Fear-potentiated Startle Response Research Articles

Acupuncture for Combat-Related Posttraumatic Stress Disorder

Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD. To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes. This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols. Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions. The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models. A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low. The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted. ClinicalTrials.gov Identifier: NCT02869646.

Manipulating expectancy violations to strengthen the efficacy of human fear extinction

Recent theoretical and clinical articles have emphasized a role for expectancy violations in improving the effectiveness of exposure therapy. Expectancy violations are critical to extinction learning and strengthening these violations has been suggested to improve the formation and retention of extinction memories, which should result in lasting symptom reductions after treatment. However, more detailed mechanistic insights in this process are needed to better inform clinical interventions. In two separate fear-conditioning experiments, we investigated whether stronger expectancy violations (Exp1) or fostering awareness of expectancy violations (Exp2) during extinction could reduce the subsequent return of fear. We measured fear potentiated startle (FPS) and skin conductance responses (SCR) as physiological indices of fear, and US expectancy ratings to assess our manipulations. While we successfully created stronger expectancy violations in Exp1, we found no evidence that these stronger violations reduced the return of fear at test. Interestingly, fostering awareness of violations (Exp2) reduced differential SCRs, but not FPS responses. These findings provide novel insights into the effect of US expectancies on fear extinction in the lab, but they also illustrate the complexity of capturing clinically relevant processes of change with fear-conditioning studies.

Fear-potentiated startle reveals diminished threat extinction in pathological anxiety.

Major theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes. Youths and adults with anxiety disorders and healthy comparisons (n=306; 178 female participants; 8-50years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients. Patients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome. ITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

Facilitated extinction but impaired extinction recall by eye movement manipulation in humans – Indications for action mechanisms and the applicability of eye movement desensitization

Eye movement desensitization and reprocessing (EMDR) therapy utilizes the manipulation of eye movements to reduce affective distress during fear-exposure. Animal research recently suggested a potential neural mechanism underlying these effects, by which increased activity of the superior colliculus (SC), mediating visual attention, increases the inhibition of the basolateral amygdala (BLA), mediating defensive plasticity.We tested such mechanism in forty healthy humans using a multiple-day single-cue fear conditioning and extinction paradigm. The activity of the SC during extinction was experimentally manipulated by eye movements, as half of the participants executed saccadic eye movements (n = 20; major SC involvement), while the other half executed smooth eye pursuits (n = 20; minor SC involvement). Amygdala-mediated fear-potentiated startle responses and fear bradycardia, as well as threat expectancy was analyzed.Saccadic eye movements facilitated the extinction of fear bradycardia and fear-potentiated startle responses. Higher saccadic accuracy and range correlated with reduced fear-potentiated startle. However, during extinction recall, fear-potentiated startle and fear bradycardia resurged and partly reached levels obtained after fear acquisition. Threat expectancy was not affected by different eye movements and was not elevated during extinction recall.Within limitations, results support an inhibitory SC-BLA pathway in humans by which eye movements may reduce low-level defensive responding, but not threat expectancy. Yet, manipulating eye movements during extinction learning seems to impair extinction recall for behavioral and physiological defensive response indices. Thus, increasing SC activity might enhance initial efficacy of exposure treatment, but additional strategies seem necessary for sustained fear attenuation.

Childhood Maltreatment in Females Is Associated with Enhanced Fear Acquisition and an Overgeneralization of Fear.

Childhood maltreatment may alter fear neurocircuitry, which results in pathological anxiety and depression. One alteration of fear-related behaviors that has been observed in several psychiatric populations is an overgeneralization of fear. Thus, we examined the association between childhood maltreatment and fear generalization in a non-clinical sample of young adults. Two hundred and ninety-one participants underwent differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli (GS) without the presence of the US. Participants also completed questionnaires that assessed symptoms of childhood maltreatment, anxiety, depression, and post-traumatic stress disorder (PTSD). Participants reporting high childhood maltreatment (n = 71; 23 males, 48 females) exhibited significantly greater anxiety, depression, and symptoms of PTSD than participants reporting low childhood maltreatment (n = 220; 133 males, 87 females). Females reporting high childhood maltreatment demonstrated significantly enhanced fear learning and greater fear generalization, based on their fear-potentiated startle responses. Our findings suggest that childhood maltreatment may sex-dependently influence the development of fear neurocircuitry and result in greater fear generalization in maltreated females.

Ionic signalling mechanisms involved in neurokinin-3 receptor-mediated augmentation of fear-potentiated startle response in the basolateral amygdala.

The tachykinin peptides include substance P (SP), neurokinin A and neurokinin B, which interact with three G-protein-coupled neurokinin receptors, NK1Rs, NK2Rs and NK3Rs, respectively. Whereas high densities of NK3Rs have been detected in the basolateral amygdala (BLA), the functions of NK3Rs in this brain region have not been determined. We found that activation of NK3Rs by application of the selective agonist, senktide, persistently excited BLA principal neurons. NK3R-elicited excitation of BLA neurons was mediated by activation of a non-selective cation channel and depression of the inwardly rectifying K+ (Kir) channels. With selective channel blockers and knockout mice, we further showed that NK3R activation excited BLA neurons by depressing the G protein-activated inwardly rectifying K+ (GIRK) channels and activating TRPC4 and TRPC5 channels. The effects of NK3Rs required the functions of phospholipase Cβ (PLCβ), but were independent of intracellular Ca2+ release and protein kinase C. PLCβ-mediated depletion of phosphatidylinositol 4,5-bisphosphate was involved in NK3R-induced excitation of BLA neurons. Microinjection of senktide into the BLA of rats augmented fear-potentiated startle (FPS) and this effect was blocked by prior injection of the selective NK3R antagonist SB218795, suggesting that activation of NK3Rs in the BLA increased FPS. We further showed that TRPC4/5 and GIRK channels were involved in NK3R-elicited facilitation of FPS. Our results provide a cellular and molecular mechanism whereby NK3R activation excites BLA neurons and enhances FPS. KEY POINTS: Activation of NK3 receptors (NK3Rs) facilitates the excitability of principal neurons in rat basolateral amygdala (BLA). NK3R-induced excitation is mediated by inhibition of GIRK channels and activation of TRPC4/5 channels. Phospholipase Cβ and depletion of phosphatidylinositol 4,5-bisphosphate are necessary for NK3R-mediated excitation of BLA principal neurons. Activation of NK3Rs in the BLA facilitates fear-potentiated startle response. GIRK channels and TRPC4/5 channels are involved in NK3R-mediated augmentation of fear-potentiated startle.

Distinctive impacts of sexual trauma versus non-sexual trauma on PTSD profiles in highly trauma-exposed, Black women

BackgroundPrior findings suggest that psychopathology following interpersonal trauma or assaultive violence may present differently from prototypical posttraumatic stress disorder (PTSD). However, whether this is true for sexual trauma (ST) in the context of other salient lifetime traumatic experiences is yet unknown. We predicted that ST exposure may result in higher avoidance and numbing symptoms and blunted fear responses, relative to non-sexual trauma (NST), particularly if ST occurred during childhood. MethodsParticipants were n = 5163 Black women recruited in an urban public hospital. We investigated effects of ST on PTSD symptoms, fear-potentiated startle (FPS) response (n = 285), and amygdala reactivity and habituation to social threat cues with fMRI (n = 95). ResultsST was associated with greater PTSD symptoms (p = 2.64 × 10−21), but this was observed across all symptom clusters. Women who experienced repeated ST in both childhood and adulthood showed greater PTSD (p = .0009) and numbing symptoms (p = .002). In the FPS paradigm, the ST group startled more on all blocks and stimulus types than the NST group (p = .004). Developmental timing of ST did not influence startle magnitude. ST was not associated with amygdala habituation or reactivity. LimitationsGeneralizability is limited to Black women with a high trauma burden. Associations are cross-sectional, limiting causal conclusions. ConclusionWhile survivors of ST may present with more severe PTSD symptoms, their profiles are not characteristically different from similar NST controls. Childhood sexual abuse exposure alone did not result in a unique symptom profile. ST represents a uniquely high-burden stressor with likelihood for more severe posttraumatic outcomes.

Effects of Multisession Transcranial Direct Current Stimulation on Stress Regulation and Emotional Working Memory: A Randomized Controlled Trial in Healthy Military Personnel

ObjectivesTop-down stress regulation, important for military operational performance and mental health, involves emotional working memory and the dorsolateral prefrontal cortex (DLPFC). Multisession transcranial direct current stimulation (tDCS) applied over the DLPFC during working memory training has been shown to improve working memory performance. This study tested the hypothesis that combined tDCS with working memory training also improves top-down stress regulation. However, tDCS response differs between individuals. Resting-state electrophysiological brain activity was post hoc explored as a possible predictor of tDCS response. The predictive value of the ratio between slow-wave theta oscillations and fast-wave beta oscillations (theta/beta ratio) was examined, together with the previously identified tDCS response predictors age, education, and baseline working memory performance. Materials and MethodsHealthy military service members (n = 79) underwent three sessions of real or sham tDCS over the right DLPFC (anode: F4, cathode: behind C2) at 2 mA for 20 minutes during emotional working memory training (N-back task). At baseline and within a week after the tDCS training sessions, stress regulation was assessed by fear-potentiated startle responses and subjective fear in a threat-of-shock paradigm with instructed emotional downregulation. Results were analyzed in generalized linear mixed-effects models. ResultsThreat-of-shock responses and emotional working memory performance showed no significant group-level effects of the real vs sham tDCS training intervention (p > 0.07). In contrast, when considering baseline theta/beta ratios or the other tDCS response predictors, exploratory results showed a trait-dependent beneficial effect of tDCS on emotional working memory training performance during the first session (p < 0.01). ConclusionsNo evidence was found for effectivity of the tDCS training intervention to improve stress regulation in healthy military personnel. The emotional working memory training results emphasize the importance of studying the effects of tDCS in relation to individual differences. Clinical Trial RegistrationThis study was preregistered on September 16, 2019, at the Netherlands Trial Register (www.trialregister.nl) with ID: NL8028.

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

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

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.

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.

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)

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.

Differences in perceptual memory determine generalization patterns

Although memory of past experiences is crucial for the ability to transfer knowledge to new situations, surprisingly little research has directly investigated the relationship between memory and generalization. The present study sought to investigate how the perceptual memory of a trained stimulus influences generalization to similar stimuli. Forty participants underwent a fear conditioning procedure on Day 1, and separate memory recall and generalization tests on Day 2. We focused on two aspects of perceptual memory: namely memory bias (i.e., over- or underestimation of stimulus magnitude) and uncertainty. We found that memory bias predicted the pattern of generalized self-reported (expectancy ratings) and psychophysiological responses (fear-potentiated startle responses). Memory uncertainty was measured in two ways: self-reported uncertainty ratings and variability in stimulus recall. We found that higher levels of self-reported memory uncertainty corresponded with a broader generalization gradient on US expectancy, while greater variability in memory recall was associated with a broader generalization gradient on fear-potentiated startle responses. Taken together, our findings suggest that memory is an important determinant of generalized behavior and illustrate the need to account for these interindividual differences in perceptual memory when examining the generalization of learned responses.

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.

Effects of verbal instructions and physical threat removal prior to extinction training on the return of conditioned fear

Instructions given prior to extinction training facilitate the extinction of conditioned skin conductance (SCRs) and fear-potentiated startle responses (FPSs) and serve as laboratory models for cognitive interventions implemented in exposure-based treatments of pathological anxiety. Here, we investigated how instructions given prior to extinction training, with or without the additional removal of the electrode used to deliver the unconditioned stimulus (US), affect the return of fear assessed 24 hours later. We replicated previous instruction effects on extinction and added that the additional removal of the US electrode slightly enhanced facilitating effects on the extinction of conditioned FPSs. In contrast, extinction instructions hardly affected the return of conditioned fear responses. These findings suggest that instruction effects observed during extinction training do not extent to tests of return of fear 24 hours later which serve as laboratory models of relapse and improvement stability of exposure-based treatments.

Enhanced noradrenergic activity by yohimbine and differential fear conditioning in patients with major depression with and without adverse childhood experiences

Major depressive disorder (MDD) has been associated with changes in the biological stress systems, including the locus coeruleus-noradrenergic system. Accumulated evidence suggests an upregulation of central alpha2-receptors, leading to decreased noradrenergic activity on a central level in MDD patients. Adverse childhood experiences (ACE) such as physical or sexual abuse might contribute to those changes. Furthermore, noradrenaline can affect cognitive processes, e.g. learning and memory. Cognitive dysfunctions constitute an important symptom of MDD.We aimed to investigate the relationship of alpha2-receptor dysregulation with learning processes in MDD by conducting a differential fear conditioning paradigm after double-blind administration of the alpha2-receptor antagonist yohimbine versus placebo. To investigate the role of ACE systematically, we included four groups of healthy participants and MDD patients with and without ACE (MDD−/ACE−: N = 44, MDD−/ACE+: N = 26, MDD+/ACE−: N = 24, MDD+/ACE+: N = 24; without antidepressant medication).We found increased noradrenergic activity after yohimbine administration across groups as measured by alpha-amylase and blood pressure. Overall, fear responses were higher after yohimbine as indicated by skin conductance responses and fear-potentiated startle responses. While we found no significant MDD effect, ACE had significant impact on the ability to discriminate between both conditioned stimuli (CS+ predicting an aversive stimulus, CS- predicting none), depending on drug condition. After yohimbine, CS discrimination decreased in individuals without ACE, but not in individuals with ACE. Differences in the response to yohimbine might be explained by aberrant alpha2-receptor regulation in individuals with ACE. Impaired discrimination of threat and safety signals might contribute to enhanced vulnerability following ACE.

Men Scare Me More: Gender Differences in Social Fear Conditioning in Virtual Reality.

Women nearly twice as often develop social anxiety disorder (SAD) compared to men. The reason for this difference is still being debated. The present study investigates gender differences and the effect of male versus female agents in low (LSA) and high socially anxious (HSA) participants regarding the acquisition and extinction of social fear in virtual reality (VR). In a social fear conditioning (SFC) paradigm, 60 participants actively approached several agents, some of which were paired with an aversive unconditioned stimulus (US) consisting of a verbal rejection and spitting simulated by an aversive air blast (CS+), or without an US (CS−). Primary outcome variables were defined for each of the 4 levels of emotional reactions including experience (fear ratings), psychophysiology (fear-potentiated startle), behavior (avoidance), and cognition (recognition task). Secondary outcome variables were personality traits, contingency ratings, heart rate (HR), and skin conductance response (SCR). As hypothesized, fear ratings for CS+ increased significantly during acquisition and the differentiation between CS+ and CS− vanished during extinction. Additionally, women reported higher fear compared to men. Furthermore, a clear difference in the fear-potentiated startle response between male CS+ and CS− at the end of acquisition indicates successful SFC to male agents in both groups. Concerning behavior, results exhibited successful SFC in both groups and a general larger distance to agents in HSA than LSA participants. Furthermore, HSA women maintained a larger distance to male compared to female agents. No such differences were found for HSA men. Regarding recognition, participants responded with higher sensitivity to agent than object stimuli, suggesting a higher ability to distinguish the target from the distractor for social cues, which were on focus during SFC. Regarding the secondary physiological outcome variables, we detected an activation in HR response during acquisition, but there were no differences between stimuli or groups. Moreover, we observed a gender but no CS+/CS− differences in SCR. SFC was successfully induced and extinguished according to the primary outcome variables. VR is an interesting tool to measure emotional learning processes on different outcome levels with enhanced ecological validity. Future research should further investigate social fear learning mechanisms for developing more efficient treatments of SAD.

Autonomic responses to fear conditioning among women with PTSD and dissociation.

Individuals with posttraumatic stress disorder (PTSD) demonstrate alterations in autonomic responses to fear conditioning, such as exaggerated startle and poor fear inhibition. However, there is a paucity of research on fear conditioning among individuals with PTSD and dissociative symptoms, which represents 10-30% of those with PTSD. The current study used a fear-potentiated startle (FPS) conditioning paradigm to examine autonomic responses among women with PTSD and a range of dissociative symptoms. Participants included 39 women with PTSD and dissociation, and 53 women with PTSD with unknown levels of dissociation. The FPS paradigm consisted of conditioned stimuli associated and not associated with an aversive unconditioned stimulus. FPS response (eyeblink startle), electrocardiogram (ECG), and skin conductance response (SCR) were collected during the FPS paradigm. Compared to the PTSD-unknown dissociation sample, the PTSD-dissociation sample demonstrated significantly lower FPS during the last block of conditioning. Among the PTSD-dissociation sample, higher dissociation scores were associated with decreased FPS and SCR, and higher respiratory sinus arrhythmia (derived from ECG). Results suggest that autonomic responses to fear conditioning differ depending on the presence and severity of dissociative symptoms. Given that treatment response may differ depending on dissociative symptoms, it is important to understand the mechanisms that underlie different subtypes of PTSD and that may affect treatment response and outcome.