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.     

Optimizing inhibitory learning during exposure therapy

Prevailing models of exposure therapy for phobias and anxiety disorders construe level of fear throughout exposure trials as an index of corrective learning. However, the evidence, reviewed herein, indicates that neither the degree by which fear reduces nor the ending fear level predict therapeutic outcome. Developments in the theory and science of fear extinction, and learning and memory, indicate that 'performance during training' is not commensurate with learning at the process level. Inhibitory learning is recognized as being central to extinction and access to secondary inhibitory associations is subject to influences such as context and time, rather than fear during extinction training. Strategies for enhancing inhibitory learning, and its retrieval over time and context, are reviewed along with their clinical implications for exposure therapy and directions for future research.     

Optimierung expositionsbasierter Therapie

Exposure is an effective approach for treating anxiety disorders, although a substantial number of individuals fail to benefit or experience a return of fear. Research results suggest that anxious individuals show deficits in the mechanisms underlying exposure therapy, such as inhibitory learning. Targeting these processes may help improve the efficacy of exposure; however, there has been little discussion of how to implement this model in clinical practice. The primary aim of this paper is to provide examples to clinicians for how to apply this model to optimize exposure therapy, in ways that distinguish it from a fear habituation approach and a belief disconfirmation approach. Optimization strategies include (1) expectancy violation, (2) deepened extinction, (3) occasional reinforced extinction, (4) removal of safety signals, (5) variability, (6) retrieval cues, (7) multiple contexts and (8) affect labeling. Case studies illustrate methods of applying these techniques with a variety of anxiety disorders.     

Subjective responses to emotional stimuli during labeling, reappraisal, and distraction

Although multiple neuroimaging studies suggest that affect labeling (i.e., putting feelings into words) can dampen affect-related responses in the amygdala, the consequences of affect labeling have not been examined in other channels of emotional responding. We conducted four studies examining the effect of affect labeling on self-reported emotional experience. In study one, self-reported distress was lower during affect labeling, compared to passive watching, of negative emotional pictures. Studies two and three added reappraisal and distraction conditions, respectively. Affect labeling showed similar effects on self-reported distress as both of these intentional emotion regulation strategies. In each of the first three studies, however, participant predictions about the effects of affect labeling suggest that unlike reappraisal and distraction, people do not believe affect labeling to be an effective emotion regulation strategy. Even after having the experience of affect labels leading to lower distress, participants still predicted that affect labeling would increase distress in the future. Thus, affect labeling is best described as an incidental emotion regulation process. Finally, study four employed positive emotional pictures and here, affect labeling was associated with diminished self-reported pleasure, relative to passive watching. This suggests that affect labeling tends to dampen affective responses in general, rather than specifically alleviating negative affect.     

Pavlovian conditioned inhibition of fear during shuttlebox avoidance behavior

Three experiments explored the development and function of conditioned inhibition of fear during the acquisition and maintenance of shuttlebox avoidance behavior. The development of inhibition to an exteroceptive feedback stimulus was found to be a function of the number of successive avoidance responses to which the animal had been trained and of the duration of the intertrial interval, a parameter shown also to affect the rate of acquisition of avoidance learning. Master animals who learned the instrumental avoidance response, and yoked animals who did not, showed equivalent inhibitory fear conditioning in each experiment. The results of one experiment suggest that conditioned inhibition plays no important role in “protecting” fear conditioned to the discrete warning signal during avoidance maintenance. These data indicate that feedback stimuli develop their inhibitory properties by a Pavlovian process and that certain aspects of their function may, therefore, be readily understood within the framework of mediational two-process learning theory.     

Different mechanisms of fear extinction dependent on length of time since fear acquisition

Fear extinction is defined as a decline in conditioned fear responses (CRs) following nonreinforced exposure to a feared conditioned stimulus (CS). Behavioral evidence indicates that extinction is a form of inhibitory learning: Extinguished fear responses reappear with the passage of time (spontaneous recovery), a shift of context (renewal), and unsignaled presentations of the unconditioned stimulus (reinstatement). However, there also is evidence to suggest that extinction is an "unlearning" process corresponding to depotentiation of potentiated synapses within the amygdala. Because depotentiation is induced more readily at short intervals following LTP induction and is not inducible at all at a sufficient delay, it may be that extinction initiated shortly following fear acquisition preferentially engages depotentiation/"unlearning," whereas extinction initiated at longer delays recruits a different mechanism. We investigated this possibility through a series of behavioral experiments examining the recoverability of conditioned fear following extinction. Consistent with an inhibitory learning mechanism of extinction, rats extinguished 24-72 h following acquisition exhibited moderate to strong reinstatement, renewal, and spontaneous recovery. In contrast, and consistent with an erasure mechanism, rats extinguished 10 min to 1 h after acquisition exhibited little or no reinstatement, renewal, or spontaneous recovery. These data support a model in which different neural mechanisms are recruited depending on the temporal delay of fear extinction.     

The Comprehensive Resource Model®: Overview of basic affects in adversity & effective treatment for complex reactions to trauma

Much of the theoretical focus in post‐traumatic stress disorder has been on the role of the amygdala, the hippocampus and the prefrontal cortex. Crucially, in unresolved traumatic experiences that underlie clinical presentations, this focus misses the brain areas key to the defence responses of fight, flight and freeze—and the associated affects of anger, fear and grief. The periaqueductal gray in the midbrain, with the hypothalamus, is essential for these somatic and emotional responses to traumatic experiences. We argue that when treatment approaches thought to work at the higher brain levels have been ineffective, it is because they have failed to engage the midbrain and hypothalamic sources of the affective responses to the trauma and to the memory of it. Basic affects have been so overwhelming that dissociation, or a similarly protective neurochemical capping mechanism, has prevented full resolution of the affective content of the adversity. Treatment with the Comprehensive Resource Model^® (CRM) aims to clear the clinically relevant residues of adverse experiences by resolving the emotional responses accessed through the body memories. When the trauma has led to overwhelming distress, and/or dissociation, there is a necessity for robust resourcing to be in place before the emotional intensity of that distress is accessed. Resourcing needs to be as proximal to the re‐experience as possible to promote complete resolution and in some psychotherapy modalities, the supports provided are somewhat remote from the crucial moments of processing. Therefore, we describe how the CRM seeks to have robustly resourced states present concurrently with traumatised states to avoid overwhelming emotional distress. This allows safe entry into the deepest pain residual from the traumatic event so that it is not overwhelming during processing of the memory, and does not lead to further dissociation, allowing the individual to remain fully present throughout. This “stepping into the affect” can then be so rapidly effective that we also argue that CRM is not an exposure treatment; re‐orientation to the deepest content of the experience resolves the residual distress quickly and permanently through memory reconsolidation. Re‐learning at upper brain levels will then follow from the revoking of the affective power, which has previously driven stimulus/context and response learning in the amygdala, hippocampus and prefrontal cortex.     

The Suitability of an Inhibitory Learning Approach in Exposure When Habituation Fails: A Clinical Application to Misophonia

Recent findings have led to a reconceptualization of the mechanisms that account for the efficacy of exposure-based treatments. Termed the “inhibitory learning model,” this approach emphasizes new learning when confronted with previously avoided stimuli rather than merely the cessation of fear or aversive emotional responding. In this paper, we propose the applicability of the inhibitory learning model for conditions and contexts in which simple exposure does not produce habituation. We illustrate this application from an in-progress randomized controlled treatment trial for adults with misophonia. Misophonia is a condition marked by strong aversive reactions to specific sounds. It is a difficult to treat and understudied syndrome. All participants in the trial received exposure, either before or after a stress management module of treatment. Exposure treatment emphasized altered expectancies for the target sounds as well as deliberate practice in hearing sounds on the individually developed hierarchy. Inhibitory learning strategies were employed to increase treatment adherence and commitment, shape patient behavior during exposures, manufacture negative prediction errors, increase perceived control over reactions, and promote learning that generalized to functional improvements. The findings are discussed in the context of future applications of the inhibitory learning model for psychopathology associated with avoidance.     

Eye movements during recall of aversive memory decreases conditioned fear

Cognitive-behavioral therapy for anxiety disorders typically involves exposure to the conditioned stimulus (CS). Despite its status as an effective and primary treatment, many patients do not show clinical improvement or relapse. Contemporary learning theory suggests that treatment may be optimized by adding techniques that aim at revaluating the aversive consequence (US) of the feared stimulus. This study tested whether US devaluation via a dual task – imagining the US while making eye movements – decreases conditioned fear. Following fear acquisition one group recalled the US while making eye movements (EM) and one group merely recalled the US (RO). Next, during a test phase, all participants were re-presented the CSs. Dual tasking, relative to the control condition, decreased memory vividness and emotionality. Moreover, only in the dual task condition reductions were observed in self-reported fear, US expectancy, and CS unpleasantness, but not in skin conductance responses. Findings provide the first evidence that the dual task decreases conditioned fear and suggest it may be a valuable addition to exposure therapy.     

Optimizing Exposure Therapy for Pathological Health Anxiety: Considerations From the Inhibitory Learning Approach

Exposure therapy has demonstrated its efficacy in the treatment of pathological health anxiety—however, psychotherapy research reveals that many patients do not show a clinically significant change. Therefore, improvements are necessary to optimize psychotherapy for pathological health anxiety. Most treatment rationales refer to habituation during exposure as the central mechanism of change. However, there is evidence that extinction learning is mediated by inhibitory learning processes. Targeting these processes may help to improve treatment outcomes in pathological health anxiety. The aim of this review was to adapt, from the inhibitory learning approach and empirical findings, the most promising strategies for the exposure-based treatment of pathological health anxiety. The exposure-optimizing strategies adapted are expectancy violation, combination, variability in contexts and stimuli, affect labeling, and removal of safety signals. A case example illustrates how to implement these methods for patients with pathological health anxiety.     

Brief Imaginal Exposure for PTSD: Trajectories of Change in Distress

Preliminary evidence shows that brief, condensed imaginal exposure only interventions can be effective in the treatment of PTSD, but we need to understand its mechanisms of action. Consistent with extinction learning and retrieval processes, the present study examined whether a pattern of between-session distress reduction observed during standard prolonged exposure (PE) therapy would be observed and predict outcome. Sixty-three patients with PTSD were enrolled in two clinical trials using our treatment protocol consisting of six daily 50-min sessions focusing on imaginal exposure and processing only. Individual patient trajectories of distress reduction were examined over the course of the five imaginal exposure sessions (Sessions 2-6). Overall, significant linear distress reduction was observed for anticipatory (d = 1.18), peak (d = 1.83), and ending imaginal exposure distress (d = 1.21). Consistent with extinction learning, the steeper slope of peak distress (d = 1.03) and end distress (d = 0.68) across imaginal exposure sessions strongly predicted decreases in PTSD symptoms. Distress reduction across sessions was predicted by higher baseline avoidance and hyperarousal but not reexperiencing symptoms. This condensed format of daily 50-min sessions without in vivo exposure may be operating via similar extinction learning processes as longer protocols. Our clinical observations suggest that the brief daily format may offer the advantage of allowing each session to build on the previous one to promote meaningful shifts in the retrieval of the trauma memory. Brief imaginal exposure and processing may be a viable option for PTSD patients in settings where brief interventions are needed. Understanding potential change processes and baseline predictors of change brings us closer toward precision medicine in treating PTSD.     

Emotion regulation of fear and disgust: differential effects of reappraisal and suppression

Although excessive fear has been central to traditional conceptualisations of the anxiety disorders, recent research suggests that disgust may also play a role in the development of some anxiety disorders. While dysregulation of emotion may confer risk for the development of anxiety disorders, it remains unclear if there are differences in the extent to which fear and disgust can be effectively regulated. To fill this important gap in the literature, unselected participants (N?=?95) experienced fear or disgust via video exposure, and they were instructed to employ either reappraisal or suppression to regulate their emotional experience while viewing the videos. For those exposed to fear-relevant content, change in emotional distress did not significantly differ between those that suppressed and those that reappraised. However, significantly less emotional distress was observed for those that reappraised compared to those that suppressed when exposed to disgust-relevant content. Although physiological arousal varied over time as a function of the emotional content of the videos, it did not vary as a function of emotion regulation strategy employed. These findings suggest that reappraisal may be especially effective in regulating verbal distress when exposed to disgusting cues in the environment. The implications of these findings for the treatment of anxiety disorders that are characterised by excessive disgust reactions will be discussed.     

Inhibitory Learning for Anxiety-Related Disorders

This article reviews the articles in this issue that describe the strategies derived from the inhibitory learning model as applied to exposure therapy for anxiety disorders. The major principles of inhibitory learning are to create and strengthen nonthreat associations in memory (largely by engaging prefrontal cortical regions), and to effectively retrieve those nonthreat associations in the long term. Several case vignettes are provided that demonstrate how the principles of inhibitory learning (which include maximizing expectancy violations, limiting distraction, fear antagonistic actions, deepened extinction, elimination of safety behaviors, occasional reinforced extinction, increasing variability of exposures and offsetting reinstatement and context renewal effects) can be applied in clinical practice.     

Dropping Safety Aids and Maximizing Retrieval Cues: Two Keys to Optimizing Inhibitory Learning During Exposure Therapy

The inhibitory learning model of exposure therapy posits that clinical anxiety is most effectively treated when clinicians employ strategies that maximize the (a) violation of negative expectancies and (b) generalization of nonthreat associations. Translation of basic learning research to exposure therapy via this explanatory model underscores two keys to optimizing inhibitory learning during exposure: dropping safety aids and maximizing retrieval cues. Although topographically similar, safety aids and retrieval cues are functionally distinct as well as therapeutically incompatible. In the present article, we delineate safety aids and retrieval cues in the context of exposure therapy from an inhibitory learning perspective, providing illustrative case examples of how clinicians may address the two when treating patients with clinical anxiety.     

Does threatening imagery sensitize distress during contaminant exposure?

Prominent models of fear focus on the role of cognition in the development and maintenance of maladaptive responses. Little research, however, has evaluated the impact of cognition on distress reduction. The current study uses an experimental design to examine the effect of different types of imagery (moving harm, static harm, and safety) on reduction of distress associated with a contaminating stimulus in a normal university sample. Results indicate that use of moving harm imagery sensitizes distress during a 30-min exposure, whereas static harm and safety imagery reduce distress. These findings demonstrate that cognitive factors can moderate affective response during exposure. Clinical implications for the treatment of anxiety disorders are discussed.     

睡眠对恐惧学习的影响及其认知神经机制

睡眠问题可能会诱发恐惧相关情绪障碍(焦虑、创伤性应激障碍、恐怖症等),研究睡眠影响恐惧学习的认知神经机制,有助于增强对恐惧相关情绪障碍的预测、诊断和治疗。以往研究表明睡眠剥夺影响恐惧习得和消退主要是通过抑制vmPFC活动,阻碍其与杏仁核的功能连接,从而导致恐惧习得增强或是消退学习受损。进一步研究发现睡眠不同阶段对恐惧学习相关脑区有独特的影响:剥夺(缺乏)快速眼动睡眠会抑制vmPFC活动、增强杏仁核、海马激活,导致恐惧习得增强,消退学习受损,此外边缘皮层的功能连接减少破坏了记忆巩固(恐惧记忆和消退记忆);而慢波睡眠主要与海马变化有关,慢波睡眠期间进行目标记忆重激活可促进恐惧消退学习。未来研究需要增加睡眠影响恐惧泛化的神经机制研究、及昼夜节律中断对恐惧消退的影响,以及关注动物睡眠研究向人类睡眠研究转化中存在的问题。     

Learning to fear a second-order stimulus following vicarious learning

Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5–11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear-related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus.     

Endocannabinoids and stress

Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans.     

Maternal positive responses to a distressed infant simulator predict subsequent negative affect in infants

Existing evidence indicates that maternal responses to infant distress, specifically more sensitive and less inconsistent/rejecting responses, are associated with lower infant negative affect (NA). However, due to ethical and methodological constraints, most existing studies do not employ methods that guarantee each mother will be observed responding to infant distress. To address such limitations, in the current study, a distressed infant simulator (SIM), programmed to be inconsolable, was employed to ensure that mothers (N = 150; 4 months postpartum) were observed responding to infant distress. Subsequently, maternal report of infant NA and an early aspect of regulatory capacity, sootheability, were collected at eight-months postpartum, and observational assessments of infant fear and frustration, fine-grained aspects of NA, were collected at 12-months of age. After controlling for infant sex, the proportion of time mothers spent using soothing touch during the SIM task was related to less overall maternal reported NA and sadness at eight-months postpartum. Similarly, greater use of touch was associated with less fear reactivity, and greater maternal use of vocalizations was related to lower infant frustration, at 12-months postpartum. Specific maternal soothing behaviors were not related to infant soothability at 8 months postpartum. Total time spent interacting with the SIM was not related to infant temperament, suggesting that type of soothing, not quantity of interactions with distressed infants, is important for reducing infant NA. The implications of these findings and important future directions are discussed.     

Cross-US reinstatement of human conditioned fear: Return of old fears or emergence of new ones?

Re-exposure to the unconditioned stimulus (US) following fear extinction in the laboratory produces reinstatement of fear. Similarly in clinical situations, anxiety patients may experience adverse events that reinstate fear following successful exposure therapy. The current study employed two USs, shock and loud noise, to examine whether a US that is qualitatively different but of the same valence as the original acquisition US can produce reinstatement in human fear conditioning. Both standard and cross-US reinstatement manipulations led to elevated fear as indexed by skin conductance. However, cross-US reinstatement was accompanied by elevated expectancy of the US that had been presented during the reinstatement manipulation, not the US that had been used to establish fear in acquisition. This result implies that reinstatement may involve the development of new fears. Context conditioning and cognitive processes were implicated as possible mechanisms. The current findings suggest that clinical relapse attributed to reinstatement may not always reflect the reactivation of old fears but may instead represent new fears worthy of clinical examination.