Fatemeh Haghighi

Suicidal ideation (SI) and behavior are complex phenotypes, with multiple contributing risk-factors. This study used longitudinal data from the Million Veteran Program Mental Health Survey to identify SI profiles among Veterans based on trajectories of ideation and depression severity and compared them to a non-suicidal (no-SI) control group. Latent profile analysis (LPA) was performed to identify SI profiles using data from Veterans (n = 34,322) endorsing SI in their electronic health record. LPA identified four highly reproducible SI profiles: mild ideators with and without depression, variable ideators, and persistent ideators. Veterans across the SI profiles were significantly more likely to have diagnoses of suicidal ideation or behavior, mental disorders, and TBI compared to Veterans with no-SI. The variable ideators showed higher rates of comorbid conditions. The mild ideators without depression and persistent ideators had a significantly higher proportion of deaths by suicide than the no-SI Veterans. European and African American GWAS and pan-ancestry meta-analyses of SI profiles compared to no-SI controls were also performed, which identified genome-wide significant loci across all SI profiles proximal to genes implicated in auditory and vestibular functioning, Alzheimer’s, diabetes, and asthma. In summary, SI profiles identified were associated with novel genetic variants not identified by previous suicide GWAS studies. Additionally, Veterans within the mild SI profile that did not present with high-risk comorbidities had the highest rate of suicide deaths, indicating the need for upstream suicide risk prevention interventions across the SI risk continuum.

Introduction: Military members are exposed in combat and training to recognized traumatic brain injury (TBI)-causing events and other sub-concussive events that result in physical, psychological, and physiological impacts. Studies by this team and others involving Service Members (SMs) engaged in tactical training operations with repeated exposure to low level blast (LLB) have shown associations with concussion-like symptomology as well as transient decrements in performance, blood-based neurotrauma biomarkers, and perturbations in epigenome and transcriptome profiles, as well as alterations in intestinal permeability (IP). The present study focused on SMs engaged in mortar fire tactical trainings, builds on our previous findings in breachers that identified associations between blast exposures and IP and neurotrauma symptoms following exposures to LLB. Materials and Methods: Self-report symptom data and blood specimens from 31 SMs were collected including 22 mortarmen who directly participated in tactical training operations and were exposed to LLB and 9 unexposed study controls. Symptom data and blood samples were collected at pre-, post, and follow-up time points, across 3 consecutive mortar fire training sessions. Blood samples were assessed across all sessions via enzyme-linked immunosorbent assay (ELISA) to measure levels of IP protein biomarkers (i.e., Zonulin, Lipopolysaccharide-Binding Protein (LBP), Claudin-3, Intestinal-Fatty Acid Biding Protein (I-FABP). Correlations between IP biomarker changes and magnitude of blast exposures in each training session were calculated and reported as effect sizes measured by Cohen’s d using correlation to effect size conversion via R package effectsize. Impact of blast magnitude on IP biomarker changes across sessions were tested using a linear mixed effect model via R package lme4 and emmeans, with similar models used to investigate associations of IP biomarker changes following blast with physical and psychological symptoms or prior history of TBI. Results: In mortarmen LLB exposure magnitudes were significantly associated with change in Intestinal-Fatty Acid Binding Protein (pre vs. post, P = .028) and Zonulin (pre vs. follow-up, P = .003) levels across training sessions. Associations with moderate to large effect sizes were observed between changes in LBP and CLDN3 levels and neurotrauma symptoms, including taking longer to think, dizziness, and concentration difficulties following exposures to LLB (Cohen’s |d| > 0.5). Associations between TBI history and blast induced alterations in LBP and CLDN3 levels were identified with large effect sizes (|d| > 0.8). Conclusions: The present study in mortarmen corroborates our prior findings showing that exposures to LLB can contribute to IP that is also associated with prior mild traumatic brain injury (mTBI) history, with concomitant decreases in self-reported cognitive functioning. These findings suggest a possible role of blast exposure in gut permeability and the importance of the gut-brain axis in blast injury, with significant clinical translational impact in how we target clinical symptoms associated with exposure to blast and long term sequalae. These results may lead to a paradigm shift in the manner by which the military can detect, mitigate, and treat blast-related sequelae.

Suicidal ideation (SI) and behavior are complex phenotypes, with multiple contributing risk-factors. This study used longitudinal data from the Million Veteran Program Mental Health Survey to identify SI profiles among Veterans based on trajectories of ideation and depression severity, and compared them to a non-suicidal (no-SI) control group. Latent profile analysis (LPA) was performed to identify SI profiles using data from Veterans (n = 34,322) endorsing SI in their electronic health record. LPA identified four highly reproducible SI profiles: mild ideators with and without depression, variable ideators, and persistent ideators. Veterans across the SI profiles were significantly more likely to have diagnoses of suicidal ideation or behavior, mental disorders, and TBI compared to Veterans with no-SI. The variable ideators showed higher rates of comorbid conditions. The mild ideators without depression and persistent ideators had a significantly higher proportion of deaths by suicide than the no-SI Veterans. European and African American GWAS and pan-ancestry meta-analyses of SI profiles compared to no-SI controls were also performed, which identified genome-wide significant loci across all SI profiles proximal to genes implicated in auditory and vestibular functioning, Alzheimer’s, Diabetes, and Asthma. In summary, SI profiles identified were associated with novel genetic variants not identified by previous suicide GWAS studies. Additionally, Veterans within the mild SI profile that did not present with high-risk comorbidities had the highest rate of suicide deaths, indicating the need for upstream suicide risk prevention interventions across the SI risk continuum.

Introduction: Blast injuries and subclinical effects are of significant concern among those Service Members (SMs) participating in military operations and tactical trainings. Studies of SMs repeatedly exposed during training find concussion-like symptomology with transient decrements in neurocognitive performance, and alterations in blood biomarkers. How prior mild TBI (mTBI) history interacts with low-level blast (LLB) exposure, however, remains unexplored, which we investigate in the present study, to identify interindividual biomarker changes from LLB exposures influenced by prior history of mTBI.Methods: Gene transcript and amyloid-beta (Aβ40 and Aβ42) protein levels were assayed using timeseries blood specimens collected at pre-blast, post-blast (within ~1 h), and follow-up-blast (~16 h) after LLB exposure for 30 SMs (age 30.3 ± 7.5) via RNA-seq and Single Molecule Array (SIMOA). Statistical models with timepoint and mTBI status interaction adjusted for age were used, and p-values adjusted for multiple testing.Results: We found enrichment of genes involved in blood brain barrier, inflammatory, and immune responses associated with blast exposure, with significant elevated expression of target genes among SMs with mTBI history. Levels of Aβ40 and Aβ42 did not differ pre-blast vs. post/follow-up-blast LLB exposure when comparing SMs by prior mTBI history. Aβ40 and Aβ42 levels were significantly decreased in response to blast at the follow-up (~16 h) LLB exposure timepoint, concomitant with elevated expression of genes involved in amyloid-beta regulation and clearance in SMs with mTBI.Conclusion: Findings show inter-individual differences in biomarker levels following exposures to blast that may be attributed to prior mTBI history.

Introduction: Military sexual trauma (MST) has been associated with long-term negative outcomes such as increased rates of cardiovascular disease, post-traumatic stress disorder (PTSD), and suicidal thoughts and behaviors. While evidence supports the effectiveness of psychotherapeutic approaches as treatments for MST and related PTSD symptoms, these interventions have limited impact, attributed to perceived stigma with high dropout rates in female Veterans. Complementary and integrative health (CIH) interventions provide an alternative that may be more acceptable and can help transition Veterans into mental health treatments. Although evidence supports the utility of individual CIH interventions to be both effective and acceptable treatments for MST-related PTSD amongst female Veterans, there are limited evaluations of interventions that combine multiple CIH modalities, specifically in populations of at-risk female Veterans with histories of suicidal ideation or behavior. Thus, this quality improvement (QI) project aimed to assess the impact of a multimodal CIH intervention on mental and physical health symptoms specifically in female at-risk Veterans with MST. Materials and Methods: A total of 19 female Veterans with histories of MST and suicidal ideation and/or behavior who participated in an interventional programming in an urban VA in New York City were included in a secondary analysis for QI evaluation. These female Veterans comprised a subset of participants who previously engaged in a larger QI multimodal CIH intervention delivered over 4-week long in a cohort setting during which Veterans (both males and females) engaged in meditation and mindfulness, physical exercise, nutrition, and motivational curricula. Integrated as part of this programming, mental health symptoms (i.e., depression, PTSD, and stress/anxiety) and other factors related to suicide risk were assessed before and after program participation for all participants. Improvements across these symptoms pre- vs. post-program participation were examined. Results: For this secondary analysis, a total of 73% of females with MST who participated in the multimodal CIH interventional programming had a prior history of suicidal ideation or behavior. These participants showed elevated levels of depression and sleep disturbance symptoms at baseline prior to engagement in the multimodal CIH interventions, with medium-to-large reductions in these symptoms following completion of the multimodal CIH programming (Cohen’s d > 0.61 magnitude differences in symptom reduction pre vs. post). Conclusions: The results of this QI evaluation add to the growing body of evidence demonstrating that CIH interventions can be effective in attenuating mental health symptom-related MST and particularly within female Veteran populations at-risk for suicide, underscoring the potential importance of investigating integration of multiple CIH interventions for treatment of at-risk populations in future clinical research studies.

Introduction: Military Sexual Trauma (MST) has been associated with long-term negative outcomes such as increased rates of cardiovascular disease, PTSD, and suicidal thoughts and behaviors. While evidence supports the effectiveness of psychotherapeutic approaches as treatments for MST and related PTSD symptoms, these interventions have limited impact, attributed to perceived stigma with high dropout rates in female Veterans. Complementary and integrative health (CIH) interventions provide an alternative that may be more acceptable and can help transition Veterans into mental health treatments. Although research has found individual CIH interventions to be both effective and acceptable treatments for MST-related PTSD amongst female Veterans, lacking are evaluations of interventions that combine multiple CIH modalities or specifically in populations of at-risk female Veterans with history of suicidal ideation or behavior. Thus, this quality improvement project aimed to assess the impact of a multimodal CIH intervention on mental and physical health symptoms specifically in female Veterans with MST. Materials and Methods: Female Veterans (N=38) with and without a history of MST participated in an ongoing multimodal CIH intervention. Programming took place over multiple 4-week long cohorts during which Veterans engaged in meditation and mindfulness, physical exercise, nutrition, and motivational curricula. Mental health symptoms and other factors related to suicide risk were assessed before and after program participation, using measures including the PTSD Checklist for DSM-5 (PCL), Perceived Stress Scale (PSS), Beck Anxiety Scale (BAS), Beck Depression Inventory II (BDI), Patient Health Questionnaire (PHQ-9), Measure of Current Status (MoCS), Pittsburgh Sleep Quality Inventory (PSQI), and the Defense and Veterans Pain Rating Scale (DVPRS). These measures were assessed for baseline differences between those with vs. without MST, pre-post intervention differences, and with ANCOVA for pre-post group differences accounting for baseline score. Results: Most participants reported a history of MST (68%), with those endorsing MST also having significantly worse baseline scores for depressive symptoms (PHQ-9 and BDI; p = 0.0402 and 0.0360 corresponding), PTSD symptoms (PCL; p =0.0360), perceived stress (PSS; p = 0.0254), and sleep quality (PSQI; p= 0.0121) than those without MST. No significant baseline differences were found for hopelessness (BHS), perceived coping ability (MoCS), anxiety (BAS), and pain (DVPRS). Significantly greater improvement in depressive symptoms (PHQ-9 and BDI; p = 0.0156, p = 0.0211), and perceived stress (PSS; p = 0.0351) was found in comparison of the MST vs. no MST group but not for the other scales; findings were no longer significant after accounting for baseline group differences across these measures. Finally, in the subset of Veterans with histories of suicide ideation or attempt, medium to large treatment effects were found for all measured outcomes (Cohen’s |d| > .54). Conclusions: The results of this quality improvement project add to the growing body of evidence demonstrating that CIH interventions can be effective in attenuating mental health symptoms related MST and extend these findings to female Veteran populations at-risk for suicide. Additionally, they lend initial weight to the ability of treatments integrating multiple CIH interventions to have similar positive impacts to the singular interventions typically studied.

Improving public health approaches to suicide prevention requires scalable evidence-based interventions that can be easily disseminated. Given empirical data supporting the association between insomnia and suicide risk, internet-delivered insomnia interventions are promising candidates to meet this need. The purpose of this study was to examine whether an unguided internet-delivered cognitive-behavioral therapy for insomnia (iCBT-I) improved insomnia severity, suicidal ideation (SI), and suicide risk correlates (depression, post-traumatic stress disorder, anxiety, hostility, belongingness, hopelessness, agitation, irritability, concentration) in a sample of veterans. Secondary data analysis of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (n = 50) with clinically significant insomnia and elevated SI drawn from a larger randomized controlled trial (RCT) of an iCBT-I, Sleep Healthy Using the Internet (SHUTi). Two-sample t-tests or Wilcoxon rank sum tests were used to evaluate between-group differences (SHUTi vs. Insomnia Education Website control) in symptom improvement from baseline to post-intervention. SHUTi participants experienced a significant improvement in insomnia severity (P < .001; d = −1.08) and a non-significant with small (subthreshold medium) effect size reduction of SI (P = .17, d = 0.40), compared to control participants. Significant improvement in hopelessness was observed (medium effect size), with non-significant small to medium effect size reductions in most remaining suicide risk correlates. Self-administered iCBT-I was associated with improvements in insomnia severity in veterans at elevated risk for suicide. These preliminary findings suggest that SI and suicide risk correlates may improve following an iCBT-I intervention, demonstrating the need for future well-powered iCBT-I RCTs targeted for populations at elevated suicide risk. In this secondary data analysis, we examined improvements in insomnia severity, suicidal ideation (SI), and suicide risk correlates in veterans with clinically significant insomnia and elevated SI drawn from a larger randomized controlled trial (RCT) examining an unguided internet-delivered cognitive-behavioral therapy for insomnia (iCBT-I). Veterans in the iCBT-I group experienced greater improvements in insomnia severity and hopelessness than veterans in the Insomnia Education Website control. Although between-group differences in SI and other suicide risk correlates were not statistically significant, effect sizes suggest that SI and symptoms of depression, irritability, concentration, post-traumatic stress disorder, and hostility may improve following iCBT-I intervention. These results suggest that digital and iCBT-I interventions may be especially powerful tools for use in suicide prevention among veterans but highlight the critical need for additional large-scale studies to examine suicide-specific mechanisms and outcomes to guide implementation efforts.

Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene expression and IP biomarker data were generated from “breachers” exposed to controlled, low-level explosive blast during training. Samples from 30 male participants at pre-, post-, and follow-up blast exposure the next day were assayed via RNA-seq and ELISA. A battery of symptom data was also collected at each of these time points that acutely showed elevated symptom reporting related to headache, concentration, dizziness, and taking longer to think, dissipating ~16 h following blast exposure. Evidence for bacterial translocation into circulation following blast exposure was detected by significant stepwise increase in microbial diversity (measured via alpha-diversity p = 0.049). Alterations in levels of IP protein biomarkers (i.e., Zonulin, LBP, Claudin-3, I-FABP) assessed in a subset of these participants (n = 23) further evidenced blast exposure associates with IP. The observed symptom profile was consistent with mild traumatic brain injury and was further associated with changes in bacterial translocation and intestinal permeability, suggesting that IP may be linked to a decrease in cognitive functioning. These preliminary findings show for the first time within real-world military operational settings that exposures to blast can contribute to IP.

Human genetic studies indicate that suicidal ideation and behavior are both heritable. Most studies have examined associations between aberrant gene expression and suicide behavior, but behavior risk is linked to the severity of suicidal ideation. Through a gene network approach, this study investigates how gene co-expression patterns are associated with suicidal ideation and severity using RNA-seq data in peripheral blood from 46 live participants with elevated suicidal ideation and 46 with no ideation. Associations with the presence of suicidal ideation were found within 18 co-expressed modules (p < 0.05), as well as in 3 co-expressed modules associated with suicidal ideation severity (p < 0.05, not explained by severity of depression). Suicidal ideation presence and severity-related gene modules with enrichment of genes involved in defense against microbial infection, inflammation, and adaptive immune response were identified and investigated using RNA-seq data from postmortem brain that revealed gene expression differences with moderate effect sizes in suicide decedents vs. non-suicides in white matter, but not gray matter. Findings support a role of brain and peripheral blood inflammation in suicide risk, showing that suicidal ideation presence and severity are associated with an inflammatory signature detectable in blood and brain, indicating a biological continuity between ideation and suicidal behavior that may underlie a common heritability.