Exposure Therapy For Anxiety Disorders Research Articles

Autonomous VR Exposure Therapy for Anxiety Disorders Using Conversational AI—Ethical and Technical Implications and Preliminary Results

Autonomous VR Exposure Therapy for Anxiety Disorders Using Conversational AI—Ethical and Technical Implications and Preliminary Results

Dissociable role of the basolateral complex of the amygdala in the acquisition and extinction of conditioned fear following reproductive experience in female rats

In female rats and humans, reproductive experience (i.e., pregnancy) alters the behavioral, hormonal and molecular substrates of fear extinction. Here, we assessed whether the role of a central neural substrate of fear extinction, the basolateral amygdala (BLA), also changes following reproductive experience. Nulliparous (virgin) and primiparous (one prior pregnancy) female rats received infusions of the GABAA agonist, muscimol, to temporarily inactivate the BLA prior to fear conditioning or extinction training. In follow up experiments, the BLA was also inactivated immediately after extinction training. BLA inactivation impaired the acquisition and expression of conditioned fear in both nulliparous and primiparous rats. In nulliparous rats, BLA inactivation prior to or immediately after extinction training impaired extinction retention. In contrast, in primiparous rats, BLA inactivation prior to or immediately after extinction training did not impair extinction retention, despite suppressing freezing during extinction training. These results suggest that, consistent with past findings in males, the BLA is a central component of the neural circuitry of fear acquisition and its extinction in virgin female rats. However, after pregnancy, female rats no longer depend on the BLA to extinguish fear, despite requiring the BLA to acquire conditioned fear. Given that fear extinction forms the basis of exposure therapy for anxiety disorders in humans, the present findings may have clinical implications. To improve the efficacy of exposure therapy for anxiety disorders, we may need to target different mechanisms in females dependent on their reproductive history.

Expanding the reach of evidence-based mental health interventions to private practice: Qualitative assessment using a policy ecology framework.

Evidence-based interventions (EBIs) for mental health disorders are underutilized in routine clinical practice. Exposure therapy for anxiety disorders is one particularly difficult-to-implement EBI that has robust empirical support. Previous research has examined EBI implementation determinants in publicly funded mental health settings, but few studies have examined EBI implementation determinants in private practice settings. Private practice clinicians likely face unique barriers to implementation, including setting-specific contextual barriers to EBI use. The policy ecology framework considers broad systemic determinants, including organizational, regulatory, social, and political contexts, which are likely relevant to EBI implementation in private practice settings but have not been examined in prior research. Qualitative interviews were conducted to assess private practice clinicians' perceptions of EBI implementation determinants using the policy ecology framework. Clinicians were asked about implementing mental health EBIs broadly and exposure therapy specifically. Mixed methods analyses compared responses from clinicians working in solo vs. group private practice and clinicians who reported high vs. low organizational support for exposure therapy. Responses highlight several barriers and facilitators to EBI implementation in private practice. Examples include determinants related to organizational support (e.g., colleagues using EBIs), payer restrictions (e.g., lack of reimbursement for longer sessions), fiscal incentives (e.g., payment for attending training), and consumer demand for EBIs. There were notable differences in barriers faced by clinicians who work in group private practices compared to those working in solo practices. Solo private practice clinicians described ways in which their practice setting limits their degree of colleague support (e.g., for consultation or exposure therapy planning), while also allowing for flexibility (e.g., in their schedules and practice location) that may not be available to clinicians in group practice. Using the policy ecology framework provides a broad understanding of contextual factors that impact private practice clinicians' use of EBIs, including exposure therapy. Findings point to potential implementation strategies that may address barriers that are unique to clinicians working in private practice.

Optimizing exposure therapy with an inhibitory retrieval approach and the OptEx Nexus

Research from recent decades has highlighted the distinction between excitatory and inhibitory Pavlovian learning mechanisms. Based on this distinction, state-of-the-art exposure therapy for anxiety disorders emphasizes inhibitory learning and retrieval as its primary mechanism for long-term reduction in fear, anxiety, and avoidance. Seven years ago, we (Craske, et al., 2014) summarized exposure therapy from an inhibitory learning approach, focusing on eight exposure optimization strategies. Here, we update this model based on recent work and describe how to conduct exposure therapy from an inhibitory retrieval approach and encourage further empirical investigation of its basic premises. To this end, we guide the reader in the use of the OptEx Nexus: a clinician's tool for conducting exposure therapy from an inhibitory retrieval approach. We categorize exposure strategies as fundamental (expectancy violation, attention to feared stimulus/situation, removal of safety signals, and mental rehearsal after exposure), advanced (deepened extinction, occasional reinforced extinction), and promoting generalization of learning (retrieval cues, multiple contexts, stimulus variability, positive affect). We additionally discuss extinction learning with distal future feared outcomes, the role of avoidance, and alternative models/approaches to exposure therapy, including counterconditioning, novelty-enhanced extinction, latent cause models, and reconsolidation. Lastly, we illustrate clinical implementation via vignettes of exposure therapy from an inhibitory retrieval approach (see Supplemental materials).

Maternal Experience Does Not Predict Fear Extinction and Anxiety-Like Behaviour in Primiparous Rats Post-weaning.

Reproductive experience leads to long-lasting changes in anxiety-like behaviour and fear extinction, the laboratory model of exposure therapy for anxiety disorders. For example, fear extinction is influenced by estrous cycle in nulliparous (no reproductive experience) female rats, but this effect is abolished in primiparous (one reproductive experience) females. It is unclear whether such changes are driven by pregnancy, maternal experience of caring for offspring during the postpartum period, or a combination of both experiences. The present study sought to determine the influence of maternal experience (i.e., exposure to pups and mother-pup interactions) on fear extinction in primiparous rats. In Experiment 1, we tested whether pup exposure is necessary to mitigate estrous effects on fear extinction in primiparous rats. Age-matched nulliparous rats, primiparous rats, and primiparous rats who experienced pregnancy but not pup exposure, underwent fear conditioning on day 1 (2 months post-parturition), extinction training during proestrus (high sex hormones) or metestrus (low sex hormones) on day 2, and extinction recall on day 3. Replicating past research, nulliparous rats showed impaired extinction recall when they were extinguished during metestrus compared to proestrus. In contrast, primiparous rats with and without pup exposure showed comparable extinction recall irrespective of estrous phase. In Experiment 2, we assessed whether naturally-occurring variation in mother-pup interactions predict future fear extinction performance and anxiety-like behaviour. During the first week of lactation, primiparous rats were measured for maternal behaviours toward pups. Primiparous rats were then tested on the light-dark box and elevated plus maze to measure anxiety-like behaviour and underwent a fear extinction protocol 1 month post-weaning. We found no significant correlations between maternal behaviour and fear extinction outcomes or anxiety-like behaviour. Our findings suggest that pregnancy, not maternal experience, mitigates the impact of estrous cycle on fear extinction. In addition, natural variation in maternal experience does not appear to contribute to variability in future fear extinction outcomes or anxiety-like behaviour in primiparous rats.

Organizational principles of amygdalar input-output neuronal circuits

The amygdala, one of the most studied brain structures, integrates brain-wide heterogeneous inputs and governs multidimensional outputs to control diverse behaviors central to survival, yet how amygdalar input-output neuronal circuits are organized remains unclear. Using a simplified cell-type- and projection-specific retrograde transsynaptic tracing technique, we scrutinized brain-wide afferent inputs of four major output neuronal groups in the amygdalar basolateral complex (BLA) that project to the bed nucleus of the stria terminals (BNST), ventral hippocampus (vHPC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), respectively. Brain-wide input-output quantitative analysis unveils that BLA efferent neurons receive a diverse array of afferents with varied input weights and predominant contextual representation. Notably, the afferents received by BNST-, vHPC-, mPFC- and NAc-projecting BLA neurons exhibit virtually identical origins and input weights. These results indicate that the organization of amygdalar BLA input-output neuronal circuits follows the input-dependent and output-independent principles, ideal for integrating brain-wide diverse afferent stimuli to control parallel efferent actions. The data provide the objective basis for improving the virtual reality exposure therapy for anxiety disorders and validate the simplified cell-type- and projection-specific retrograde transsynaptic tracing method.

Moving from VR into AR using bio-cybernetic loops and physiological sensory devices for intervention on anxiety disorders

Anxiety disorders comprise different clinical conditions that affect individuals in their personal, professional and social domains. The development of new intervention approaches for the treatment of anxiety disorders is crucial. As a step forward into promoting the well-being through adaptive physiological responses, we developed an augmented reality (AR)-based system using bio-cybernetic loops to create an adaptive system for exposure therapy in anxiety disorders. The system was built using open-source software (e.g., NyARToolkit and Unity 3D). AR technology uses computer-generated information to enrich the real world. It can be used with less intrusive devices to collect physiological data (e.g., Bitalino) describing human behavior in a cycle. In this context, our research project aims to study behavior during exposure to biologically relevant stimuli such as snakes. Phobia is described as an irrational fear to an object/stimulus. This fear triggers several physiological responses from sensors as increased heart rate (ECG) and skin conductance (EDA), which are responses from the autonomous nervous system. This approach can be used in several sessions, where the system through machine learning algorithms adapts the thresholds to the individual profile of each participant from historical data. Our study has been carried out in two stages: (1) The participants in a total of 35 students (30 males and 5 females with ages ranging from 19 to 29 years) were invited to fill a snake questionnaire (SNAQ). (2) A subsample was enrolled in an exposure session in AR using a virtual snake while collecting psychophysiological responses from sensors data. The results have shown increased physiological responses in two AR exposure sessions using snakes as stimuli. Therefore we conclude that the system was efficient to detect changes in physiological responses during the exposure sessions.

Virtual Reality Therapy in Mental Health.

Initially designed for the treatment of phobias, the use of virtual reality in phobic disorders has expanded to other mental health disorders such as posttraumatic stress disorder, substance-related disorders, eating disorders, psychosis, and autism spectrum disorder. The goal of this review is to provide an accessible understanding of why this approach is important for future practice, given its potential to provide clinically relevant information associated with the assessment and treatment of people suffering from mental illness. Most of the evidence is available for the use of virtual reality exposure therapy in anxiety disorders and posttraumatic stress disorder. There is hardly any evidence that virtual reality therapy is effective in generalized anxiety disorder and obsessive-compulsive disorder. There is increasing evidence that cue exposure therapy is effective in addiction and eating disorders. Studies into the use of virtual reality therapy in psychosis, autism spectrum disorder, and attention deficit hyperactivity disorder (ADHD) are promising.

Lessons Learned From a Randomized Controlled Pilot Trial Testing an Inhibitory Learning Approach to Exposure in Anxious Youth

Accumulating evidence from basic and translational research indicates that fear extinction may be best explained by principles of “inhibitory learning,” by which prefrontal cortical structures inhibit activity in the amygdala. New guidelines for the clinical practice of exposure therapy have arisen from research on inhibitory learning, but these guidelines have received little empirical testing in clinical samples of youth receiving treatment for anxiety disorders. We investigated the acceptability, feasibility, and initial efficacy of conducting exposure therapy for anxiety disorders in youth according to clinical guidelines developed from basic research on inhibitory learning principles, using a pilot randomized controlled trial design. Thirteen youths (ages 7 to 16) were recruited from a university hospital-based pediatric outpatient clinic to participate in a 9-week treatment study and were randomized to either an inhibitory learning-based exposure condition or a standard exposure condition. Results supported the feasibility and acceptability of an inhibitory learning-based approach to exposure therapy in youth and, despite the small sample size, effect sizes were in favor of the inhibitory learning approach on several measures. Differences between the standard exposure and inhibitory learning conditions are discussed using two case examples. Discussion of results and lessons learned may contribute to changes in clinical guidelines for optimally effective practice of exposure.

Exposure Therapy for Anxiety Disorders in Schools: Getting Started

Exposure and response prevention is an evidence-based intervention recommended as a first-line treatment for childhood anxiety disorders. Despite over a century of research establishing its efficacy, many school- and college-aged youth fail to receive timely and effective treatment. This brief review will summarize the rationale and efficacy of exposure-based cognitive-behavioral therapy, highlight the challenges of treatment implementation, and provide resources for practitioners seeking to apply exposure therapy in practice.

Identifying the organizational innovation-specific capacity needed for exposure therapy.

Current approaches to increasing the rates of clinician use of exposure therapy for anxiety disorders in community settings are limited. Research underscores the importance of addressing contextual variables to facilitate clinician use of evidence-based practices; however, no studies have identified the innovation-specific organizational capacity necessary to implement exposure therapy. Such work is critical to ensure that treatment-seeking individuals with anxiety receive effective care. We used a two-step process to identify the innovation-specific organizational capacity necessary to deliver exposure. First, 24 leaders of specialty anxiety clinics in the United States (50% female, mean [M]age = 47.7 years) completed a survey about the organizational innovation-specific capacity (e.g., policies and procedures) they employ to support their providers in delivering exposure therapy. Second, 19 community clinicians (79% female, M age = 42.9 years) reported on the extent to which these characteristics were present in their settings. In Step 1, specialty clinic leaders unanimously endorsed six organizational characteristics as essential and five as important within the areas of organizational policies, supervisory support, and peer clinician support. These characteristics were present in more than 90% of specialty clinics. In Step 2, therapists in community clinics reported these characteristics were minimally present in their organizations. Specialty clinic leaders exhibited consensus on the innovation-specific organizational capacity necessary to implement exposure therapy. Identified characteristics were largely absent from community clinics. Developing fiscal, policy, or organizational strategies that enhance the organizational capacity within community settings may improve the patients' access to effective treatment for anxiety disorders.

Progesterone levels predict reductions in behavioral avoidance following cognitive restructuring in women with spider phobia

BackgroundOvarian hormones have been implicated as a potential source of variability in the effectiveness of exposure therapy for anxiety disorders in women. Additionally, preclinical studies in healthy women indicate that ovarian hormones are related to cognitive modes of emotion regulation, like cognitive restructuring. The purpose of the current study was to determine whether a relationship exists between endogenous ovarian hormones and the outcomes of cognitive restructuring in clinically anxious women. MethodsNinety women with spider phobia received training in cognitive restructuring or a control task and provided a blood sample for the measurement of serum estradiol and progesterone levels. Behavioral avoidance, using a behavioral approach task with a live spider, and self-reported fear of spiders were measured at baseline and 1-week post-treatment. ResultsThe results indicated that heightened levels of progesterone, but not estradiol, at the time of cognitive restructuring predicted greater post-treatment reductions in behavioral avoidance, but not self-reported fear, amongst women who received cognitive restructuring but not those in the control group. LimitationsAs menstrual cycle phase was not assessed; the present study provides information regarding how the benefits of cognitive therapy are predicted by between-person individual differences in absolute hormone levels, but does not examine the relationship between within-person fluctuations in hormone levels and outcomes. ConclusionsThese results suggest the effectiveness of cognitive therapy for anxiety disorders in women may differ depending on endogenous levels of progesterone, and raise the possibility that progesterone could be a useful pharmacological adjunct to cognitive therapy.

Neurocognitive processes in d-cycloserine augmented single-session exposure therapy for anxiety: A randomized placebo-controlled trial

Drugs targeting N-methyl-d-aspartate (NMDA) receptors and the ability to learn new associations have been proposed as adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment. Panic disorder patients were randomised to single-dose d-cycloserine (250 mg; N = 17) or matching placebo (N = 16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces (primary outcome) and amygdala response to threat (secondary outcome). Clinical symptom severity was measured the day before and after treatment, and at 1- and 6-months follow-up (secondary outcome). d-cycloserine was associated with greater clinical recovery at 1-month follow-up than placebo (d-cyloserine 71% vs placebo 25%), with the placebo group matching the clinical gains of the d-cycloserine group during 6-months follow-up (d-cycloserine 71% vs placebo 44%). One day after treatment, threat bias for fearful faces and amygdala threat response was lower in the drug compared to placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. While this experimental study is of a preliminary nature due to the limited sample size, these findings highlight a neurocognitive potential mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate development of combination treatments for anxiety. (d-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107).

Augmenting extinction learning with D-cycloserine reduces return of fear: a randomized, placebo-controlled fMRI study.

D-cycloserine (DCS), a partial NMDA-receptor agonist, seems to be a promising enhancer for exposure therapy in anxiety disorders. It has been tested successfully in animal models of fear extinction, where DCS enhanced extinction learning. Applied in clinical studies, results of DCS-augmented exposure therapy remain ambiguous, calling for a deeper understanding of the underlying mechanisms of DCS and its exact effect on extinction learning and return of fear (ROF) in humans. In the present study, we investigated the effect of DCS-augmented extinction learning on behavioral, psychophysiological, and neural indices of ROF during a 24-h delayed recall test. Thirty-seven participants entered a randomized, placebo-controlled, double-blind, 3-day fear conditioning and delayed extinction fMRI design. One hour before extinction training, participants received an oral dose of 50 mg ofDCS or a placebo. Behavioral arousal ratings revealed a generalized ROF during extinction recall in the placebo but not DCS group. Furthermore, participants receiving DCS compared to placebo showed attenuated differential BOLD responses in left posterior hippocampus and amygdala from extinction learning to extinction recall, due to increased hippocampal recruitment in placebo and trendwise decreased amygdala responding in DCS subjects. Our finding that DCS reduces ROF in arousal ratings and neural structures subserving defensive reactions support a role for NMDA receptors in extinction memory consolidation and encourage further translational research.

No pills, more skills: The adverse effect of hormonal contraceptive use on exposure therapy benefit

Hormonal contraceptive use can aggravate existing symptoms of anxiety and depression and influence the response to pharmacologic treatment. The impact of hormonal contraceptive use on non-pharmacological treatment efficacy in anxiety disorders is less well explored. Oral contraceptives, which suppress endogenous sex hormone secretion, can alter fear extinction learning. Fear extinction is considered the laboratory proxy of exposure therapy in anxiety disorders. This study set out to examine whether oral contraceptive use is related to exposure-based treatment response in specific phobia. We recruited spider-phobic women (n = 28) using oral contraceptives (OC) and free-cycling women (n =26, No-OC). All participants were subjected to an identical in-vivo exposure. Exposure-based symptom improvement was assessed with several behavioral and subjective indices at pre-treatment, post-treatment and six-weeks follow-up. No–OC women showed higher pre-exposure fear levels on the FSQ and SPQ. OC women showed slightly less pronounced exposure benefit compared to their free-cycling counterparts (No-OC woman) as reflected by lower levels of fear reduction from pre-treatment to follow-up on the subjective level. After correction for multiple testing, OC and No-OC women showed differences in self-report measures (SPQ, FAS and SBQ) from pre- to follow-up treatment but not from pre-to post-treatment. These findings implicate that oral contraceptive use can account for differential exposure-based fear symptom improvement. Our study highlights the importance of monitoring and managing hormonal contraceptives use in the context of non-pharmacological exposure-based interventions.

Optimizing Exposure Therapy for Anxiety Disorders

Optimizing Exposure Therapy for Anxiety Disorders

Development of virtual reality as an exposure technique

Virtual reality (VR) has been investigated as amedium for exposure therapy of anxiety disorders for 20years. Various meta-analyses have provided convincing evidence of the therapeutic efficacy of exposure therapy in VR. In recent years VR technology and its applications have considerably improved. Therefore, the current state of the art of VR exposure therapy is presented. This article provides anarrative review of current research on VR exposure therapy for anxiety disorders and major directions of development in this area. After an almost exclusive focus on specific phobias in the early days, research on more complex anxiety disorders (particularly on social anxiety disorder) is increasing. In addition, VR has become established as an experimental method to probe psychopathological processes and to elucidate the mechanism of action of (VR) exposure therapy. There is still aneed for more research into VR exposure therapy, especially in complex anxiety disorders (e. g. panic disorder, agoraphobia and social anxiety disorder) and trauma-related disorders. Furthermore, VR has become established as aresearch tool. The rapid technological development gives reason to expect acontinuing increase in VR research, in clinical as well as basic research.

Systemic administration of a delta opioid receptor agonist, KNT-127, facilitates extinction learning of fear memory in rats

Strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of a delta opioid receptor agonist, KNT-127, has clear anxiolytic-like effects in rats, without impairing memory. These observations led us to hypothesize that KNT-127 might be an appropriate therapeutic agent for anxiety disorders when combined with exposure therapy. In the present study, we demonstrate that KNT-127 (3 mg/kg) facilitates extinction learning of fear memory using the contextual fear conditioning test. As expected, a partial agonist at the glycine-binding site on the glutamatergic N-methyl-d-aspartate receptor, d-cycloserine (15 mg/kg), facilitated extinction learning of contextual fear in rats. In contrast, a benzodiazepine anxiolytic, diazepam (1 mg/kg), impaired the fear extinction learning. Interestingly, the facilitatory effect of KNT-127 on extinction learning was observed not only after a 10-min re-exposure, but also after a much shorter (2-min) re-exposure to the context, while d-cycloserine was ineffective at facilitating extinction when a short-duration exposure was given. Our findings may suggest that administration of a delta opioid receptor agonist might have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders.

A Randomized Double-Blind Trial of D-Cycloserine Augmented Single-Session Exposure Therapy for Anxiety: Neurocognitive Mechanisms

Background - Drugs targeting the N-Methyl-D-aspartic acid (NMDA) system and learning rates have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We therefore investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure therapy using a single-session testbed, to inform the optimal combination of this and similar agents with psychological treatment. Methods - This randomized double-blind study was run at a single location (university environment). Unmedicated patients with panic disorder received single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Neurocognitive markers were assessed one day after treatment, including two primary outcome measures threat bias for fearful faces (FDOT) and implicit panic associations (IAT) and a secondary outcome measure amygdala response to threat. Analysis was by intention-to-treat. Outcome - Threat bias (FDOT) reduced to a larger extent following d-cycloserine (CYC) versus placebo (PLAC) but failed to reach the corrected level of significance (p < 0·025) (mean difference -19·0, 95% CI -38·04 to -0·14; p=0·042, d=0·77). There were no significant drug effects on the IAT (mean difference -0·01, 95% CI -0·32 to 0·29; p=0·93, d=0·11). On the day after treatment, amygdala threat response was lower in the drug compared to the placebo group (mean difference -0·32, 95% CI -0·61 to -0·03; p=0·023, d=1·08), with lower magnitude predicting greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (CYC 71% versus PLAC 25%, RR 2·55, CI 1·16-5·61, p=0·015). No serious side effects were reported. Interpretation - D-cycloserine-augmented single-session exposure therapy reduces amygdala response to threat, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. Trial Registration Number: clinicaltrials.gov, NCT01680107 Funding - Medical Research Council, Oxford University John-Fell-Fund (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107). Declaration of Interest: AR and AN report no conflicts of interest. MB has received travel expenses from Lundbeck for attending conferences and has acted as a consultant for J&J. CH has received consultancy fees from Lundbeck, P1vital, J&J, Pfizer and Servier. Ethical Approval: Ethical approval was obtained from the South Central - Hampshire research ethics committee. All participants gave written informed consent.

Fibroblast growth factor-2 enhancement of extinction recall depends on the success of within-session extinction training in rats: a re-analysis.

One approach to improving exposure therapy for anxiety disorders has focused on developing pharmacological adjuncts to enhance extinction, but these efforts have produced modest success in clinical trials. Understanding the factors that predict the efficacy of adjuncts will help to develop personalized treatments for anxiety. We assessed whether individual differences in within-session extinction (fear reduction during extinction training) predict the extent to which the neurotrophin fibroblast growth factor-2 (FGF2) enhances extinction recall in rats. We re-analyzed data from five experiments that involved administering FGF2 immediately after extinction training; extinction recall was assessed the following day. Regression analyses revealed that fear responses at the end, but not the start, of extinction training predicted extinction recall in FGF2- but not vehicle-treated rats. Comparisons between FGF2- and vehicle-treated rats that exhibited better or worse extinction recall (determined by a median split in freezing during extinction recall) confirmed that FGF2-treated rats exhibiting better extinction recall had significantly lower freezing at the end of extinction training relative to FGF2-treated rats exhibiting poorer extinction recall. In contrast, vehicle-treated rats did not differ in within-session extinction based on their performance at extinction recall. Finally, even when classified as having poorer extinction recall, FGF2-treated rats had stronger extinction recall than vehicle-treated rats. These results suggest that FGF2 may be most effective amongst rats that exhibit the lowest fear responses at the end of extinction training. Furthermore, FGF2 does not appear to exacerbate fear in rats that exhibit minimal fear reduction during extinction training.