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BackgroundPervasive use of improvised explosive devices (IEDs), rocket-propelled grenades, and land mines in the recent conflicts in Iraq and Afghanistan has brought traumatic brain injury (TBI) and its impact on health outcomes into public awareness. Blast injuries have been deemed signature wounds of these wars. War-related TBI is not new, having become prevalent during WWI and remaining medically relevant in WWII and beyond. Medicine's past attempts to accurately diagnose and disentangle the pathophysiology of war-related TBI parallels current lines of inquiry and highlights limitations in methodology and attribution of symptom etiology, be it organic, psychological, or behavioral. New approaches and biomarkers are needed.PreclinicalSerological biomarkers and biomarkers of injury obtained with imaging techniques represent cornerstones in the translation between experimental data and clinical observations. Experimental models for blast related TBI and PTSD can generate critical data on injury threshold, for example for white matter injury from acceleration. Carefully verified and validated models can be evaluated with gene expression arrays and proteomics to identify new candidates for serological biomarkers. Such models can also be analyzed with diffusion MRI and microscopy in order to identify criteria for detection of diffuse white matter injuries, such as DAI (diffuse axonal injury). The experimental models can also be analyzed with focus on injury outcome in brain stem regions, such as locus coeruleus or nucleus raphe magnus that can be involved in response to anxiety changes.ClinicalMild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. There is accumulating evidence that injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4Hz) that can be measured and localized by magnetoencephalography (MEG). MEG imaging detects TBI abnormalities at the rates of 87% for the mild TBI, group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities are 96% and 77% for the blast and non-blast TBI groups, respectively. There is emerging evidence based on fMRI and MEG studies showing hyper-activity in the amygdala and hypo-activity in pre-frontal cortex in individuals with PTSD. MEG signal may serve as a sensitive imaging marker for mTBI, distinguishable from abnormalities generated in association with PTSD. More work is needed to fully describe physiological mechanisms of post-concussive symptoms.

BackgroundPervasive use of improvised explosive devices (IEDs), rocket-propelled grenades, and land mines in the recent conflicts in Iraq and Afghanistan has brought traumatic brain injury (TBI) and its impact on health outcomes into public awareness. Blast injuries have been deemed signature wounds of these wars. War-related TBI is not new, having become prevalent during WWI and remaining medically relevant in WWII and beyond. Medicine's past attempts to accurately diagnose and disentangle the pathophysiology of war-related TBI parallels current lines of inquiry and highlights limitations in methodology and attribution of symptom etiology, be it organic, psychological, or behavioral. New approaches and biomarkers are needed.PreclinicalSerological biomarkers and biomarkers of injury obtained with imaging techniques represent cornerstones in the translation between experimental data and clinical observations. Experimental models for blast related TBI and PTSD can generate critical data on injury threshold, for example for white matter injury from acceleration. Carefully verified and validated models can be evaluated with gene expression arrays and proteomics to identify new candidates for serological biomarkers. Such models can also be analyzed with diffusion MRI and microscopy in order to identify criteria for detection of diffuse white matter injuries, such as DAI (diffuse axonal injury). The experimental models can also be analyzed with focus on injury outcome in brain stem regions, such as locus coeruleus or nucleus raphe magnus that can be involved in response to anxiety changes.ClinicalMild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. There is accumulating evidence that injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4Hz) that can be measured and localized by magnetoencephalography (MEG). MEG imaging detects TBI abnormalities at the rates of 87% for the mild TBI, group ...

Previous studies have found an association between childhood maltreatment (CM) and health-related quality of life (HRQoL), and to a lesser extent have considered whether psychiatric symptoms may explain the relationship. This study aimed to further our understanding of the link between CM and HRQoL by testing whether posttraumatic stress disorder (PTSD) or depressive symptoms mediate the relationship between childhood maltreatment and physical HRQoL. Mediation models were examined in a sample of male Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) active duty and combat veterans (n=249). PTSD and depressive symptoms mediated the relationship between CM and overall physical HRQoL, as well as participation in daily activities due to physical health, bodily pain, and social functioning. Mediation of the relationship between childhood maltreatment and physical and social functioning by depression and PTSD symptoms may lend support to neurobiological hypotheses that childhood maltreatment sensitizes the nervous system and after repeated trauma may lead to the development of psychiatric symptoms, which have a major impact on morbidity and mortality.

BackgroundHeightened startle response is a symptom of PTSD, but evidence for exaggerated startle in PTSD is inconsistent. This prospective study aimed to clarify whether altered startle reactivity represents a trait risk-factor for developing PTSD or a marker of current PTSD symptoms.MethodsMarines and Navy Corpsmen were assessed before (n = 2,571) and after (n = 1,632) deployments to Iraq or Afghanistan with the Clinician-Administered PTSD Scale (CAPS). A predeployment startle-threshold task was completed with startle probes presented over 80-114 dB[A] levels. Latent class mixture modeling identified three growth classes of startle performance: "high," "low," and "moderate" threshold classes. Zero-inflated negative binomial regression was used to assess relationships between predeployment startle threshold and pre- and postdeployment psychiatric symptoms.ResultsAt predeployment, the low-threshold class had higher PTSD symptom scores. Relative to the moderate-threshold class, low-threshold class membership was associated with decreased likelihood of being symptom-free at predeployment, based on CAPS, with particular associations with numbing and hyperarousal subscales, whereas high-threshold class membership was associated with more severe predeployment PTSD symptoms, in particular avoidance. Associations between low-threshold membership and CAPS symptoms were independent from measures of trauma burden, whereas associations between high-threshold membership and CAPS were not. Predeployment startle threshold did not predict postdeployment symptoms.ConclusionsThis study found that both low startle threshold (heightened reactivity) and high startle threshold (blunted reactivity) were associated with greater current PTSD symptomatology, suggesting that startle reactivity is associated with current PTSD rather than a risk marker for developing PTSD.

BackgroundIt is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change.MethodsEight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment. Assessments included TBI history, PTSD symptoms, combat trauma and deployment stress, and a fear-potentiated startle task of fear acquisition and extinction. Startle response and self-reported expectancy and anxiety served as measures of fear conditioning, and PTSD symptoms were measured with the Clinician-Administered PTSD Scale.ResultsIndividuals endorsing "multiple hit" exposure (both deployment TBI and a prior TBI) showed the strongest fear acquisition and highest fear expression compared to groups without multiple hits. Extinction did not differ across groups. Endorsing a deployment TBI was associated with higher anxiety to the fear cue compared to those without deployment TBI. The association of deployment TBI with increased postdeployment PTSD symptoms was mediated by postdeployment fear expression when recent prior-TBI exposure was included as a moderator. TBI associations with increased response to threat cues and PTSD symptoms remained when controlling for deployment trauma and postdeployment PTSD diagnosis.ConclusionsDeployment TBI, and multiple-hit TBI in particular, are associated with increases in conditioned fear learning and expression that may contribute to risk for developing PTSD symptoms.

ObjectivesWe aimed to describe differences in combat experience for male and female veterans and characterize differential effects on postdeployment physical and mental health symptoms, including aggression.MethodsRetrospective cross-sectional health screening data from 554 Operation Enduring Freedom and Operation Iraqi Freedom veterans who enrolled for Veterans Affairs health care in San Diego were examined including measures of combat experience, pain intensity, traumatic brain injury symptoms, military sexual trauma, post-traumatic stress disorder, depression, alcohol use, and aggression.ResultsAlthough male veterans (n = 458) experienced significantly higher rates of combat than female veterans (n = 96), both experienced similar levels of postdeployment post-traumatic stress disorder and depression symptoms as well self-reported aggressive behavior compared to male veterans. Female veterans had higher rates of military sexual trauma and lower alcohol consumption than male veterans.ConclusionsAll Operation Enduring Freedom and Operation Iraqi Freedom veterans returning from deployment may benefit from broad-based screening of physical and mental health symptoms, beyond those currently mandated by Veterans Affairs, including anger and aggression.

ImportanceDisrupted autonomic nervous system functioning as measured by heart rate variability (HRV) has been associated with posttraumatic stress disorder (PTSD). It is not clear, however, whether reduced HRV before trauma exposure contributes to the risk for development of PTSD.ObjectiveTo examine whether HRV before combat deployment is associated with increased risk of a PTSD diagnosis after deployment when accounting for deployment-related combat exposure.Design, setting, and participantsBetween July 14, 2008, and May 24, 2012, active-duty Marines were assessed 1 to 2 months before a combat deployment and again 4 to 6 months after their return. The first phase of the Marine Resiliency Study (MRS-I) included 1415 male Marines, 59 of whom developed PTSD after deployment. Participants in the second phase of the Marine Resiliency Study (MRS-II) included 745 male Marines, 25 of whom developed PTSD after deployment. Analysis was conducted from November 25, 2013, to April 16, 2015.Main outcomes and measuresPredeployment HRV was measured via finger photoplethysmography during a 5-minute period of rest. Frequency-domain measures of HRV were generated. Diagnosis of PTSD was determined using the Clinician-Administered PTSD Scale.ResultsAfter accounting for deployment-related combat exposure, lower HRV before deployment as measured by an increased low-frequency (LF) to high-frequency (HF) ratio of HRV was associated with risk of PTSD diagnosis after deployment (combined MRS-I and MRS-II cohort meta-analysis odds ratio, 1.47; 95% CI, 1.10-1.98; P = .01). The prevalence of postdeployment PTSD was higher in participants with high predeployment LF:HF ratios (15.8% [6 of 38 participants]) compared with participants who did not have high LF:HF ratios (3.7% [78 of 2122 participants]).Conclusions and relevanceThis prospective longitudinal study provides initial and modest evidence that an altered state of autonomic nervous system functioning contributes to PTSD vulnerability, taking into account other key risk factors. If these findings are replicated, interventions that change autonomic nervous system function may open novel opportunities for prevention and treatment of PTSD.

ObjectivesWe aimed to describe differences in combat experience for male and female veterans and characterize differential effects on postdeployment physical and mental health symptoms, including aggression.MethodsRetrospective cross-sectional health screening data from 554 Operation Enduring Freedom and Operation Iraqi Freedom veterans who enrolled for Veterans Affairs health care in San Diego were examined including measures of combat experience, pain intensity, traumatic brain injury symptoms, military sexual trauma, post-traumatic stress disorder, depression, alcohol use, and aggression.ResultsAlthough male veterans (n = 458) experienced significantly higher rates of combat than female veterans (n = 96), both experienced similar levels of postdeployment post-traumatic stress disorder and depression symptoms as well self-reported aggressive behavior compared to male veterans. Female veterans had higher rates of military sexual trauma and lower alcohol consumption than male veterans.ConclusionsAll Operation Enduring Freedom and Operation Iraqi Freedom veterans returning from deployment may benefit from broad-based screening of physical and mental health symptoms, beyond those currently mandated by Veterans Affairs, including anger and aggression.

ObjectiveHeart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression.MethodsFour battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5-minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively.ResultsWhen adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (β = -0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033).ConclusionsThis cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure.

ObjectiveHeart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression.MethodsFour battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5-minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively.ResultsWhen adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (β = -0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033).ConclusionsThis cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure.

To examine whether cause, severity, and frequency of traumatic brain injury (TBI) increase risk of postdeployment tinnitus when accounting for comorbid posttraumatic stress disorder.Self-report and clinical assessments were done before and after an "index" deployment to Iraq or Afghanistan.Assessments took place on Marine Corps bases in southern California and the VA San Diego Medical Center. Participants were 1647 active-duty enlisted Marine and Navy servicemen who completed pre- and postdeployment assessments of the Marine Resiliency Study. The main outcome was the presence of tinnitus at 3 months postdeployment.Predeployment TBI increased the likelihood of new-onset postdeployment tinnitus (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.28-2.70). Deployment-related TBIs increased the likelihood of postdeployment tinnitus (OR = 2.65; 95% CI, 1.19-5.89). Likelihood of new-onset postdeployment tinnitus was highest for those who were blast-exposed (OR = 2.93; 95% CI, 1.82-6.17), who reported moderate-severe TBI symptoms (OR = 2.22; 95% CI, 1.22-3.40), and who sustained multiple TBIs across study visits (OR = 2.27; 95% CI, 1.44-4.24). Posttraumatic stress disorder had no effect on tinnitus outcome.Participants who were blast-exposed, sustained multiple TBIs, and reported moderate-severe TBI symptoms were most at risk for new-onset tinnitus.

Abstract Background Posttraumatic stress disorder (PTSD) is one of the most commonly observed stress-related conditions following combat exposure and its effective prevention is a high health-care priority. Reports of peritraumatic reactions have been shown to be highly associated with PTSD among combat exposed service members. However, existing instruments measuring peritraumatic symptoms were not specifically developed to assess combat-related peritraumatic stress and each demonstrates a different peritraumatic focus. We therefore developed the Peritraumatic Behavior Questionnaire (PBQ), a new military-specific rating scale focused upon the wide range of symptoms suggestive of combat-related peritraumatic distress in actively deployed Service Members. This study describes the development of the PBQ and reports on the psychometric properties of its self-rated version (PBQ-SR). Methods 688 Marine infantry service members were retrospectively assessed by the PBQ-SR within the scope of the Marine Resiliency Study after their deployment to war zone. Participants have been additionally assessed by a variety of questionnaires, as well as clinical interviews both pre and post-deployment. Results The PBQ-SR demonstrated satisfactory internal consistency, convergent and discriminant validity, as well as high correlation with trait dissociation prior to deployment. Component analysis suggested a latent bi-dimensional structure separating a peritraumatic emotional distress and physical awareness factor. The PBQ-SR total score showed high correlation to general anxiety, depression, poorer general health and posttraumatic symptoms after deployment and remained a significant predictor of PTSD severity, after controlling for those measures. The suggested screening cut-off score of 12 points demonstrated satisfactory predictive power. Conclusions This study confirms the ability of the PBQ-SR to unify the underlying peritraumatic symptom dimensions and reliably assess combat-related peritraumatic reaction as a general construct. The PBQ-SR demonstrated promise as a potential standard screening measure in military clinical practice, while It's predictive power should be established in prospective studies.

Abstract Background Posttraumatic stress disorder (PTSD) is one of the most commonly observed stress-related conditions following combat exposure and its effective prevention is a high health-care priority. Reports of peritraumatic reactions have been shown to be highly associated with PTSD among combat exposed service members. However, existing instruments measuring peritraumatic symptoms were not specifically developed to assess combat-related peritraumatic stress and each demonstrates a different peritraumatic focus. We therefore developed the Peritraumatic Behavior Questionnaire (PBQ), a new military-specific rating scale focused upon the wide range of symptoms suggestive of combat-related peritraumatic distress in actively deployed Service Members. This study describes the development of the PBQ and reports on the psychometric properties of its self-rated version (PBQ-SR). Methods 688 Marine infantry service members were retrospectively assessed by the PBQ-SR within the scope of the Marine Resiliency Study after their deployment to war zone. Participants have been additionally assessed by a variety of questionnaires, as well as clinical interviews both pre and post-deployment. Results The PBQ-SR demonstrated satisfactory internal consistency, convergent and discriminant validity, as well as high correlation with trait dissociation prior to deployment. Component analysis suggested a latent bi-dimensional structure separating a peritraumatic emotional distress and physical awareness factor. The PBQ-SR total score showed high correlation to general anxiety, depression, poorer general health and posttraumatic symptoms after deployment and remained a significant predictor of PTSD severity, after controlling for those measures. The suggested screening cut-off score of 12 points demonstrated satisfactory predictive power. Conclusions This study confirms the ability of the PBQ-SR to unify the underlying peritraumatic symptom dimensions and reliably assess combat-related peritraumatic reaction as a general construct. The PBQ-SR demonstrated promise as a potential standard screening measure in military clinical practice, while It's predictive power should be established in prospective studies.