The effect of gradual extinction training on the renewal of electrodermal conditional responses.

Extinction, the repeated presentation of a conditional stimulus (CS) without the unconditional stimulus (US), is the standard paradigm to reduce conditional responding acquired by the repeated pairing of CS and US in acquisition. However, this reduction of conditional responding is prone to relapse. In rodent fear-conditioning, gradual extinction, the fading out of CS-US pairings during extinction, has been shown to reduce the return of fear. The current study replicated the gradual extinction procedure in human fear conditioning and assessed whether it reduced the return of fear due to ABA renewal and reacquisition. During extinction, one group received standard extinction, a second received gradual extinction (increasing the spacing of USs presented after the 1st, 3rd, 6th, 10th, and 15th CS+ trials), and a third received reversed extinction training (decreasing the spacing of USs presented after the 1st, 6th, 10th, 13th, and 15th CS+ trials). Larger renewal and faster reacquisition of differential electrodermal responses to CS+ and CS- were expected after standard and reversed extinction than after gradual extinction training. The results were inconclusive due to the failure to find extinction of differential electrodermal responses and US expectancy ratings in both gradual and reversed extinction groups. Despite successful extinction in group standard, renewal was only observed in US expectancy. Visualization of US expectancy ratings during extinction suggested that potential identification of the US presentation patterns during extinction in the gradual and reversed groups delayed extinction learning.

Signalling unpaired unconditional stimuli during extinction does not impair their effect to reduce renewal of conditional fear.

Presenting unpaired unconditional stimuli (US) during extinction training reduces the renewal of conditional fear due to context change and slows re-acquisition. The present study investigated whether this reduced return of fear is mediated by Pavlovian inhibitory conditioning to the conditional stimulus paired with the US during acquisition (CS+) that is acquired when this stimulus is presented without the US in an excitatory extinction context. Using an ABA renewal paradigm that trained extinction in a context different from acquisition and renewal test, participants either received no USs (Standard), five unsignalled US presentations (Unsignalled) or five presentations of the US preceded by a novel, third CS (Signalled) during extinction training. Extinction was followed by tests for renewal and re-acquisition. Replicating previous results, renewal of electrodermal conditional responses was observed in group Standard, but not in group Unsignalled. Signalling the additional USs, and thus reducing context conditioning and the potential for inhibitory conditioning, did not reduce their effect in that renewal was absent in group Signalled. These results are inconsistent with an inhibitory conditioning account of the effects of unpaired US presentations during extinction. A trial sequence learning account or an arousal account may explain the effects of unpaired presentations of the US during extinction.

Using electrodermal activity to estimate fear learning differences in anxiety: A multiverse analysis.

Meta-analyses indicate differences in Pavlovian fear responses between anxious and non-anxious individuals using electrodermal activity (EDA). Recent research, however, has cast doubt on whether these effects are robust to different analytic choices. Using the multiverse approach conceived by Steegen et al. (2016), we surveyed analytic choices typically implemented in clinical fear conditioning research by conducting 1240 analyses reflecting different choice permutations. Only 1.45% of our analyses produced theoretically congruent statistically significant effects, and the strength and direction of the estimated effects varied substantially across EDA processing methods. We conclude that EDA-estimated fear learning differences are vulnerable to researcher degrees of freedom and make recommendations regarding which analytical choices should be approached with a high degree of caution.

Exploration of stress reactivity and fear conditioning on intrusive memory frequency in a conditioned-intrusion paradigm.

BACKGROUND AND OBJECTIVES: The conditioned-intrusion paradigm was designed to provide insight into the relationship between fear conditioning and intrusive memory formation, which is relevant to understanding posttraumatic stress disorder symptoms and treatment. However, boundary conditions of this new paradigm have not been explored and it is currently not known whether findings from this work are valid in a clinical context. METHODS: In the current study, we explored the relationship between stress reactivity to trauma film clips, usual exposure to violent media, renewal of fear conditioning using skin conductance as well as subjective ratings, and the effect of shock versus film clip during conditioning on the frequency of intrusive memories. An adapted fear conditioning paradigm using trauma clips as unconditional stimuli was used, and participants subsequently reported intrusive memories of the trauma clips. RESULTS: Skin conductance responses to conditioned stimuli paired with shocks and film clips were significantly higher than conditioned stimuli paired with film clips alone. Subjective stress reactivity, previous exposure to violent media, and film valence rating were associated with the frequency of intrusive memories. No aspects of fear conditioning were associated with intrusive memories, and factor analysis suggested the fear conditioning and stress related to film clip viewing were mostly separate constructs. Similarly, content and triggers of intrusive memories were usually film-clip related rather than conditional stimulus related. LIMITATIONS: We did not observe strong conditioning effects of the unconditional stimuli to conditional stimuli, which were shapes rather than high frequency stimuli such as faces. CONCLUSIONS: These findings provide potential boundary conditions for this paradigm and suggest multiple ways in which the validity of the paradigm can be tested in the future.

Advances in targeted liquid chromatography-tandem mass spectrometry methods for endocannabinoid and N-acylethanolamine quantification in biological matrices: A systematic review.

Liquid chromatography paired with tandem mass spectrometry (LC-MS/MS) is the gold standard in measurement of endocannabinoid concentrations in biomatrices. We conducted a systematic review of literature to identify advances in targeted LC-MS/MS methods in the period 2017-2024. We found that LC-MS/MS methods for endocannabinoid quantification are relatively consistent both across time and across biomatrices. Recent advances have primarily been in three areas: (1) sample preparation techniques, specific to the chosen biomatrix; (2) the range of biomatrices tested, recently favoring blood matrices; and (3) the breadth of endocannabinoid and endocannabinoid-like analytes incorporated into assays. This review provides a summary of the recent literature and a guide for researchers looking to establish the best methods for quantifying endocannabinoids in a range of biomatrices.

Sex-Specific Changes to Brain Fatty Acids, Plasmalogen, and Plasma Endocannabinoids in Offspring Exposed to Maternal and Postnatal High-Linoleic-Acid Diets.

Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring's brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.

Renewal in human fear conditioning: A systematic review and meta-analysis.

Renewal is a 'return of fear' manipulation in human fear conditioning to investigate learning processes underlying anxiety and trauma. Even though renewal paradigms are widely used, no study has compared the strength of different renewal paradigms. We conduct a systematic review (N = 80) and meta-analysis (N = 23) of human fear conditioning studies assessing renewal. Our analysis shows that the classic ABA design is the most effective paradigm, compared to ABC and ABBA designs. We present evidence that conducting extinction in multiple contexts and increasing the similarity between acquisition and extinction contexts reduce renewal. Furthermore, we show that additional cues can be used as safety and 'protection from extinction' cues. The review shows that alcohol weakens the extinction process and that older adults appear less sensitive to context changes and thus show less renewal. The large variability in approaches to study renewal in humans suggests that standardisation of fear conditioning procedures across laboratories would be of great benefit to the field.

Trauma film viewing and intrusive memories: Relationship between salivary alpha amylase, endocannabinoids, and cortisol.

The endogenous cannabinoid (ECB) system is a small molecule lipid signalling system that is involved in stress response activation and is associated with PTSD, but it is unclear whether salivary ECBs are part of the sympathetic nervous system response to stress. We conducted an adapted trauma film paradigm, where participants completed a cold pressor test (or control) while watching a 10-minute trauma film. We also collected saliva and hair samples and tested them for ECBs, cortisol, and salivary alpha amylase (sAA). As hypothesised, there were significant positive correlations between sAA activity and salivary ECB levels, particularly 2-arachidonoyl glycerol (2-AG), though ECBs were not correlated with sAA stress reactivity. Participants who had a significant cortisol response to the trauma film/stressor reported less intrusive memories, which were also less distressing and less vivid. This effect was moderated by arachidonoyl ethanolamide (AEA), where decreases in AEA post-stress were associated with more intrusive memories in cortisol non-responders only. This study provides new evidence for the role of ECBs in the sympathetic nervous system.

Examining the reliability of the emotional conflict resolution and adaptation effects in the emotional conflict task via secondary data analysis, systematic review, and meta-analysis.

The emotional conflict task measures emotional conflict resolution and adaptation, but some studies are unable to find resolution or adaptation effects using this task. We examined boundary conditions and replicability of the emotional conflict resolution and adaptation effects through secondary data analysis, systematic review, and meta-analysis of studies in the field. In our data, we were unable to fully replicate the emotional conflict resolution or adaptation effects and found that most studies using this task (n = 94) do not report analysis of emotional conflict resolution, with only 28% (n = 26) studies doing so. Our meta-analysis suggests that studies reporting emotional conflict resolution and adaptation analyses overall report significant but small effects, suggesting the effect is difficult to consistently replicate. Our meta-analysis revealed that controlling for contingency learning may impact the ability of studies to identify conflict resolution. These findings have implications for assessment and interpretation of the emotional conflict task. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Trauma and Mental Health Impacts of Coercive Control: A Systematic Review and Meta-Analysis.

Coercive control is an under researched type of intimate partner violence (IPV). The aims of this review were to (a) synthesize all available evidence regarding associations with coercive control and mental health outcomes including post-traumatic stress disorder (PTSD), complex PTSD, and depression; and (b) compare these with associations involving broader categories of psychological IPV. Primary studies which measured associations of coercive control with PTSD, complex PTSD, depression, or other mental health symptoms, were identified via a systematic search of electronic databases (PsycINFO, Medline, CINAHL, Scopus). Eligible studies involved observational designs and reported associations between coercive control and mental health outcomes, among participants who were at least 18 years old. Studies were published in peer-reviewed journals and English language. Random-effects meta-analyses were used to synthesize correlational data from eligible studies. The search identified 68 studies while data from 45 studies could be included in the meta-analyses. These indicated moderate associations involving coercive control and PTSD (r = .32; 95% confidence interval [.28, .37]) and depression (r = .27; [.22, .31]). These associations were comparable to those involving psychological IPV and PTSD (r = .34; [.25, .42]) and depression (r = .33; [.26, .40]). Only one study reported on the relationship between coercive control and complex PTSD and meta-analyses could not be performed. This review indicated that coercive control exposure is moderately associated with both PTSD and depression. This highlights that mental health care is needed for those exposed to coercive control, including trauma-informed psychological interventions.

Sex-dimorphism in human serum endocannabinoid and n-acyl ethanolamine concentrations across the lifespan.

The endocannabinoid (ECB) system has recently been considered a potential treatment target for various clinical disorders. However, research around age- and sex-related changes within the ECB system is relatively limited. To improve our understanding of these changes, the current study measured arachidonoyl ethanolamide (AEA), 2-arachidonoyl glycerol (2-AG), oleoylethanolamine (OEA), palmitoylethanolamine (PEA), arachidonic acid (AA), cortisol, and progesterone in pooled serum samples stratified by sex (male and female) and age groups (5-15; 15-30; 30-45; 45-60; 60-75; 85+), using liquid-chromatography tandem mass spectrometry. Serum progesterone levels significantly increased in females of the 15-30 and 30-45 age groups, before declining. Significantly higher cortisol, AEA, 2-AG, OEA, and PEA were found in males and in older age, while significantly higher AA was found in females. Our results indicate that ECBs and related hormones exhibit sexual dimorphism in the age ranges that correspond with female pregnancy, menopause, and post menopause. Male testosterone levels most likely influences male ECB changes throughout the lifespan. Future research could capitalise on these findings by performing repeated measurements in individuals in a longitudinal style, to further refine the temporal profile of age-specific changes to the ECB system identified here.

Challenges and considerations for treating PTSD with medicinal cannabis: the Australian clinician's perspective.

INTRODUCTION: Preclinical and experimental research have provided promising evidence that medicinal cannabis may be efficacious in the treatment of posttraumatic stress disorder (PTSD). However, implementation of medicinal cannabis into routine clinical therapies may not be straightforward. AREAS COVERED: In this review, we describe some of the clinical, practical, and safety challenges that must be addressed for cannabis-based treatment of PTSD to be feasible in a real-world setting. These issues are especially prevalent if medicinal cannabis is to be combined with trauma-focused psychotherapy. EXPERT OPINION: Future consideration of the clinical and practical considerations of cannabis use in PTSD therapy will be essential to both the efficacy and safety of the treatment protocols that are being developed. These issues include dose timing and titration, potential for addiction, product formulation, windows of intervention, and route of administration. In particular, exposure therapy for PTSD involves recall of intense emotions, and the interaction between cannabis use and reliving of trauma memories must be explored in terms of patient safety and impact on therapeutic outcomes.

The next frontier: Moving human fear conditioning research online.

Fear conditioning is a significant area of research that has featured prominently among the topics published in Biological Psychology over the last 50 years. This work has greatly contributed to our understanding of human anxiety and stressor-related disorders. While mainly conducted in the laboratory, recently, there have been initial attempts to conduct fear conditioning experiments online, with around 10 studies published on the subject, primarily in the last two years. These studies have demonstrated the potential of online fear conditioning research, although challenges to ensure that this research meets the same methodological standards as in-person experimentation remain, despite recent progress. We expect that in the coming years new outcome measures will become available online including the measurement of eye-tracking, pupillometry and probe reaction time and that compliance monitoring will be improved. This exciting new approach opens new possibilities for large-scale data collection among hard-to-reach populations and has the potential to transform the future of fear conditioning research.

Reaction time as an outcome measure during online fear conditioning: Effects of number of trials, age, and levels of processing.

Recent studies have shown that fear conditioning experiments can be successfully conducted online. However, there is limited evidence that measures other than subjective ratings of threat expectancy can be collected, which means that online research may not be able to adequately replace laboratory experiments. In the current study, we conducted an online fear conditioning experiment consisting of habituation, acquisition, extinction and 48 h delayed extinction recall using ratings of threat expectancy and conditional stimulus pleasantness, and probe reaction time as outcome measures. The conditional stimuli were categories of words and a levels of processing manipulation explored whether words that were processed at a deeper level during extinction evoked smaller differential threat responses during extinction recall. Although the levels of processing manipulation did not produce a significant outcome, we found that extinction recall was successfully operationalised in our study. Reaction time indicated differential responding during both acquisition and extinction recall, and age of participants was correlated in one of two experiments with differential threat expectancy and reaction time, such that older participants showed better safety learning. The outcomes of this experiment provide multiple novel tools for researchers to explore fear conditioning, especially in an online environment.

Hair endocannabinoids predict physiological fear conditioning and salivary endocannabinoids predict subjective stress reactivity in humans.

On the basis of substantial preclinical evidence, the endogenous cannabinoid system has been proposed to be closely involved in stress reactivity and extinction of fear. Existing human research supports this proposal to some extent, but existing studies have used only a narrow range of tools and biomatrices to measure endocannabinoids during stress and fear experiments. In the present study we collected hair and saliva samples from 99 healthy participants who completed a fear conditioning and intrusive memory task. Subjective, physiological and biological stress reactivity to a trauma film, which later served as unconditional stimulus during fear conditioning, was also measured. We found that salivary endocannabinoid concentrations predicted subjective responses to stress, but not cortisol stress reactivity, and replicated previous findings demonstrating a sex dimorphism in hair and salivary endocannabinoid levels. Hair 2-arachidonoyl glycerol levels were significantly associated with better retention of safety learning during extinction and renewal phases of fear conditioning, while hair concentrations of oleoylethanolamide and palmitoylethanolamide were associated with overall physiological arousal, but not conditional learning, during fear conditioning. This study is the first to test the relationship between hair and salivary endocannabinoids and these important psychological processes. Our results suggest that these measures may serve as biomarkers of dysregulation in human fear memory and stress.

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.

Fear conditioning depends on the nature of the unconditional stimulus and may be related to hair levels of endocannabinoids.

The replicability of fear conditioning research has come under recent scrutiny, with increasing acknowledgment that the use of differing materials and methods may lead to incongruent results. Direct comparisons between the main two unconditional stimuli used in fear conditioning - an electric shock or a loud scream-are scarce, and yet these stimuli are usually used interchangeably. In the present study, we tested whether a scream, a shock, or an unpredictable combination of the two affected fear acquisition, extinction, and return of fear amongst healthy participants (N = 109, 81 female). We also collected hair samples and tested the relationship between fear conditioning and hair endocannabinoid levels. Our findings suggest that, although subjective ratings of pleasantness, arousal, and anxiety were similar regardless of the unconditional stimuli used, skin conductance responses were significantly lower for stimuli paired with the scream compared to a shock alone. Further, reducing the predictability of the unconditional stimulus reduced habituation of skin conductance responses during acquisition and reacquisition, but did not produce stronger conditioning compared to shock alone. Exploratory analyses suggested that hair endocannabinoids were associated with overall physiological arousal during fear conditioning, as well as higher return of fear to the threat cue, but not to the safety cue. These findings have multiple implications for the design and replicability of fear conditioning research and provide the first evidence for an association between hair levels of endocannabinoids and human fear conditioning.

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.

Intolerance of uncertainty affects electrodermal responses during fear acquisition: Evidence from electrodermal responses to unconditional stimulus omission.

Past research has shown that Intolerance of Uncertainty (IU) affects Pavlovian fear conditioning processes. In particular, extinction of learned fear is delayed in those reporting high IU. Reports of differences during acquisition are less consistent with most of the studies reporting no evidence for effects of IU. This may be due to past studies' focus on first interval electrodermal responses or fear potentiated startle, rather than on indices that may better capture uncertainty - like the response to the absence of a probabilistic unconditional stimulus. The current analysis combined data across three experiments that employed a 50 % reinforcement schedule and assessed electrodermal responses and (in two experiments) ratings of conditional stimulus pleasantness. Participants scoring high on IU showed overall larger electrodermal first interval responses during habituation and acquisition but did not differ from those scoring low on IU in differential conditioning (the difference between CS+ and CS-), as indicated by electrodermal first or second interval responses or ratings of CS pleasantness. However, participants high in IU showed larger differential third interval electrodermal responses to the omission of the electro-tactile unconditional stimulus during acquisition. Some evidence for this difference emerged in each experiment, supporting the reliability of the result. The current results suggest that effects of IU emerge in conditions of high uncertainty in Pavlovian fear learning tasks, such as during the omission of probabilistic unconditional stimuli.