Fear-potentiated Startle Research Articles

The relationship of fear-potentiated startle and polysomnography-measured sleep in trauma-exposed men and women with and without PTSD: testing REM sleep effects and exploring the roles of an integrative measure of sleep, PTSD symptoms, and biological sex.

Published research indicates that sleep is involved in emotional information processing. Using a fear-potentiated startle (FPS) and nap sleep protocol, we examined the relationship of emotional learning with REM sleep (REMS) in trauma-exposed participants. We also explored the roles of posttraumatic stress disorder (PTSD) symptoms, biological sex, and an integrative measure of polysomnography-measured (PSG) sleep in the learning-sleep relationship. After an adaptation nap, participants (N = 46) completed two more visits (counterbalanced): a stress-condition visit, which included FPS conditioning procedures prior to a nap and assessment of learning retention and fear extinction training after the nap, and a control visit, which included a nap opportunity without stressful procedures. FPS conditioning included a "fear" visual stimulus paired with an air blast to the neck and a "safety" visual stimulus never paired with an air blast. Retention and extinction involved presentation of the visual stimuli without the air blast. Primary analyses examined the relationship between FPS responses pre- and post-sleep with stress-condition REMS duration, controlling for control-nap REMS duration. Higher safety learning predicted increased REMS and increased REMS predicted more rapid extinction learning. Similar relationships were observed with an integrative PSG sleep measure. They also showed unexpected effects of PTSD symptoms on learning and showed biological sex effects on learning-sleep relationships. Findings support evidence of a relationship between adaptive emotional learning and REMS. They underscore the importance of examining sex effects in sleep-learning relationships. They introduce an integrative PSG sleep measure with potential relevance to studies of sleep and subjective and biological outcomes.

Indoor or Outdoor? Generalization of Costly Pain-Related Avoidance Behavior to Conceptually Related Contexts

When pain persists beyond healing time and becomes a “false alarm” of bodily threat, protective strategies, such as avoidance, are no longer adaptive. More specifically, generalization of avoidance based on conceptual knowledge may contribute to chronic pain disability. Using an operant robotic-arm avoidance paradigm, healthy participants (N = 50), could perform more effortful movements in the threat context (eg, pictures of outdoor scenes) to avoid painful stimuli, whereas no pain occured in the safe context (eg, pictures of indoor scenes). Next, we investigated avoidance generalization to conceptually related contexts (ie, novel outdoor/indoor scenes). As expected, participants avoided more when presented with novel contexts conceptually related to the threat context than in novel exemplars of the safe context. Yet, exemplars belonging to one category (outdoor/indoor scenes) were not interchangeable; there was a generalization decrement. Posthoc analyses revealed that contingency-aware participants (n = 27), but not non-aware participants (n = 23), showed the avoidance generalization effect and also generalized their differential pain-expectancy and pain-related fear more to novel background scenes conceptually related to the original threat context. In contrast, the fear-potentiated startle response was not modulated by context. PerspectiveThis article provides evidence for contextual modulation of avoidance behavior and its generalization to novel exemplars of the learned categories based on conceptual relatedness. Our findings suggest that category-based generalization is a plausible mechanism explaining why patients display avoidance behavior in novel situations that were never directly associated with pain.

Secure attachment priming protects against relapse of fear in Young adults

Previous studies have shown that activating the attachment system attenuates fear learning. This study aimed to explore whether attachment priming can also impact on fear extinction processes, which underpin the management of anxiety disorders. In this study, 81 participants underwent a standard fear conditioning and extinction protocol on day 1 and returned 24 h later for an extinction recall and reinstatement test. Half the participants were primed to imagine their closest attachment figure prior to undergoing extinction training, while the other half were instructed to imagine a positive situation. Fear-potentiated startle and subjective expectancies of shock were measured as the primary indicators of fear. Attachment priming led to less relapse during the reinstatement test at the physiological but not subjective levels. These findings have translational potential to imply that activating awareness of attachment figures might augment long-term safety memories acquired in existing treatments to reduce relapse of fear.

Developmental Timing of Trauma in Women Predicts Unique Extracellular Vesicle Proteome Signatures

BackgroundExposure to traumatic events is a risk factor for negative physical and mental health outcomes. However, the underlying biological mechanisms that perpetuate these lasting effects are not known. MethodsWe investigated the impact and timing of sexual trauma, a specific type of interpersonal violence, experienced during key developmental windows of childhood, adolescence, or adulthood on adult health outcomes and associated biomarkers, including circulating cell-free mitochondrial DNA levels and extracellular vesicles (EVs), in a predominantly Black cohort of women (N = 101). ResultsSignificant changes in both biomarkers examined, circulating cell-free mitochondrial DNA levels and EV proteome, were specific to developmental timing of sexual trauma. Specifically, we identified a large number of keratin-related proteins from EVs unique to the adolescent sexual trauma group. Remarkably, the majority of these keratin proteins belong to a 17q21 gene cluster, which suggests a potential local epigenetic regulatory mechanism altered by adolescent trauma to impact keratinocyte EV secretion or its protein cargo. These results, along with changes in fear-potentiated startle and skin conductance detected in these women, suggest that sexual violence experienced during the specific developmental window of adolescence may involve unique programming of the skin, the body’s largest stress organ. ConclusionsTogether, these descriptive studies provide novel insight into distinct biological processes altered by trauma experienced during specific developmental windows. Future studies will be required to mechanistically link these biological processes to health outcomes.

Response to sertraline is associated with reduction in anxiety-potentiated startle in premenstrual dysphoric disorder.

Women with premenstrual dysphoric disorder (PMDD) appear to have altered central nervous system sensitivity to neuroactive steroid hormones, manifesting as affective symptoms and heightened arousal in the luteal phase of the menstrual cycle. In particular, women with PMDD appear less sensitive to allopregnanolone, a positive allosteric GABA-A receptor (GABA-A-R) modulator. This study evaluated psychophysiologic reactivity in women with PMDD in the follicular and luteal phases of the menstrual cycle, utilizing anxiety-potentiated startle (APS), a potential translational marker of GABA-A-R sensitivity. The study also assessed APS response to low-dose sertraline treatment in women with PMDD. Participants' APS and fear-potentiated startle (FPS) were assessed in the follicular and luteal phases. Women with PMDD received 50mg sertraline in the following luteal phase to examine impact on APS and FPS. There were no significant differences between controls (n = 41) and PMDD participants (n = 36) in change from follicular to luteal phases in baseline startle, APS nor FPS. However, among participants who responded to sertraline, APS was higher in the untreated luteal phase than the follicular phase, but lower in the treated luteal phase than the follicular phase. These data demonstrate elevated psychophysiologic arousal in the luteal phase among some women with PMDD, suggesting impaired ability to modulate arousal reactivity. Specifically, alterations in APS suggest potential GABA-A-R changes across the menstrual cycle and in response to sertraline among treatment responders.

Thalamic volume and fear extinction interact to predict acute posttraumatic stress severity

Posttraumatic stress disorder (PTSD) is associated with lower gray matter volume (GMV) in brain regions critical for extinction of learned threat. However, relationships among volume, extinction learning, and PTSD symptom development remain unclear. We investigated subcortical brain volumes in regions supporting extinction learning and fear-potentiated startle (FPS) to understand brain-behavior interactions that may impact PTSD symptom development in recently traumatized individuals. Participants (N = 99) completed magnetic resonance imaging and threat conditioning two weeks following trauma exposure as part of a multisite observational study to understand the neuropsychiatric effects of trauma (AURORA Study). Participants completed self-assessments of PTSD (PTSD Checklist for DSM-5; PCL-5), dissociation, and depression symptoms two- and eight-weeks post-trauma. We completed multiple regressions to investigate relationships between FPS during late extinction, GMV, and PTSD symptom development. The interaction between thalamic GMV and FPS during late extinction at two weeks post-trauma predicted PCL-5 scores eight weeks (t (75) = 2.49, β = 0.28, p = 0.015) post-trauma. Higher FPS predicted higher PCL-5 scores in the setting of increased thalamic GMV. Meanwhile, lower FPS also predicted higher PCL-5 scores in the setting of decreased thalamic GMV. Thalamic GMV and FPS interactions also predicted posttraumatic dissociative and depressive symptoms. Amygdala and hippocampus GMV by FPS interactions were not associated with posttraumatic symptom development. Taken together, thalamic GMV and FPS during late extinction interact to contribute to adverse posttraumatic neuropsychiatric outcomes. Multimodal assessments soon after trauma have the potential to distinguish key phenotypes vulnerable to posttraumatic neuropsychiatric outcomes.

Behavioral Expression of Contextual Fear in Male and Female Rats.

The study of fear conditioning has led to a better understanding of fear and anxiety-based disorders such as post-traumatic stress disorder (PTSD). Despite the fact many of these disorders are more common in women than in men, the vast majority of work investigating fear conditioning in rodents has been conducted in males. The goal of the work presented here was to better understand how biological sex affects contextual fear conditioning and expression. To this end, rats of both sexes were trained to fear a specific context and fear responses were measured upon re-exposure to the conditioning context. In the first experiment, male and female rats were given context fear conditioning and tested the next day during which freezing behavior was measured. In the second experiment, rats were trained and tested in a similar fashion while fear-potentiated startle and defecation were measured. We found that males showed more freezing behavior than females during a fear expression test. The expression of fear-potentiated startle did not differ between sexes, while males exhibited more defecation during a test in a novel context. These data suggest that the expression of defensive behavior differs between sexes and highlight the importance of using multiple measures of fear when comparing between sexes.

Effects of prediction error and acute stress on retrieval-extinction of fear memories of different strengths

<p id="p00005">Under the framework of Reconsolidation Interference of conditioned fear memory, Prediction Error (PE) has been demonstrated as a necessary condition of memory destabilization. However, the role of PE in destabilizing fear memories of different strengths is unclear. The degree of PE that is needed to effectively reactivate fear memories may be dependent on the strength of memory. It is unknown whether the PE used to reactivate weak memories is also effective in destabilizing stronger memories. Memory strength was proved to be an important boundary condition of memory reconsolidation; however, explorations of solutions to overcome the boundary are rare. Among factors that are possible to help to overcome the boundary condition, the effects of stress hormones are worth exploring. However, the manipulation of memory strength in human laboratory studies has not been well developed. Thus, the present study has three main aims: (1) to test the effect of fear memory strength in a human laboratory setting based on previous results in animal studies; (2) to examine the effect of PE during reactivation on destabilizing different strength memories and (3) to test the possible influence of post-reactivation exogenous stress to the retrieval-extinction of fear memories. <p id="p00010">These results indicate that PE used to destabilize weak memories is insufficient to destabilize strong memories; and that post-reactivation acute stress cannot nullify this deficit which is due to boundary conditions (e.g., strength). We discuss possible interpretations of these results and the implications for the translation of retrieval-extinction to clinical practice. <p id="p00015">The three days retrieval-extinction paradigm was adopted in the present study. We manipulated memory strength through two kinds of acquisition procedures on the first day, which varied the predictability of the unconditioned stimulus (US) occurrence after the conditioned stimulus (CS). Twenty-four hours later, a reminder containing a single PE was used to reactivate memories, which was followed by a stress task (Social Evaluate Cold Pressor test, SECPT) or not before extinction. After 24 hours, a test of spontaneous recovery and reinstatement was utilized to measure the return of fear in each condition. All participants were divided into three conditions: CS-Predictable US_no Stress Group, CS-Unpredictable US_no Stress Group and the CS-Unpredictable US_Stress Group. Skin conductance response (SCR) and fear-potentiated startle response (FPS) were used as measurements of conditioned fear. <p id="p00020">The results showed that there was a relatively stronger increase in fear response (SCR) from Day 1 to Day 2 in the CS-Unpredictable US condition than the CS-Predictable US condition, which may suggest a difference in memory strength between conditions. And for the weak fear memory (CS-predictable US), the reactivation that involved a single PE and was followed by extinction training prevented the spontaneous recovery, especially on the SCR measurement. On the other hand, in the enhanced memory condition (CS-unpredictable US), the extinguished memory returned in the memory test on the third day, which suggests a failure of memory destabilization. Furthermore, when the post-reactivation acute stress task was adopted in the enhanced memory condition, the return of fear further increased, compared with the no stress manipulation conditions.

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study

Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin's role in the regulation of anxiety and fear in humans. Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat). Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5-7-day wash-out period. Threat consisted of unpleasant electric shocks. The "NPU" threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle). As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle. As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

Secure attachment primes reduce fear consolidation.

Recent studies have found that attachment security primes can inhibit fear acquisition. This current study aimed to examine whether a brief imaginal prime of one's attachment figure could impact on fear consolidation. A total of 75 participants underwent fear conditioning on Day 1 and fear recall was tested on Day 2. Immediately following conditioning, half the participants were instructed to imagine an attachment figure while the other half imagined a nonattachment positive situation. Fear-potentiated startle and subjective expectancy of shock ratings were used as the measures of fear learning across trials. The attachment group showed significantly lower levels of fear recall on Day 2 at both physiological and subjective levels. Furthermore, this effect was moderated by attachment anxiety, such that it was greatest for individuals who were securely attached. These findings suggest that attachment relationships are protective during the consolidation of fear memories, and may have implications for how social attachments may impact how anxiety disorders can develop.

047 Fear-Potentiated Startle and Sleep in Trauma-Exposed Men and Women with and without PTSD

Abstract Introduction Animal and human studies indicate that fear conditioning disrupts subsequent sleep, including REM sleep (REMS). REMS is thought to be central to fear information processing. We utilized an afternoon nap protocol to examine the effects of fear-potentiated startle (FPS), a variant of fear conditioning, on subsequent sleep integrity and REMS in trauma-exposed participants with varying levels of PTSD. We also examined the effects of changes in sleep integrity and REMS on subsequent retention and extinction of pre-sleep learning. Methods Participants (N=47) participated in 3 nap visits. The first was an adaptation nap. The second and third nap visits were counterbalanced: a stress-condition nap, during which participants underwent FPS procedures prior to a nap and assessment of retention of fear and safety signal learning and fear extinction after the nap, and a control visit during which participants had a nap opportunity without stressful procedures. Canonical correlation analysis assessed the relationship between FPS responses and change in subsequent sleep relative to a control nap, as well as the relationship between change in sleep from control to stress condition and both subsequent fear and safety learning retention, and subsequent extinction. Results Results demonstrated a relationship between fear learning and change in sleep and supported a relationship between safety signal learning and subsequent REMS, as well as differential conditioning and wake after sleep onset. Sleep did not predict measures of fear retention or extinction. PTSD symptoms did not predict fear learning or sleep measures. Conclusion These findings replicate prior work showing a relationship between safety learning and REMS, suggesting that this is a core mechanism through which stress impacts fear processing. Further research is critical to further understand this effect, and to examine how different aspects of fear learning impact different components of sleep. This study also demonstrates that nap studies can be a valuable approach for studying the stress-sleep relationship. Support (if any) VA Career Development Award to Dr. Richards (5IK2CX000871-05)

Fear Potentiated Startle to Safety Cues is Related to Anxious Arousal in PTSD

The inability to inhibit fear is a hallmark of posttraumatic stress disorder (PTSD). Prior research has shown that hyperarousal symptoms of PTSD are related to greater fear-potentiated startle (FPS) to safe stimuli, particularly during the middle and late phases of fear acquisition. Factor analysis models of PTSD symptom structure have shown that hyperarousal symptoms can be separated into anxious and dysphoric arousal clusters. This study tested the hypothesis that anxious but not dysphoric arousal symptoms would be significantly related to FPS to safe stimuli (CS-) during middle and late fear acquisition.

Oxytocin Receptors Inhibit Output Neurons of the Bed Nucleus of the Stria Terminalis (BNST) and Promote Fear Responses to Predictable Threats

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear measured in the fear-potentiated startle. However, the mechanisms of these OT effects in the BNSTDL remain elusive.

Influence of estrous cycle stage on acquisition and expression of fear conditioning in female rats

It is unclear whether all animal models of anxiety-like states developed using males are appropriate for use in females. In females, tests involving a learning component might be influenced not only by estrous cycle stage on the test day but also by the stage during the conditioning process. We used two tests - conditioned freezing (CF) and fear potentiated startle (FPS) to compare responsiveness of male rats and females conditioned and/or tested in proestrus (P) or late diestrus (LD). For CF all rats displayed a similar freezing response regardless of sex or estrous cycle stage. In terms of FPS, males and females conditioned in P and tested in P or LD, and females conditioned in LD and tested in LD all showed potentiated startle. The response waned during the test session in males and in females conditioned in P, but not in those conditioned in LD. In contrast, FPS was not apparent in the first half of the test session in females conditioned in LD and tested in P but developed in the second half. We suggest that fear learning during P and LD is robust but may be initially be obscured in rats tested in P because of generalization to the CS due to high estrogen. Estrous cycle stage is an important consideration which must be taken into account in designing behavioural tests in females.

Destabilizing Different Strengths of Fear Memories Requires Different Degrees of Prediction Error During Retrieval.

Reactivation of consolidated memories can induce a labile period, in which these reactivated memories might be susceptible to change and need reconsolidation. Prediction error (PE) has been recognized as a necessary boundary condition for memory destabilization. Moreover, memory strength is also widely accepted as an essential boundary condition to destabilize fear memory. This study investigated whether different strengths of conditioned fear memories require different degrees of PE during memory reactivation in order for the memories to become destabilized. Here, we assessed the fear-potentiated startle and skin conductance response, using the post-retrieval extinction procedure. A violation of expectancy (PE) was induced during retrieval to reactivate enhanced (unpredictable-shock) or ordinary (predictable-shock) fear memories that were established the day before. Results showed that a PE retrieval before extinction can prevent the return of predictable-shock fear memory but cannot prevent the return of unpredictable-shock fear memory, indicating that a single PE is insufficient to destabilize enhanced fear memory. Therefore, we further investigated whether increasing the degree of PE could destabilize enhanced fear memory using different retrieval strategies (multiple PE retrieval and unreinforced CS retrieval). We found that spontaneous recovery of enhanced fear memory was prevented in both retrieval strategies, but reinstatement was only prevented in the multiple PE retrieval group, suggesting that a larger amount of PE is needed to destabilize enhanced fear memory. The findings suggest that behavioral updating during destabilization requires PE, and the degree of PE needed to induce memory destabilization during memory retrieval depends on the strength of fear memory. The study indicates that memory reconsolidation inference can be used to destabilize stronger memories, and the findings shed lights on the treatment of posttraumatic stress disorders and anxiety disorders.

RUNNING HEAD: CUE-COMPETITION IN FEAR POTENTIATED STARTLE CUE-COMPETITION IN FEAR POTENTIATED STARTLE CONDITIONING IN HUMANS

In two experiments of fear-potentiated startle, human participants were trained in a discrimination task, in which a stimulus A was paired with a wrist shock, while another stimulus, B, was not (A+B-). In a test, participants were assessed for startle by presenting an air-puff either alone or in the presence of the trained stimulus. In Experiment 1, evidence of discriminative learning was found in the form of a reliably greater startle to the air-puff in the presence of A than in the presence of B, and in the absence of any cue. In Experiment 2, after A+B- training (counterbalanced visual and vibrotactile cues), cues A and B were compounded with novel auditory cues X and Y and reinforced (AX+BY+), which is the standard design for cue-competition. In test, there was evidence of cue competition only in those participants in which A and B were the visual and vibrotactile cues, respectively. In this subgroup, responding in the presence of the redundant cue X was reliably lower than in the presence of Y, and not different from responding to the air-puff alone, indicating that X was blocked by A. We speculate that the absence of such an effect in the subgroup in which A was vibrotactile and B was visual might be due to some unexpected generalization between vibrotactile and auditory cues.

A legacy of fear: Physiological evidence for intergenerational effects of trauma exposure on fear and safety signal learning among African Americans

ObjectiveTo determine the influence of maternal trauma and posttraumatic stress disorder (PTSD) symptoms on children’s physiological response to threat and safety signals during a fear conditioning task in trauma-exposed mothers and children. MethodParticipants were African American mother-child dyads (N = 137; children aged 8–13 years). Mothers’ trauma history and PTSD symptoms were assessed; Latent Class Analysis (LCA) was conducted from these measures to identify distinct classes. Children reported violence exposure and completed a differential fear conditioning task using fear-potentiated startle (FPS) responses to conditioned danger (CS+) and safety (CS-) signals. ResultsFour classes of maternal trauma history and PTSD symptoms emerged: 1) Lower Trauma, 2) Moderate Trauma, 3) High Sexual Abuse, and 4) High Trauma and PTSD Symptoms. Children’s FPS to CS + and CS- were tested with maternal class as the between-subjects factor. FPS to the danger signal was not significantly different across maternal classes, but FPS to safety (CS-) was significantly higher for the Lower Trauma and High Trauma and PTSD Symptoms classes than either the Moderate Trauma or the High Sexual Abuse classes. ConclusionsResults indicate that maternal trauma impacts children’s ability to modulate fear responses in the presence of a safety signal, independent of the children’s own trauma exposure. To our knowledge, this is the first study to demonstrate that children’s fear inhibition is impacted by maternal trauma exposure. Prior studies have linked fear inhibition to mental health outcomes, highlighting the need to understand intergenerational modulation of fear learning and physiology.

Juvenile stress facilitates safety learning in male and female high alcohol preferring mice

Adversities during juvenility increase the risk for stress-related disorders, such as post-traumatic stress disorder (PTSD) and alcohol use disorder. However, stress can also induce coping mechanisms beneficial for later stressful experiences. We reported previously that mice selectively bred for high alcohol preference (HAP) exposed to stress during adolescence (but not during adulthood) showed enhanced fear-conditioned responses in adulthood, as measured by fear-potentiated startle (FPS). However, HAP mice also showed enhanced responding to safety cues predicting the absence of foot shocks in adulthood. Here, we pursue these findings in HAP mice by investigating in further detail how juvenile stress impacts the acquisition of safety and fear learning. HAP mice were subjected to three days of juvenile stress (postnatal days 25, 27, 28) and discriminative safety/fear conditioning in adulthood. FPS was used to assess safety versus fear cue discrimination, fear learning, and fear inhibition by the safety cue. Both stressed and unstressed HAP mice were able to discriminate between both cues as well as learn the fear cue-shock association. Interestingly, it was only the previously stressed mice that were able to inhibit their fear response when the fear cue was co-presented with the safety cue, thus demonstrating safety learning. We also report an incidental finding of alopecia in the juvenile stress groups, a phenotype seen in stress-related disorders. These results in HAP mice may be relevant to understanding the influence of juvenile trauma for individual risk and resilience toward developing PTSD and how individuals might benefit from safety cues in behavioral psychotherapy.

Puberty drives fear learning during adolescence.

Risk for adverse outcomes, including the onset of mental illness, increases during adolescence. This increase may be linked to both new exposures, such as violence at home or in the community, or to physiological changes driven by puberty. There are significant sex differences in adolescent risk, for instance, anxiety disorders are significantly more prevalent in girls than boys. Fear learning is linked to mental health and may develop during adolescence, but the role of puberty in adolescent-specific change has not yet been systematically evaluated. We conducted a longitudinal study of fear learning that tested fear-potentiated startle (FPS) in 78 children (40 girls) aged 8-16years. Participants completed two to three visits that included a differential fear conditioning task and self-report of both pubertal status and violence exposure. We tested for effects of sex, pubertal status, and violence exposure on FPS over time with latent growth curve models. We also examined the association between FPS and later anxiety symptoms. We found significant changes in FPS to the threat cue, but not the safety cue, across visits. Higher pubertal status was significantly associated with increased FPS to threat cues at each visit, whereas sex and violence exposure were not. FPS to threat during the baseline visit also predicted later anxiety symptoms. These findings suggest that puberty drives increased fear response to threat cues similarly for girls and boys, and that this effect may not be significantly impacted by individual differences in violence exposure during early adolescence.

An experimental investigation into the mediating role of pain-related fear in boosting nocebo hyperalgesia.

Nocebo hyperalgesia refers to increases in perceived pain that putatively result from negative expectations regarding a nocebo stimulus (eg, an inert treatment, compared with no treatment). The precise cognitive-emotional factors contributing to the origins of nocebo effects are poorly understood. We aimed to test the effects of experimentally induced pain-related fear on the acquisition and extinction of nocebo hyperalgesia in healthy participants (N = 72). Acquisition and extinction of nocebo hyperalgesia were compared between a group receiving standard nocebo conditioning (Control group) and 2 groups receiving distinct fear inductions: high intensity of pain stimulations (High-pain group) or a threat manipulation (High-threat group). During nocebo acquisition, the Control and High-threat groups were administered thermal pain stimulations of moderate intensity paired with sham electrical stimulation (nocebo trials), whereas high pain intensity was administered to the High-pain group. During extinction, equivalent pain intensities were administered across all trials. Pain-related fear was measured by eyeblink startle electromyography and self-report. Nocebo hyperalgesia occurred in all groups. Nocebo effects were significantly larger in the High-pain group than those in the Control group. This effect was mediated by self-reported fear, but not by fear-potentiated startle. Groups did not differ in the extinction rate. However, only the High-pain group maintained significant nocebo responses at the end of extinction. Anticipatory pain-related fear induced through a threat manipulation did not amplify nocebo hyperalgesia. These findings suggest that fear of high pain may be a key contributor to the amplification of nocebo hyperalgesia, only when high pain is experienced and not when it is merely anticipated.