Neurocognitive and psychiatric outcomes associated with postacute COVID-19 infection without severe medical complication: a meta-analysis.

BACKGROUND: Cognitive symptoms are often reported by those with a history of COVID-19 infection. No comprehensive meta-analysis of neurocognitive outcomes related to COVID-19 exists despite the influx of studies after the COVID-19 pandemic. This study meta-analysed observational research comparing cross-sectional neurocognitive outcomes in adults with COVID-19 (without severe medical/psychiatric comorbidity) to healthy controls (HCs) or norm-referenced data. METHODS: Data were extracted from 54 studies published between January 2020 and June 2023. Hedges' g was used to index effect sizes, which were pooled using random-effects modelling. Moderating variables were investigated using meta-regression and subgroup analyses. RESULTS: Omnibus meta-analysis of 696 effect sizes extracted across 54 studies (COVID-19 n=6676, HC/norm-reference n=12 986; average time since infection=~6 months) yielded a small but significant effect indicating patients with COVID-19 performed slightly worse than HCs on cognitive measures (g=-0.36; 95% CI=-0.45 to -0.28), with high heterogeneity (Q=242.30, p<0.001, τ=0.26). Significant within-domain effects was yielded by cognitive screener (g=-0.55; 95% CI=-0.75 to -0.36), processing speed (g=-0.44; 95% CI=-0.57 to -0.32), global cognition (g=-0.40; 95% CI=-0.71 to -0.09), simple/complex attention (g=-0.38; 95% CI=-0.46 to -0.29), learning/memory (g=-0.34; 95% CI=-0.46 to -0.22), language (g=-0.34; 95% CI=-0.45 to -0.24) and executive function (g=-0.32; 95% CI=-0.43 to -0.21); but not motor (g=-0.40; 95% CI=-0.89 to 0.10), visuospatial/construction (g=-0.09; 95% CI=-0.23 to 0.05) and orientation (g=-0.02; 95% CI=-0.17 to 0.14). COVID-19 samples with elevated depression, anxiety, fatigue and disease severity yielded larger effects. CONCLUSION: Mild cognitive deficits are associated with COVID-19 infection, especially as detected by cognitive screeners and processing speed tasks. We failed to observe clinically meaningful cognitive impairments (as measured by standard neuropsychological instruments) in people with COVID-19 without severe medical or psychiatric comorbidities.

Importance of validity testing in psychiatric assessment: evidence from a sample of multimorbid post-9/11 veterans.

OBJECTIVE: Performance validity (PVTs) and symptom validity tests (SVTs) are necessary components of neuropsychological testing to identify suboptimal performances and response bias that may impact diagnosis and treatment. The current study examined the clinical and functional characteristics of veterans who failed PVTs and the relationship between PVT and SVT failures. METHOD: Five hundred and sixteen post-9/11 veterans participated in clinical interviews, neuropsychological testing, and several validity measures. RESULTS: Veterans who failed 2+ PVTs performed significantly worse than veterans who failed one PVT in verbal memory (Cohen's d = .60-.69), processing speed (Cohen's d = .68), working memory (Cohen's d = .98), and visual memory (Cohen's d = .88-1.10). Individuals with 2+ PVT failures had greater posttraumatic stress (PTS; ß = 0.16; p = .0002), and worse self-reported depression (ß = 0.17; p = .0001), anxiety (ß = 0.15; p = .0007), sleep (ß = 0.10; p = .0233), and functional outcomes (ß = 0.15; p = .0009) compared to veterans who passed PVTs. 7.8% veterans failed the SVT (Validity-10; ≥19 cutoff); Multiple PVT failures were significantly associated with Validity-10 failure at the ≥19 and ≥23 cutoffs (p's < .0012). The Validity-10 had moderate correspondence in predicting 2+ PVTs failures (AUC = 0.83; 95% CI = 0.76, 0.91). CONCLUSION: PVT failures are associated with psychiatric factors, but not traumatic brain injury (TBI). PVT failures predict SVT failure and vice versa. Standard care should include SVTs and PVTs in all clinical assessments, not just neuropsychological assessments, particularly in clinically complex populations.

Association of mild traumatic brain injury, post-traumatic stress disorder, and other comorbidities on photosensitivity.

SIGNIFICANCE: Photosensitivity is common after mild traumatic brain injury. However, this study demonstrates that photosensitivity is also impacted by common comorbidities that often occur with mild traumatic brain injury. Understanding how physical and psychological traumas impact photosensitivity can help improve provider care to trauma survivors and guide novel therapeutic interventions. PURPOSE: This study aimed to characterize the association between mild traumatic brain injury and common comorbidities on photosensitivity in post-9/11 veterans. METHODS: Existing data from the Translational Research Center for TBI and Stress Disorders cohort study were analyzed including traumatic brain injury history and post-traumatic stress disorder clinical diagnostic interviews; sleep quality, anxiety, and depression symptoms self-report questionnaires; and photosensitivity severity self-report from the Neurobehavioral Symptom Inventory. Analysis of covariance and multiple ordinal regression models were used to assess associations between mild traumatic brain injury and common comorbidities with photosensitivity severity. RESULTS: Six hundred forty-one post-9/11 veterans were included in this study. An initial analysis showed that both mild traumatic brain injury and current post-traumatic stress disorder diagnosis were independently associated with higher photosensitivity ratings compared with veterans without either condition, with no interaction observed between these two conditions. Results of the ordinal regression models demonstrated positive associations between degree of photosensitivity and the number of mild traumatic brain injuries during military service and current post-traumatic stress disorder symptom severity, particularly hyperarousal symptoms, even when controlling for other factors. In addition, the degree of sleep disturbances and current anxiety symptoms were both positively associated with photosensitivity ratings, whereas depression symptoms, age, and sex were not. CONCLUSIONS: Repetitive mild traumatic brain injury, post-traumatic stress disorder, anxiety, and sleep disturbances were all found to significantly impact photosensitivity severity and are therefore important clinical factors that eye care providers should consider when managing veterans with a history of deployment-related trauma reporting photosensitivity symptoms.

The Impact of Blast Exposure-With or Without Traumatic Brain Injury-on Metabolic Abnormalities in Post-9/11 Veterans.

OBJECTIVE: The primary aim included explorations of: (1) the associations between the history of blast exposure (BE), close blast exposure (CBE), and blast-related traumatic brain injury (bTBI) and metabolic abnormality; and (2) the potential mediating effect of comorbid psychological and somatic conditions on these associations. The secondary aim explored the association of dose-response impact of BE, CBE, and bTBI and metabolic abnormality. SETTING: Data were collected by the Translational Research Center for TBI and Stress Disorders (TRACTS). PARTICIPANTS: Post-9/11 veterans from the TRACTS baseline sample who had conflict-zone deployment experience ( N = 734). DESIGN: Cross-sectional secondary data analysis. We computed relative risks (RRs) and 95% CI using modified Poisson regression. We quantified the impact of co-occurring psychological and somatic conditions on this association using mediation analyses. MAIN MEASURES: Exposures included BE (<100 m), CBE (<10 m), and bTBI. Metabolic abnormality outcomes included (1) overweight/obesity (defined by abnormal waist-hip ratio [WHR] and abnormal waist circumference [WC]); (2) glucose dysregulation; and (3) meeting criteria for cardiometabolic syndrome (defined by guidelines). RESULTS: The sample was majority male (91%) and White (68%), with a mean age of 34.6 years (SD = 8.99). Most participants had 1 or more BE (83%); 48% experienced 1 or more CBE. Overweight/obesity was highly prevalent in the sample (51% had abnormal WHR and 60% abnormal WC). There was no significant direct or indirect association between BE, CBE, and bTBI and metabolic abnormalities (RRs: 0.70-1.51; P 's > .05). CONCLUSION: Future research is needed to investigate the association of BE with metabolic abnormalities with larger, more targeted sample selection, and longer follow-up. Effective and sustainable weight management and metabolic health prevention interventions for this veteran cohort are needed.

Accelerated longitudinal cortical atrophy in OEF/OIF/OND veterans with severe PTSD and the impact of comorbid TBI.

Veterans who deployed in support of Operation Enduring Freedom (OEF), Iraqi Freedom (OIF), and New Dawn (OND) commonly experience severe psychological trauma, often accompanied by physical brain trauma resulting in mild traumatic brain injury (mTBI). Prior studies of individuals with posttraumatic stress disorder (PTSD) have revealed alterations in brain structure, accelerated cellular aging, and impacts on cognition following exposure to severe psychological trauma and potential interactive effects of military-related mTBI. To date, however, little is known how such deployment-related trauma changes with time and age of injury of the affected veteran. In this study, we explored changes in cortical thickness, volume, and surface area after an average interval of approximately 2 years in a cohort of 254 OEF/OIF/OND Veterans ranging in age from 19 to 67 years. Whole-brain vertex-wise analyses revealed that veterans who met criteria for severe PTSD (Clinician-Administered PTSD Scale ≥60) at baseline showed greater negative longitudinal changes in cortical thickness, volume, and area over time. Analyses also revealed a significant severe-PTSD by age interaction on cortical measures with severe-PTSD individuals exhibiting accelerated cortical degeneration with increasing age. Interaction effects of comorbid military-related mTBI within the severe-PTSD group were also observed in several cortical regions. These results suggest that those exhibiting severe PTSD symptomatology have accelerated atrophy that is exacerbated with increasing age and history of mTBI.

Research utility of a CAPS-IV and CAPS-5 hybrid interview: Posttraumatic stress symptom and diagnostic concordance in recent-era U.S. veterans.

The Clinician-Administered PTSD Scale (CAPS) is used to measure posttraumatic stress symptoms (PTSS) and diagnose posttraumatic stress disorder (PTSD). However, its use, particularly in settings involving longitudinal assessment, has been complicated by changes in the diagnostic criteria between the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (i.e., DSM-IV and DSM-5, respectively). The current sample included trauma-exposed U.S. veterans who were deployed in support of military operations following the September 11, 2001, terrorist attacks (N = 371) and were enrolled in a longitudinal study focused on deployment-related stress and traumatic brain injury. A hybrid clinical interview using item wording from the CAPS for DSM-IV (CAPS-IV) with the addition of items unique to the CAPS for DSM-5 (CAPS-5) was used to assess both DSM-IV and DSM-5 PTSD diagnostic criteria, allowing for the calculation of separate total scores and diagnoses. Diagnostic agreement, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and interrater reliability between CAPS-IV and CAPS-5 were evaluated for the entire sample and stratified by gender. We found high diagnostic agreement (92.9%-95.4%), sensitivity (94.4%-98.2%), specificity (91.7%-92.8%), PPV (89.5%-93.0%), NPV (95.7%-98.1%), and interrater reliability,κ = 0.86-0.91,) for both men and women. The current study supports the use of a hybrid PTSD diagnostic interview assessing both DSM-IV and DSM-5 diagnostic criteria, particularly in situations such as longitudinal studies that may require a feasible method of incorporating changes in diagnostic criteria from the DSM-IV to the DSM-5.

Associations between changes in somatic and psychiatric symptoms and disability alterations in recent-era U.S. veterans.

Cross-sectional work suggests that deployment-related posttraumatic sequelae are associated with increased disability in U.S. veterans deployed following the September 11, 2001 (9/11), terrorist attacks. However, few studies have examined the psychiatric and somatic variables associated with changes in functional disability over time. A total of 237 post-9/11 veterans completed comprehensive assessments of psychiatric and cognitive functioning, as well as a disability questionnaire, at baseline and 2-year follow-up. At baseline, higher levels of PTSD, depressive, and pain-related symptoms were associated with baseline global functional disability, semipartial r2 = .036-.044. Changes in symptoms of PTSD, depression, pain, and sleep, but not anxiety or alcohol use, were independently associated with changes in functional disability, semipartial r2 = .017-.068. Baseline symptoms of these conditions were unrelated to changes in disability, and cognitive performance was unrelated to disability at any assessment point. Together, this suggests that changes in psychiatric and somatic symptoms are tightly linked with changes in functional disability and should be frequently monitored, and even subclinical symptoms may be a target of intervention.

Network analysis of mild traumatic brain injury, persistent neurobehavioral and psychiatric symptoms, and functional disability among recent-era United States veterans.

Recent-era U.S. veterans are clinically complex, with a high prevalence of co-occurring mild traumatic brain injury (mTBI), psychiatric conditions, and behavioral dysfunction. The current study examined the direct and indirect associations between mTBI and persistent neurobehavioral, psychiatric, and functional disability symptoms among recent-era U.S. veterans and service members (n = 648). We evaluated the postconcussive syndrome (PCS) potential causal model with two network analysis modeling approaches. Separate analyses were conducted for military mTBI and lifetime mTBI. An exploratory factor analysis was conducted to limit topological overlap in the network analysis. The most influential symptoms (i.e., the unique variables most strongly associated with the rest of the network) in the military mTBI network were behavioral disengagement, expected influence (EI) = 1.10; cognitive difficulties, EI = 1.08; agitation/irritability, EI = 1.05; and PTSD-related reexperiencing and avoidance symptoms, EI = 0.98. After accounting for other symptoms, mTBI was only minimally informative, EI = 0.34. Additionally, military mTBI did not moderate the association between symptoms or the overall connectivity of the network. The results for lifetime mTBI were consistent with those for military mTBI. The present analyses identified a variety of behavioral, cognitive, and emotional symptoms that play an important role in understanding comorbidity and daily functioning among recent-era U.S. veterans. Associations between cumulative mTBI that occurred in civilian or military settings were indirect and relatively small in magnitude. The current results add to a growing literature raising doubts about the PCS model.

Associations among clinical variables and anger differ by early life adversity among post-9/11 veterans.

Maladaptive anger and aggression are common in US military veterans and increase risk for impaired social relationships and functioning, justice-involvement and violence. Early life (before age 18) adversity predisposes veterans to later life psychopathology, though the link to increased later life anger is unclear. We analysed cross-sectional data of 158 post-9/11 veterans from the Translational Research Center for Traumatic Brain Injury and Stress Disorders study with and without a history of early life adversity (ns = 109 and 49, respectively). We explored the relationship among major clinical variables and current veteran anger (Dimensions of Anger Reactions) and whether the associations with these variables differed among participants with and without a history of retrospective self-reported early life adversity (Childhood Trauma Questionnaire). In the overall sample, posttraumatic stress disorder (PTSD) and depression severities had the strongest associations with current veteran anger (ßs = 0.261 and 0.263; p-values = 0.0022 and 0.0103, respectively). In the subsample without early life adversity, only PTSD severity was significantly associated with anger (ß = 0.577, p = 0.0004). In the early life adversity subsample, this strong association weakened and was no longer significant (ß = 0.168, p = 0.1007); instead, anxiety and depression severities showed moderate associations with anger (ßs = 0.243 and 0.287, p-values = 0.0274 and 0.0130, respectively). Findings suggest that clinicians should screen veterans with history of early life adversity for depression and anxiety when anger is present.

Childhood trauma differentially impacts depression and stress associations with reintegration challenges among post-9/11 U.S. veterans.

BACKGROUND: Post-9/11 veterans exhibit high prevalence of deployment stress, psychological conditions, and traumatic brain injury (TBI) which impact reintegration, especially among those with a history of interpersonal early life trauma (I-ELT). The relative importance of each risk factor is unclear. PURPOSE: We examined major deployment and clinical exposures of reintegration challenges among veterans with and without I-ELT. METHOD: We analyzed cross-sectional data of 155 post-9/11 veterans from the Translational Research Center for TBI and Stress Disorders study. FINDINGS: Depression severity had the strongest association with reintegration challenges, followed by posttraumatic stress disorder (PTSD) severity, post-deployment stress, and deployment safety concerns. Deployment safety concerns had a stronger, significant association among veterans with I-ELT. In nearly every model, PTSD and depression severities were weaker for veterans with I-ELT, compared to those without. DISCUSSION: Clinicians should consider the relative risk of concurrent clinical conditions and trauma histories when considering veterans' reintegration needs.

PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.

Age of onset of adolescent binge drinking is differentially associated with cortical thickness in post-9/11 adult Veterans.

BACKGROUND: Adolescence is a critical period for neural development and has been associated with high rates of alcohol abuse. This research examined potential long-term brain and behavioral effects of early versus late-onset adolescent binge drinking in an adult sample of post-9/11 Veterans. METHODS: We compared cortical thickness measures in Veterans with a history of binge drinking that began before the age of 15 (n = 50; mean age = 32.1 years) to those with a history of binge drinking with onset after the age of 15 (n = 300; mean age = 32.1 years). Data processing was conducted with FreeSurfer. A targeted neuropsychological battery (Digit Span test, Delis-Kaplan Executive Function System Color-Word Interference Test, California Verbal Learning Test-II) was used to examine the relationships between cortical thickness and attention, memory, and inhibition. A reference group of social drinkers with no history of early binge drinking (n = 31) was used to provide normative data. RESULTS: Early-onset adolescent binge drinkers (EBD) had greater cortical thickness in several regions than late-onset adolescent binge drinkers (LBD); both binge-drinking groups had greater cortical thickness than the reference group. There was a stronger negative association between cortical thickness and age in EBDs than LBDs in the (i) lateral orbitofrontal cortex, (ii) supramarginal gyrus, (iii) paracentral lobule, and (iv) anterior caudal cingulate. Poorer performance on the attention and inhibition tasks in the EBDs was also associated with thicker cortices. CONCLUSIONS: This study demonstrates greater cortical thickness across frontoparietal regions in adults who began binge drinking in early versus late adolescence. A stronger negative association between cortical thickness and age in the EBDs suggests that early-onset adolescent binge drinking may be associated with accelerated cortical thinning. Thicker cortex in these regions, which are known to mediate inhibitory control, may increase impulsive behavior and contribute to the risk of alcohol addiction.

Early Adolescent Binge Drinking Increases Risk of Psychopathology in Post-9/11 Veterans and Mild Traumatic Brain Injury Exacerbates Symptom Severity.

AIMS: To demonstrate that early adolescent binge drinking (BD) increases the risk for and/or severity of psychopathology in post-9/11 Veterans and determine if mild traumatic brain injury (mTBI) modifies risk. METHODS: Post-9/11 Veterans (n = 375) were classified into two groups: 57 Veterans with a history of early adolescent BD (E-BD; age of onset <15) and 318 who did not BD until age 15 or older (late-BD or L-BD; age of onset ≥15). History of military mTBI and mental health disorders were also assessed following military service. RESULTS: Logistic regression and analysis of variance (ANOVA) analyses revealed that the E-BD's had significantly higher prevalence of alcohol use disorders (AUDs) and more severe symptoms of AUD, substance use disorder (SUD), depression and stress. Two-way ANOVAs showed that history of military mTBI was differentially associated with posttraumatic stress disorder (PTSD) incidence and severity among Veterans who had engaged in early adolescent BD. Specifically, Veterans with a history of both early adolescent BD and military mTBI were at greater risk for a PTSD diagnosis and had more severe symptoms of PTSD than those with only a history of adolescent BD. The greater PTSD symptom severity in the comorbid group was driven by hyperarousal symptoms. CONCLUSIONS: A history of BD during early adolescence is prevalent among Veterans and is related to higher risk for AUD and more severe AUD, SUD, mood and stress symptoms later in life. Veterans with early BD and military mTBI showed greater incidence and severity of PTSD, indicating that mTBI, a common comorbidity among post-9/11 Veterans, exacerbates risk.

Test-retest reliability of FreeSurfer automated hippocampal subfield segmentation within and across scanners.

The human hippocampus is vulnerable to a range of degenerative conditions and as such, accurate in vivo measurement of the hippocampus and hippocampal substructures via neuroimaging is of great interest for understanding mechanisms of disease as well as for use as a biomarker in clinical trials of novel therapeutics. Although total hippocampal volume can be measured relatively reliably, it is critical to understand how this reliability is affected by acquisition on different scanners, as multiple scanning platforms would likely be utilized in large-scale clinical trials. This is particularly true for hippocampal subregional measurements, which have only relatively recently been measurable through common image processing platforms such as FreeSurfer. Accurate segmentation of these subregions is challenging due to their small size, magnetic resonance imaging (MRI) signal loss in medial temporal regions of the brain, and lack of contrast for delineation from standard neuroimaging procedures. Here, we assess the test-retest reliability of the FreeSurfer automated hippocampal subfield segmentation procedure using two Siemens model scanners (a Siemens Trio and Prismafit Trio upgrade). T1-weighted images were acquired for 11 generally healthy younger participants (two scans on the Trio and one scan on the Prismafit). Each scan was processed through the standard cross-sectional stream and the recently released longitudinal pipeline in FreeSurfer v6.0 for hippocampal segmentation. Test-retest reliability of the volumetric measures was examined for individual subfields as well as percent volume difference and Dice overlap among scans and intra-class correlation coefficients (ICC). Reliability was high in the molecular layer, dentate gyrus, and whole hippocampus with the inclusion of three time points with mean volume differences among scans less than 3%, overlap greater than 80%, and ICC >0.95. The parasubiculum and hippocampal fissure showed the least improvement in reliability with mean volume difference greater than 5%, overlap less than 70%, and ICC scores ranging from 0.78 to 0.89. Other subregions, including the CA regions, were stable in their mean volume difference and overlap (<5% difference and >75% respectively) and showed improvement in reliability with the inclusion of three scans (ICC â€‹> â€‹0.9). Reliability was generally higher within scanner (Trio-Trio), however, Trio-Prismafit reliability was also high and did not exhibit an obvious bias. These results suggest that the FreeSurfer automated segmentation procedure is a reliable method to measure total as well as hippocampal subregional volumes and may be useful in clinical applications including as an endpoint for future clinical trials of conditions affecting the hippocampus.

Traumatic Brain Injury and Opioid Overdose Among Post-9/11 Veterans With Long-Term Opioid Treatment of Chronic Pain.

OBJECTIVE: To evaluate the association between traumatic brain injury (TBI) and nonfatal opioid overdose, and the role of psychiatric conditions as mediators of this association. SETTING: Post-9/11 veterans receiving care at national Department of Veterans Affairs (VA) facilities from 2007 to 2012. PARTICIPANTS: In total, 49 014 veterans aged 18 to 40 years receiving long-term opioid treatment of chronic noncancer pain. DESIGN: Longitudinal cohort study using VA registry data. MAIN MEASURES: TBI was defined as a confirmed diagnosis (28%) according to VA comprehensive TBI evaluation; no TBI was defined as a negative primary VA TBI screen (ie, no head injury). Nonfatal opioid overdose was defined using ICD-9 (International Classification of Diseases, Ninth Revision) codes. We performed demographic-adjusted Cox proportional hazards regression. We quantified the impact of co-occurring and individual psychiatric conditions (mood, anxiety, substance use, and posttraumatic stress disorder) on this association using mediation analyses. RESULTS: Veterans with TBI had more than a 3-fold increased risk of opioid overdose compared with those without (adjusted hazards ratio [aHR] = 3.22; 95% confidence interval [CI], 2.13-4.89). This association was attenuated in mediation analyses of any co-occurring psychiatric condition (aHR = 1.77; 95% CI, 1.25-2.52) and individual conditions (aHR range, 1.52-2.95). CONCLUSION: TBI status, especially in the context of comorbid conditions, should be considered in clinical decisions regarding long-term use of opioids in patients with chronic pain.

The Impact of Common Psychiatric and Behavioral Comorbidities on Functional Disability Across Time and Individuals in Post-9/11 Veterans.

Returning veterans often face multiple concurrent psychiatric and behavioral conditions that negatively impact reintegration into civilian life and are associated with functional disability. Understanding how conditions interact to negatively impact functioning is an important step toward developing holistic treatment approaches optimized for this population. This study utilized a cross-sectional and prospective longitudinal cohort design, applying regression algorithms to understand the relative contribution of common clinical issues to functional disability in U.S. veterans who served after the September 11, 2001 (9/11), terror attacks. Community-dwelling post-9/11 veterans (N = 397) completed detailed assessments, including common clinical condition diagnoses, combat experience, and demographics, which were used to predict functional disability (World Health Organization Disability Assessment Schedule); 205 participants were reassessed approximately 1-2 years after enrollment. Regression analyses showed a strong association between the predictor variables and functional disability, f 2 = 1.488. Validation analyses showed a high prediction ability of functional disability to independent samples, r = .719, and across time in the same individuals, r = .780. The strongest predictors included current posttraumatic stress disorder, depressive disorder, sleep disturbance, and pain diagnoses. These results demonstrate the importance of considering multiple common co-occurring conditions when assessing functional disability in post-9/11 veterans and suggest that certain syndromes contribute the most unique information to predicting functional disability with high confidence. As most U.S. veterans utilize private healthcare systems, these results have clinical utility for both Veterans Affairs and civilian healthcare practitioners in assessing and monitoring functional disability in post-9/11 veterans over time.

Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation.

BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock). METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments. RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging. CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing.

BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders. METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes. RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs. CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging.

BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging. METHODS: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. RESULTS: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = 0.044) and sleep disturbance (peak corrected p = 0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = 0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = 0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = 0.049), and white matter microstructural integrity in two tracts (corrected ps = 0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = 0.015). Effects were generally accentuated in older subjects. CONCLUSIONS: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.

Verbal Memory Deficits in OEF/OIF/OND Veterans Exposed to Blasts at Close Range.

OBJECTIVES: This study investigated the relationship between close proximity to detonated blast munitions and cognitive functioning in OEF/OIF/OND Veterans. METHODS: A total of 333 participants completed a comprehensive evaluation that included assessment of neuropsychological functions, psychiatric diagnoses and history of military and non-military brain injury. Participants were assigned to a Close-Range Blast Exposure (CBE) or Non-Close-Range Blast Exposure (nonCBE) group based on whether they had reported being exposed to at least one blast within 10 meters. RESULTS: Groups were compared on principal component scores representing the domains of memory, verbal fluency, and complex attention (empirically derived from a battery of standardized cognitive tests), after adjusting for age, education, PTSD diagnosis, sleep quality, substance abuse disorder, and pain. The CBE group showed poorer performance on the memory component. Rates of clinical impairment were significantly higher in the CBE group on select CVLT-II indices. Exploratory analyses examined the effects of concussion and multiple blasts on test performance and revealed that number of lifetime concussions did not contribute to memory performance. However, accumulating blast exposures at distances greater than 10 meters did contribute to poorer performance. CONCLUSIONS: Close proximity to detonated blast munitions may impact memory, and Veterans exposed to close-range blast are more likely to demonstrate clinically meaningful deficits. These findings were observed after statistically adjusting for comorbid factors. Results suggest that proximity to blast should be considered when assessing for memory deficits in returning Veterans. Comorbid psychiatric factors may not entirely account for cognitive difficulties. (JINS, 2018, 24, 466-475).