Pavlovian-to-instrumental transfer in individuals with chronic pain.

Avoidance of pain has been argued to be key factor leading pain events to chronic disability. In this respect, research has focused on investigating the working mechanisms of avoidance's acquisition. Avoidance of painful stimuli has been traditionally studied using a combination of Pavlovian and Instrumental procedures. However, such approach seems to go against real-life scenarios where avoidance is commonly acquired more readily. Using a novel pain avoidance paradigm, we tested whether pain avoidance can be installed in absence of associations between a cue and pain omission, and whether such avoidance differs between pain patients and healthy controls. Participants first learned to avoid painful stimuli by pressing a grip bar. Then, they passively encountered pairings of one geometrical shape with pain and of another geometrical shape without pain. Lastly, participants encountered the geometrical shapes while being able to use the grip bar. Results showed that participants pressed the bar more vigorously when encountering the previously pain-related shape compared to the pain-unrelated shape. This effect did not seem to differ between pain patients and healthy control. Our study could inspire a new way in measuring avoidance in pain, possibly paving the way to better understanding how avoidance is installed in chronic pain.

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.

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.

Experimental boundary conditions of reinstatement-induced return of fear in humans: Is reinstatement in humans what we think it is?

Experimental paradigms used to study reinstatement of fear in humans are characterized by procedural heterogeneity. Reinstatement protocols involve unexpected (re)-presentations of the unconditioned stimulus (USs) after fear extinction training. Here, we address the number of reinstatement USs administered as a potential boundary condition that may explain divergent findings in the field. A sample of 171 participants is exposed to a fear acquisition training, immediate extinction training, and reinstatement test experiment. Three groups differing in the number of reinstatement US are employed: one (n = 57) or four (n = 55) in experimental groups and zero (n = 59) in the control group. We adopt Bayesian statistical approaches beyond classical null hypothesis significance testing (NHST) to qualify evidence for or against this potential methodological boundary condition in reinstatement-induced return of fear. Startle potentiation to the reinstatement administration context was increased for the RI-USone compared to the RI-USzero group, supporting the role of context conditioning in reinstatement. This effect was weaker in the RI-USfour group. This, however, did not transfer to responding to conditioned stimuli during the return of fear-test: no evidence for an effect of the number of reinstatement USs (zero, one, four) was observed in behavioral or physiological measures. In sum, our results speak against the number of reinstatement USs as a potential boundary condition in experimentally induced return of fear in humans. This may challenge what we think we know about the reinstatement phenomenon in humans and call for critical reconsideration of paradigms as well as mechanisms that may underlie some reinstatement effects in the literature.

The Neurofunctional Basis of Affective Startle Modulation in Humans: Evidence From Combined Facial Electromyography and Functional Magnetic Resonance Imaging.

BACKGROUND: The startle eye-blink is the cross-species translational tool to study defensive behavior in affective neuroscience with relevance to a broad range of neuropsychiatric conditions. It makes use of the startle reflex, a defensive response elicited by an immediate, unexpected sensory event, which is potentiated when evoked during threat and inhibited during safety. In contrast to skin conductance responses or pupil dilation, modulation of the startle reflex is valence specific. Rodent models implicate a modulatory pathway centering on the brainstem (i.e., nucleus reticularis pontis caudalis) and the centromedial amygdala as key hubs for flexibly integrating valence information into differential startle magnitude. Technical advances now allow for the investigation of this pathway using combined facial electromyography and functional magnetic resonance imaging in humans. METHODS: We employed a multimethodological approach combining trial-by-trial facial eye-blink startle electromyography and brainstem- and amygdala-specific functional magnetic resonance imaging in humans. Validating the robustness and reproducibility of our findings, we provide evidence from two different paradigms (fear-potentiated startle, affect-modulated startle) in two independent studies (N = 43 and N = 55). RESULTS: We provide key evidence for a conserved neural pathway for acoustic startle modulation between humans and rodents. Furthermore, we provide the crucial direct link between electromyography startle eye-blink magnitude and neural response strength. Finally, we demonstrate a dissociation between arousal-specific amygdala responding and triggered valence-specific amygdala responding. CONCLUSIONS: We provide neurobiologically based evidence for the strong translational value of startle responding and argue that startle-evoked amygdala responding and its affective modulation may hold promise as an important novel tool for affective neuroscience and its clinical translation.

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.

Don't startle me-Interference of startle probe presentations and intermittent ratings with fear acquisition.

Reproducibility is fundamental to science and a recent matter of discussion. We report challenges for conceptual replications when employing different readout measures to target the same theoretical construct, particularly those requiring probed reactions. This was addressed in a fear conditioning paradigm, a prototype of emotional learning, in three experimental groups (Ntotal = 57). We demonstrate that the inclusion of startle probes (95 dB burst of white noise) to elicit a startle reflex delays the acquisition of fear as reflected by skin conductance responses and intermittent fear ratings. The inclusion of fear ratings in turn did not significantly affect fear acquisition. Hence, subtle differences in experimental design, such as the inclusion of a single additional outcome measure, may substantially impact on study results and interpretations. Thus, small effects, as are common in between-group comparisons, may be particularly susceptible to this, which has strong implications for the replication of findings across studies employing slightly different experimental designs.

Contextual Change After Fear Acquisition Affects Conditioned Responding and the Time Course of Extinction Learning-Implications for Renewal Research.

Context plays a central role in retrieving (fear) memories. Accordingly, context manipulations are inherent to most return of fear (ROF) paradigms (in particular renewal), involving contextual changes after fear extinction. Context changes are, however, also often embedded during earlier stages of ROF experiments such as context changes between fear acquisition and extinction (e.g., in ABC and ABA renewal). Previous studies using these paradigms have however focused exclusively on the context switch after extinction (i.e., renewal). Thus, the possibility of a general effect of context switch on conditioned responding that may not be conditional to preceding extinction learning remains unstudied. Hence, the current study investigated the impact of a context switch between fear acquisition and extinction on immediate conditioned responding and on the time-course of extinction learning by using a multimodal approach. A group that underwent contextual change after fear conditioning (AB; n = 36) was compared with a group without a contextual change from acquisition to extinction (AA; n = 149), while measuring physiological (skin conductance and fear potentiated startle) measures and subjective fear ratings. Contextual change between fear acquisition and extinction had a pronounced effect on both immediate conditioned responding and on the time course of extinction learning in skin conductance responses and subjective fear ratings. This may have important implications for the mechanisms underlying and the interpretation of the renewal effect (i.e., contextual switch after extinction). Consequently, future studies should incorporate designs and statistical tests that disentangle general effects of contextual change from genuine ROF effects.

Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.