Dimensionality and optimal combination of autonomic fear-conditioning measures in humans.

Fear conditioning, also termed threat conditioning, is a commonly used learning model with clinical relevance. Quantification of threat conditioning in humans often relies on conditioned autonomic responses such as skin conductance responses (SCR), pupil size responses (PSR), heart period responses (HPR), or respiration amplitude responses (RAR), which are usually analyzed separately. Here, we investigate whether inter-individual variability in differential conditioned responses, averaged across acquisition, exhibits a multi-dimensional structure, and the extent to which their linear combination could enhance the precision of inference on whether threat conditioning has occurred. In a mega-analytic approach, we re-analyze nine data sets including 256 individuals, acquired by the group of the last author, using standard routines in the framework of psychophysiological modeling (PsPM). Our analysis revealed systematic differences in effect size between measures across datasets, but no evidence for a multidimensional structure across various combinations of measures. We derive the statistically optimal weights for combining the four measures and subsets thereof, and we provide out-of-sample performance metrics for these weights, accompanied by bias-corrected confidence intervals. We show that to achieve the same statistical power, combining measures allows for a relevant reduction in sample size, which in a common scenario amounts to roughly 24%. To summarize, we demonstrate a one-dimensional structure of threat conditioning measures, systematic differences in effect size between measures, and provide weights for their optimal linear combination in terms of maximal retrodictive validity.

The impact of doxycycline on human contextual fear memory.

RATIONALE:  Previous work identified an attenuating effect of the matrix metalloproteinase (MMP) inhibitor doxycycline on fear memory consolidation. This may present a new mechanistic approach for the prevention of trauma-related disorders. However, so far, this has only been unambiguously demonstrated in a cued delay fear conditioning paradigm, in which a simple geometric cue predicted a temporally overlapping aversive outcome. This form of learning is mainly amygdala dependent. Psychological trauma often involves the encoding of contextual cues, which putatively necessitates partly different neural circuits including the hippocampus. The role of MMP signalling in the underlying neural pathways in humans is unknown. METHODS: Here, we investigated the effect of doxycycline on configural fear conditioning in a double-blind placebo-controlled randomised trial with 100 (50 females) healthy human participants. RESULTS: Our results show that participants successfully learned and retained, after 1 week, the context-shock association in both groups. We find no group difference in fear memory retention in either of our pre-registered outcome measures, startle eye-blink responses and pupil dilation. Contrary to expectations, we identified elevated fear-potentiated startle in the doxycycline group early in the recall test, compared to the placebo group. CONCLUSION: Our results suggest that doxycycline does not substantially attenuate contextual fear memory. This might limit its potential for clinical application.

Attenuating human fear memory retention with minocycline: a randomized placebo-controlled trial.

Pavlovian fear conditioning is widely used as a pre-clinical model to investigate methods for prevention and treatment of anxiety and stress-related disorders. In this model, fear memory consolidation is thought to require synaptic remodeling, which is induced by signaling cascades involving matrix metalloproteinase 9 (MMP-9). Here we investigated the effect of the tetracycline antibiotic minocycline, an inhibitor of MMP-9, on fear memory retention. We conducted a pre-registered, randomized, double-blind, placebo-controlled trial in N = 105 healthy humans (N = 70 female), using a configural fear conditioning paradigm. We administered a single dose of minocycline before configural fear memory acquisition and assessed fear memory retention seven days later in a recall test. To index memory retention, we pre-registered fear-potentially startle (FPS) as our primary outcome, and pupil dilation as the secondary outcome. As control indices of memory acquisition, we analyzed skin conductance responses (SCR) and pupil dilation. We observed attenuated retention of configural fear memory in individuals treated with minocycline compared to placebo, as measured by our primary outcome. In contrast, minocycline did not affect fear memory acquisition or declarative contingency memory. Our findings provide in-vivo evidence for the inhibition of fear memory consolidation by minocycline. This could motivate further research into primary prevention, and given the short uptake time of minocycline, potentially also secondary prevention of PTSD after trauma.

Psychometrics in experimental psychology: A case for calibration.

Psychometrics is historically grounded in the study of individual differences. Consequently, common metrics such as quantitative validity and reliability require between-person variance in a psychological variable to be meaningful. Experimental psychology, in contrast, deals with variance between treatments, and experiments often strive to minimise within-group person variance. In this article, I ask whether and how psychometric evaluation can be performed in experimental psychology. A commonly used strategy is to harness between-person variance in the treatment effect. Using simulated data, I show that this approach can be misleading when between-person variance is low, and in the face of methods variance. I argue that this situation is common in experimental psychology, because low between-person variance is desirable, and because methods variance is no more problematic in experimental settings than any other source of between-person variance. By relating validity and reliability with the corresponding concepts in measurement science outside psychology, I show how experiment-based calibration can serve to compare the psychometric quality of different measurement methods in experimental psychology.

Functional sophistication in human escape.

Animals including humans must cope with immediate threat and make rapid decisions to survive. Without much leeway for cognitive or motor errors, this poses a formidable computational problem. Utilizing fully immersive virtual reality with 13 natural threats, we examined escape decisions in N = 59 humans. We show that escape goals are dynamically updated according to environmental changes. The decision whether and when to escape depends on time-to-impact, threat identity and predicted trajectory, and stable personal characteristics. Its implementation appears to integrate secondary goals such as behavioral affordances. Perturbance experiments show that the underlying decision algorithm exhibits planning properties and can integrate novel actions. In contrast, rapid information-seeking and foraging-suppression are only partly devaluation-sensitive. Instead of being instinctive or hardwired stimulus-response patterns, human escape decisions integrate multiple variables in a flexible computational architecture. Taken together, we provide steps toward a computational model of how the human brain rapidly solves survival challenges.

Immersive VR for investigating threat avoidance: The VRthreat toolkit for Unity.

All animals have to respond to immediate threats in order to survive. In non-human animals, a diversity of sophisticated behaviours has been observed, but research in humans is hampered by ethical considerations. Here, we present a novel immersive VR toolkit for the Unity engine that allows assessing threat-related behaviour in single, semi-interactive, and semi-realistic threat encounters. The toolkit contains a suite of fully modelled naturalistic environments, interactive objects, animated threats, and scripted systems. These are arranged together by the researcher as a means of creating an experimental manipulation, to form a series of independent "episodes" in immersive VR. Several specifically designed tools aid the design of these episodes, including a system to allow for pre-sequencing the movement plans of animal threats. Episodes can be built with the assets included in the toolkit, but also easily extended with custom scripts, threats, and environments if required. During the experiments, the software stores behavioural, movement, and eye tracking data. With this software, we aim to facilitate the use of immersive VR in human threat avoidance research and thus to close a gap in the understanding of human behaviour under threat.

Acceleration of inferred neural responses to oddball targets in an individual with bilateral amygdala lesion compared to healthy controls.

Detecting unusual auditory stimuli is crucial for discovering potential threat. Locus coeruleus (LC), which coordinates attention, and amygdala, which is implicated in resource prioritization, both respond to deviant sounds. Evidence concerning their interaction, however, is sparse. Seeking to elucidate if human amygdala affects estimated LC activity during this process, we recorded pupillary responses during an auditory oddball and an illuminance change task, in a female with bilateral amygdala lesions (BG) and in n = 23 matched controls. Neural input in response to oddballs was estimated via pupil dilation, a reported proxy of LC activity, harnessing a linear-time invariant system and individual pupillary dilation response function (IRF) inferred from illuminance responses. While oddball recognition remained intact, estimated LC input for BG was compacted to an impulse rather than the prolonged waveform seen in healthy controls. This impulse had the earliest response mean and highest kurtosis in the sample. As a secondary finding, BG showed enhanced early pupillary constriction to darkness. These findings suggest that LC-amygdala communication is required to sustain LC activity in response to anomalous sounds. Our results provide further evidence for amygdala involvement in processing deviant sound targets, although it is not required for their behavioral recognition.

Measuring human context fear conditioning and retention after consolidation.

Fear conditioning is a laboratory paradigm commonly used to investigate aversive learning and memory. In context fear conditioning, a configuration of elemental cues (conditioned stimulus [CTX]) predicts an aversive event (unconditioned stimulus [US]). To quantify context fear acquisition in humans, previous work has used startle eyeblink responses (SEBRs), skin conductance responses (SCRs), and verbal reports, but different quantification methods have rarely been compared. Moreover, preclinical intervention studies mandate recall tests several days after acquisition, and it is unclear how to induce and measure context fear memory retention over such a time interval. First, we used a semi-immersive virtual reality paradigm. In two experiments (N = 23 and N = 28), we found successful declarative learning and memory retention over 7 d but no evidence of other conditioned responses. Next, we used a configural fear conditioning paradigm with five static room images as CTXs in two experiments (N = 29 and N = 24). Besides successful declarative learning and memory retention after 7 d, SCR and pupil dilation in response to CTX onset differentiated CTX+/CTX- during acquisition training, and SEBR and pupil dilation differentiated CTX+/CTX- during the recall test, with medium to large effect sizes for the most sensitive indices (SEBR: Hedge's g = 0.56 and g = 0.69; pupil dilation: Hedge's g = 0.99 and g = 0.88). Our results demonstrate that with a configural learning paradigm, context fear memory retention can be demonstrated over 7 d, and we provide robust and replicable measurement methods to this end.

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.

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory.

Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP)9 signaling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signaling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomized controlled trial with 101 (50 females) human participants. We find no impact of the drug in our preregistered analyses. Exploratory post hoc analyses of memory retention suggested a serum level-dependent effect of doxycycline on trace fear memory retention. However, effect size to distinguish CS+/CS- in the placebo group turned out to be smaller than in previously used delay fear conditioning protocols, which limits the power of statistical tests. Our results suggest that doxycycline effect on trace fear conditioning in healthy individuals is smaller and less robust than anticipated, potentially limiting its clinical application potential.

Experiment-based calibration in psychology: Optimal design considerations.

Psychological theories are often formulated at the level of latent, not directly observable, variables. Empirical measurement of latent variables ought to be valid. Classical psychometric validity indices can be difficult to apply in experimental contexts. A complementary validity index, termed retrodictive validity, is the correlation of theory-derived predicted scores with actually measured scores, in specifically designed calibration experiments. In the current note, I analyse how calibration experiments can be designed to maximise the information garnered and specifically, how to minimise the sample variance of retrodictive validity estimators. First, I harness asymptotic limits to analytically derive different distribution features that impact on estimator variance. Then, I numerically simulate various distributions with combinations of feature values. This allows deriving recommendations for the distribution of predicted values, and for resource investment, in calibration experiments. Finally, I highlight cases in which a misspecified theory is particularly problematic.

Asymmetric representation of aversive prediction errors in Pavlovian threat conditioning.

Survival in biological environments requires learning associations between predictive sensory cues and threatening outcomes. Such aversive learning may be implemented through reinforcement learning algorithms that are driven by the signed difference between expected and encountered outcomes, termed prediction errors (PEs). While PE-based learning is well established for reward learning, the role of putative PE signals in aversive learning is less clear. Here, we used functional magnetic resonance imaging in humans (21 healthy men and women) to investigate the neural representation of PEs during maintenance of learned aversive associations. Four visual cues, each with a different probability (0, 33, 66, 100%) of being followed by an aversive outcome (electric shock), were repeatedly presented to participants. We found that neural activity at omission (US-) but not occurrence of the aversive outcome (US+) encoded PEs in the medial prefrontal cortex. More expected omission of aversive outcome was associated with lower neural activity. No neural signals fulfilled axiomatic criteria, which specify necessary and sufficient components of PE signals, for signed PE representation in a whole-brain search or in a-priori regions of interest. Our results might suggest that, different from reward learning, aversive learning does not involve signed PE signals that are represented within the same brain region for all conditions.

Measuring human trace fear conditioning.

Trace fear conditioning is an important research paradigm to model aversive learning in biological or clinical scenarios, where predictors (conditioned stimuli, CS) and aversive outcomes (unconditioned stimuli, US) are separated in time. The optimal measurement of human trace fear conditioning, and in particular of memory retention after consolidation, is currently unclear. We conducted two identical experiments (N1  = 28, N2  = 28) with a 15-s trace interval and a recall test 1 week after acquisition, while recording several psychophysiological observables. In a calibration approach, we explored which learning and memory measures distinguished CS+ and CS- in the first experiment and confirmed the most sensitive measures in the second experiment. We found that in the recall test without reinforcement, only fear-potentiated startle but not skin conductance, pupil size, heart period, or respiration amplitude, differentiated CS+ and CS-. During acquisition without startle probes, skin conductance responses and pupil size responses but not heart period or respiration amplitude differentiated CS+ and CS-. As a side finding, there was no evidence for extinction of fear-potentiated startle over 30 trials without reinforcement. These results may be useful to inform future substantive research using human trace fear conditioning protocols.

Aversive conditioning: Principles of memory storage in sensory cortex.

Sensory cortices exhibit plasticity after aversive learning and may have a crucial role in memory storage. A human neuroimaging study has now addressed neural principles underlying olfactory disgust conditioning.

Inhibiting Human Aversive Memory by Transcranial Theta-Burst Stimulation to the Primary Sensory Cortex.

BACKGROUND: Predicting adverse events from past experience is fundamental for many biological organisms. However, some individuals suffer from maladaptive memories that impair behavioral control and well-being, e.g., after psychological trauma. Inhibiting the formation and maintenance of such memories would have high clinical relevance. Previous preclinical research has focused on systemically administered pharmacological interventions, which cannot be targeted to specific neural circuits in humans. Here, we investigated the potential of noninvasive neural stimulation on the human sensory cortex in inhibiting aversive memory in a laboratory threat conditioning model. METHODS: We build on an emerging nonhuman literature suggesting that primary sensory cortices may be crucially required for threat memory formation and consolidation. Immediately before conditioning innocuous somatosensory stimuli (conditioned stimuli [CS]) to aversive electric stimulation, healthy human participants received continuous theta-burst transcranial magnetic stimulation (cTBS) to individually localized primary somatosensory cortex in either the CS-contralateral (experimental) or CS-ipsilateral (control) hemisphere. We measured fear-potentiated startle to infer threat memory retention on the next day, as well as skin conductance and pupil size during learning. RESULTS: After overnight consolidation, threat memory was attenuated in the experimental group compared with the control cTBS group. There was no evidence that this differed between simple and complex CS or that CS identification or initial learning were affected by cTBS. CONCLUSIONS: Our results suggest that cTBS to the primary sensory cortex inhibits threat memory, likely by an impact on postlearning consolidation. We propose that noninvasive targeted stimulation of the sensory cortex may provide a new avenue for interfering with aversive memories in humans.

Current trends and opportunities in the methodology of electrodermal activity measurement.

Electrodermal activity (EDA) has been measured in the laboratory since the late 1800s. Although the influence of sudomotor nerve activity and the sympathetic nervous system on EDA is well established, the mechanisms underlying EDA signal generation are not completely understood. Owing to simplicity of instrumentation and modern electronics, these measurements have recently seen a transfer from the laboratory to wearable devices, sparking numerous novel applications while bringing along both challenges and new opportunities. In addition to developments in electronics and miniaturization, current trends in material technology and manufacturing have sparked innovations in electrode technologies, and trends in data science such as machine learning and sensor fusion are expanding the ways that measurement data can be processed and utilized. Although challenges remain for the quality of wearable EDA measurement, ongoing research and developments may shorten the quality gap between wearable EDA and standardized recordings in the laboratory. In this topical review, we provide an overview of the basics of EDA measurement, discuss the challenges and opportunities of wearable EDA, and review recent developments in instrumentation, material technology, signal processing, modeling and data science tools that may advance the field of EDA research and applications over the coming years.

Cross-species anxiety tests in psychiatry: pitfalls and promises.

Behavioural anxiety tests in non-human animals are used for anxiolytic drug discovery, and to investigate the neurobiology of threat avoidance. Over the past decade, several of them were translated to humans with three clinically relevant goals: to assess potential efficacy of candidate treatments in healthy humans; to develop diagnostic tests or biomarkers; and to elucidate the pathophysiology of anxiety disorders. In this review, we scrutinise these promises and compare seven anxiety tests that are validated across species: five approach-avoidance conflict tests, unpredictable shock anticipation, and the social intrusion test in children. Regarding the first goal, three tests appear suitable for anxiolytic drug screening in humans. However, they have not become part of the drug development pipeline and achieving this may require independent confirmation of predictive validity and cost-effectiveness. Secondly, two tests have shown potential to measure clinically relevant individual differences, but their psychometric properties, predictive value, and clinical applicability need to be clarified. Finally, cross-species research has not yet revealed new evidence that the physiology of healthy human behaviour in anxiety tests relates to the physiology of anxiety symptoms in patients. To summarise, cross-species anxiety tests could be rendered useful for drug screening and for development of diagnostic instruments. Using these tests for aetiology research in healthy humans or animals needs to be queried and may turn out to be unrealistic.

Social motives in a patient with bilateral selective amygdala lesions: Shift in prosocial motivation but not in social value orientation.

Humans hold social motives that are expressed in social preferences and influence how they evaluate and share payoffs. Established models in psychology and economics quantify social preferences such as general social value orientation, which captures people's tendency to be prosocial or individualistic. Prosocials further differ by how much they maximize joint gains or minimize inequality. Functional neuroimaging studies have linked increased amygdala activity in prosocials to payoff inequality between self and other. However, it is unclear whether amygdala lesions alter social motives. We used two tasks to test a patient with selective bilateral amygdala lesions and three healthy samples (a priori matched control sample N = 20, online sample N = 603, student sample N = 40), which allowed us to assess and model social motives across a relatively large number of participants. In a social value orientation task, the patient was categorized as prosocial and her social value orientation score did not differ from healthy participants. Importantly, the patient differed in prosocial motivation by maximizing joint gains rather than minimizing payoff inequality. In a joint payoff evaluation task, Bayesian model comparisons revealed that participants' evaluations were best described by models, which link participants' evaluations to the payoff magnitude and to inequality. Overall, amygdala lesions did not seem to alter general social value orientation but shifted prosocial motivation toward maximizing joint gains.