How adverse childhood experiences get under the skin: A systematic review, integration and methodological discussion on threat and reward learning mechanisms.

Adverse childhood experiences (ACEs) are a major risk factor for the development of multiple psychopathological conditions, but the mechanisms underlying this link are poorly understood. Associative learning encompasses key mechanisms through which individuals learn to link important environmental inputs to emotional and behavioral responses. ACEs may impact the normative maturation of associative learning processes, resulting in their enduring maladaptive expression manifesting in psychopathology. In this review, we lay out a systematic and methodological overview and integration of the available evidence of the proposed association between ACEs and threat and reward learning processes. We summarize results from a systematic literature search (following PRISMA guidelines) which yielded a total of 81 articles (threat: n=38, reward: n=43). Across the threat and reward learning fields, behaviorally, we observed a converging pattern of aberrant learning in individuals with a history of ACEs, independent of other sample characteristics, specific ACE types, and outcome measures. Specifically, blunted threat learning was reflected in reduced discrimination between threat and safety cues, primarily driven by diminished responding to conditioned threat cues. Furthermore, attenuated reward learning manifested in reduced accuracy and learning rate in tasks involving acquisition of reward contingencies. Importantly, this pattern emerged despite substantial heterogeneity in ACE assessment and operationalization across both fields. We conclude that blunted threat and reward learning may represent a mechanistic route by which ACEs may become physiologically and neurobiologically embedded and ultimately confer greater risk for psychopathology. In closing, we discuss potentially fruitful future directions for the research field, including methodological and ACE assessment considerations.

Neuropsychobiology of fear-induced bradycardia in humans: progress and pitfalls.

In the last century, the paradigm of fear conditioning has greatly evolved in a variety of scientific fields. The techniques, protocols, and analysis methods now most used have undergone a progressive development, theoretical and technological, improving the quality of scientific productions. Fear-induced bradycardia is among these techniques and represents the temporary deceleration of heart beats in response to negative outcomes. However, it has often been used as a secondary measure to assess defensive responding to threat, along other more popular techniques. In this review, we aim at paving the road for its employment as an additional tool in fear conditioning experiments in humans. After an overview of the studies carried out throughout the last century, we describe more recent evidence up to the most contemporary research insights. Lastly, we provide some guidelines concerning the best practices to adopt in human fear conditioning studies which aim to investigate fear-induced bradycardia.

Mental health improvement after the COVID-19 pandemic in individuals with psychological distress.

The COVID-19 pandemic and associated countermeasures had an immensely disruptive impact on people's lives. Due to the lack of systematic pre-pandemic data, however, it is still unclear how individuals' psychological health has been affected across this incisive event. In this study, we analyze longitudinal data from two healthy samples (N = 307) to provide quasi-longitudinal insight into the full trajectory of psychological burden before (baseline), during the first peak, and at a relative downturn of the COVID-19 pandemic. Our data indicated a medium rise in psychological strain from baseline to the first peak of the pandemic (d = 0.40). Surprisingly, this was overcompensated by a large decrease of perceived burden until downturn (d = - 0.93), resulting in a positive overall effect of the COVID-19 pandemic on mental health (d = 0.44). Accounting for this paradoxical positive effect, our results reveal that the post-pandemic increase in mental health is driven by individuals that were already facing psychological challenges before the pandemic. These findings suggest that coping with acute challenges such as the COVID-19 pandemic can stabilize previously impaired mental health through reframing processes.

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.

Recent advances in studying brain-behavior interactions using functional imaging: The primary startle response pathway and its affective modulation in humans.

The startle response is a cross-species defensive reflex that is considered a key tool for cross-species translational emotion research. While the neural pathway mediating (affective) startle modulation has been extensively studied in rodents, human work on brain-behavior interactions has lagged in the past due to technical challenges, which have only recently been overcome through non-invasive simultaneous EMG-fMRI assessments. We illustrate key paradigms and methodological tools for startle response assessment in rodents and humans and review evidence for primary and modulatory neural circuits underlying startle responses and their affective modulation in humans. Based on this, we suggest a refined and integrative model for primary and modulatory startle response pathways in humans concluding that there is strong evidence from human work on the neurobiological pathway underlying the primary startle response while evidence for the modulatory pathway is still sparse. In addition, we provide methodological considerations to guide future work and provide an outlook on new and exciting perspectives enabled through technical and theoretical advances outlined in this work.

Consensus design of a calibration experiment for human fear conditioning.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

Watching with Argus eyes: Characterization of emotional and physiological responding in adults exposed to childhood maltreatment and/or recent adversity.

Exposure to adverse experiences is a well-established major risk factor for affective psychopathology. The vulnerability of deleterious sequelae is assumed in maladaptive processes of the defensive system, particularly in emotional processing. More specifically, childhood maltreatment has been suggested to be associated with the recruitment of specific and distinct defensive response profiles. To date, it remains unclear whether these are specific or generalizable to recent adversity in adulthood. This pre-registered study aimed to investigate the impact of exposure to childhood and recent adversity on emotional processing in 685 healthy adults with the "Affective Startle Modulation" Paradigm (ASM). First, we replicated higher trait anxiety and depression levels in individuals exposed to both types of adversity. Second, we observed increased general skin conductance reactivity in individuals exposed to recent adversity. Third, individuals exposed to childhood maltreatment showed reduced, while individuals exposed to recent adversity showed increased discrimination between pictures of negative and neutral valence, compared with non-exposed individuals in SCR. No association between exposure to adversity and fear potentiated startle was observed. Furthermore, explorative analyses revealed moderate dimensional and categorical agreement between two childhood maltreatment questionnaires and provide insight into potential adversity-type specific effects. Our results support experience-dependent plasticity in sympathetic nervous system reactivity and suggest distinct response profiles in affective modulation in individuals exposed to early versus recent adversity. We emphasize the need to further explore distinct adversity profiles to further our understanding on specific psychophysiological profiles and their potential implication for prevention and intervention.

Data sharing in experimental fear and anxiety research: From challenges to a dynamically growing database in 10 simple steps.

Data sharing holds promise for advancing and accelerating science by facilitating and fostering collaboration, reproducibility and optimal use of sparse resources. We argue that despite the existence of general data sharing guidelines (e.g, FAIR-principles), their translation and implementation requires field-specific considerations. Here, we addressed this timely question for the field of experimental research on fear and anxiety and showcase the enormous prospects by illustrating the wealth and richness of a curated data collection of publicly available datasets using the fear conditioning paradigm based on 103 studies and 8839 participants. We highlight challenges encountered when aiming to reuse the available data corpus and derive 10 simple steps for making data sharing in the field more efficient and sustainable and hence facilitating collaboration, cumulative knowledge generation and large scale mega-, meta- and psychometric analyses. We share our vision and first steps towards transforming such curated data collections into a homogenized and dynamically growing database allowing for easy contributions and for living analysis tools for the collective benefit of the research community.

Robust group- but limited individual-level (longitudinal) reliability and insights into cross-phases response prediction of conditioned fear.

Here, we follow the call to target measurement reliability as a key prerequisite for individual-level predictions in translational neuroscience by investigating (1) longitudinal reliability at the individual and (2) group level, (3) internal consistency and (4) response predictability across experimental phases. One hundred and twenty individuals performed a fear conditioning paradigm twice 6 months apart. Analyses of skin conductance responses, fear ratings and blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) with different data transformations and included numbers of trials were conducted. While longitudinal reliability was rather limited at the individual level, it was comparatively higher for acquisition but not extinction at the group level. Internal consistency was satisfactory. Higher responding in preceding phases predicted higher responding in subsequent experimental phases at a weak to moderate level depending on data specifications. In sum, the results suggest that while individual-level predictions are meaningful for (very) short time frames, they also call for more attention to measurement properties in the field.

A data multiverse analysis investigating non-model based SCR quantification approaches.

Electrodermal signals are commonly used outcome measures in research on arousal, emotion, and habituation. Recently, we reported on heterogeneity in skin conductance response quantification approaches and its impact on replicability. Here we provide complementary work focusing on within-approach heterogeneity of specifications for skin conductance response quantification. We focus on heterogeneity within the baseline-correction approach (BLC) which appeared as particularly heterogeneous-for instance with respect to the pre-CS baseline window duration, the start, and end of the peak detection window. We systematically scrutinize the robustness of results when applying different BLC approach specifications to one representative pre-existing data set (N = 118) in a (partly) pre-registered study. We report high agreement between different BLC approaches for US and CS+ trials, but moderate to poor agreement for CS- trials. Furthermore, a specification curve of the main effect of CS discrimination during fear acquisition training from all potential and reasonable combinations of specifications (N = 150) and a prototypical trough-to-peak (TTP) approach indicates that resulting effect sizes are largely comparable. A second specification curve (N = 605 specific combinations) highlights a strong impact of different transformation types. Crucially, however, we show that BLC approaches often misclassify the peak value-particularly for CS- trials, leading to stimulus-specific biases and challenges for post-processing and replicability of CS discrimination across studies applying different approaches. Lastly, we investigate how negative skin conductance values in BLC, appearing most frequently for CS- (CS- > CS+ > US), correspond to values in TTP quantification. We discuss the results considering prospects and challenges of the multiverse approach and future directions.

Open and reproducible science practices in psychoneuroendocrinology: Opportunities to foster scientific progress.

This perspective article was written by invitation of the editors in chief as a summary and extension of the symposium entitled Psychoneuroendocrine Research in the Era of the Replication Crisis which was held at the virtual meeting of the International Society of Psychoneuroendocrinology 2021. It highlights the opportunities presented by the application of open and reproducible scientific practices in psychoneuroendocrinology (PNE), an interdisciplinary field at the intersection of psychology, endocrinology, immunology, neurology, and psychiatry. It conveys an introduction to the topics preregistration, registered reports, quantifying the impact of equally-well justifiable analysis decisions, and open data and scripts, while emphasizing 'selfish' reasons to adopt such practices as individual researcher. Complementary to the call for adoption of open science practices, we highlight the need for methodological best practice guidelines in the field of PNE, which could further contribute to enhancing replicability of results. We propose concrete steps for future actions and provide links to additional resources for those interested in adopting open and reproducible science practices in future studies.

Multiverse analyses in fear conditioning research.

There is heterogeneity in and a lack of consensus on the preferred statistical analyses in light of a multitude of potentially equally justifiable approaches. Here, we introduce multiverse analysis for the field of experimental psychopathology research. We present a model multiverse approach tailored to fear conditioning research and, as a secondary aim, introduce the R package 'multifear' that allows to run all the models though a single line of code. Model specifications and data reduction approaches were identified through a systematic literature search. The heterogeneity of statistical models identified included Bayesian ANOVA and t-tests as well as frequentist ANOVA, t-test as well as mixed models with a variety of data reduction approaches. We illustrate the power of a multiverse analysis for fear conditioning data based on two pre-existing data sets with partial (data set 1) and 100% reinforcement rate (data set 2) by using CS discrimination in skin conductance responses (SCRs) during fear acquisition and extinction training as case examples. Both the effect size and the direction of effect was impacted by choice of the model and data reduction techniques. We anticipate that an increase in multiverse-type of studies will aid the development of formal theories through the accumulation of empirical evidence and ultimately aid clinical translation.

Effects of intolerance of uncertainty on subjective and psychophysiological measures during fear acquisition and delayed extinction.

Individuals who score high in self-reported Intolerance of Uncertainty (IU) tend to find uncertainty unacceptable and aversive. In recent years, research has shed light on the role of IU in modulating subjective (i.e. expectancy ratings) and psychophysiological responses (i.e. skin conductance) across different classical fear conditioning procedures. In particular, during immediate extinction higher IU is associated with disrupted safety learning. However, there remain gaps in understanding how IU, in comparison to other negative emotionality traits (STAI-T), impact different types of subjective and psychophysiological measures during different classical fear conditioning procedures. In our exploratory study, we analyzed IU, STAI-T, subjective (i.e. fear ratings) and psychophysiological (i.e. skin conductance, auditory startle blink) data recorded during fear acquisition training and 24 h-delayed extinction training (n = 66). Higher IU, controlled for STAI-T, was: (1) significantly associated with greater fear ratings to the learned fear cue during fear acquisition training, and (2) at trend associated with greater fear ratings to the learned fear versus safe cue during delayed extinction training. Null results were observed for both IU and STAI-T in relation to skin conductance and auditory startle blink during fear acquisition training and delayed extinction training. These results add to and extend our current understanding of the role of IU on subjective and physiological measures during different fear conditioning procedures particularly that of subjective fear ratings during acquisition and delayed extinction training. Implications of these findings and future directions are discussed.

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.

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.

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

Revisiting potential associations between brain morphology, fear acquisition and extinction through new data and a literature review.

Inter-individual differences in defensive responding are widely established but their morphological correlates in humans have not been investigated exhaustively. Previous studies reported associations with cortical thickness of the dorsal anterior cingulate cortex, insula and medial orbitofrontal cortex as well as amygdala volume in fear conditioning studies. However, these associations are partly inconsistent and often derived from small samples. The current study aimed to replicate previously reported associations between physiological and subjective measures of fear acquisition and extinction and brain morphology. Structural magnetic resonance imaging was performed on 107 healthy adults who completed a differential cued fear conditioning paradigm with 24 h delayed extinction while skin conductance response (SCR) and fear ratings were recorded. Cortical thickness and subcortical volume were obtained using the software Freesurfer. Results obtained by traditional null hypothesis significance testing and Bayesians statistics do not support structural brain-behavior relationships: Neither differential SCR nor fear ratings during fear acquisition or extinction training could be predicted by cortical thickness or subcortical volume in regions previously reported. In summary, the current pre-registered study does not corroborate associations between brain morphology and inter-individual differences in defensive responding but differences in experimental design and analyses approaches compared to previous work should be acknowledged.

Individual differences in fear acquisition: multivariate analyses of different emotional negativity scales, physiological responding, subjective measures, and neural activation.

Negative emotionality is a well-established and stable risk factor for affective disorders. Individual differences in negative emotionality have been linked to associative learning processes which can be captured experimentally by computing CS-discrimination values in fear conditioning paradigms. Literature suffers from underpowered samples, suboptimal methods, and an isolated focus on single questionnaires and single outcome measures. First, the specific and shared variance across three commonly employed questionnaires [STAI-T, NEO-FFI-Neuroticism, Intolerance of Uncertainty (IU) Scale] in relation to CS-discrimination during fear-acquisition in multiple analysis units (ratings, skin conductance, startle) is addressed (NStudy1 = 356). A specific significant negative association between STAI-T and CS-discrimination in SCRs and between IU and CS-discrimination in startle responding was identified in multimodal and dimensional analyses, but also between latent factors negative emotionality and fear learning, which capture shared variance across questionnaires/scales and across outcome measures. Second, STAI-T was positively associated with CS-discrimination in a number of brain areas linked to conditioned fear (amygdala, putamen, thalamus), but not to SCRs or ratings (NStudy2 = 113). Importantly, we replicate potential sampling biases between fMRI and behavioral studies regarding anxiety levels. Future studies are needed to target wide sampling distributions for STAI-T and verify whether current findings are generalizable to other samples.