Unpredictable threat increases early event-related potential amplitudes and cardiac acceleration: A brain-heart coupling study.

In the face of unpredictable threat, rapid processing of external events and behavioral mobilization through early psychophysiological responses are crucial for survival. While unpredictable threat generally enhances early processing, it would seem adaptive to particularly increase sensitivity for unexpected events as they may signal danger. To examine this possibility, n = 77 participants performed an auditory oddball paradigm and received unpredictable shocks in threat but not in safe contexts while a stream of frequent (standard) and infrequent (deviant) tones was presented. We assessed event-related potentials (ERP), heart period (HP), and time-lagged within-subject correlations of single-trial EEG and HP (cardio-EEG covariance tracing, CECT) time-locked to the tones. N1 and P2 ERP amplitudes were generally enhanced under threat. The P3 amplitude was enhanced to deviants versus standards and this effect was reduced in the threat condition. Regarding HP, both threat versus safe and unexpected versus expected tones led to stronger cardiac acceleration, suggesting separate effects of threat and stimulus expectancy on HP. Finally, CECTs revealed two correlation clusters, indicating that single-trial EEG magnitudes in the N1/P2 and P3 time-windows predicted subsequent cardiac acceleration. The current results show that an unpredictable threat context enhances N1 and P2 amplitudes and cardiac acceleration to benign auditory stimuli. They further suggest separable cortical correlates of different effects on cardiac activity: an early N1/P2 correlate associated with threat-effects on HP and a later P3 correlate associated with expectedness-effects. Finally, the results indicate that unpredictable threat attenuates rather than enhances the processing of unexpected benign events during the P3 latency.

The influence of psychological traits and prior experience on treatment expectations.

BACKGROUND: Placebo and nocebo responses are modulated by the treatment expectations of participants and patients. However, interindividual differences predicting treatment expectations and placebo responses are unclear. In this large-scale pooled analysis, we aim to investigate the influence of psychological traits and prior experiences on treatment expectations. METHODS: This paper analyses data from six different placebo studies (total n = 748). In all studies, participants' sociodemographic information, treatment expectations and prior treatment experiences and traits relating to stress, somatization, depression and anxiety, the Big Five and behavioral inhibition and approach tendencies were assessed using the same established questionnaires. Correlation coefficients and structural equation models were calculated to investigate the relationship between trait variables and expectations. RESULTS: We found small positive correlations between side effect expectations and improvement expectations (r = 0.187), perceived stress (r = 0.154), somatization (r = 0.115), agitation (r = 0.108), anhedonia (r = 0.118), and dysthymia (r = 0.118). In the structural equation model previous experiences emerged as the strongest predictors of improvement (ß = 0.32, p = .005), worsening (ß = -0.24, p = .005) and side effect expectations (ß = 0.47, p = .005). Traits related to positive affect (ß = - 0.09; p = .007) and negative affect (ß = 0.04; p = .014) were associated with side effect expectations. DISCUSSION: This study is the first large analysis to investigate the relationship between traits, prior experiences and treatment expectations. Exploratory analyses indicate that experiences of symptom improvement are associated with improvement and worsening expectations, while previous negative experiences are only related to side effect expectations. Additionally, a proneness to experience negative affect may be a predictor for side effect expectation and thus mediate the occurrence of nocebo responses.

Dissociable feedback valence effects on frontal midline theta during reward gain versus threat avoidance learning.

While frontal midline theta (FMθ) has been associated with threat processing, with cognitive control in the context of anxiety, and with reinforcement learning, most reinforcement learning studies on FMθ have used reward rather than threat-related stimuli as reinforcer. Accordingly, the role of FMθ in threat-related reinforcement learning is largely unknown. Here, n = 23 human participants underwent one reward-, and one punishment-, based reversal learning task, which differed only with regard to the kind of reinforcers that feedback was tied to (i.e., monetary gain vs. loud noise burst, respectively). In addition to single-trial EEG, we assessed single-trial feedback expectations based on both a reinforcement learning computational model and trial-by-trial subjective feedback expectation ratings. While participants' performance and feedback expectations were comparable between the reward and punishment tasks, FMθ was more reliably amplified to negative vs. positive feedback in the reward vs. punishment task. Regressions with feedback valence, computationally derived, and self-reported expectations as predictors and FMθ as criterion further revealed that trial-by-trial variations in FMθ specifically relate to reward-related feedback-valence and not to threat-related feedback or to violated expectations/prediction errors. These findings suggest that FMθ as measured in reinforcement learning tasks may be less sensitive to the processing of events with direct relevance for fear and anxiety.

The role of mindful acceptance and lucid dreaming in nightmare frequency and distress.

A theoretical and empirical association between lucid dreaming and mindfulness, as well as lucid dreaming and nightmares has previously been observed; however, the relationship between nightmares and mindfulness has received surprisingly little attention. Here, we present the findings of two studies exploring the relation of nightmare frequency and distress with two components of mindfulness, termed presence and acceptance, as well as lucid dreaming. Study 1 (N = 338) consisted of a low percentage of frequent lucid dreamers whereas Study 2 (N = 187) consisted primarily of frequent lucid dreamers that used lucid dream induction training techniques and meditation. Across studies, nightmare-related variables showed a more robust association with mindful acceptance as opposed to mindful presence. Moreover, individuals with high levels of meditation expertise and practice of lucid dreaming induction techniques reported lower nightmare frequency. Finally, in Study 2, which consisted of frequent lucid dreamers, a positive correlation between lucid dreaming frequency and mindfulness was apparent. The present findings support the notion that wakeful mindfulness is associated with the quality of dreams and extend previous research by suggesting a disentangled role of the two facets of mindfulness in dream variation. This association remains open for experimental manipulation, the result of which could have clinical implications.

Alpha-2 Adrenoreceptor Antagonist Yohimbine Potentiates Consolidation of Conditioned Fear.

BACKGROUND: Hyperconsolidation of aversive associations and poor extinction learning have been hypothesized to be crucial in the acquisition of pathological fear. Previous animal and human research points to the potential role of the catecholaminergic system, particularly noradrenaline and dopamine, in acquiring emotional memories. Here, we investigated in a between-participants design with 3 groups whether the noradrenergic alpha-2 adrenoreceptor antagonist yohimbine and the dopaminergic D2-receptor antagonist sulpiride modulate long-term fear conditioning and extinction in humans. METHODS: Fifty-five healthy male students were recruited. The final sample consisted of n = 51 participants who were explicitly aware of the contingencies between conditioned stimuli (CS) and unconditioned stimuli after fear acquisition. The participants were then randomly assigned to 1 of the 3 groups and received either yohimbine (10 mg, n = 17), sulpiride (200 mg, n = 16), or placebo (n = 18) between fear acquisition and extinction. Recall of conditioned (non-extinguished CS+ vs CS-) and extinguished fear (extinguished CS+ vs CS-) was assessed 1 day later, and a 64-channel electroencephalogram was recorded. RESULTS: The yohimbine group showed increased salivary alpha-amylase activity, confirming a successful manipulation of central noradrenergic release. Elevated fear-conditioned bradycardia and larger differential amplitudes of the N170 and late positive potential components in the event-related brain potential indicated that yohimbine treatment (compared with a placebo and sulpiride) enhanced fear recall during day 2. CONCLUSIONS: These results suggest that yohimbine potentiates cardiac and central electrophysiological signatures of fear memory consolidation. They thereby elucidate the key role of noradrenaline in strengthening the consolidation of conditioned fear associations, which may be a key mechanism in the etiology of fear-related disorders.

A Revised Framework for the Investigation of Expectation Update Versus Maintenance in the Context of Expectation Violations: The ViolEx 2.0 Model.

Expectations are probabilistic beliefs about the future that shape and influence our perception, affect, cognition, and behavior in many contexts. This makes expectations a highly relevant concept across basic and applied psychological disciplines. When expectations are confirmed or violated, individuals can respond by either updating or maintaining their prior expectations in light of the new evidence. Moreover, proactive and reactive behavior can change the probability with which individuals encounter expectation confirmations or violations. The investigation of predictors and mechanisms underlying expectation update and maintenance has been approached from many research perspectives. However, in many instances there has been little exchange between different research fields. To further advance research on expectations and expectation violations, collaborative efforts across different disciplines in psychology, cognitive (neuro)science, and other life sciences are warranted. For fostering and facilitating such efforts, we introduce the ViolEx 2.0 model, a revised framework for interdisciplinary research on cognitive and behavioral mechanisms of expectation update and maintenance in the context of expectation violations. To support different goals and stages in interdisciplinary exchange, the ViolEx 2.0 model features three model levels with varying degrees of specificity in order to address questions about the research synopsis, central concepts, or functional processes and relationships, respectively. The framework can be applied to different research fields and has high potential for guiding collaborative research efforts in expectation research.

Cardiac response in aversive and appetitive olfactory conditioning: Evidence for a valence-independent CS-elicited bradycardia.

While the examination of conditioned cardiac responses is well established in human fear conditioning research, comparable studies using less-aversive or rather appetitive unconditioned stimuli (UCS) are sparse and results are mixed. Therefore, the aim of this study was a systematic analysis of cardiac reactions in aversive and appetitive conditioning. Olfactory stimuli were used as unconditioned stimuli as they are suitable reinforcers in both an aversive and an appetitive conditioning offering the opportunity for a comparison between conditioned responses. In total, n = 86 participants took part in both an aversive and an appetitive differential conditioning task with a counterbalanced order across participants. Aversive or appetitive odors, respectively, served as UCS and neutral geometrical figures as CS. Subjective ratings, skin conductance response (SCRs), and evoked cardiac reactions were analyzed and compared between tasks. Conditioned responses in subjective ratings could be observed in both aversive conditioning and appetitive conditioning, while SCRs discriminated between CS+ and CS- in aversive conditioning only. Regarding conditioned cardiac responses, the deceleration for the CS+ was longer than for the CS- in both tasks. In addition, a higher deceleration magnitude and a shorter acceleration for the CS+ as compared to the CS- were found in aversive but not in appetitive conditioning. There were medium-size correlations between aversive and appetitive CRs for subjective ratings and none for physiological responses. The results suggest similarities between cardiac response patterns in aversive and appetitive conditioning, which implies that bradycardia in conditioning might not be fear-specific but presents a valence-independent CS-elicited bradycardia.

Serum midkine as non-invasive biomarker for detection and prognosis of non-small cell lung cancer.

Lung cancer continues to be the leading cause for cancer-related deaths in men and women worldwide. Sufficient screening tools enabling early diagnosis are essential to improve patient outcomes. The aim of this study was to evaluate serum midkine (S-MK) both as a diagnostic and prognostic biomarker in non-small cell lung cancer (NSCLC). This single-center analysis included 59 NSCLC patients counting 30 squamous cell cancers and 29 adenocarcinomas. Preoperative S-MK concentration was determined using ELISA. Patients were followed up to five years. S-MK was found to be significantly overexpressed in patients with NSCLC compared to healthy controls (p < 0.001). The discriminative power of S-MK to differentiate NSCLC subjects from controls was fairly high with an area under the receiver operating characteristic curve of 0.83 (p < 0.001). Optimal sensitivity of 92% and reasonable specificity of 68% was reached at a threshold of 416 pg/ml S-MK. Patients with high S-MK concentration showed a significantly shorter overall survival compared to patients with low S-MK expression (p < 0.05). In conclusion, S-MK is overexpressed in patients with NSCLC and serves as an independent prognostic factor for overall survival. S-MK may thus be considered as an additional non-invasive biomarker not only for NSCLC screening but also for outcome prediction.

Nightmare Distress Questionnaire: associated factors.

STUDY OBJECTIVES: The diagnosis of a nightmare disorder is based on clinically significant distress caused by the nightmares, eg, sleep or mood disturbances during the day. The question what factors might be associated with nightmare distress in addition to nightmares frequency is not well studied. METHODS: Overall, 1,474 persons (893 women, 581 men) completed an online survey. Nightmare distress was measured with the Nightmare Distress Questionnaire. RESULTS: The findings indicated that nightmare distress, measured by the Nightmare Distress Questionnaire, correlated with a variety of factors in addition to nightmare frequency: neuroticism, female sex, low education, extraversion, low agreeableness, and sensation seeking. Moreover, the percentage of replicative trauma-related nightmares was also associated with higher nightmare distress. CONCLUSIONS: A large variety of factors are associated with nightmare distress, a finding that is of clinical importance. The construct harm avoidance, however, was not helpful in explaining interindividual differences in nightmare distress. Furthermore, the relationship between nightmare distress and other factors, eg, education or agreeableness, is not yet understood.

Learning dynamics of electrophysiological brain signals during human fear conditioning.

Electrophysiological studies in rodents allow recording neural activity during threats with high temporal and spatial precision. Although fMRI has helped translate insights about the anatomy of underlying brain circuits to humans, the temporal dynamics of neural fear processes remain opaque and require EEG. To date, studies on electrophysiological brain signals in humans have helped to elucidate underlying perceptual and attentional processes, but have widely ignored how fear memory traces evolve over time. The low signal-to-noise ratio of EEG demands aggregations across high numbers of trials, which will wash out transient neurobiological processes that are induced by learning and prone to habituation. Here, our goal was to unravel the plasticity and temporal emergence of EEG responses during fear conditioning. To this end, we developed a new sequential-set fear conditioning paradigm that comprises three successive acquisition and extinction phases, each with a novel CS+/CS- set. Each set consists of two different neutral faces on different background colors which serve as CS+ and CS-, respectively. Thereby, this design provides sufficient trials for EEG analyses while tripling the relative amount of trials that tap into more transient neurobiological processes. Consistent with prior studies on ERP components, data-driven topographic EEG analyses revealed that ERP amplitudes were potentiated during time periods from 33-60 ms, 108-200 ms, and 468-820 ms indicating that fear conditioning prioritizes early sensory processing in the brain, but also facilitates neural responding during later attentional and evaluative stages. Importantly, averaging across the three CS+/CS- sets allowed us to probe the temporal evolution of neural processes: Responses during each of the three time windows gradually increased from early to late fear conditioning, while long-latency (460-730 ms) electrocortical responses diminished throughout fear extinction. Our novel paradigm demonstrates how short-, mid-, and long-latency EEG responses change during fear conditioning and extinction, findings that enlighten the learning curve of neurophysiological responses to threat in humans.

Analyzing Targeted Violence Against Medical Workers and EVD Incidence in the 2018-19 Democratic Republic of the Congo Outbreak Using Vector Autoregression and Granger Causality.

The purpose of this study was to evaluate the relationship between violent events targeted against aid workers and the incidence of Ebola virus disease (EVD) during the 2018-19 Democratic Republic of the Congo (DRC) outbreak in the North Kivu and Ituri provinces. Time series models using vector autoregression were constructed using violent event data confined to the outbreak region from the Armed Conflict Location and Event Dataset (ACLED), in combination with EVD incidence reporting from the World Health Organization and DRC Ministry of Health, to examine intervariable temporal relationships, paired with Granger causality testing to assess both uni- and multidirectional associations. Violent events against aid workers and Granger-causing EVD incidence were found to be significant across 2 principal lag-ranges, 8 to 14 days and 22 to 29 days, both suggesting plausible causal associations. The multivariate model for violent events and violence-related fatalities Granger-causing EVD incidence was also found to be significant at lags greater than 9, reinforcing the plausible causal association. Findings from the study suggested that the relationship between targeted violence and EVD incidence may be explained etiologically, as significant lag-ranges corresponded to plausible patient presentation timeframes, based on the incubation period for EVD. Additionally, the findings may also be explained through impact on operations, when events targeting facilities, supply lines, and personnel affect treatment capability.

Extinction-resistant attention to long-term conditioned threat is indexed by selective visuocortical alpha suppression in humans.

Previous electrophysiological studies in humans have shown rapid modulations of visual attention after conditioned threat vs. safety cues (<500 ms post-stimulus), but it is unknown whether this attentional prioritization is sustained throughout later time windows and whether it is robust to extinction. To investigate sustained visual attention, we assessed visuocortical alpha suppression in response to conditioned and extinguished threat. We reanalysed data from N = 87 male participants that had shown successful long-term threat conditioning and extinction in self reports and physiological measures in a two-day conditioning paradigm. The current EEG time-frequency analyses on recall test data on Day 2 revealed that previously threat-conditioned vs. safety cues evoked stronger occipital alpha power suppression from 600 to 1200 ms. Notably, this suppression was resistant to previous extinction. The present study showed for the first time that threat conditioning enhances sustained modulation of visuocortical attention to threat in the long term. Long-term stability and extinction resistance of alpha suppression suggest a crucial role of visuocortical attention mechanisms in the maintenance of learned fears.

Aversive Imagery Causes De Novo Fear Conditioning.

In classical fear conditioning, neutral conditioned stimuli that have been paired with aversive physical unconditioned stimuli eventually trigger fear responses. Here, we tested whether aversive mental images systematically paired with a conditioned stimulus also cause de novo fear learning in the absence of any external aversive stimulation. In two experiments (N = 45 and N = 41), participants were first trained to produce aversive, neutral, or no imagery in response to three different visual-imagery cues. In a subsequent imagery-based differential-conditioning paradigm, each of the three cues systematically coterminated with one of three different neutral faces. Although the face that was paired with the aversive-imagery cue was never paired with aversive external stimuli or threat-related instructions, participants rated it as more arousing, unpleasant, and threatening and displayed relative fear bradycardia and fear-potentiated startle. These results could be relevant for the development of fear and related disorders without trauma.

Oxytocin reduces the link between neural and affective responses after social exclusion.

Being socially excluded triggers negative emotional and behavioral reactions. We examined the influence of oxytocin on the processing of social exclusion. To this end, intranasal oxytocin or placebo were administered in a double-blind trial to 90 females while neurophysiological and emotional reactions to exclusion in a Cyberball game were assessed. In the placebo group a positive correlation was found between self-reports of rejection and late positive potential (LPP) amplitude when being omitted in the game. This correlation was absent in the oxytocin group. No main effects of oxytocin on the self-reports of rejection or the LPP in exclusion trials were found. The hypothesis that oxytocin exacerbates feeling rejected after social exclusion via enhancing the salience of social cues could not be confirmed. However, our results show that the link between neural and affective reactions to social exclusion is eliminated by oxytocin. This mechanism might explain how oxytocin enacts its multiple influences on behavior.

Fear Extinction Recall Modulates Human Frontomedial Theta and Amygdala Activity.

Human functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) studies, as well as animal studies, indicate that the amygdala and frontomedial brain regions are critically involved in conditioned fear and that frontomedial oscillations in the theta range (4-8 Hz) may support communication between these brain regions. However, few studies have used a multimodal approach to probe interactions among these key regions in humans. Here, our goal was to bridge the gap between prior human fMRI, EEG, and animal findings. Using simultaneous EEG-fMRI recordings 24 h after fear conditioning and extinction, conditioned stimuli presented (CS+E, CS-E) and not presented during extinction (CS+N, CS-N) were compared to identify effects specific to extinction versus fear recall. Differential (CS+ vs. CS-) electrodermal, frontomedial theta (EEG) and amygdala responses (fMRI) were reduced for extinguished versus nonextinguished stimuli. Importantly, effects on theta power covaried with effects on amygdala activation. Fear and extinction recall as indicated by theta explained 60% of the variance for the analogous effect in the right amygdala. Our findings show for the first time the interplay of amygdala and frontomedial theta activity during fear and extinction recall in humans and provide insight into neural circuits consistently linked with top-down amygdala modulation in rodents.

Threat-conditioned contexts modulate the late positive potential to faces-A mobile EEG/virtual reality study.

In everyday life, the motivational value of faces is bound to the contexts in which faces are perceived. Electrophysiological studies have demonstrated that inherent negatively valent contexts modulate cortical face processing as assessed with ERP components. However, it is not well understood whether learned (rather than inherent) and three-dimensional aversive contexts similarly modulate the neural processing of faces. Using full immersive virtual reality (VR) and mobile EEG techniques, 25 participants underwent a differential fear conditioning paradigm, in which one virtual room was paired with an aversive noise burst (threat context) and another with a nonaversive noise burst (safe context). Subsequently, avatars with neutral or angry facial expressions were presented in the threat and safe contexts while EEG was recorded. Analysis of the late positive potential (LPP), which presumably indicates motivational salience, revealed a significant interaction of context (threat vs. safe) and face type (neutral vs. angry). Neutral faces evoked increased LPP amplitudes in threat versus safe contexts, while angry faces evoked increased early LPP amplitudes regardless of context. In addition to indicating that threat-conditioned contexts alter the processing of ambiguous faces, the present study demonstrates the successful integration of EEG and VR with particular relevance for affective neuroscience research.

Fearfulness, neuroticism/anxiety, and COMT Val158Met in long-term fear conditioning and extinction.

Individual differences in long-term stability of fear memories are of potential relevance for stable dispositions related to threat processing, such as neuroticism/anxiety and fearfulness. As previous research suggests a prominent role of dopamine for the retention of conditioned and extinguished fear, dopaminergic gene polymorphisms may also relate to individual differences in fear stability. While the COMT Val158Met polymorphism causes individual differences in prefrontal dopamine, its associations with human long-term fear extinction are currently unknown. Here, n = 30/29/28 healthy male Val/Val, Val/Met and Met/Met carriers, respectively, underwent a two-day differential conditioning paradigm with fear acquisition and extinction on Day 1 and a recall test on Day 2 with recordings of EEG and ECG. Fearfulness but not neuroticism/anxiety predicted fear bradycardia (i.e., heart period slowing) during Day 1 fear acquisition while it did not affect extinction or Day 2 fear recall. In contrast, COMT Val158Met significantly modulated Day 2 fear recall as evident in fear bradycardia and Late Positive Potential (LPP) amplitudes while it did not affect Day 1 fear or extinction learning. Furthermore, exploratory analyses revealed that individual differences in fear bradycardia during Day 2 extinction recall depended on Day 1 extinction success. Importantly, this contingency was (a) modulated by COMT Val158Met and (b) significantly reduced in high vs. low neuroticism/anxiety. The present study indicates that (a) individual differences in dopaminergic genotypes may affect the long-term stability of fear memories and (b) fearfulness vs. neuroticism/anxiety might play distinct roles in initial fear reactions vs. long-term stability of fear memories, respectively.

Reliability and robustness of feedback-evoked brain-heart coupling after placebo, dopamine, and noradrenaline challenge.

External and internal performance feedback triggers not only neural but also cardiac modulations, suggesting communication between brain and heart during feedback processing. Using Cardio-Electroencephalographic Covariance Tracing (CECT), it has accordingly been shown that feedback-evoked centromedial single-trial EEG at the P300 latency intraindividually predicts subsequent changes in heart period - the so called N300H phenomenon. While previous findings suggest that the N300H depends on serotonin, its relationship to central dopamine and noradrenaline is currently unknown. Here, we tested (1) the psychometric properties of this CECT-based component and (2) its putative catecholaminergic mechanisms. N = 54 healthy male participants received either a α2-adrenoceptor antagonist (yohimbine, 10 mg; n = 18), D2-dopamine-receptor antagonist (sulpiride, 200 mg; n = 18), or a placebo (n = 18). Afterwards, they performed a gambling task with feedback after each trial, while EEG and ECG were recorded. Feedback successfully evoked a significant N300H both across all 54 participants and within each substance group. Importantly, we show that N300H can be reliably measured in a priori defined time windows with as few as 240 feedback trials and is relatively unaffected when removing extreme single-trial values. However, we could not find any significant substance effects on N300H magnitude as well as on univariate feedback-related measures (FRN, P300, heart period). Altogether, the N300H component proves as a robust and reliable marker of cortico-cardiac coupling evoked by feedback. Furthermore, these findings suggest a subordinate role of catecholamines (i.e., noradrenaline and dopamine) and sympathetic pathways in feedback-evoked brain-heart communication as measured with N300H.

Self-relevant threat contexts enhance early processing of fear-conditioned faces.

Anxiety states are characterized by attentional biases to threat and increased early brain responses to potentially threat signaling stimuli. How such stimuli are processed further depends on prior learning experiences (e.g. conditioning and extinction) and the context in which a stimulus appears. Whether context information and prior learning experiences interact with early threat processing in humans is largely unknown. Here, EEG was recorded while healthy participants (N=20) viewed faces that were fear-conditioned and/or extinguished 24h before. Faces were either passively viewed or presented within different contexts, which were created by describing scenarios that could either involve participants directly (self-threatening), or made them observers (other-threatening) of a potentially dangerous situation. Early brain responses (i.e., P1 amplitudes) were specifically enhanced during the self-threatening condition in response to non-extinguished versus extinguished fear-conditioned faces. This finding suggests that top-down contextual information is incorporated into early attention modulation of previously learned threat signals.

A pragmatic comparison of noise burst and electric shock unconditioned stimuli for fear conditioning research with many trials.

Several methods that are promising for studying the neurophysiology of fear conditioning (e.g., EEG, MEG) require a high number of trials to achieve an adequate signal-to-noise ratio. While electric shock and white noise burst are among the most commonly used unconditioned stimuli (US) in conventional fear conditioning studies with few trials, it is unknown whether these stimuli are equally well suited for paradigms with many trials. Here, N = 32 participants underwent a 260-trial differential fear conditioning and extinction paradigm with a 240-trial recall test 24 h later and neutral faces as conditioned stimuli. In a between-subjects design, either white noise bursts (n = 16) or electric shocks (n = 16) served as US, and intensities were determined using the most common procedure for each US (i.e., a fixed 95 dB noise burst and a work-up procedure for electric shocks, respectively). In addition to differing US types, groups also differed in closely linked US-associated characteristics (e.g., calibration methods, stimulus intensities, timing). Subjective ratings (arousal/valence), skin conductance, and evoked heart period changes (i.e., fear bradycardia) indicated more reliable, extinction-resistant, and stable conditioning in the white noise burst versus electric shock group. In fear conditioning experiments where many trials are presented, white noise burst should serve as US.