Thomas A. Mellman - US grants

Sleep disturbances are prominent features of post-traumatic syndromes. There is evidence that sleep loss may exacerbate or predispose to psychiatric disorders. Post-disaster studies indicate varying risk for psychiatric morbidity. We postulate persisting sleep disturbance to be a marker and possible mediator of increased risk. Hurricane Andrew has been characterized as the most extensive natural disaster in United States history. Most victims are likely to have experienced sleep disruption. We plan to recruit subjects with continuing sleep distur- bance, initially provoked by the hurricane, and a comparison group of victims without persisting sleep impairment. Subjects will be evaluated cross-sectionally to determine how sleep disturbance, psychiatric symptoms and disorders, and known psychiatric risk factors are associated in the wake of a disaster; and longitudinally to assess the risk of worsening symptoms and new onset disorders associated with persisting sleep disturbance. In order to provide validation of subjective reports of disturbed sleep, a sub-group of subjects will be evaluated in the sleep laboratory. Laboratory evaluations and longitudinal follow up will be expanded in future studies.

Post-traumatic Stress Disorder or PTSD is a common sequela of life threatening stressors and is associated with significant chronicity and psychosocial morbidity. Severe accidents are common life threatening events yet PTSD related to accidental injury remains under-investigated. Sleep disturbance is an integral feature of PTSD and may have a role in the development and maintenance of the disorder. We propose to study PTSD symptoms and their relationship to sleep phenomena during an acute phase following severe accidental injury. Patients hospitalized for life threatening accidents at a regional Trauma Center will be screened, and if appropriate, PTSD and other psychiatric and medical parameters will be evaluated. Patients' sleep will then be recorded with a portable polysomnographic unit. Associations of sleep measures with PTSD symptom severity will be determined. Attempts will have been made to reduce the impact of medical/surgical factors on sleep through screening procedures. Possible relationships of these factors, as well as that of other psychiatric variables to sleep measures, will be explored in analyses. The final aim of the study is to evaluate the relationship of sleep consolidation and PTSD symptom reduction. Symptomatic patients will be randomly assigned to a 7 day course of hypnotic medication versus placebo while receiving clinical management, during a 2 week treatment phase. Sleep, PTSD, and mood symptoms will be assessed prior to initiating and at the completion of the treatment phase. The final study evaluation for symptom severity and functional adjustment will occur 1 month later (6 weeks from baseline assessments) for all of the original subjects.

Post-traumatic Stress Disorder or PTSD is a common sequela of life threatening stressors and is associated with significant chronicity and psychosocial morbidity. Severe accidents are common life threatening events yet PTSD related to accidental injury remains under-investigated. Sleep disturbance is an integral feature of PTSD and may have a role in the development and maintenance of the disorder. We propose to study PTSD symptoms and their relationship to sleep phenomena during an acute phase following severe accidental injury. Patients hospitalized for life threatening accidents at a regional Trauma Center will be screened, and if appropriate, PTSD and other psychiatric and medical parameters will be evaluated. Patients' sleep will then be recorded with a portable polysomnographic unit. Associations of sleep measures with PTSD symptom severity will be determined. Attempts will have been made to reduce the impact of medical/surgical factors on sleep through screening procedures. Possible relationships of these factors, as well as that of other psychiatric variables to sleep measures, will be explored in analyses. The final aim of the study is to evaluate the relationship of sleep consolidation and PTSD symptom reduction. Symptomatic patients will be randomly assigned to a 7 day course of hypnotic medication versus placebo while receiving clinical management, during a 2 week treatment phase. Sleep, PTSD, and mood symptoms will be assessed prior to initiating and at the completion of the treatment phase. The final study evaluation for symptom severity and functional adjustment will occur 1 month later (6 weeks from baseline assessments) for all of the original subjects.

posttraumatic stress disorder; sleep disorders; accidents; injury; functional ability; coping; wakefulness; sedative /hypnotic; REM sleep; disease /disorder proneness /risk; arousal; sleep; polysomnography; adult human (21+); neuropsychological tests; human subject; placebos; clinical research;

[unreadable] DESCRIPTION (provided by applicant): Thomas Mellman is a psychiatrist and clinical investigator with interests in psychopathology, trauma, sleep, psychopharmacology and related neuroscience. His principal research focus has been sleep disturbances occurring with posttraumatic stress disorder (PTSD). His recent investigations have recruited patients with recent traumatic injuries in order to understand factors that contribute to the early development of PTSD. Dr. Mellman left Dartmouth Medical School and joined the faculty of Howard University School of Medicine in January 2004 and is research director for the Howard-NIMH Mood and Anxiety Collaborative Research Program. The present application is to competitively renew funding of his K-24 Award in order to continue and extend the work in the setting of Howard University. Projects on acute trauma, PTSD and sleep disturbances are being continued. The relocation to Howard provides access to urban populations with recent and chronic trauma exposure. An extension of the research focus to issues that are of specific relevance to African American populations is proposed (sleep phenomena of isolated sleep paralysis and non-dipping of nocturnal blood pressure). Collaborations with NIMH and Howard's National Human Genome Center provide opportunities to further knowledge of molecular genetic neuroscience and to incorporate molecular genetic analyses into developing investigations via collaborations. Collaborations with NIMH staff will also provide opportunities to develop new experiments that address sleep and learning. Dr. Mellman has a key role in research training in the Department of Psychiatry of Howard University. A core mission of the University is developing minority investigators. Plans are proposed to continue and expand providing research training experiences and individual mentoring. [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed study aims investigate candidate mechanisms for linking PTSD to cardiovascular regulation and, in particular, the role of nocturnal blood pressure regulation along with hypothesized modifiers of the relationship of trauma exposure and nocturnal blood pressure including the role of trait anger and exposure to prejudice and discrimination. In a subsequent phase of the research we will also evaluate relationships to genetic polymorphisms of adrenergic receptors. Healthy volunteers and people who report having experinced a traumatic event and current endorse experiencing PTSD symptoms will be recruited to participate in the study. During their initial evaluation, all participants will complete self-report measures which assess for trauma exposure and PTSD related symptoms, depression, experiences of discrimination and prejudice, anger management, sensitivity of negative events, orientation towards pleasing others, dietary salt intake, and personal and medical history. Following initial assessment, consenting participants who meet criteria will complete a clinical review to further assess for intensity and severity of PTSD symptoms, physical exam and urine toxicology screen, overnight sleep recording, monitoring of blood pressure and activity level, and , in a subsequent phase of the research, a blood draws.

[unreadable] DESCRIPTION (provided by applicant): Emerging evidence implicates posttraumatic stress disorder (PTSD) as a risk factor for medical morbidity including cardiovascular conditions. African Americans have higher rates of HTN and its consequences than Americans of European ancestry. Clinical and epidemiological studies that indicate a relationship between PTSD and HTN had substantial minority participation while the subjects of a large study that failed to find this relationship were predominately white. An absence of the normal "dip" of blood pressure (BP) at night is an important risk factor for HTN and for its end-organ complications. "Non-dipping" of nocturnal BP is common among people of African descent. A study of African American adolescents found an association between "non-dipping" and exposure to violence. Research findings implicate sympathetic nervous system (SNS) activity and alpha1-adrenergic mechanisms in non-dipping of nocturnal BP and in the sleep disturbance of PTSD. Our pilot data supports a relationship between PTSD and nocturnal BP non-dipping in a group of young adult African Americans. The goal for the present study is to more definitively evaluate this relationship and characterize the contributions of sleep factors, nocturnal SNS activity, chronic stress, coping responses, and behavioral/life style factors. This will be accomplished by recruiting healthy young adult African American men and women. The initial study phase will screen for trauma exposure and PTSD symptoms. From the initial phase participants we will select a group for laboratory procedures that is balanced for the presence or absence of lifetime PTSD. The procedures include polysomnographic evaluation, and 2, 24 hour blood pressure, heart rate, and activity monitoring recordings conducted a week apart. As the relationship between BP non-dipping and PTSD, and the role of contributing factors are elucidated, we plan to develop preventive interventions. PUBLIC HEALTH RELEVANCE: Trauma exposure is common among urban residing African Americans who also disproportionately experience hypertension and consequent cardiovascular morbidity and mortality. This study will elucidate a mechanism by which trauma exposure through PTSD effects cardiovascular morbidity that has preventive implications. [unreadable] [unreadable] [unreadable]

The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators; 2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship; and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science. RELEVANCE (See instructions):

DESCRIPTION (provided by applicant): There is substantial evidence that inadequate sleep contributes to health disparities that burden African Americans. Our recent data implicate the fear of losing vigilance to be an important contributor to compromised sleep in the lower socio-economic urban environments in which African Americans are disproportionately represented. Participants with PTSD had reduced slow wave sleep (SWS) and shorter continuous segments of rapid eye movement (REM) sleep. Some of the participants from stressed neighborhoods, however, do not report or exhibit curtailed or disturbed sleep. The purpose of the proposed research is to obtain ecologically valid assessments of the sleep disruptive effects of a stressful neighborhood environment, and determine what contributes resilience versus vulnerability to these effects. We will identify good and poor sleepers living in high crime urban areas. We will incorporate evaluation of the contributions of genotypes previously implicated in sleep tendencies or response to experimental sleep manipulations into models that will also consider life style, trauma exposure, and PTSD. We will monitor pre-sleep behaviors and cognitions and determine how in-home sleep relates to measures obtained in a laboratory setting and contribute to functional outcomes. Insights from this study will inform individual and public healt approaches to ameliorating health disparities attributable to compromised sleep.

DESCRIPTION (provided by applicant): Sleep appears to contribute in important ways to the development and maintenance of posttraumatic stress disorder or PTSD as well as to recovery from, and resilience to adverse effects of trauma. However, uncertainty regarding relationships between sleep and PTSD exists such that opposing views of sleep's role as consolidating versus adaptively processing trauma memories have both been recently expressed in the literature. The goal for this exploratory/developmental research application is to establish a paradigm for testing relationships between sleep parameters and processing trauma memories. If successful, and hypotheses are supported, the procedures will be applied to developing pharmacological and other interventions to enhance sleep's benefits, and to evaluate thresholds for detrimental effects of sleep restriction and disruption. In developing a novel approach we will also be evaluating the effects of written narrative disclosure sessions in the evening and morning with intervening sleep (overnight and daytime to evaluate for time of day effects) or wake, including its potential impact on sleep, PTSD symptoms, and non-specific distress. We will utilize a within subjects cross-over design to determine whether sessions of narrative disclosure with an intervening sleep period will be more effective than sessions separated by a wake period in effecting habituation and other indices of adaptive emotional processing. We will determine which indices of emotional processing are most sensitive to sleep effects. We will also evaluate the influence of characteristics of intervening sleep including measures of REM continuity.

Contact PD/PI: VERBALIS, JOSEPH G PROJECT ABSTRACT The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MHRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (DCVAMC). The specific aims of GHUCCTS are: 1) to improve the infrastructure that supports high quality interdisciplinary clinical and translational research, both via inter-institutional collaborations between all GHUCCTS institutions as well as multicenter clinical trials across the national CTSA consortium, with increasing levels of speed and efficiency, and to develop innovative computational methods to speed and enhance translation; 2) to continue to develop GHUCCTS as a model of inter-institutional collaboration that leverages the strengths and attributes of its diverse participating institutions to evolve GHUCCTS into regional CTSA hub with unique and synergistic strengths; 3) to leverage our location, expertise and the co-leadership of a minority-serving institution to design and implement research that will have a high impact on underserved populations with health disparities, including minorities, people with disabilities, and elderly populations; 4) to design and disseminate vibrant and innovative educational programs at multiple levels (undergraduate, medical school, graduate, study coordinators, research nurses, and junior faculty) that promote team science and provides the highest quality of career development training for the clinical and translational investigators of the future; and 5) to both draw from and contribute to the collective efforts of the national CTSA consortium to advance each of the Strategic Goals of GHUCCTS, the National Center for Advancing Translational Science (NCATS), and the CTSA national consortium. The integration of multiple clinical and translational resources across the diverse GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of clinical and translational researchers. Our innovative approaches to collaboration and interdisciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will ensure that our institutions and our community in the Washington, DC area benefit maximally from the generation and application of new discoveries in clinical and translational science. Project Summary/Abstract Page 124 Contact PD/PI: VERBALIS, JOSEPH G

Distressed neighborhood environments, posttraumatic stress, and compromised sleep are inter-related problems that have all been implicated in the health disparities affecting urban minorities. In our recent work we found significant relationships between self-reported and census-derived indices of neighborhood disorder, and self-reported, habitual wake after sleep onset (WASO), with diminished nocturnal blood pressure (BP) dipping, which is a well-established risk factor for adverse cardiovascular outcomes and is over-represented among African Americans. In addition to reduction of BP there is normally a shift toward parasympathetic dominance of the autonomic nervous system (ANS) during sleep and evidence suggests that such shifts are important for healthy cardiovascular homeostasis. Are preliminary findings indicate that this shift can be compromised with PTSD and nocturnal vigilance in stressful neighborhood environments. The goal for the proposed study is to further establish and extend a model where trauma exposure and threatening environments elicit nocturnal vigilance and sleep-related fears that compromise the healthy reduction of SNS and rise in PNS activity during sleep which in turn stimulates secretion of atherogenic humoral factors, arterial stiffening, and cardiovascular disease risk. We will examine the roles of pre-sleep cognition using a questionnaire and real time assessment, and modifiable strategies for coping with sleep disruptive cognitions. We will then evaluate the impact of providing personalized feedback and recommendations based on study observations on how participants cope with potentially sleep disruptive cognitions and sleep efficiency. We will also determine whether healthier sleep-related behaviors (however achieved) will influence changes in ANS balance during sleep and cardiovascular risk biomarkers. Thus study findings will confirm and reveal biomarkers of cardiovascular pathogenesis related to stress and sleep disruption that precede diagnosable illness, identify targets for preventive interventions, and provide evaluation of a brief intervention that can be scaled up or built upon as study findings indicate.

PROJECT ABSTRACT In the U.S., from 2011 to 2014, 7,208 maternal fatalities, with the trend worsening year-on-year (CDC, 2016). In addition to the 700+ fatalities, at least 50,000 woman experienced life-threatening complications, annually. According to CDC (2019) for every fatality, 70 more women suffer avoidable, traumatic complications as a result of pregnancy. Medstar Health Research Institute and Invaryant, Inc, propose the evaluation of a cardiac risk assessment tool for pregnant and postpartum women; this tool updates automatically directly from patient medical records; wearable devices; and patient surveys. Success implies disruptive improvement in women's health. Proposed research involves three key elements: technology, data, and social determinants of health (SDOH) using geospatial mapping of patient locations. Technology: Study technology shall be based on the Invaryant Health Platform (IHP), a technology that automatically ingests data, from medical records, wearable devices, and other sources using proprietary AI based interoperability technology called Mesh-Complex Method Exchange (Mesh-CMX). We propose using the IHP in conjunction with novel prototype-level technology, namely Healthy Outcomes for all Pregnancy Experiences-Cardiovascular-risk Assessment Technology (HOPE-CAT) and the Invaryant machine learning technologies to monitor the patient, based on signals, out-of-range ?trip-wires?, and trends in the mother's health data that merit medical intervention. By extending the proof of concept into an early commercial version of the software, and integrating it to the IHP which will automatically update changes in the patient's medical record, we will provide an ?early warning? system for mothers and their providers. Data: The study will be tested on patients' medical records using the MedStar's Analytics Platform (MAP), a registry of over 5 Million unique patients. The tool will subsequently have the potential to be leveraged to over 90 million medical records for the MedStar and Cerner hospital systems, distilled down to meet specific eligibility criteria including, gender, age, race, pregnancy and medical outcomes. A second phase of this project would take the findings from the retrospective study (this grant request) and use the technology within the Medstar hospital system, to validate the efficacy of the findings in a ?real-world setting?. Using our proprietary AI technology, we will compare each mother's progress against a cohort of retrospective data to enhance diagnostics and provide real-time feedback to caregivers and patients. Geospatial mapping: Mapping the patient medical record and the health information to their social setting is vital for understanding the underlying social constructs that affect the health of mothers in different regions.