PTSD: National Center for PTSD
Clinical Neurosciences Division Research
Clinical Neurosciences Division Research
The Clinical Neurosciences Division, located in West Haven, CT, supports the National Center's mission through its specialization in neurobiological, imaging, and genetic studies of the physical basis of traumatic stress, risk and resilience factors, and pharmacotherapy and rehabilitation for PTSD and comorbid conditions.
The Division continues to grow its clinical trials program, which is essential in translating neurobiological knowledge into tangible benefits for patients suffering from PTSD and comorbid disorders. Investigators are examining several new pharmacotherapeutic agents to target PTSD, including: 1) the glutamate modulating agent Riluzole, 2) the N-methyl-D-asparate (NMDA) receptor antagonist Ketamine 3) the metabotropic glutamate receptor 2/3 (mGlu2/3) agonist Pomaglumetad Methionil in civilian trauma survivors, 4) the fatty acid amid hydrolase (FAAH) inhibitor URB597, 5) the endogenous hormone neuropeptide Y (NPY), and 6) the low-trapping NMDA receptor antagonist Lanicemine, which may have a better side effect profile than Ketamine. The Lanicemine project will include electrophysiological and functional neuroimaging studies to confirm target engagement and examine potential biomarker applications.
Other trials examine the immunosuppressant Rapamycin for depression and the sulfonamide anticonvulsant Zonisamide plus enhanced Cognitive Processing Therapy for PTSD and comorbid alcohol dependence. Investigators are planning studies of Buprenorphine and Naloxone for PTSD and co-morbid opioid dependence, as well as a trial to see if progesterone may reduce stress reactivity in individuals with alcohol use disorder and PTSD that also examines gender differences on stress and cravings. A trial comparing standard care with an intensive integrated treatment trial for OEF/OIF Veterans with comorbid chronic pain and PTSD is ongoing, while a study of the alpha-1 adrenergic receptor antagonist Prazosin for PTSD and alcohol use was recently completed.
The Division is a leader in neuroimaging and contributes to the Center's strategic objective of developing PTSD biomarkers. The Division is co-directing the STRONG STAR Consortium to Alleviate PTSD (CAP) Neuroimaging Core, which will capitalize on the extensive neuroimaging expertise available through the National Center, Yale University, and the STRONG STAR infrastructures. A main objective of the Neuroimaging Core is the development of new technology and methods to non-invasively investigate in vivo, human neuronal chemicals, structure, and function. Additionally, investigators will conduct an innovative project to develop a testable hypothesis explaining the mechanism linking social and environmental stress to changes in brain structure and function commonly observed in stress-related disorders. Specifically, studies will be performed to examine the effects of glutamate transporter expression on stress response and resilience.
Several other projects are ongoing using advanced neuroimaging methodologies, in conjunction with the aforementioned pharmacotherapy trials. These projects will yield additional insight into the neurobiology of PTSD and the neural mechanisms involved in treatment response or resistance. Work also continues on a biomarker informed placebo controlled trial designed to investigate the utility of a recently developed 7 Tesla 1H-MRS methods combined with magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) to evaluate the psychopharmacologic effects of riluzole on PTSD symptoms, hippocampal volume and anterior cingulate glutamate levels.
The Division is also employing positron emission tomography (PET) techniques to integrate complex neurobiological models across several neurochemical systems and structures in order to provide a more comprehensive understanding of PTSD. Preliminary work is underway within the PET lab to develop the necessary technology to perform awake nonhuman primate PET imaging, which will add to preclinical datasets and provide a foundation for additional clinical studies. PET techniques are also being used in the investigation of several neurotransmitter systems. Investigators are using a newly developed paradigm to study the effects of ketamine on mGluR5 availability in humans to will better understand the neural effects of ketamine and its efficacy for PTSD and a new radioligand to examine the cholinergic system in PTSD and mood disorders. A third ongoing study is evaluating kappa opioid receptor availability in an amygdala-ventral striatal-anterior cingulate cortical circuit and its relationship to a heterogeneous NIMH Research Domain Criteria (RDoC) based phenotypic expression of depression.
The Division has a number of ongoing cognitive neuroscience studies using fMRI. Areas being explored include: 1) the neural correlates of aversive learning, 2) contextual fear conditioning, 3) vulnerability to cognitive-affective interference within the inescapable stress model of PTSD, 4) neurocognitive mechanisms related to impaired decision-making, valuation, and choice under conditions of uncertainty and 5) reconsolidation-extinction learning. Taken together, this work may yield insights into real-world clinical phenomena and decision making in individuals with PTSD. Cognitive neuroscientists at the Division are also continuing to evaluate the effect of the cannabinoid system on extinction learning using Delta9-THC and a novel fatty acid amide hydrolase (FAAH) inhibitor.
Investigators are exploring the efficacy of neurofeedback in conjunction with real-time functional magnetic imaging (rt-fMRI) for reducing psychiatric symptoms associated with PTSD and related conditions. The use of real-time neurofeedback to target specific brain regions is a promising application to treat many psychiatric conditions and may aid in emotional control, and self-regulation of negative affect, such as fear and anxiety. Data analysis on other neuroimaging projects may yield key clinical information to establish relevant biomarkers of NMDA-R dysfunction.
Molecular Neuroscience, Genetics, and Stress Vulnerability
The Division is the main research site for the Leahy-Friedman National PTSD Brain Bank, which will characterize the molecular and cellular pathophysiology underlying PTSD and provide the postmortem samples required for continued studies. The results of these studies will be made available to the scientific community via a web-based system to allow for the greatest, widespread use of this novel and critical information. Together these studies will clarify alterations at the molecular and cellular levels that are associated with PTSD and may lead to better treatments for this disorder.
The Division continues work on the molecular mechanisms and circuitry underlying the role of ketamine in extinction of fear memory, which has further informed plans for clinical studies, including the ketamine memory reconsolidation study and the Rapamycin clinical trial. Preclinical work also includes studies of whole genome microarray expression to examine abnormally expressed gene products, including SGK1 and REDD1, in postmortem brain samples from individuals with a history of PTSD, as compared to matched controls.
Studies of the impact of stress on cellular physiology may help to identify novel treatment strategies and diagnostic approaches. A project recently underway involves assessment of cortical thinning using structural MRI to study if a history of childhood trauma increases the risk of vulnerability to negative outcomes following exposure to trauma or military combat. Ongoing Brain & Behavior Research Foundation (NARSAD) funded clinical imaging studies are evaluating the role of social and environmental stress in changes in brain structure and function commonly observed in PTSD. Results from some of this work suggest that glutamatergic based pharmacotherapies which act to enhance the function of the primary glutamate transporter GLT1 may attenuate and/or reverse the effects of stress in the prefrontal cortex and hippocampus. New clinical imaging trials to examine the effects of glutamate transporter expression on stress response and resilience to stress are being planned.
Over the past year, Division investigators have built upon their published work from the genome-wide association study (GWAS) that identified TLL1 as a new susceptibility gene for PTSD. The Division has also maintained involvement with the Psychiatric Genomics Consortium PTSD group, and co-leads a VA PTSD GWAS project with colleagues from University of California, San Diego. This project has been highly productive in its application of linkage and association paradigms to identify chromosomal regions likely to harbor genes influencing risk for anxiety disorders and for anxiety-related traits. Projects involving an analysis of PTSD-associated DNA methylation changes and a study to model sex effects in PTSD are continuing. Another project is utilizing a new modeling strategy by adding an interaction term of sex and genetic variant in the statistical model. Genetic variants that differentially contribute to the likelihood of PTSD between men and women are being mapped separately in a combined single model without stratifying men and women to increase power. This new modeling approach is expected to detect more novel genetic variants in a genome-wide scan, which is in the process of data analysis. Findings may help explain why the prevalence of PTSD is higher in women than in men after exposure to a traumatic event.
An R01 supported gene-environment-wide interaction study (GEWIS) of smoking, hazardous drinking, and other health risk behaviors is being planned for 2015. This project will conduct secondary analyses using data from the Army Study to Assess Risk and Resilience in Service members (Army STARRS) and will include data from 16,000 Servicemembers. The goal of this proposal is to identify genetic and gene-environmental (GxE) predictors of health risk behaviors that are associated with significant morbidity and mortality.
Epigenetic studies in support of the NIMH RDoC initiative aims to develop a database necessary to derive a new psychiatric nomenclature informed by neuroscience, genetics, and psychology, and investigate risk and resilience in maltreated children. These two interrelated lines of research, conducted in a sample of maltreated children, have a number of advantages for the RDoC project, including: study of a patient cohort that is frequently treatment resistant to standard clinical interventions; examination of a relatively homogenous sample with the onset of psychopathology proposed to be associated with stress-related mechanisms; and well-established relevant animal models to facilitate translational research.
Additional research investigating stress vulnerability involves children and their families who have been exposed to high levels of stress and trauma. Over the past 4 years, in collaboration with the Yale Child Study Center, Division researchers collected and are analyzing surveys from both national and international locations, which were completed by children and their parents with severe medical illness and their parents. The goal is to identify strategies to enhance resilience and well-being among children and their families faced with serious medical illnesses. Data collection is also ongoing in a study of child and family adjustment to parental combat deployment and soldier reintegration among active duty military families at Ft. Drum, NY.
Several projects examine the epidemiology of traumatic stress and related disorders. The National Health and Resilience in Veterans Study aims to characterize psychosocial, genetic, environmental, and gene- environmental (GxE) determinants of PTSD and related health outcomes in a nationally representative sample of Veterans, with a special emphasis on older Veterans. A major focus is to increase understanding of protective psychosocial factors that promote resilience. This work has led to publications in the areas of posttraumatic growth, correlates of successful aging, the national prevalence of lifetime and current PTSD and a model of PTSD typologies among Veterans.
With funding from the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health, population-based epidemiologic studies aim is to identify risk and protective factors associated with trauma-related symptoms and resilience. These projects are examining a host of psychosocial, genetic, epigenetic and neuroendocrine factors associated with different longitudinal trajectories of PTSD symptoms in a very large cohort of professional (i.e., police) and nontraditional (i.e., construction workers) workers involved in the response to the attacks on the World Trade Center.