Increased Neural Activity in Mesostriatal Regions after Prefrontal Transcranial Direct Current Stimulation and l-DOPA Administration.

Dopamine dysfunction is associated with a wide range of neuropsychiatric disorders commonly treated pharmacologically or invasively. Recent studies provide evidence for a nonpharmacological and noninvasive alternative that allows similar manipulation of the dopaminergic system: transcranial direct current stimulation (tDCS). In rodents, tDCS has been shown to increase neural activity in subcortical parts of the dopaminergic system, and recent studies in humans provide evidence that tDCS over prefrontal regions induces striatal dopamine release and affects reward-related behavior. Based on these findings, we used fMRI in healthy human participants and measured the fractional amplitude of low-frequency fluctuations to assess spontaneous neural activity strength in regions of the mesostriatal dopamine system before and after tDCS over prefrontal regions (n = 40, 22 females). In a second study, we examined the effect of a single dose of the dopamine precursor levodopa (l-DOPA) on mesostriatal fractional amplitude of low-frequency fluctuation values in male humans (n = 22) and compared the results between both studies. We found that prefrontal tDCS and l-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. We furthermore assessed the spatial similarity of whole-brain statistical parametric maps, indicating tDCS- and l-DOPA-induced activation, and >100 neuronal receptor gene expression maps based on transcriptional data from the Allen Institute for Brain Science. In line with a specific activation of the dopaminergic system, we found that both interventions predominantly activated regions with high expression levels of the dopamine receptors D2 and D3.SIGNIFICANCE STATEMENT Studies in animals and humans provide evidence that transcranial direct current stimulation (tDCS) allows a manipulation of the dopaminergic system. Based on these findings, we used fMRI to assess changes in spontaneous neural activity strength in the human dopaminergic system after prefrontal tDCS compared with the administration of the dopamine precursor and standard anti-Parkinson drug levodopa (l-DOPA). We found that prefrontal tDCS and l-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. Using whole-brain transcriptional data of >100 neuronal receptor genes, we found that both interventions specifically activated regions with high expression levels of the dopamine receptors D2 and D3.

Replication study on the role of dopamine-dependent prefrontal reactivations in human extinction memory retrieval.

Even after successful extinction, conditioned fear can return. Strengthening the consolidation of the fear-inhibitory safety memory formed during extinction is one way to counteract return of fear. In a previous study, we found that post-extinction L-DOPA administration improved extinction memory retrieval 24 h later. Furthermore, spontaneous post-extinction reactivations of a neural activation pattern evoked in the ventromedial prefrontal cortex (vmPFC) during extinction predicted extinction memory retrieval, L-DOPA increased the number of these reactivations, and this mediated the effect of L-DOPA on extinction memory retrieval. Here, we conducted a preregistered replication study of this work in healthy male participants. We confirm that spontaneous post-extinction vmPFC reactivations predict extinction memory retrieval. This predictive effect, however, was only observed 90 min after extinction, and was not statistically significant at 45 min as in the discovery study. In contrast to our previous study, we find no evidence that L-DOPA administration significantly enhances retrieval and that this is mediated by enhancement of the number of vmPFC reactivations. However, additional non-preregistered analyses reveal a beneficial effect of L-DOPA on extinction retrieval when controlling for the trait-like stable baseline levels of salivary alpha-amylase enzymatic activity. Further, trait salivary alpha-amylase negatively predicts retrieval, and this effect is reduced by L-DOPA treatment. Importantly, the latter findings result from non-preregistered analyses and thus further investigation is needed.

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.

In search of the behavioral effects of fear: A paradigm to assess conditioned suppression in humans.

Conditioned fear can substantially reduce the likelihood that an individual will engage in reward-related behavior--a phenomenon coined conditioned suppression. Despite the unmistakable relevance of conditioned suppression for excessive fears and their adverse consequences, the phenomenon has primarily been observed in animal models and is not yet well understood. Here, we aimed to develop a conditioned suppression paradigm that enables a robust quantification of the effect of Pavlovian fear on subsequent reward-related behavior in humans and assess its potential relation to physiological measures of fear. In phase 1, an instrumental response was incentivized with monetary rewards. In phase 2, one of two conditioned stimuli (CS+) was reinforced with an aversive unconditioned stimulus (US, i.e., electric stimulus). During Pavlovian fear learning we assessed differential skin conductance (SCR) and fear- potentiated startle responses (FPS). Lastly, we tested the effect of the fear conditioned CS+ on the response rate of the instrumental response in a transfer phase. Despite strong Pavlovian fear conditioning, as indicated by large effect sizes in differential SCR and FPS, we did not find any evidence for conditioned suppression: that is, there was no significant reduction of instrumental responding in the presence of the CS+ compared to a new control stimulus. This lack of conditioned suppression is in line with previous studies that reported difficulties inducing conditioned suppression and points toward a general challenge in investigating conditioned suppression in humans. Implications and directions for future research on the highly relevant behavioral effects of fear and anxiety are discussed.

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.

Pupil dilation and skin conductance as measures of prediction error in aversive learning.

Notwithstanding the success of CBT, it is relatively unknown how individuals can better profit from corrective learning experiences. Various theories postulate that prediction errors - the difference between what is occurring and what is expected - are the driving force of associative (re)learning. While prediction errors are typically operationalized as violations of cognitive outcome expectancies, direct physiological indices of prediction errors could capture potentially more essential automatic and emotional processes in associative learning. Although physiological responses have previously been suggested to reflect prediction errors, it remains elusive if these measures actually predict changes in subsequent conditioned responding. In three fear-conditioning experiments, we compared pupil dilation and skin conductance responses to unexpected outcomes - unconditioned stimulus (US) presentations or omissions - with expected outcomes, and tested whether outcome responses predicted actual changes in subsequent conditioned responding. We found evidence for increased physiological responses to unexpected outcomes, but the results were inconsistent across experiments. Furthermore, only pupil responses to US presentations consistently predicted an increase in conditioned responding, making it difficult to reconcile our findings with associative learning models. Both pupil dilation and skin conductance can thus index unexpected outcomes, but the relationship of these responses to future learning is not evident and requires further investigation.

Do your troubles today seem further away than yesterday? On sleep's role in mitigating the blushing response to a reactivated embarrassing episode.

The "sleep to forget and sleep to remember hypothesis" proposes that sleep weakens the emotional tone of an experience while preserving or even enhancing its content. Prior experimental research however shows contradictory findings on how emotional reactivity changes after a period of sleep, likely explained by methodological variations. By addressing these inconsistencies, we investigated the mitigating effect of overnight sleep on emotional reactivity triggered by memory reactivation. Using a karaoke paradigm, we recorded participants' singing of two songs, followed by exposing them to one of the recordings (rec1) to induce an embarrassing episode. After a 12-hr period of either day-time wakefulness (N = 20) or including nighttime sleep (N = 20), we assessed emotional reactivity to the previously exposed recording (rec1) and the newly exposed recording (rec2). Emotional reactivity was assessed with a physiological measure of facial blushing as the main outcome and subjective ratings of embarrassment and valence. Sleep and wake were monitored with diaries and actigraphy. The embarrassing episode was successfully induced as indicated by objective and subjective measures. After controlling for an order effect in stimulus presentation, we found a reduction in blushing response to the reactivated recording (rec1) from pre- to post-sleep compared to wakefulness. However, emotional reactivity to the reactivated recording (rec1) and the new recording (rec2) did not differ after sleep and wakefulness. This study shows that facial blushing was reduced following overnight sleep, while subjective ratings were unaffected. Whether the beneficial effect of sleep is due to changes in memory representation or rather emotion regulation remains elusive.

A Dopaminergic Basis for Fear Extinction.

It is a joyous relief when an event we dread fails to materialize. In fear extinction, the appetitive nature of an omitted aversive event is not a mere epiphenomenon but drives the reduction of fear responses and the formation of long-term extinction memories. Dopamine emerges as key neurobiological mediator of these related processes.

Navigating the garden of forking paths for data exclusions in fear conditioning research.

In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradigms with a learning element. We illustrate this empirically through case examples from human fear conditioning research, in which the exclusion of 'non-learners' and 'non-responders' is common - despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria identified in a systematic literature search and highlight the potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. On the basis of these studies, we propose a consensus on evidence-based rather than idiosyncratic criteria, including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element.

Population-based validation of a German version of the Brief Resilience Scale.

Smith and colleagues developed the Brief Resilience Scale (BRS) to assess the individual ability to recover from stress despite significant adversity. This study aimed to validate the German version of the BRS. We used data from a population-based (sample 1: n = 1.481) and a representative (sample 2: n = 1.128) sample of participants from the German general population (age ≥ 18) to assess reliability and validity. Confirmatory factor analyses (CFA) were conducted to compare one- and two-factorial models from previous studies with a method-factor model which especially accounts for the wording of the items. Reliability was analyzed. Convergent validity was measured by correlating BRS scores with mental health measures, coping, social support, and optimism. Reliability was good (α = .85, ω = .85 for both samples). The method-factor model showed excellent model fit (sample 1: χ2/df = 7.544; RMSEA = .07; CFI = .99; SRMR = .02; sample 2: χ2/df = 1.166; RMSEA = .01; CFI = 1.00; SRMR = .01) which was significantly better than the one-factor model (Δχ2(4) = 172.71, p < .001) or the two-factor model (Δχ2(3) = 31.16, p < .001). The BRS was positively correlated with well-being, social support, optimism, and the coping strategies active coping, positive reframing, acceptance, and humor. It was negatively correlated with somatic symptoms, anxiety and insomnia, social dysfunction, depression, and the coping strategies religion, denial, venting, substance use, and self-blame. To conclude, our results provide evidence for the reliability and validity of the German adaptation of the BRS as well as the unidimensional structure of the scale once method effects are accounted for.

Making a mountain out of a molehill: on the role of the rostral dorsal anterior cingulate and dorsomedial prefrontal cortex in conscious threat appraisal, catastrophizing, and worrying.

According to appraisal theories fear and anxiety are elicited by the subjective evaluation of a situation or internal state as threatening. From this perspective anxiety disorders result from maladaptive, exaggerated threat appraisals that over-estimate the threatening consequences of often innocuous stimuli and situations. When these threat over-estimations occur at the level of conscious processing, they are referred to as catastrophizing and worrying. Both are major pathogenic processes in many clinical theories of anxiety. Until recently, little has been known about the neurobiological basis of normal and pathological conscious threat appraisal. Here, we review functional neuroimaging studies which draw a consistent picture of the rostral part of the dorsal anterior cingulate (dACC) and the adjacent dorsomedial prefrontal cortex (dmPFC) as the likely key neural substrate of conscious threat appraisal. Moreover, findings of hyper-activation of the rostral dACC/dmPFC during catastrophizing and worrying emphasize its relevance to aberrant neural processing in anxiety disorders. These insights open a new avenue for improving the prevention and treatment of mental disorders that involve pathological appraisal.

Emotional facial expressions reduce neural adaptation to face identity.

In human social interactions, facial emotional expressions are a crucial source of information. Repeatedly presented information typically leads to an adaptation of neural responses. However, processing seems sustained with emotional facial expressions. Therefore, we tested whether sustained processing of emotional expressions, especially threat-related expressions, would attenuate neural adaptation. Neutral and emotional expressions (happy, mixed and fearful) of same and different identity were presented at 3 Hz. We used electroencephalography to record the evoked steady-state visual potentials (ssVEP) and tested to what extent the ssVEP amplitude adapts to the same when compared with different face identities. We found adaptation to the identity of a neutral face. However, for emotional faces, adaptation was reduced, decreasing linearly with negative valence, with the least adaptation to fearful expressions. This short and straightforward method may prove to be a valuable new tool in the study of emotional processing.