Less is more: Smaller hippocampal subfield volumes predict greater improvements in posttraumatic stress disorder symptoms over 2 years.

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder, and symptom severity varies over time. Neurobiological factors that predict PTSD symptoms and their chronicity remain unclear. This study investigated whether the volume of the hippocampus and its subfields, particularly cornu ammonis (CA) 1, CA3, and dentate gyrus, are associated with current PTSD symptoms and whether they predict PTSD symptom changes over 2 years. We examined clinical and structural magnetic resonance imaging measures from 252 trauma-exposed post-9/11 veterans (159 with Time 1 PTSD diagnosis) during assessments approximately 2 years apart. Automated hippocampal subfield segmentation was performed with FreeSurfer Version 7.1, producing 19 bilateral subfields. PTSD symptoms were measured at each assessment using the Clinician-Administered PTSD Scale-IV (CAPS). All models included total intracranial volume as a covariate. First, similar to previous reports, we showed that smaller overall hippocampal volume was associated with greater PTSD symptom severity at Time 1. Notably, when examining regions of interest (CA1, CA3, dentate gyrus), we found that smaller Time 1 hippocampal volumes in the bilateral CA1-body and CA2/3-body predicted decreased PTSD symptom severity at Time 2. These findings were not accounted for by combat exposure or treatment history. Additionally, both Time 1 CA1-body and CA2/3-body volume showed unique associations with changes in avoidance/numbing, but not with changes in reexperiencing or hyperarousal symptoms. This supports a more complex and nuanced relationship between hippocampal structure and PTSD symptoms, where during the posttrauma years bigger may not always mean better, and suggests that the CA1-body and CA2/3-body are important factors in the maintenance of PTSD symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.

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.

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.

Inhibitory control and alcohol use history predict changes in posttraumatic stress disorder symptoms.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with significant disability and can become chronic. Predictors of PTSD symptom changes over time, especially in those with a PTSD diagnosis, remain incompletely characterized. METHOD: In the present study, we examined 187 post-9/11 veterans (Mage = 32.8 years, 87% male) diagnosed with PTSD who performed two extensive clinical and cognitive evaluations approximately 2 years apart. RESULTS: We found that greater PTSD symptom reductions over time were related to lower lifetime drinking history and better baseline inhibitory control ability (Color-Word Inhibition and Inhibition/Switching), though not performance on other executive function tasks. Further, groups with reliably Improved, Worsened, or Chronic PTSD symptoms demonstrated significant differences in baseline inhibitory control and lifetime drinking history, with marked drinking differences starting in the early-to-mid 20s. We also found that PTSD symptom changes showed little-to-no associations with changes in inhibitory control or alcohol consumption. CONCLUSIONS: Together, these findings suggest that, in those diagnosed with PTSD, inhibitory control and alcohol use history reflect relatively stable risk/resiliency factors predictive of PTSD chronicity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Semantic Priming from Uncued Distractors in Alzheimer's Disease.

RESEARCH QUESTION: Are semantic impairments in Alzheimer's disease (AD) partially due to deficits in spatial attention? METHODS AND RESULTS: In a target detection task, both older adults (OAs) and AD individuals were facilitated by valid spatial cues, but only OAs were impaired by invalid cues compared to neutral. In a reading task, spatial cues validly or invalidly cued the location of pictures, which were related or unrelated to subsequent, centrally presented, words. OAs showed semantic priming only after valid cues, whereas AD individuals showed priming after valid and invalid cues. DISCUSSION: Failure to inhibit uncued locations results in processing of potentially distracting semantic information in AD.

Neurobiological and genetic correlates of the dissociative subtype of posttraumatic stress disorder.

Approximately 10%-30% of individuals with posttraumatic stress disorder (PTSD) exhibit a dissociative subtype of the condition defined by symptoms of depersonalization and derealization. This study examined the psychometric evidence for the dissociative subtype of PTSD in a sample of young, primarily male post-9/11-era Veterans (n = 374 at baseline and n = 163 at follow-up) and evaluated its biological correlates with respect to resting state functional connectivity (default mode network [DMN]; n = 275), brain morphology (hippocampal subfield volume and cortical thickness; n = 280), neurocognitive functioning (n = 337), and genetic variation (n = 193). Multivariate analyses of PTSD and dissociation items suggested a class structure was superior to dimensional and hybrid ones, with 7.5% of the sample comprising the dissociative class; this group showed stability over 1.5 years. Covarying for age, sex, and PTSD severity, linear regression models revealed that derealization/depersonalization severity was associated with: decreased DMN connectivity between bilateral posterior cingulate cortex and right isthmus (p = .015; adjusted-p [padj] = .097); increased bilateral whole hippocampal, hippocampal head, and molecular layer head volume (p = .010-.034; padj = .032-.053); worse self-monitoring (p = .018; padj = .079); and a candidate genetic variant (rs263232) in the adenylyl cyclase 8 gene (p = .026), previously associated with dissociation. Results converged on biological structures and systems implicated in sensory integration, the neural representation of spatial awareness, and stress-related spatial learning and memory, suggesting possible mechanisms underlying the dissociative subtype of PTSD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sleep Quality Disturbances Are Associated with White Matter Alterations in Veterans with Post-Traumatic Stress Disorder and Mild Traumatic Brain Injury.

Sleep disturbances are strongly associated with mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI have been linked to alterations in white matter (WM) microstructure, but whether poor sleep quality has a compounding effect on WM remains largely unknown. We evaluated sleep and diffusion magnetic resonance imaging (dMRI) data from 180 male post-9/11 veterans diagnosed with (1) PTSD (n = 38), (2) mTBI (n = 25), (3) comorbid PTSD+mTBI (n = 94), and (4) a control group with neither PTSD nor mTBI (n = 23). We compared sleep quality (Pittsburgh Sleep Quality Index, PSQI) between groups using ANCOVAs and calculated regression and mediation models to assess associations between PTSD, mTBI, sleep quality, and WM. Veterans with PTSD and comorbid PTSD+mTBI reported poorer sleep quality than those with mTBI or no history of PTSD or mTBI (p = 0.012 to <0.001). Poor sleep quality was associated with abnormal WM microstructure in veterans with comorbid PTSD+mTBI (p < 0.001). Most importantly, poor sleep quality fully mediated the association between greater PTSD symptom severity and impaired WM microstructure (p < 0.001). Our findings highlight the significant impact of sleep disturbances on brain health in veterans with PTSD+mTBI, calling for sleep-targeted interventions.

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.

Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults.

Background and Objectives: Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and ß-amyloid (Aß). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and Aß and change in brain cortical thickness among veterans stratified by genetic risk for AD. Methods: Participants consisted of post-9/11 veterans (N = 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimer's Disease Project. T-tau and Aß40 and Aß42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions. Results: Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not Aß42/40 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change. Discussion: Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.

Poorer Inhibitory Control Uniquely Contributes to Greater Functional Disability in Post-9/11 Veterans.

OBJECTIVE: Post-9/11 Veterans endorse greater self-reported functional disability than 80% of the adult population. Previous studies of trauma-exposed populations have shown that increased post-traumatic stress disorder (PTSD) and depressive symptoms are consistently associated with greater disability. Additionally, poorer cognitive performance in the domain of executive functions, particularly inhibitory control, has been associated with disability, though it is unclear if this effect is independent of and/or interacts with PTSD and depression. METHOD: Three overlapping samples of n = 582, 297, and 183 combat-deployed post-9/11 Veterans completed comprehensive assessments of executive functions, PTSD and depressive symptoms, and self-reported World Health Organization Disability Assessment Schedule-II (WHODAS II). RESULTS: Poorer performance on measures of inhibitory control (Delis-Kaplan Executive Functioning System Color-Word Interference-CWI Test and gradual-onset Continuous Performance Test-gradCPT), but not other executive functions, were significantly associated with greater disability on the WHODAS II (ρ's = -.13 and -.13, p = .002 and .026, respectively). CWI inhibitory control measures accounted for unique variance in disability after controlling for PTSD and depressive symptoms (R2 change = 0.02, p < .001). Further, CWI significantly moderated the effect of depressive symptoms on disability, such that better inhibitory control weakened the relationship between depression and disability. CONCLUSIONS: Inhibitory control deficits are uniquely associated with increased disability in combat-deployed post-9/11 Veterans, and better inhibitory control abilities may serve as a protective factor for depressive symptoms leading to increased disability.

Changes in Mild Neurocognitive Disorder Status in Mobility Limited Older Primary Care Patients: Implications for Rehabilitative Care.

OBJECTIVE: The aim of the study is to identify potential rehabilitative treatment targets associated with participants' annual cognitive status. DESIGN: A cohort study patients with self-reported mobility limitation who completed neuropsychological, physical performance testing, and questionnaires at baseline to 2-year follow-up were categorized into three groups (persistently cognitively normal, nonpersistent mild neurocognitive disorder, and persistently mild neurocognitive disorder) based on their annual cognitive status using baseline, years 1 and 2 performance on Hopkins Verbal Learning, Trail Making, and Digit Symbol Substitution Tests. Repeated measures multinomial regression analysis was used to examine the differences between groups and associated characteristics. RESULTS: Study included 349 participants (mean age, 76 ± 7) with 57% of participants were persistently cognitively normal, 16% persistently mild neurocognitive disorder, and 27% nonpersistent mild neurocognitive disorder over 2 yrs of follow-up. Faster gait speed (relative risk reduction, 0.64-0.89) was associated with risk reduction and increase in depressive symptoms (relative risk reduction, 1.09-1.12) was associated with greater risk of being classified into the nonpersistent or persistently mild neurocognitive disorder compared with persistently cognitively normal. CONCLUSIONS: Variability across cognitive status over time was observed. Gait speed and depressive symptoms were modifiable risk factors associated with nonpersistent and persistent mild neurocognitive disorder status. This study reinforces the potential benefit of multifaceted rehabilitation for preventing and treating older adults with mobility and/or cognitive problems.

Association of War Zone-Related Stress With Alterations in Limbic Gray Matter Microstructure.

Importance: Military service members returning from theaters of war are at increased risk for mental illness, but despite high prevalence and substantial individual and societal burden, the underlying pathomechanisms remain largely unknown. Exposure to high levels of emotional stress in theaters of war and mild traumatic brain injury (mTBI) are presumed factors associated with risk for the development of mental disorders. Objective: To investigate (1) whether war zone-related stress is associated with microstructural alterations in limbic gray matter (GM) independent of mental disorders common in this population, (2) whether associations between war zone-related stress and limbic GM microstructure are modulated by a history of mTBI, and (3) whether alterations in limbic GM microstructure are associated with neuropsychological functioning. Design, Setting, and Participants: This cohort study was part of the TRACTS (Translational Research Center for TBI and Stress Disorders) study, which took place in 2010 to 2014 at the Veterans Affair Rehabilitation Research and Development TBI National Network Research Center. Participants included male veterans (aged 18-65 years) with available diffusion tensor imaging data enrolled in the TRACTS study. Data analysis was performed between December 2017 to September 2021. Exposures: The Deployment Risk and Resilience Inventory (DRRI) was used to measure exposure to war zone-related stress. The Boston Assessment of TBI-Lifetime was used to assess history of mTBI. Stroop Inhibition (Stroop-IN) and Inhibition/Switching (Stroop-IS) Total Error Scaled Scores were used to assess executive or attentional control functions. Main Outcomes and Measures: Diffusion characteristics (fractional anisotropy of tissue [FAT]) of 16 limbic and paralimbic GM regions and measures of functional outcome. Results: Among 384 male veterans recruited, 168 (mean [SD] age, 31.4 [7.4] years) were analyzed. Greater war zone-related stress was associated with lower FAT in the cingulate (DRRI-combat left: P = .002, partial r = -0.289; DRRI-combat right: P = .02, partial r = -0.216; DRRI-aftermath left: P = .004, partial r = -0.281; DRRI-aftermath right: P = .02, partial r = -0.219), orbitofrontal (DRRI-combat left medial orbitofrontal cortex: P = .02, partial r = -0.222; DRRI-combat right medial orbitofrontal cortex: P = .005, partial r = -0.256; DRRI-aftermath left medial orbitofrontal cortex: P = .02, partial r = -0.214; DRRI-aftermath right medial orbitofrontal cortex: P = .005, partial r = -0.260; DRRI-aftermath right lateral orbitofrontal cortex: P = .03, partial r = -0.196), and parahippocampal (DRRI-aftermath right: P = .03, partial r = -0.191) gyrus, as well as with higher FAT in the amygdala-hippocampus complex (DRRI-combat: P = .005, partial r = 0.254; DRRI-aftermath: P = .02, partial r = 0.223). Lower FAT in the cingulate-orbitofrontal gyri was associated with impaired response inhibition (Stroop-IS left cingulate: P < .001, partial r = -0.440; Stroop-IS right cingulate: P < .001, partial r = -0.372; Stroop-IS left medial orbitofrontal cortex: P < .001, partial r = -0.304; Stroop-IS right medial orbitofrontal cortex: P < .001, partial r = -0.340; Stroop-IN left cingulate: P < .001, partial r = -0.421; Stroop-IN right cingulate: P < .001, partial r = -0.300; Stroop-IN left medial orbitofrontal cortex: P = .01, partial r = -0.223; Stroop-IN right medial orbitofrontal cortex: P < .001, partial r = -0.343), whereas higher FAT in the mesial temporal regions was associated with improved short-term memory and processing speed (left amygdala-hippocampus complex: P < .001, partial r = -0.574; right amygdala-hippocampus complex: P < .001, partial r = 0.645; short-term memory left amygdala-hippocampus complex: P < .001, partial r = 0.570; short-term memory right amygdala-hippocampus complex: P < .001, partial r = 0.633). A history of mTBI did not modulate the association between war zone-related stress and GM diffusion. Conclusions and Relevance: This study revealed an association between war zone-related stress and alteration of limbic GM microstructure, which was associated with cognitive functioning. These results suggest that altered limbic GM microstructure may underlie the deleterious outcomes of war zone-related stress on brain health. Military service members may benefit from early therapeutic interventions after deployment to a war zone.

For whom the bell tolls: psychopathological and neurobiological correlates of a DNA methylation index of time-to-death.

Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge ("GrimAge residuals"), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, Mage = 52], n = 434 [90% male, Mage = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps < 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (padj = 0.021), poorer memory recall (padj = 0.023), cardiometabolic pathology (padj < 0.001), oxidative stress (padj = 0.003), astrocyte damage (padj = 0.021), inflammation (C-reactive protein: padj < 0.001; IL-6: padj < 0.001), and immune functioning (padj < 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: padj < 0.001; TNF-α: padj < 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (padj = 0.018) and left fusiform gyrus (padj = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment.

PTSD symptomatology is selectively associated with impaired sustained attention ability and dorsal attention network synchronization.

Posttraumatic Stress Disorder (PTSD) symptomatology is associated with dysregulated sustained attention, which produces functional impairments. Performance on sustained attention paradigms such as continuous performance tasks are influenced by both the ability to sustain attention and response strategy. However, previous studies have not dissociated PTSD-related associations with sustained attention ability and strategy, which limits characterization of neural circuitry underlying PTSD-related attentional impairments. Therefore, we characterized and replicated PTSD-related associations with sustained attention ability and response strategy in trauma-exposed Veterans, which guided characterization of PTSD-related differences in neural circuit function. In Study 1, PTSD symptoms were selectively associated with reduced sustained attention ability, but not more impulsive response strategies. In Study 2, we utilized task and resting-state fMRI to characterize neural circuitry underlying PTSD-related differences in sustained attention ability. Both PTSD symptomatology and sustained attention ability exhibited converging associations with reduced dorsal attention network (DAN) synchronization to endogeneous attentional fluctuations. Post-hoc time course analyses demonstrated that PTSD symptoms were most accurately characterized by delayed, rather than globally reduced, DAN synchronization to endogenous attentional fluctuations. Together, these findings suggest that PTSD symptomatology may selectively impair sustained attention ability by disrupting proactive engagement of attentional control circuitry.

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.

An executive function subtype of PTSD with unique neural markers and clinical trajectories.

Previous work identified a cognitive subtype of PTSD with impaired executive function (i.e., impaired EF-PTSD subtype) and aberrant resting-state functional connectivity between frontal parietal control (FPCN) and limbic (LN) networks. To better characterize this cognitive subtype of PTSD, this study investigated (1) alterations in specific FPCN and LN subnetworks and (2) chronicity of PTSD symptoms. In a post-9/11 veteran sample (N = 368, 89% male), we identified EF subgroups using a standardized neuropsychological battery and a priori cutoffs for impaired, average, and above-average EF performance. Functional connectivity between two subnetworks of the FPCN and three subnetworks of the LN was assessed using resting-state fMRI (n = 314). PTSD chronicity over a 1-2-year period was assessed using a reliable change index (n = 175). The impaired EF-PTSD subtype had significantly reduced negative functional connectivity between the FPCN subnetwork involved in top-down control of emotion and two LN subnetworks involved in learning/memory and social/emotional processing. This impaired EF-PTSD subtype had relatively chronic PTSD, while those with above-average EF and PTSD displayed greater symptom reduction. Lastly, FPCN-LN subnetworks partially mediated the relationship between EF and PTSD chronicity (n = 121). This study reveals (1) that an impaired EF-PTSD subtype has a specific pattern of FPCN-LN subnetwork connectivity, (2) a novel above-average EF-PTSD subtype displays reduced PTSD chronicity, and (3) both cognitive and neural functioning predict PTSD chronicity. The results indicate a need to investigate how individuals with this impaired EF-PTSD subtype respond to treatment, and how they might benefit from personalized and novel approaches that target these neurocognitive systems.

Post-traumatic stress disorder and depression are uniquely associated with disability and life dissatisfaction in post-9/11 veterans.

Veterans who served in post-9/11 conflicts and experience deployment trauma sequelae frequently endorse disability and dissatisfaction with life. Although correlated, disability and life dissatisfaction represent distinct constructs with separate implications for quality of life. We examined associations between deployment trauma sequelae, disability and life dissatisfaction in 288 post-9/11 Veterans. Participants completed assessments of psychiatric, somatic and social functioning. Self-reports evaluating disability and life dissatisfaction were used to group participants based on established criteria (i.e., Disability and Dissatisfaction, Disability Only, Dissatisfaction Only, or No Disability or Dissatisfaction). Multinomial logistic regressions revealed that greater post-traumatic stress disorder (PTSD) and depressive symptom severity were independently associated with increased odds of being in the Disability and Dissatisfaction group, the Disability Only group and the Dissatisfaction Only group, relative to the No Disability or Dissatisfaction group. Number of prior mild traumatic brain injuries (mTBI) was not associated with disability or dissatisfaction after accounting for other trauma sequelae. Social support attenuated the relationship between depression and membership in the Disability and Dissatisfaction group. Participants who reported greater dissatisfaction than disability endorsed greater depression and mTBI frequency. Overall, PTSD and depression convey a heightened risk of both disability and life dissatisfaction, while social support may be protective.

Associations between Post-Traumatic stress disorder symptoms and automobile driving behaviors: A review of the literature.

Human factors are responsible for most motor vehicle accidents that occur on the road. Recent work suggests that symptoms of posttraumatic stress disorder (PTSD) are linked to reduced driving safety, yet none have provided a comprehensive review of this small, emerging literature. The present review identified twenty-two studies reporting associations between PTSD and driving behaviors. Among these, longitudinal designs (k = 3) and studies using objective driving performance measures (e.g., simulators) (k = 2) were rare. Most studies (k = 18) relied on brief screener measures of PTSD status/symptoms or a prior chart diagnosis, while few used a standardized structured interview measure to determine PTSD status (k = 4), and only a small number of studies assessed PTSD symptom clusters (k = 7). PTSD was most frequently associated with increased rates of hostile driving behaviors (e.g., cutting off others), unintentional driving errors (e.g., lapses in attention) and negative thoughts and emotions experienced behind the wheel. Findings regarding risk of motor vehicle accident and driving-related legal issues were variable, however relatively few studies (k = 5) explored these constructs. Future directions are discussed, including the need for work focused on concurrent PTSD symptom/driving-related changes, more comprehensive PTSD and driving assessment, and consideration of the contributions of comorbid traumatic brain injury history and other neurological and psychiatric conditions on driving outcomes.