowledge, no formal framework for the evaluation of robustness analyses exists to date, but we may borrow some criteria from a framework suggested for the evaluation of "replicability" in general. Our results from seven different SCR quantification approaches applied to two data sets with different paradigms suggest that there may be no single approach that consistently yields larger effect sizes and could be universally considered "best." Yet, at least some of the approaches employed show consistent effect sizes within each data set indicating comparability. Finally, we highlight substantial heterogeneity also within most quantification approaches and discuss implications and potential remedies

A Longitudinal Study

Adverse experiences interact with individual vulnerability in the etiology of mental disorders, but due to the paucity of longitudinal studies, their precise interplay remains unclear. Here, we investigated how individual differences in threat responsiveness modulated adjustments in negative affect during the COVID-19 pandemic. Participants (N = 441) underwent a fear conditioning and generalization experiment between 2013 and 2020 and were reassessed regarding anxiety and depression symptoms after the pandemic outbreak. Participants showed increased levels of negative affect following pandemic onset, which were partly modulated by laboratory measures of threat responsiveness. Decreased differentiation of threat and safety signals in participants with higher prepandemic depression and anxiety scores in the laboratory assessment were most predictive of increased symptom levels after the onset of the pandemic. However, effects were small and should be replicated in independent samples to further characterize how individual differences in threat processing interact with adverse experiences in the development of psychopathology.Peer Reviewe

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans

<p>Abstract</p> <p>Background</p> <p>There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on μ-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders.</p> <p>Results</p> <p>At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (S_A/S_Aand S_A/L_G) as compared to those with high expression(L_A/L_A), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression.</p> <p>Conclusion</p> <p>This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.</p

Intolerance of uncertainty and threat generalization: a replication and extension

Intolerance of uncertainty (IU) is a transdiagnostic risk factor for internalizing disorders. Prior work has found that IU may be associated with either increased reactivity to threat or, alternatively, with decreased differential responding between threat and nonthreat/safety cues (i.e., threat generalization). For example, work by Morriss, Macdonald, & van Reekum (2016) found that higher IU was associated with increased threat generalization during acquisition (using skin conductance response (SCR)), as well as less differentiation between acquisition and extinction (using subjective uneasiness ratings). Here, three labs attempted direct and conceptual replications of Morriss, Macdonald, et al. (2016). Results showed that the direct replication failed, despite being conducted at the same lab site as the original study; moreover, in contrast to Morriss, Macdonald, et al. (2016), the direct replication found that higher IU was associated with greater SCR discrimination between threat and safety cues (across acquisition and extinction), as well as greater differences in uneasiness ratings between acquisition and extinction. Nonetheless, in the conceptual replications, higher IU was associated with greater threat generalization, as well as less discrimination between acquisition and extinction, as measured using SCR. Higher IU was also associated with larger late positive potentials to threat versus safety cues during extinction—results that mirror those observed by Morriss, Macdonald, et al. (2016) using SCR. Results are discussed with regards to the challenge involved in defining a successful replication attempt, the benefits of collaborative replication and the use and reliability of multiple measures

Enhancing precision in human neuroscience

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience

Making translation work: Harmonizing cross-species methodology in the behavioural neuroscience of Pavlovian fear conditioning

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation : a potential neurogenetic pathway to panic disorder

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG - related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1,370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, p=3.3x10-8; rs191260602, p=3.9x10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2,547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3,845) and a case control sample with the categorical phenotype PD/AG (Ncombined =1,012) obtaining highly significant p-values also for GLRB single nucleotide variants rs17035816 (p=3.8x10-4) and rs7688285 (p=7.6x10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout-mice demonstrated an agoraphobic phenotype. In conjunction withthe clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, though functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.PostprintPeer reviewe