Far from the threatening crowd: Generalisation of conditioned threat expectancy and fear in COVID-19 lockdown.

Fear and anxiety are rarely confined to specific stimuli or situations. In fear generalisation, there is a spread of fear responses elicited by physically dissimilar generalisation stimuli (GS) along a continuum between danger and safety. The current study investigated fear generalisation with a novel online task using COVID-19-relevant stimuli (i.e., busy or quiet shopping street/mall scenes) during pandemic lockdown restrictions in the United Kingdom. Participants (N = 50) first completed clinically relevant trait measures before commencing a habituation phase, where two conditioned stimuli (CSs; i.e., a busy or quiet high street/mall scene) were presented. Participants then underwent fear conditioning where one conditioned stimulus (CS+) was followed by an aversive unconditioned stimulus (US; a loud female scream accompanied by a facial photograph of a female displaying a fearful emotion) and another (CS-) was not. In a test phase, six generalisation stimuli were presented where the US was withheld, and participants provided threat expectancy and fear ratings for all stimuli. Following successful conditioning, fear generalization was observed for both threat expectancy and fear ratings. Trait worry partially predicted generalised threat expectancy and COVID-19 fear strongly predicted generalised fear. In conclusion, a generalisation gradient was evident using an online remote generalisation task with images of busy/quiet streets during the pandemic. Worry and fear of COVID-19 predicted fear generalisation.

Cannabinoid polymorphisms interact with plasma endocannabinoid levels to predict fear extinction learning.

BACKGROUND: The endocannabinoid system is gaining increasing attention as a favorable target for improving posttraumatic stress disorder (PTSD) treatments. Exposure therapy is the gold-standard treatment for PTSD, and fear extinction learning is a key concept underlying successful exposure. METHODS: This study examined the role of genetic endocannabinoid polymorphisms in a fear extinction paradigm with PTSD compared to healthy participants (N = 220). Participants provided saliva for genotyping, completed a fear conditioning and extinction task, with blood samples taken before and after the task (n = 57). Skin conductance was the outcome and was analyzed using mixed models. RESULTS: Results for cannabinoid receptor type 1 polymorphisms suggested that minor alleles of rs2180619 and rs1049353 were associated with poorer extinction learning in PTSD participants. The minor allele of the fatty acid amide hydrolase (FAAH) polymorphism rs324420 was associated with worse extinction in PTSD participants. Subanalysis of healthy participants (n = 57) showed the FAAH rs324420 genotype effect was dependent on plasma arachidonoyl ethanolamide (AEA) level, but not oleoylethanolamide or 2-arachidonoyl glycerol. Specifically, higher but not lower AEA levels in conjunction with the minor allele of FAAH rs324420 were associated with better extinction learning. CONCLUSIONS: These findings provide translational evidence that cannabinoid receptor 1 and AEA are involved in extinction learning in humans. FAAH rs324420's effect on fear extinction is moderated by AEA plasma level in healthy controls. These findings imply that FAAH inhibitors may be effective for targeting anxiety in PTSD, but this effect needs to be explored further in clinical populations.

The Effect of Self-Reported REM Behavior Disorder Symptomology on Intrusive Memories in Post-Traumatic Stress Disorder.

Background: PTSD is characterised by severe sleep disturbances, which is increasingly recognised to in many cases consist of similar symptomology to sleep disorders such as REM Behaviour Disorder (RBD). The present study aimed to investigate whether different aspects of sleep quality influence intrusive memory development and whether PTSD status moderates this relationship. Participants and Methods: 34 PTSD, 52 trauma-exposed (TE) and 42 non-trauma exposed (NTE) participants completed an emotional memory task, where they viewed 60 images (20 positive, 20 negative and 20 neutral) and, two days later, reported how many intrusive memories they had of each valence category. Participants also completed three measures of sleep quality: the Pittsburgh Sleep Quality Index, the REM Behaviour Disorder Screening Questionnaire and total hours slept before each session. Results: The PTSD group reported poorer sleep quality than both TE and NTE groups on all three measures, and significantly more negative intrusive memories than the NTE group. Mediation analyses revealed that self-reported RBD symptomology before the second session mediated the relationship between PTSD status and intrusive memories. Follow-up moderation analyses revealed that self-reported RBD symptomology before the second session was only a significant predictor of intrusion in the PTSD group, though with a small effect size. Conclusions: These findings suggest that RBD symptomology is an indicator of consolidation of intrusive memories in PTSD but not trauma-exposed or healthy participants, which supports the relevance of characterising RBD in PTSD.

Neural activity and emotional processing following military deployment: Effects of mild traumatic brain injury and posttraumatic stress disorder.

Posttraumatic Stress Disorder (PTSD) and mild traumatic brain injury (mTBI) are common comorbidities during military deployment that affect emotional brain processing, yet few studies have examined the independent effects of mTBI and PTSD. The purpose of this study was to examine distinct differences in neural responses to emotional faces in mTBI and PTSD. Twenty-one soldiers reporting high PTSD symptoms were compared to 21 soldiers with low symptoms, and 16 soldiers who reported mTBI-consistent injury and symptoms were compared with 16 soldiers who did not sustain an mTBI. Participants viewed emotional face expressions while their neural activity was recorded (via event-related potentials) prior to and following deployment. The high-PTSD group displayed increased P1 and P2 amplitudes to threatening faces at post-deployment compared to the low-PTSD group. In contrast, the mTBI group displayed reduced face-specific processing (N170 amplitude) to all facial expressions compared to the no-mTBI group. Here, we identified distinctive neural patterns of emotional face processing, with attentional biases towards threatening faces in PTSD, and reduced emotional face processing in mTBI.

IMPAIRED FEAR EXTINCTION ASSOCIATED WITH PTSD INCREASES WITH HOURS-SINCE-WAKING.

BACKGROUND: Prior research has demonstrated that time-of-day may play an important role in the extinction of conditioned fear, with extinction better learned earlier in the day rather than later. Impaired fear extinction memory is widely considered a key mechanism of posttraumatic stress disorder (PTSD). The relationship between fear extinction and PTSD symptoms may be moderated by hours-since-waking. METHOD: In the present experiment, we examined whether hours-since-waking would moderate fear extinction learning ability in a clinical PTSD sample (n = 15), compared to trauma-exposed (n = 33) and nonexposed controls (n = 22). Participants completed a standardized differential fear conditioning and extinction paradigm, providing skin conductance response measures to quantify conditioned responding. RESULTS: Mixed-model analysis of variance revealed a PTSD-specific impairment in extinction learning ability in the late extinction phase. A moderation analysis showed that hours-since-waking was a significant moderator of the relationship between impaired late extinction and PTSD symptoms. Specifically, we found that participants with higher PTSD symptoms demonstrated poorer fear extinction learning ability as they were awake for longer. CONCLUSIONS: The results of the current study add to a growing literature indicating deficits in fear extinction learning in PTSD samples, compared to trauma-exposed and nonexposed controls. These results support previous findings that fear extinction is impaired later in the day, and extends this to a clinical sample, suggesting that exposure-therapy may be optimized by scheduling sessions in the morning.

Online counterconditioning with COVID-19-relevant stimuli in lockdown: Impact on threat expectancy, fear, and persistent avoidance.

BACKGROUND AND OBJECTIVES: In counterconditioning, a conditioned aversive stimulus (CS) is paired with an appetitive stimulus to reduce fear and avoidance. Findings are, however, mixed on the relative impact of counterconditioning versus standard extinction, where the CS is presented in the absence of the aversive event. This analogue treatment study investigated the impact of counterconditioning relative to standard extinction on threat expectancy, fear, and persistent avoidance with an online fear-conditioning task conducted with COVID-19-relevant appetitive stimuli during the pandemic. METHODS: Following habituation, in which two CSs (male faces wearing face-coverings) were presented in the absence of the unconditioned stimulus (US; a loud female scream), participants (n = 123) underwent threat-conditioning where one stimulus (CS+) was followed by the US and another (CS-) was not. In avoidance learning, the US could be prevented by making a simple response in the presence of the CS+. Next, participants received either counterconditioning in which trial-unique positively rated images of scenes from before the COVID-19 pandemic and its associated restrictions (e.g., hugging others and holding hands) were presented with the CS + or no-counterconditioning (i.e., extinction). In the final test phase, avoidance was available, and all US deliveries were withheld. RESULTS: Counterconditioning led to diminished threat expectancy and reduced avoidance relative to no-counterconditioning. Fear ratings did not differ between groups. LIMITATIONS: No physiological measures were obtained. CONCLUSIONS: Implemented online during the pandemic with COVID-19-relevant appetitive stimuli, counterconditioning was effective at reducing persistent avoidance and threat expectancy.

Longitudinal assessment of COVID-19 fear and psychological wellbeing in the United Kingdom.

The COVID-19 pandemic continues to impact global psychological wellbeing. To investigate the sustained impact of COVID-19 on wellbeing, the current study longitudinally assessed fear of COVID-19, anxiety, depression, intolerance of uncertainty, worry, sleep quality, loneliness and alcohol use during the pandemic in the United Kingdom. Timepoint 1 (T1; N = 445) took place in February 2021 following the highest number of pandemic-related deaths in the UK. Timepoint 2 (T2, N = 198) took place in June 2021 when pandemic-related deaths had declined considerably, and many had been vaccinated. At T1, COVID-19 fear predicted elevated levels of anxiety, depression, intolerance of uncertainty, worry, sleep quality and loneliness. At T2, we observed that levels of COVID-19 fear, depression, loneliness and sleep quality decreased. However, COVID-19 fear continued to predict elevated intolerance of uncertainty, worry and impaired sleep quality. These findings demonstrate the longitudinal impact of COVID-19 fear on psychological wellbeing.

Working hard to avoid: Fixed-ratio response effort and maladaptive avoidance in humans.

Maladaptive avoidance of safe stimuli is a defining feature of anxiety and related disorders. Avoidance may involve physical effort or the completion of a fixed series of responses to prevent occurrence of, or cues associated with, the aversive event. Understanding the role of response effort in the acquisition and extinction of avoidance may facilitate the development of new clinical treatments for maladaptive avoidance. Despite this, little is known about the impact of response effort on extinction-resistant avoidance in humans. Here, we describe findings from two laboratory-based treatment studies designed to investigate the impact of high and low response effort on the extinction (Experiment 1) and return (Experiment 2) of avoidance. Response effort was operationalised as completion of fixed-ratio (FR) reinforcement schedules for both danger and safety cues in a multi-cue avoidance paradigm with behavioural, self-report, and physiology measures. Completion of the FR response requirements cancelled upcoming shock presentations following danger cues and had no impact on the consequences that followed safety cues. Both experiments found persistence of high response-effort avoidance across danger and safety cues and sustained (Experiment 1) and reinstated (Experiment 2) levels of fear and threat expectancy. Skin conductance responses evoked by all cues were similar across experiments. The present findings and paradigm have implications for translational research on maladaptive anxious coping and treatment development.

The influence of the BDNF Val66Met genotype on emotional recognition memory in post-traumatic stress disorder.

Dysregulated consolidation of emotional memories is a core feature of posttraumatic stress disorder (PTSD). Brain Derived Neurotrophic Factor (BDNF) influences synaptic plasticity and emotional memory consolidation. The BDNF Val66Met polymorphism has been associated with PTSD risk and memory deficits respectively, although findings have been inconsistent, potentially due to a failure to control for important confounds such as sex, ethnicity, and the timing/extent of previous trauma experiences. Furthermore, very little research has examined the impact of BDNF genotypes on emotional memory in PTSD populations. This study investigated the interaction effects of Val66Met and PTSD symptomatology in an emotional recognition memory task in 234 participants divided into healthy control (n = 85), trauma exposed (TE: n = 105) and PTSD (n = 44) groups. Key findings revealed impaired negative recognition memory in PTSD compared to control and TE groups and in participants with the Val/Met compared to the Val/Val genotype. There was a group × genotype interaction showing no Met effect in the TE group despite significant effects in PTSD and controls. Results suggest that people previously exposed to trauma who do not develop PTSD may be protected from the BDNF Met effect, however more research is needed to replicate findings and to explore the epigenetic and neural processes involved.

Methodological implications of sample size and extinction gradient on the robustness of fear conditioning across different analytic strategies.

Fear conditioning paradigms are critical to understanding anxiety-related disorders, but studies use an inconsistent array of methods to quantify the same underlying learning process. We previously demonstrated that selection of trials from different stages of experimental phases and inconsistent use of average compared to trial-by-trial analysis can deliver significantly divergent outcomes, regardless of whether the data is analysed with extinction as a single effect, as a learning process over the course of the experiment, or in relation to acquisition learning. Since small sample sizes are attributed as sources of poor replicability in psychological science, in this study we aimed to investigate if changes in sample size influences the divergences that occur when different kinds of fear conditioning analyses are used. We analysed a large data set of fear acquisition and extinction learning (N = 379), measured via skin conductance responses (SCRs), which was resampled with replacement to create a wide range of bootstrapped databases (N = 30, N = 60, N = 120, N = 180, N = 240, N = 360, N = 480, N = 600, N = 720, N = 840, N = 960, N = 1080, N = 1200, N = 1500, N = 1750, N = 2000) and tested whether use of different analyses continued to produce deviating outcomes. We found that sample size did not significantly influence the effects of inconsistent analytic strategy when no group-level effect was included but found strategy-dependent effects when group-level effects were simulated. These findings suggest that confounds incurred by inconsistent analyses remain stable in the face of sample size variation, but only under specific circumstances with overall robustness strongly hinging on the relationship between experimental design and choice of analyses. This supports the view that such variations reflect a more fundamental confound in psychological science-the measurement of a single process by multiple methods.

Sex differences in the effect of subjective sleep on fear conditioning, extinction learning, and extinction recall in individuals with a range of PTSD symptom severity.

Sleep has been found to play a key role in fear conditioning, extinction learning and extinction recall, and sleep disturbances are linked to many mental disorders including post-traumatic stress disorder (PTSD). Previous studies examining associations between sleep and fear or extinction processes primarily focused on objectively measured sleep architecture. Little research has so far focused on subjective sleep measures and particularly in clinical populations, which often experience subjectively poor sleep, including PTSD. Here we investigated whether subjective sleep disturbance, sleep onset latency, wake after sleep onset or sleep efficiency were related to fear conditioning, extinction learning or extinction recall in a large sample of individuals with a range of PTSD symptom severity (n = 248). Overall, we did not find that subjective sleep was associated with fear conditioning or extinction processes. However, exploratory analyses examining the moderating effect of sex found that shorter sleep onset latency and greater sleep efficiency were associated with improved extinction recall in women with higher PTSD symptom severity. This suggests that less time falling asleep and longer time asleep while in bed may be protective in highly symptomatic women against the commonly observed impaired extinction recall in PTSD. More studies are needed to explore sex-specific effects further.

The role of intolerance of uncertainty in classical threat conditioning: Recent developments and directions for future research.

Intolerance of uncertainty (IU), the tendency to find uncertainty aversive, is an important transdiagnostic dimension in mental health disorders. Over the last decade, there has been a surge of research on the role of IU in classical threat conditioning procedures, which serve as analogues to the development, treatment, and relapse of anxiety, obsessive-compulsive, and trauma- and stressor-related disorders. This review provides an overview of the existing literature on IU in classical threat conditioning procedures. The review integrates findings based on the shared or discrete parameters of uncertainty embedded within classical threat conditioning procedures. Under periods of unexpected uncertainty, where threat and safety contingencies change, high IU, over other self-reported measures of anxiety, is specifically associated with poorer threat extinction learning and retention, as well as overgeneralisation. Under periods of estimation and expected uncertainty, where the parameters of uncertainty are being learned or have been learned, such as threat acquisition training and avoidance learning, the findings are mixed for IU. These findings provide evidence that individual differences in IU play a significant role in maintaining learned fear and anxiety, particularly under volatile environments. Recommendations for future research are outlined, with discussion focusing on how parameters of uncertainty can be better defined to capture how IU is involved in the maintenance of learned fear and anxiety. Such work will be crucial for understanding the role of IU in neurobiological models of uncertainty-based maintenance of fear and anxiety and inform translational work aiming to improve the diagnosis and treatment of relevant psychopathology.

Lower estradiol predicts increased reinstatement of fear in women.

Low levels of estradiol in women have been associated with impaired fear extinction recall, with suggestions this may promote the return of fear and heighten the female vulnerability for anxiety disorders. A particularly important measure for the return of fear is reinstatement, but no human studies to date have examined the impact of estradiol on fear reinstatement. Forty-two healthy females completed a differential fear conditioning, extinction and reinstatement task with skin conductance response (SCR) amplitude indexing level of conditioned fear. Saliva samples were taken to measure estradiol and progesterone. To examine fear reinstatement, SCR amplitude was compared between the last trial of the late extinction phase to the first re-extinction trial following the unsignaled presentation of two aversive electric shocks. No significant effects of estradiol were found for acquisition of fear conditioning or fear extinction learning. Lower estradiol predicted a significantly larger generalized SCR amplitude at re-extinction (post-reinstatement) in women. This provides novel evidence suggesting a protective role of estradiol in potentially reducing the relapse of fear following re-exposure to aversive stimuli, although further research is necessary in clinical populations to clarify this effect.

Negative reinforcement rate and persistent avoidance following response-prevention extinction.

Persistent avoidance may be influenced by prior negative reinforcement rate (i.e., how effective the response is at controlling threat). In clinical settings, the effectiveness of extinction-based methods for treating anxiety-related avoidance may be impacted by prior reinforcement rate. Here, we conducted a laboratory-based treatment study to investigate the persistence of avoidance following response-prevention extinction (RPE) when prior avoidance had been differentially effective at cancelling shock. Participants in three negative reinforcement rate groups (100%, 50%, and 0%) completed a validated avoidance conditioning paradigm involving Pavlovian fear extinction, RPE, and re-extinction phases. It was hypothesised that partially reinforced avoidance would lead to diminished resistance to fear extinction following response prevention, compared to continuously- or never-reinforced avoidance. Persistent avoidance was related to prior negative reinforcement rate, with higher rates more resistant to extinction. These findings illustrate the role of reinforcement rate in the persistence of avoidance and may aid understanding of treatment relapse.

Inconsistent analytic strategies reduce robustness in fear extinction via skin conductance response.

Robustness of fear conditioning and extinction paradigms has become increasingly important for many researchers interested in improving the study of anxiety and trauma disorders. We recently illustrated the wide variability in data analysis techniques in this paradigm, which we argued may result in a lack of robustness. In the current study, we resampled data from six of our own fear acquisition and extinction data sets, with skin conductance as the outcome. In the resampled and original data sets, we found that effect sizes that were calculated using discrepant statistical strategies, sourced from a non-exhaustive search of high-impact articles, were often poorly correlated. The main contributors to poor correlations were the selection of trials from different stages of each experimental phase and the use of average compared to trial-by-trial analysis. These findings reinforce the importance of focusing on robustness in the psychophysiological measurement of fear acquisition and extinction in the laboratory and may guide prospective researchers in which decisions may most impact the robustness of their results.

The clinical applications and practical relevance of human conditioning paradigms for posttraumatic stress disorder.

The classical conditioning paradigm of fear learning has spawned a number of experimental variations for the explanation of posttraumatic stress disorder (PTSD) etiology. These paradigms include extinction learning and recall, fear inhibition, fear generalization, and conditioned avoidance. As such, each of these paradigms have significant applications for understanding the development, maintenance, treatment, and relapse of the fear-related features of PTSD. In the present review, we describe each of these conditioning-based paradigms with reference to the clinical applications, and supported by case examples from patients with severe PTSD symptoms. We also review the neurobiological models of conditioning and extinction in animals, psychiatrically healthy humans, and PTSD patients, and discuss the current balance of evidence suggesting a number of biological, behavioral, and cognitive mechanisms/moderators of the conditioning and extinction process in experimental and clinical contexts.

Endogenous salivary α-amylase does not interact with skin conductance response during fear extinction in posttraumatic stress disorder.

Posttraumatic Stress Disorder (PTSD) is associated with elevated noradrenergic signaling, which has an impact on emotional learning and memory. Fear extinction is thought to underlie the processes of exposure therapy, however the relationship between noradrenaline and extinction in PTSD is unclear. Participants with PTSD (n = 21), trauma-exposure without PTSD (TC; n = 36), and non-trauma-exposed controls (NTC; n = 27) completed a fear conditioning and extinction paradigm, and conditioned fear was indexed by skin conductance response (SCR). Salivary α-amylase (sAA) collected at baseline and immediately post-fear acquisition was used as an index of noradrenaline, and we examined whether sAA in response to fear acquisition was a moderator between fear extinction and PTSD symptoms. While there was a significant increase in sAA from baseline to post-fear acquisition, this was not modulated by group. Compared to TC and NTC, the PTSD group displayed a slower decline in SCRs during early extinction, which generalized across stimulus type, and was not moderated by sAA. These findings suggest that the relationship between fear extinction and PTSD symptoms does not change as a function of sAA levels; however previous research suggests other processes of fear learning may be associated with noradrenergic activity in PTSD.

Greater sleep disturbance and longer sleep onset latency facilitate SCR-specific fear reinstatement in PTSD.

Fear reinstatement is one of several paradigms designed to measure fear return following extinction, as a laboratory model for the relapse of Posttraumatic Stress Disorder (PTSD) symptoms. Sleep is a key factor in emotional memory consolidation, and here we examined the relationship between sleep quality and fear reinstatement in PTSD, relative to trauma-exposed and non-exposed controls. The Pittsburgh Sleep Quality Index (PSQI) was used as a subjective measure of sleep quality, and skin conductance responses (SCR) and unconditioned stimulus (US)-expectancy ratings were used to index threat responses during a differential fear conditioning, extinction, and reinstatement paradigm. There were no significant between-group differences in the reinstatement of conditioned responding. Sleep disturbance and sleep onset latency were significant moderators between reinstatement of fear and PTSD symptom severity, such that there was a positive relationship between PTSD symptoms and fear reinstatement for higher levels - but not lower levels - of sleep disturbance and sleep onset latency. To our knowledge, this is the first study to investigate PTSD-specific reinstatement patterns and sleep as a boundary condition of reinstatement. Future research using polysomnographic measures of sleep-wave architecture may further clarify the relationship between fear reinstatement and sleep quality in clinical samples with PTSD relative to controls.

Sex differences in intrusive memories following trauma.

BACKGROUND: A key mechanism thought to underlie Posttraumatic Stress Disorder (PTSD) is enhanced emotional memory consolidation. Recent evidence in healthy controls revealed that women have greater negative memory consolidation following stress relative to men. This study examined emotional memory consolidation in women and men with PTSD, and in trauma-exposed and non-trauma controls to test the hypothesis that emotionally negative memory consolidation would be greater in women with PTSD. METHOD: One hundred and forty-seven men and women (47 with PTSD, 49 trauma-exposed controls, and 51 non-trauma controls) completed an emotional memory task where they looked at negative, neutral and positive images from the International Affective Picture System (IAPS). Delayed recall and an intrusive memory diary were completed two days later. RESULTS: Women displayed greater recall, and reported more negative intrusive memories than men. A gender x group interaction effect showed that both women with PTSD and trauma-exposed women reported more intrusive memories than women without trauma exposure or men. CONCLUSION: This study provided preliminary evidence of sex differences in intrusive memories in those with PTSD as well as those with a history of trauma exposure. Future research should include measures of sex hormones to further examine sex differences on memory consolidation in the context of trauma exposure and PTSD.

The BDNF Val66Met polymorphism moderates the relationship between Posttraumatic Stress Disorder and fear extinction learning.

The low expression Met allele of the BDNF Val66Met polymorphism is associated with impaired fear extinction in healthy controls, and poorer response to exposure therapy in patients with Posttraumatic Stress Disorder (PTSD). Given that fear extinction underlies exposure therapy, this raises the question of the impact of BDNFVal66Met polymorphism on fear extinction in PTSD, yet this question has not yet been examined. One hundred and six participants (22 PTSD, 46 trauma-exposed controls (TC) and 38 non-trauma exposed controls (NTC)) completed a fear conditioning and extinction task and saliva samples were taken for DNA extraction and genotyped for the BDNF Val66Met polymorphism. Moderation analyses using PROCESS examined whether BDNF genotype (Val-Val vs Met carriers) moderated the relationship between PTSD symptom severity (and diagnostic status) and skin conductance response (SCR) amplitude during fear extinction. The PTSD group displayed significantly slower fear extinction learning compared to TC and NTC in the early extinction phase. The BDNF Val66Met polymorphism moderated the relationship between PTSD and fear extinction learning, such that poorer fear extinction learning was associated with greater PTSD symptom severity (and PTSD diagnostic status) in individuals with the low-expression Met allele, but no relationship was demonstrated in individuals with the Val-Val allele. This study reveals that impaired fear extinction learning is particularly evident in individuals with PTSD who carry the low-expression BDNF Met allele and importantly not in those with the Val-Val allele. This provides novel evidence of a link between BDNF and impaired fear extinction learning in PTSD, which may contribute to poorer response to exposure therapy.