My goal is to understand the mechanisms of fear and fear-related disorders, and to translate this understanding into treatment and prevention of stress- and trauma-related psychiatric disorders. These disorders include post-traumatic stress disorder (PTSD) and depression, primarily, but numerous other psychopathologies share stress as a critical risk factor.
I focus on these disorders because they both contribute to a huge amount of world-wide morbidity, they are the only psychiatric disorders with known time-points of initiation (the traumatic event), and they can be modeled effectively. More is understood about the behavioral neurobiology underlying fear in mammals than any other complex behavioral system (Figure 1). The neurobiology of emotional learning provides tremendous insight into human fear-related disorders. For these reasons, my preclinical laboratory examines the molecular neurobiology of brain systems (focusing on the amygdala) that mediate fear in animal models.
An understanding of the genes and neural systems involved in Pavlovian fear conditioning and in the extinction of fear may make it possible to understand and treat these disorders in humans. In the clinic, we are working to identify (1) candidate genes, novel biomarkers, and endophenotypes that identify enhanced risk for fear- and stress-related disorders; (2) novel treatments that enhance recovery from chronic stress-related illness; and (3) interventions that will prevent the development of PTSD and depression following acute trauma.
Diagnosing and Predicting Fear Disorders: The Discovery of Genes and Biomarkers Related to Trauma Disorders
Progress in psychiatry depends on the identification of genes and biomarkers as proxies for psychopathology, because behavioral symptoms are variable and nonspecific. We are examining the contribution of genetic and trauma-related risk factors to post-traumatic stress disorder (PTSD) in a cross-sectional study of a highly traumatized, low socioeconomic status, minority population. Although some level of fear and stress is normal after a traumatic experience, a critical question is why chronic symptoms do not occur in all who experience trauma. Individuals appear to have different vulnerabilities in their traumatic stress response. It is likely that PTSD results from an interaction of predisposing genetic and environmental risks that enhance the likelihood of a pathological stress response following severe trauma. However, almost nothing is known of the nature of the genetic contributions to PTSD and how they interact with other risk factors.
We are completing this study through a two-phase process of gathering phenotype data from nonpsychiatric patients from the general medical clinic at Grady Memorial Hospital in Atlanta. We are gathering basic demographic, child and adult trauma, depression, and PTSD phenotype data from more than 3,000 subjects, and considerably more data from 1,000 of these subjects.
PTSD is a complex disorder with symptomatic variants. Successful genetic association studies in other complex disorders have analyzed specific traits, or endophenotypes, that comprise separate aspects of the disorder. This study is also examining secondary dependent trait variables, or endophenotypes, of PTSD: (1) intrusive, hyperarousal, and avoidant symptoms; (2) physiological markers of hypothalamic-pituitary-adrenal (HPA) dysregulation; and (3) the acoustic startle response. This examination of candidate genes, trauma history, and PTSD diagnosis (as well as its component traits) will increase understanding of the vulnerability factors, both genetic and environmental, that contribute to pathological fear and stress following a trauma. This work will further the development of model systems, as well as provide novel intervention, diagnostic, and treatment approaches for this debilitating disorder.
One risk factor for PTSD following a severe trauma is past history of trauma. Through numerous studies, child abuse has been shown to impact risk of PTSD following trauma in adults. It is not, however, the only important variable. FKBP5 is an immunophilin that acts as a chaperone protein for steroid receptors, assisting in their translocation into the nucleus. My colleague, Elisabeth Binder (Max Planck Institute of Psychiatry, Munich), has shown that FKBP5 moderates emotional stability and the rate of antidepressant response. Data from our group have now demonstrated that polymorphisms at the FKBP5 locus also mediate the effect of child abuse on development of PTSD in adults (Figure 2).
These gene × environment studies are just the beginning of what will be available over the next few years from this large genotype/phenotype/biomarker data-gathering study. This study will be the largest of its kind to examine gene x environment interactions of a traumatized population. These patient-oriented data will inform the translational studies of stress and fear learning in animal models. Furthermore, with this large amount of genetic and biological data, we will also be able to ask new questions related to genetic and biological modulation of fear and stress as new discoveries are made in the laboratory.
Treatment of Fear Disorders: Extinction of Fear Memories
We use a variety of transgenic, genetically modified virus, and pharmacological approaches to enhance extinction of fear. This decrease in fear occurs when a fearful situation or memory is repeatedly encountered in the absence of negative consequences—the underlying mechanism of exposure-based psychotherapy for fear disorders.
BDNF is required for the consolidation of extinction. Brain-derived neurotrophic factor (BDNF), acting through the tyrosine receptor kinase B receptor (TrkB), is a critical mediator of learning. As there are no available selective antagonists of TrkB, we used a lentivirus encoding a dominant-negative TrkB (TrkB.t1) to antagonize BDNF signaling during extinction of conditioned fear (see Figure 3). Whereas TrkB.t1-infected rats showed normal within-session extinction of fear, their retention of extinction was impaired, suggesting that amygdala TrkB activation is required for the consolidation of stable extinction memories. This work suggests that pharmacological agonists of the TrkB receptor would act as cognitive enhancers to augment extinction-based psychotherapy in human patients with fear disorders, as we have demonstrated with an NMDA-acting agent.
D-cycloserine, an N-methyl-D-aspartate glutamate (NMDA) receptor partial agonist, enhances extinction of fear in rodent models and in humans. Knowing that extinction of fear is dependent on NMDA, we initially reasoned that the partial NMDA agonist D-cycloserine (DCS) would enhance extinction of fear if given prior to extinction learning. In collaboration with Michael Davis, David Walker, and colleagues (Emory University), we initially demonstrated this effect in rat models of conditioned fear. These results, which were the first to demonstrate clearly the selective ability to enhance the inhibitory process of extinction learning, have now been replicated in more than 20 studies by other groups using rats and mice.
With Barbara Rothbaum (Emory University), we next examined whether DCS would similarly affect the extinction of fear memories in humans. Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia (fear of heights) symptoms on all main outcome measures, including measure of fear within a virtual heights environment (Figure 4), psychophysical measures of fear, and general measures of real-world acrophobia symptoms. These improvements were evident early in treatment and were maintained at 3 months. They demonstrate that administration of DCS enhances clinically meaningful extinction of fear in humans.
These findings, which have now been replicated several times in social phobia and obsessive compulsive disorder, have generated excitement in the scientific and psychiatric community and offer a powerful approach to combining medication to enhance emotional learning with certain types of learning paradigms (e.g., behavioral exposure therapy). More than 10 clinical studies by different investigators are now under way to examine the effect of DCS on exposure for other anxiety- and fear-based disorders. We are currently examining the effect of DCS in the treatment of soldiers returning from the Iraq and Afghanistan wars.
These translational approaches allow for unique interchange of clinical and preclinical data to inform significant progress in understanding and treating psychopathology, specifically disorders of fear, which utilize a well-understood emotional circuit in the brain.
This work is supported in part by the National Institute of Mental Health, the National Institute on Drug Abuse, the National Science Foundation, and the Burroughs Wellcome Foundation.
As of April 20, 2009