Biological Signature and Safety of an Immunomodulatory Probiotic Intervention of Veterans with PTSD (PI: Brenner, Lisa) NIH 5R01AT010005 [https://medschool.cuanschutz.edu/physical-medicine-and-rehabilitation/research/selected-research-projects/ptsd] 

Abstract

United States military Veterans from recent conflicts are coping with symptoms related to posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy), and often symptoms are not significantly improved by traditional treatments. Alternative treatment methods are needed. An underlying feature of PTSD is exaggerated inflammation, both peripherally and in the central nervous system, which is thought to play an important role in the vulnerability to, aggravation of, and perpetuation of adverse consequences of this condition. Therefore, an innovative intervention strategy would be the use of anti-inflammatory/immunoregulatory probiotics to reduce inflammation. In this study, we will investigate the effects of an 8-week oral administration of Lactobacillus rhamnosus GG (LGG; ATCC53103), a probiotic shown to have anti-inflammatory and immunoregulatory effects on both biological signatures of systemic inflammatory processes and proximal signatures of probiotic administration. LGG is a commensal organism that colonizes the human gut mucosa and suppresses mucosal inflammation via inhibition of the production of proinflammatory cytokines. The specific aim of the study is to identify the effect of probiotics on systemic inflammation, as well as PTSD symptoms, microbiota composition, gut permeability, stress response, and decision-making. Outcomes will be assessed using a longitudinal, double blind, randomized placebo-controlled design. After initial evaluation procedures to confirm PTSD and Functional Bowel Disorder diagnoses, 59 participants will be randomized to probiotic supplementation and 59 will be randomized to placebo supplementation. The proposed line of research addresses the NIH funding opportunity purpose, “to accelerate translational and clinical Phase IIa” trials regarding “probiotic[s]” to increase “understanding regarding underlying mechanisms of their action(s), and variability in responses to these interventions”. Long-term, this study may lead to a paradigm shift in the manner by which we target clinical symptoms associated with PTSD by beginning the process of supporting a multitargeted, neuroprotective approach.

Total Brain Diagnostics (TBD): Analyzing the Impact of Functional Symptom and Clinical Measures on Co-Morbid Mental Health Conditions after TBI (PI: Brenner, Lisa) NIH 5I01RX004911

Abstract

Mild traumatic brain injuries (mTBI) were commonly sustained among those who served in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) and are associated with increased rates of mental health disorders, including posttraumatic stress disorder (PTSD). Indeed, among a cohort of those who served in the conflicts and sought Veterans Health Administration care, 89% of Veterans with a mTBI had a comorbid psychiatric disorder, with PTSD being the most common (73%). Unfortunately, symptom overlap between mTBI and mental health conditions can impact diagnostic clarity and prognosis. This can hamper implementation of personalized approaches (i.e., precision medicine) focused on enhancing assessment and treatment to ensure brain health and associated optimal psychosocial functioning. Moreover, such personalized care strategies would also be expected to decrease risk for negative outcomes like suicide. Based on increased risk for suicide among both younger and older cohorts of Veterans, suicide prevention remains the highest clinical priority within the VHA. One solution to overcoming existing data and clinical challenges is the integration of existing data sets focused on both clinical outcomes (e.g., PTSD symptom severity) and physiologic biosignals/functional measures (e.g., electroencephalogram [EEG] activity, computerized posturography, computerized eye tracking). Such an approach would allow the application of advanced analytic techniques to develop algorithms (e.g., diagnostic, prognostic) that can be used to promote brain health among Veterans with co-occurring mTBI and mental health sequelae (e.g., PTSD). To carry this out, members of this team with significant expertise in mental health and suicide prevention will collaborate with other teams engaged in the Total Brain Diagnostics (TBD) Proof of Concept linked submissions. As a first step, we will create a unified/harmonized dataset of measures collected as part of the Long-Term Impact of Military Brain Injury (LIMBIC) and Translational Research Center for TBI and Stress Disorders (TRACTS) protocols. Based on LIMBIC and TRACTS longitudinal data collection, clinical and physiologic biosignals/functional measures will be available. The goal of this mental-health focused TBD submission will be to explore associations between physiologic measures and mental health outcomes, including depression, anxiety, substance/alcohol use, PTSD, and suicidal thoughts and behaviors. Specific efforts will focus on identifying key objective, functional physiologic measures within the harmonized longitudinal dataset which predict: 1) the presence of mental health outcomes/conditions (e.g., symptoms, suicidal thoughts and behaviors) after combat-related mTBI; and 2) distinct trajectories of mental health outcomes/conditions (e.g., symptoms, suicidal thoughts and behaviors) post-combat-related mTBI. Study Aims are as follows: Aim 1. Work with the LIMBC- TRACTS harmonization team to construct and become familiarized with the unified dataset. Aim 2. Identify one or more uniform analytic approaches (e.g., machine learning) to facilitate analysis of this unified dataset. Aim 3. Analyze the impact of physiological biosignals/functional indicators on the longitudinal trajectory of mental health symptoms and conditions. Aim 4. Collaborate with behavioral and biomarker measure experts to conduct multimodal factor analyses. A key project deliverable is the development of the LIMBC-TRACTS combined data set. Initial findings from this proposed effort will be foundational for subsequent inquiry focused on enhancing diagnostic and prognostic efforts to improve brain health and psychosocial functioning among Veterans living with mTBI and mental health conditions.

Beyond Mild, Moderate, and Severe: Evaluating the Clinical, Biomarkers, Imaging, and Modifiers (CBI-M) Classification System for Traumatic Brain Injury (PI: Brenner, Lisa) CDMRP HT94252510962

Abstract

The project aims to increase understanding regarding the utility of existing TBI classification systems/criteria. The proposed project aims to improve understanding regarding three diagnostic strategies that are currently being used (VA/DoD and ACRM systems), or have been proposed to be used (CBI-M system), to classify TBI severity among those with milder injuries. In addition, efforts will be focused on exploring relationships between these classification systems and: self-reported TBI-related and mental health outcomes (e.g., post concussive symptoms, post traumatic symptoms); objective functional outcomes (e.g., employment, death by suicide); and objective cognitive outcomes (e.g., executive functioning). A focus across aims is the exploration of how social determinants of health impact such longitudinal outcomes.

Computerized Cognitive Behavioral Therapy-Depression (cCBT-D) for Caregivers of Veterans (PI: Brenner, Lisa) Face-the-Fight

Abstract

As highlighted in the Department of Veterans Affairs National Strategy for Preventing Veteran Suicide (2018-2028), the enterprise has adopted a public health approach to suicide prevention (https://www.mentalhealth.va.gov/suicide_prevention/docs/Office-of-Mental-Health-and-Suicide-Prevention-National-Strategy-for-Preventing-Veterans-Suicide.pdf). This entails implementing both clinical- and community-based strategies. Towards this end, the Veterans Health Administration (VHA) has been focused on the implementation of evidence-based psychotherapies (EPBs) for selected (e.g., Veterans with depression) and indicated (e.g. Veterans with a history of suicidal thoughts and behaviors) populations. As part of the transformation of its mental health care system, the VHA promoted the national dissemination and implementation of EBPs in VHA. However, significant barriers exist in terms of wide-spread implementation of face-to-face interventions. A solution has been the development of online tools and courses for Veterans at-risk for suicide.

Within the United States (US), paid and un-paid caregivers play an important role in providing material and emotional support to those living with chronic health conditions and associated impairments. For many reasons (e.g., limited economic resources, living in rural communities) this is particularly true in terms of Service Members and Veterans, who often have unique healthcare needs related to their history of military service. Research suggests that over time caregivers experience declines in both their physical and mental health, including depression. Also of note, high caregiver burden has been associated with increased physical and psychological symptom burden, mortality, and hospitalization among care recipients. At present evidence-based interventions specifically focused on caregiver depression are limited. Moreover, due to the time and fiscal demands of being a caregiver, such interventional approaches must be easy to access and low cost.

To address this gap, we will be modifying and evaluating an existing computerized Cognitive Behavioral Therapy for Depression (cCBT-D) course to create and evidence-based resource specifically for caregivers of Service Members and Veterans. Although this course is being developed for caregivers, it is expected that the resource will meet the needs of a broader audience of individuals providing support to Service Members/Veterans (e.g., spouses, family members). To ensure that this is the case, feedback will be sought from such individuals via the Community Engagement Board (CEB).

The existing cCBT-D course (which is Veteran-focused) is comprised of 12 online sessions. Sessions all have a similar structure that includes: 1) Weekly symptom ratings; 2) Review of practice assignments completed since last session; 3) Presentation of new material; and, 4) Practice assignments to be completed in the coming week. Individuals can complete assignments within the course website or by printing out the worksheets. Their course “dashboard,” which they see each time they log into the course, allows them to review past and upcoming course activities, read information about skills, and make notes about what was learned.

Microbiome-Gut-Brain Axis Biomarkers for Prevention of Persistent Symptoms-TBI (MAPPS-TBI) (PI: Brenner, Lisa) National Football League Players Association [https://medschool.cuanschutz.edu/physical-medicine-and-rehabilitation/research/selected-research-projects/microbiome-gut-brain-axis-biomarkers-for-prevention-of-persistent-symptoms-traumatic-brain-injury-(mapps-tbi)] 

Abstract

Among those who played contact sports (e.g., retired National Football League [NFL] players), lifetime repetitive head impacts and concussions (i.e., mild traumatic brain injury [mTBI]) have been associated with increased risk for adverse brain health and mental health outcomes, including suicide. Inflammation resulting from contact sport-related injuries is an underexplored factor that may explain these poor health outcomes. Although post-injury inflammation is a necessary and expected part of recovery, excessive inflammation within the first 24 hours post-trauma also leads to worse outcomes. Likewise, persistent elevation of chronic-low grade inflammation is associated with increased risk of negative psychiatric outcomes. Excessive post-injury inflammatory responses are further exacerbated by failing immunoregulation, attributable to reduced exposure to diverse microbial environments (e.g., within the gut microbiome). Recent research suggests that gut microbial diversity and microbiome community composition are further negatively impacted after even mTBIs. Nonetheless, work on identifying “key gut microbiome biomarkers linked to brain health” remains nascent. Members of this team have been engaged in both observational and experimental efforts to increase understanding regarding TBI, inflammation, and the gut microbiome to promote overall brain health and symptom resolution post-injury, even among those with persistent complaints. In this project, we are leveraging our unique collective knowledge and experience, as well as existing longitudinal gut microbiome samples (animal, human [acute, post-acute]), to map microbiota-host interactions that support brain health among NFL players, over their lifespans, to identify phenotypes and associated personalized medicine approaches to prevent and mitigate symptoms.

Together with Veterans: Rural Veteran Suicide Prevention Program (PI Brenner, Lisa) Department of Veterans Affairs, Veterans Health Administration, Office of Rural Health NOMAD #PRFY-00676 [https://www.mirecc.va.gov/visn19/togetherwithveterans/]

Together With Veterans (TWV) is a multilevel suicide prevention program for rural Veterans in which evidence-based strategies are selected and implemented by community members to promote suicide prevention. This Enterprise-Wide Initiative, Together with Veterans (TWV), was designed and is being implemented and evaluated to promote community-based suicide prevention in rural communities throughout the United States. TWV is a multilevel, evidence-based suicide prevention program for rural Veterans. TWV is carried out via collaboration between the Rocky Mountain Veterans, the Western Interstate Commission for Higher Education Behavioral Health Program (WICHE BHP), local Veterans, and other community stakeholders. Through these partnerships, TWV supports the dissemination of best practices in public health suicide prevention to rural communities consistent with the goals of the National Strategy for Preventing Veteran Suicide. The TWV guiding principles are as follows: Veteran-Driven; Collaborative; Evidence-Informed; and, Community-Centered. The Together With Veterans Suicide Prevention Strategies are implemented using a five-phase process to support rural communities in developing a local Veteran suicide prevention action plan. Six evidence-based suicide prevention strategies (Provide Suicide Prevention Training, Enhance Primary Care Suicide Prevention, Promote Connectedness and Help Seeking, Improving Communication Across Veteran Serving Programs, Enhance Behavioral Health Suicide Prevention, Promote Lethal Means Safety) are used by TWV to support the local planning efforts. These strategies are designed for community-wide implementation to increase awareness and knowledge about Veteran suicide and improve community response to the needs of local Veterans.

Brain Health Coordinating Center (Co-Directors: Brenner, Lisa and Cifu, David) Department of Veterans Affairs, Office of Research And Development [https://www.research.va.gov/resources/bhcc/]  

The Brain Health Coordinating Center (BHCC) is an exciting new initiative with the primary goal of serving as an enterprise-wide resource for improving brain health for Veterans across the Department of Veterans Affairs (VA). This will be accomplished through leveraging existing tools (e.g., eMetrics, VA/DoD Clinical Practice Guidelines) to facilitate better Veteran brain health via the following:

• Engagement – Strengthening communication and collaboration across the VA community and with external partners
• Quality Improvement – Advancing best clinical practices through continuous, data-informed improvement
• Research – Supporting innovative investigations that drive better outcomes
• Education – Enhancing clinical knowledge and practice through ongoing learning

Military and Veteran Microbiome Consortium for Research and Education (MVM CoRE)[https://www.mirecc.va.gov/visn19/mvm/research.asp] 

Microbiome research has the potential to impact prevention and interventions for many conditions. The Military and Veteran Microbiome Consortium for Research and Education (MVM CoRE) remains committed to exploring the complexities of the human microbiome in pursuit of healthier lives for all members of our Veteran and military community.