Translating Across Circuits and Genetics Toward Progress in Fear- and Anxiety-Related Disorders

The symptoms of PTSD, panic, and other fear- and anxiety-related disorders can be explained, at least in part, as an inability to inhibit learned fear even during times and contexts that are safe. Notably, multiple studies have demonstrated that fear inhibition or extinction is impaired across PTSD and other anxiety-related disorders (23, 35, 39–41, 52–59). Some of the earliest reports of naturalistic observation following trauma exposure suggested that a failure to naturally recover or to learn to inhibit trauma-based fear reactions is central to these disorders (60). Other work has demonstrated that amygdala activation is high in individuals with PTSD and that there are delays in inhibition or extinction of fear. Thus, deficits in inhibiting or extinguishing fear are considered a crucial central intermediate phenotype in PTSD and related anxiety- and fear-related disorders.

The observation of failure to extinguish as an important construct in fear- and anxiety-related disorders is exciting for several reasons. From a clinical perspective, exposure-based therapy techniques—which are a central element of cognitive-behavioral therapy (CBT) and its many more specific versions, including cognitive processing therapy, eye movement desensitization and reprocessing, skill training in affective regulation, and of course prolonged exposure therapy—are among the best empirically supported treatments across the range of fear- and anxiety-related disorders. Increasingly, the elements that underscore the emotional learning process of extinction of threat behaviors are appreciated to be the same elements underlying the efficacy of exposure to feared cues and contexts. This provides for a relatively straightforward target for intervention, in which neural circuitry and behavioral psychology intersect in a predictable, reliable, and robust manner.

Notably, the Research Domain Criteria project (RDoC) of the National Institute of Mental Health (61) chose “negative valence systems” and, specifically, the constructs of acute threat (fear), potential threat (anxiety), and sustained threat (chronic stress) as among the first RDoC templates. This was in part due to the progress in understanding the neurocircuitry of fear, threat, and aversive behaviors across levels of analyses and model systems. The translation of extinction of fear across species and interventions provides a great example.

Pavlov initially defined extinction of conditioned fear in his classic studies (22). Decades later, historical leaders in the field such as Rescorla and Bouton provided behavioral evidence that extinction of a prior fear memory did not lead to its forgetting or erasure, but rather to an apparent new memory trace representing fear memory inhibition (62–65). In the early 1990s, Michael Davis’s lab at Yale University initially demonstrated the critical observation that extinction of fear required active new amygdala-dependent synaptic plasticity (66, 67). In the past two decades, a considerable amount of additional research has examined cellular and molecular mechanisms of fear inhibition and extinction. Substantial data now support a variety of mechanisms underlying synaptic plasticity as critical for new extinction learning. For example, brain-derived neurotrophic factor (BDNF) and its receptor TrkB have been shown to be required for memory formation related to fear and its extinction (68–71). Furthermore, following the demonstration that extinction memories required N-methyl-d-aspartate (NMDA)–dependent plasticity, we demonstrated that a partial agonist at the NMDA receptor, d-cycloserine, enhances the consolidation of extinction of fear in rodents (72) and began to translate this finding to enhancement of extinction paradigms in humans (73). This finding has now been replicated repeatedly in rodents and humans (74–81).

Notably, additional studies that failed to replicate the d-cycloserine effect, along with a number of more recent negative findings, have now begun to be better understood with the observation that NMDA-dependent plasticity enhances both memory reconsolidation and memory extinction (43, 82, 83). These two opposing processes of strengthening versus inhibiting preexisting memory traces always appear to be at odds on reactivation of a prior fearful memory. This is particularly interesting with clinical translation, given the long-standing observation that reexposure is not always successful, and a variety of tools have been implemented clinically to try to ensure and improve extinction processes over sensitization or reconsolidation processes during memory exposure. The use of cognitive enhancers to improve extinction is now an accepted translational paradigm from bench to bedside and is considered a paradigm-shifting approach. However, this approach has the limitation that both BDNF- and NMDA-dependent plasticity support both extinction and fear learning. Next-generation approaches, as discussed later, hope to identify cell populations or microcircuits, based on translational neuroscience, that are valence-specific and support fear inhibition or extinction and not fear acquisition, expression, or reconsolidation. Targeting cells and circuits, either pharmacologically or neurotherapeutically, that directly enhance extinction or block reconsolidation could provide a true intersection of targeted intervention, combining neurobiological insights with psychotherapeutic tools to drive specific memories.

In addition to the amygdala, the anterior cingulate cortex (ACC) is one region involved in associative memory formation, conflict and aversive memory expression, and PTSD and anxiety disorders (34, 84, 85). A study reported in this issue of the Journal by Yang et al. (86) examines both the behavioral and semantic representation, as well as neural activation of the ACC, in panic-related representations and exposure therapy in panic disorder. From a translational perspective, this work is exciting in a number of ways. While the concept of priming is primarily a human psychology construct, behavioral studies in model systems have long demonstrated the role of “preparedness” for a threat and overactivation of a threat network, via generalization of cues and contexts that are more likely to contribute to a threat response, despite a relatively low actual probability of danger. Extinction of cues (which appears to depend on the hippocampus/amygdala and mPFC/ACC) in large part is context based, and successful extinction often leads to generalization of the extinction contexts as well (50, 87). Thus, it is exciting and promising that exposure-based CBT for panic disorder results in decreased priming and, possibly, increased generalization of extinguished cues (with decreased negative valence), along with decreased brain network activity corresponding to such processes.

Recent work has also examined unbiased data-driven approaches to understanding brain activity patterns that may underlie different biologically distinct forms of anxiety and fear-related disorders. In another article in this issue, Maron-Katz et al. (88) examine resting-state functional MRI (fMRI) and dynamic brain activity to detect subtypes of PTSD. In parallel with neuroimaging, new analytic approaches with high-density EEG are allowing unsurpassed collection of real-time brain activity in a low-cost fashion that might be more feasible to disseminate. Toll et al. (89) further demonstrate progress in biotyping in PTSD using EEG in this issue of the Journal. In addition to the possibility of novel pathways and subgrouping tools, it is interesting that among the primary fMRI findings in the Maron-Katz et al. study (88) was the identification of visual and sensorimotor findings important in PTSD. As noted by the authors, although abnormalities in frontoparietal connectivity and activity in PTSD case subjects have been reported in several studies, abnormalities in connectivity and activity of sensorimotor and visual regions have been less often seen. Importantly, the translational literature would suggest that these areas are highly likely to be involved in the aftermath of trauma exposure. In fact, in mice, repeated auditory tone–paired foot shocks have been shown to increase voxel-based morphometry gray matter density, likely a result of increased spine and dendritic spine density, in the auditory cortex, sensorimotor regions, and amygdala (90–93). These data, combined with a robust literature on structural representation of memory engrams across a large range of primary and secondary sensory areas, suggest that while the amygdala, dorsal ACC, and hippocampus may be “hubs” for memory formation, the actual encoding and sensitization of trauma is likely distributed across the full network encoding the memory (2, 94–96). Thus, in addition to the important and hopefully soon-to-be-clinically-utilized tools of EEG- and MRI-based biotyping for anxiety disorders, understanding the networks that may be differentially regulated in these biotypes will expand our neuroscience understanding of risk and resilience.

The “holy grail” of a neural circuit model of anxiety disorders would be to utilize the mechanistic understanding of neural circuitry for direct intervention and treatment. Denys et al. (97), in a study reported in this issue, add to the growing literature suggesting the effectiveness and safety of deep brain stimulation (DBS) in treatment-refractory OCD. Of note, their target—the anterior limb of the internal capsule—is a critical white matter juncture involved in amygdala, ventromedial PFC, and nucleus accumbens (NAcc) connectivity that has been demonstrated across animal model systems to mediate aspects of anxiety and repetitive behaviors (98–101). Furthermore, amygdala-striatal circuit activation has been shown to decrease long-term fear and threat processing in model systems, and the NAcc and broader striatum have long been associated with avoidance responses in behavioral learning models (101–103)—and, notably, avoidance is often among the most refractory of clinical symptoms in treatment of OCD. This literature also brings together interesting findings associating threat/fear/amygdala networks with addiction/appetitive/NAcc networks. Such preclinical work has recently influenced novel approaches to behavioral exposure therapy as well, by actively bringing reward systems online at the culmination of threat exposures, which appears to enhance the efficacy of extinction and exposure for anxiety- and fear-related disorders (104, 105).

In addition to interesting neural circuit approaches for discovery and intervention, ongoing work by large groups of investigators, including the Psychiatric Genomics Consortium Anxiety and PTSD work groups, the UK Biobank, and the Million Veteran Program, have worked to gather data on hundreds of thousands of individuals for large-scale discovery of the genetic architecture underlying anxiety- and fear-related disorders. The latest of these groundbreaking studies is published in this issue by Levey et al. (106), who examine the largest GWAS of anxiety to date. Notably, with fear- and anxiety-related disorders having approximately twice the incidence in females as males, the authors’ identification of the estrogen receptor gene (ESR1) as one of the genes robustly associated with anxiety symptoms was particularly exciting. Additionally, they identified the CRHR1 gene (Corticotropin Releasing Hormone Receptor 1) in gene-based association analyses. This is particularly exciting given the previous findings that the locus—including single-nucleotide polymorphisms associated with gene expression within the CRHR1 locus (among a number of other genes)—was a top hit meeting genome-wide significance for hyperarousal symptoms in PTSD and alcohol intake in previous recent publications from the same group (21, 107). This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders. From a translational perspective, some of these findings are enormously exciting. For example, the role of estrogen in the regulation of fear and fear extinction has been gaining much traction recently, and the underlying mechanisms for ESR1 functioning in the neural circuits of threat are being identified (108–112). Certainly, identification of gene pathways that were previously unknown will lead to a whole array of new biology to integrate within the known neural circuit pathways. Perhaps the most exciting development from these recent large-scale GWASs is that they may also provide some GWAS-level biological support for the role of the hypothalamic-pituitary-adrenal (HPA) axis in fear- and anxiety-related disorders. Since its discovery, corticotropin-releasing hormone (CRH) has been a leading translational target in understanding amygdala-hypothalamic-pituitary and other subcortical regulation of the threat reflex (113–118). Preclinically, overexpression of CRH or genetic activation of CRH-expressing neurons leads to increased fear and deficits in fear extinction. Conversely, CRH knockout or silencing these cells has opposite effects (114, 119–123).

Of note, given the tremendous amount of support for HPA dysregulation and CRH overactivity in depression, PTSD, and fear-related disorders, antagonists targeting CRHR1 were developed with tremendous excitement. Unfortunately, recent trials of these compounds were negative in depression, social anxiety, and PTSD (124–127). The assumption is that the drugs, based on our preclinical model of stress disorders, are not effective in the human disorders and that this may represent a failure of translation, which may still be true. However, an important and yet untested possibility is that at the level of precision of a specific neuropeptide antagonist, there may be either sufficient redundancy in the system that monotherapy is inadequate or, perhaps more likely, biological heterogeneity is such that until the appropriate, perhaps transdiagnostic, biological subtypes of patients with specific dysregulation in their CRH systems are stratified for treatment and the ideal treatment conditions (e.g., baseline or with exposure therapy, etc.) are identified, translation of such biological findings will not be successful. Notably, secondary analysis of the PTSD–CRHR1 antagonist study suggests exactly this—that it may be helpful for targeted patients and targeted intermediate phenotypes (124, 128).

The unbiased identification of the CRHR1 locus in large-scale anxiety- and fear-related disorder GWASs surely should make the field reexamine the disconnect between the biology and targeted pharmacotherapy trials to date. Importantly, how best to integrate data from many gene pathways, each with small effect size, into appropriate treatment targets, perhaps by targeting hub genes or identifying the correct combination of therapies to target the correct combination of critical genes, remains a challenge across all genome-driven approaches to new therapies.