CTBI: Traumatic brain injury-induced inflammation effects on cognitive evaluations and response inhibition: Mechanisms of increased risk for suicidality

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This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine human biomarker analysis, with human imaging studies, and with neurobiological mechanistic studies in animals, to understand the manner in which TBI influences impulsivity and suicidal behavior. Preventing suicide is a major priority for the VA. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide, particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. At the Indianapolis VA (INDVA) site, in order first to test our overarching hypothesis, and second to gain a more comprehensive understanding, we propose to translationally integrate human studies of subjects with TBI and suicidality with animal model studies of TBI, using blood biomarkers as a bridge. This will be accomplished via the following Aims: Aim 1 is Human biomarker studies. Aim 1.1. will focus on state aspects, by conducting transcriptomic analyses on blood samples collected in Indianapolis. We will have two groups: suicidality with TBI (n= 70) and suicidality without TBI (n= 70). We will not be conducting imaging studies, but rather use a longitudinal design, by testing the subjects first during an acute inpatient psychiatric hospitalization for suicidality (severe ideation, plan, attempt), and then 3-6 months later for a follow-up visit in a low suicidality state. We hypothesize that inflammatory and serotonin related transcripts will be decrease between acute inpatient and non-acute follow-up testing, but less so in suicidality with TBI compared to suicidality without TBI. Aim 1.2. will focus on trait aspects, by conducting transcriptomic analyses on samples from the Bronx VA (JJPVA) (n=140). We hypothesize that inflammatory and serotonin related transcripts will be increased most in suicidality with TBI compared to suicidality without TBI, TBI without suicidality, and non-TBI, non- suicidality. Aim 2 is Animal model brain and blood biomarkers convergence studies. We will conduct transcriptomic analyses of brain and blood samples from the animal model studies (n= 160) at the New Jersey VA (VANJHCS), a more experimentally tractable way of studying TBI and impulsivity. We hypothesize that we will identify biomarkers that are co- directionally changed in brain and blood. Aim 3 is Translational convergence of human and animal model biomarker data, using Convergent Functional Genomics analyses. We hypothesize that the candidate state and trait biomarkers that track suicidality (ideation, attempts) related to TBI (TBI-S) in the human studies will cross- validate with the brain-blood biomarkers from the animal model studies. We will also test hypothesis driven a series of known biomarkers related to inflammation (IL6, IFNG), serotonin (5HT2A, SLC6A4), and TBI (UCH-L1, GFAP- FDA approved in 2018). Exploratory Aim 4 will focus on convergence of biomarkers and phenomic data (neurobehavioral testing, imaging). We hypothesize that we can link different biomarkers to different behavioral aspects in the same individual and across individuals, resulting in a better understanding of the pathophysiological links between TBI, impulsivity, and suicidality. We will use a PhenoChipping approach (Niculescu et al. 2006)6, that clusters phenomics and genomics data. The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI is a risk factor for suicidality. Moreover, increased impulsivity is one of the most prevalent symptoms following TBI, and is itself a risk factor for suicide, depression and drug abuse. Thus, finding objective biomarkers of increased risk of suicide and understanding the mechanisms responsible for high impulsivity following TBI are key to severing the link between TBI and suicide.