Publications

Deficits in impulse control are increasingly recognized in association with posttraumatic stress disorder (PTSD). To our further understanding of the neurobiology of PTSD-related disinhibition, we examined alterations in brain morphology and network connectivity associated with response inhibition failures and PTSD severity. The sample consisted of 189 trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom veterans (89% male, ages 19-62) presenting with a range of current PTSD severity. Disinhibition was measured using commission errors on a Go/No-Go (GNG) task with emotional stimuli, and PTSD was assessed using a measure of current symptom severity. Whole-brain vertex-wise analyses of cortical thickness revealed two clusters associated with PTSD-related disinhibition (Monte Carlo cluster corrected P < 0.05). The first cluster included portions of right inferior and middle frontal gyri and frontal pole. The second cluster spanned portions of left medial orbital frontal, rostral anterior cingulate, and superior frontal gyrus. In both clusters, commission errors were associated with reduced cortical thickness at higher (but not lower) levels of PTSD symptoms. Resting-state functional magnetic resonance imaging analyses revealed alterations in the functional connectivity of the right frontal cluster. Together, study findings suggest that reductions in cortical thickness in regions involved in flexible decision-making, emotion regulation, and response inhibition contribute to impulse control deficits in PTSD. Furthermore, aberrant coupling between frontal regions and networks involved in selective attention, memory/learning, and response preparation suggest disruptions in functional connectivity may also play a role.

Oxidative stress has been implicated in many common age-related diseases and is hypothesized to play a role in posttraumatic stress disorder (PTSD)-related neurodegeneration (Miller and Sadeh, 2014). This study examined the influence of the oxidative stress-related genes ALOX 12 and ALOX 15 on the association between PTSD and cortical thickness. Factor analyses were used to identify and compare alternative models of the structure of cortical thickness in a sample of 218 veterans. The best-fitting model was then used for a genetic association analysis in White non-Hispanic participants (n=146) that examined relationships between 33 single nucleotide polymorphisms (SNPs) spanning the two genes, 8 cortical thickness factors, and each SNP×PTSD interaction. Results identified a novel ALOX12 locus (indicated by two SNPs in perfect linkage disequilibrium: rs1042357 and rs10852889) that moderated the association between PTSD and reduced thickness of the right prefrontal cortex. A whole-cortex vertex-wise analysis showed this effect to be localized to clusters spanning the rostral middle frontal gyrus, superior frontal gyrus, rostral anterior cingulate cortex, and medial orbitofrontal cortex. These findings illustrate a novel factor-analytic approach to neuroimaging-genetic analyses and provide new evidence for the possible involvement of oxidative stress in PTSD-related neurodegeneration.

Although there is mounting evidence that greater PTSD symptoms are associated with reduced executive functioning, it is not fully understood whether this association is more global or specific to certain executive function subdomains, such as inhibitory control. We investigated the generality of the association between PTSD symptoms and executive function by administering a broad battery of sensitive executive functioning tasks to a cohort of returning Operation Enduring Freedom/Operation Iraqi Freedom Veterans with varying PTSD symptoms. Only tasks related to inhibitory control explained significant variance in PTSD symptoms as well as symptoms of depression, while measures of working memory, measures of switching, and measures simultaneously assessing multiple executive function subdomains did not. Notably, the two inhibitory control measures that showed the highest correlation with PTSD and depressive symptoms, measures of response inhibition and distractor suppression, explained independent variance. These findings suggest that greater posttraumatic psychological symptoms are not associated with a general decline in executive functioning but rather are more specifically related to stopping automatic responses and resisting internal and external distractions.

Pain, a debilitating condition, is frequently reported by U.S. veterans returning from Afghanistan and Iraq. This study investigated how commonly reported clinical factors were associated with pain and whether these associations differed for individuals with a history of chronic pain. From the Boston metropolitan area, 171 veterans enrolled in the Veterans Affairs Center of Excellence were assessed for current posttraumatic stress disorder (PTSD) symptom severity, current mood and anxiety diagnoses, lifetime traumatic brain injury, combat experiences, sleep quality, and alcohol use. Hierarchical regression models were used to determine the association of these conditions with current pain. Average pain for the previous 30 days, assessed with the McGill Pain Questionnaire, was 30.07 out of 100 (SD = 25.43). Sleep quality, PTSD symptom severity, and alcohol use were significantly associated with pain (R(2) = .24), as were reexperiencing symptoms of PTSD (R(2) = .25). For participants with a history of chronic pain (n = 65), only PTSD symptoms were associated with pain (R(2) = .19). Current pain severity was associated with increased PTSD severity (notably, reexperiencing symptoms), poor sleep quality, and increased alcohol use. These data support the hypothesis that PTSD symptoms influence pain, but suggest that problems with sleep and alcohol use may exacerbate the relationship.

OBJECTIVE: Report the prevalence of lifetime and military-related traumatic brain injuries (TBIs) in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans and validate the Boston Assessment of TBI-Lifetime (BAT-L). SETTING: The BAT-L is the first validated, postcombat, semistructured clinical interview to characterize head injuries and diagnose TBIs throughout the life span. PARTICIPANTS: Community-dwelling convenience sample of 131 OEF/OIF veterans. DESIGN: TBI criteria (alteration of mental status, posttraumatic amnesia, and loss of consciousness) were evaluated for all possible TBIs, including a novel evaluation of blast exposure. MAIN MEASURES: BAT-L, Ohio State University TBI Identification Method (OSU-TBI-ID). RESULTS: About 67% of veterans incurred a TBI in their lifetime. Almost 35% of veterans experienced at least 1 military-related TBI; all were mild in severity, 40% of them were due to blast, 50% were due to some other (ie, blunt) mechanism, and 10% were due to both types of injuries. Predeployment TBIs were frequent (45% of veterans). There was strong correspondence between the BAT-L and the OSU-TBI-ID (Cohen κ = 0.89; Kendall τ-b = 0.95). Interrater reliability of the BAT-L was strong (κs >0.80). CONCLUSIONS: The BAT-L is a valid instrument with which to assess TBI across a service member's lifetime and captures the varied and complex nature of brain injuries across OEF/OIF veterans' life span.

This study examined the performance of veterans and active duty personnel who served in Operation Enduring Freedom and/or Operation Iraqi Freedom (OEF/OIF) on a basic associative learning task. Eighty-eight individuals participated in this study. All received a comprehensive clinical evaluation to determine the presence and severity of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). The eyeblink conditioning task was composed of randomly intermixed delay and trace conditioned stimulus (CS) and unconditioned stimulus (US) pairs (acquisition) followed by a series of CS only trials (extinction). Results revealed that those with a clinical diagnosis of PTSD or a diagnosis of PTSD with comorbid mTBI acquired delay and trace conditioned responses (CRs) to levels and at rates similar to a deployed control group, thus suggesting intact basic associative learning. Differential extinction impairment was observed in the two clinical groups. Acquisition of CRs for both delay and trace conditioning, as well as extinction of trace CRs, was associated with alcoholic behavior across all participants. These findings help characterize the learning and memory function of individuals with PTSD and mTBI from OEF/OIF and raise the alarming possibility that the use of alcohol in this group may lead to more significant cognitive dysfunction.

This study examined the performance of 198 Veteran research participants deployed during Operation Enduring Freedom, Operation Iraqi Freedom, and/or Operation New Dawn (OEF/OIF/OND) on four measures of performance validity: the Medical Symptom Validity Test (MSVT), California Verbal Learning Test: Forced Choice Recognition (FCR), Reliable Digit Span (RDS), and TOVA Symptom Exaggeration Index (SEI). Failure on these performance validity tests (PVTs) ranged from 4% to 9%. The overall base rate of poor performance validity, as measured by failure of the MSVT in conjunction with an embedded PVT (FCR, RDS, SEI), was 5.6%. Regression analyses revealed that poor performance validity predicted cognitive test performance and self-reported psychological symptom severity. Furthermore, a greater prevalence of traumatic brain injury (TBI), Post-Traumatic Stress Disorder (PTSD), co-morbid TBI/PTSD, and other Axis I diagnoses, was observed among participants with poor effort. Although poor performance validity is relatively uncommon in a research setting, these findings demonstrate that clinicians should be cautious when interpreting psychological symptoms and neuropsychological test performance of Veteran participants who fail effort measures.

Studies have shown that early life trauma may influence neural development and increase the risk of developing psychological disorders in adulthood. We used magnetic resonance imaging to examine the impact of early life trauma on the relationship between current posttraumatic stress disorder (PTSD) symptoms and cortical thickness/subcortical volumes in a sample of deployed personnel from Operation Enduring Freedom/Operation Iraqi Freedom. A group of 108 service members enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) were divided into those with interpersonal early life trauma (EL-Trauma+) and Control (without interpersonal early life trauma) groups based on the Traumatic Life Events Questionnaire. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale. Cortical thickness and subcortical volumes were analyzed using the FreeSurfer image analysis package. Thickness of the paracentral and posterior cingulate regions was positively associated with PTSD severity in the EL-Trauma+ group and negatively in the Control group. In the EL-Trauma+ group, both the right amygdala and the left hippocampus were positively associated with PTSD severity. This study illustrates a possible influence of early life trauma on the vulnerability of specific brain regions to stress. Changes in neural morphometry may provide information about the emergence and maintenance of symptoms in individuals with PTSD.

Alcoholism frequently occurs in returning U.S. Veterans, and is often comorbid with Post Traumatic Stress Disorder (PTSD). The goal of this study was to investigate the relationship between white matter changes and neuropsychological alterations in Operation Enduring Freedom, and/or Operation Iraqi Freedom (OEF/OIF) alcoholic Veterans with two primary aims: (1) to examine the relationship of alcoholism to brain structure and function while controlling for the potential effects of comorbid PTSD, and (2) to examine whether the effects of alcoholism are moderated by the quantity of lifetime alcohol consumption. Our sample consisted of 71 deployed OEF/OIF Veterans stratified into four groups: alcoholics without PTSD, alcoholics with PTSD, participants with PTSD without comorbid alcoholism, and control participants without alcoholism or PTSD. Participants were given an extensive neuropsychological and psychiatric assessment battery, as well as Magnetic Resonance Diffusion Tensor Imaging (DT-MRI) scans. Results showed that disruption of executive functioning, and abnormal fractional anisotropy (FA; a measure of axonal integrity) within the frontal subcortical and dorsolateral frontal-parietal regions, occurred independently of the effects of PTSD. Furthermore, these cognitive and neuronal alterations were unique to the most severe subgroup of alcoholics who consumed the greatest amount of alcohol over the course of their lifetime, as compared to the rest of the sample. Axonal integrity within this subgroup, in regions underlying the frontal subcortical area, was shown to be decreased independently of cognitive changes. Integrity of axons underlying the dorsolateral frontal-parietal region, however, was increased. We hypothesized that this is a compensatory mechanism for executive dysfunction.

Driving simulator performance was examined in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans to objectively evaluate driving abilities among this cohort who self-report poorer driving safety postdeployment. OIF/OEF Veterans (n = 25) and age- and education-matched civilian controls (n = 25) participated in a 30 min driving simulator assessment that measured the frequency of minor, moderate, and severe driving errors. Frequency of errors in specific content domains (speed regulation, positioning, and signaling) was also calculated. All participants answered questions about number of lifetime traffic "warnings," moving violation tickets, and accidents. Veterans completed the Posttraumatic Stress Disorder (PTSD) Checklist-Military Version. On the driving simulator assessment, Veterans committed more minor, moderate, severe, and speeding errors and reported poorer lifetime driving records than the civilian control group. Exploratory analyses revealed an association between increasing errors on the driving simulator with increasing symptoms of PTSD, although statistically this correlation did not reach significance. These findings suggest that Veterans perform more poorly on an objective evaluation of driving safety and that the presence of PTSD could be associated with worse performance on this standardized driving simulator assessment.

Individuals with post-traumatic stress disorder (PTSD) show a cognitive bias for threatening information, reflecting dysregulated executive control for affective stimuli. This study examined whether comorbid mild Traumatic Brain Injury (mTBI) with PTSD exacerbates this bias. A computer-administered Affective Go/No-Go task measured reaction times (RTs) and errors of omission and commission to words with a non-combat-related positive or negative valence in 72 deployed United States service members from the wars in Iraq and Afghanistan. Incidents of military-related mTBI were measured with the Boston Assessment of Traumatic Brain Injury-Lifetime. PTSD symptoms were measured with the Clinician-Administered PTSD Scale. Participants were divided into those with (mTBI+, n = 34) and without a history of military-related mTBI (mTBI-, n = 38). Valence of the target stimuli differentially impacted errors of commission and decision bias (criterion) in the mTBI+ and mTBI- groups. Specifically, within the mTBI+ group, increasing severity of PTSD symptoms was associated with an increasingly liberal response pattern (defined as more commission errors to negative distractors and greater hit rate for positive stimuli) in the positive compared to the negative blocks. This association was not observed in the mTBI- group. This study underscores the importance of considering the impact of a military-related mTBI and PTSD severity upon affective executive control.

Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) in military personnel is increasing dramatically following the OEF/OIF conflicts and is associated with alterations to brain structure. The present study examined the relationship between PTSD and cortical thickness, and its possible modification by mTBI, in a 104-subject OEF/OIF veteran cohort ranging in age from 20 to 62 years. For each participant, two T1-weighted scans were averaged to create high-resolution images for calculation of regional cortical thickness. PTSD symptoms were assessed using the Clinician Administered PTSD Scale (CAPS) and scores were derived based on the previous month's symptoms ("current") and a Cumulative Lifetime Burden of PTSD (CLB-P) reflecting the integral of CAPS scores across the lifetime. Mild TBI was diagnosed using the Boston Assessment of TBI-Lifetime (BAT-L). Results demonstrated a clear negative relationship between current PTSD severity and thickness in both postcentral gyri and middle temporal gyri. This relationship was stronger and more extensive when considering lifetime burden (CLB-P), demonstrating the importance of looking at trauma in the context of an individual's lifetime, rather than only at their current symptoms. Finally, interactions with current PTSD only and comorbid current PTSD and mTBI were found in several regions, implying an additive effect of lifetime PTSD and mTBI on cortical thickness.

Research has shown that attention can be abnormally drawn to salient threat- or trauma-related information in individuals with posttraumatic stress and related psychological symptoms. The nature of this attentional bias is thought to derive from capture of attention toward potential threat overpowering the volitional, goal-directed attentional system. However, it is unclear whether this pattern of attentional dysregulation generalizes to salient, but non-emotional types of information. Using a well-established and sensitive measure of attentional capture, the current study demonstrates that posttraumatic psychological symptom severity is associated with the capture of attention by visually salient, non-emotional distractors. Specifically, during visual search for a unique shape, the presence of a task-irrelevant but salient color singleton disrupted search efficiency, and this disruption was correlated with both posttraumatic stress disorder (PTSD) and depression symptom severity as assessed by self-report. These findings suggest that posttraumatic stress and depression may be characterized as involving a general alteration of the balance between salience-based and goal-directed attentional systems.

BACKGROUND: Chronic misuse of alcohol results in widespread damage to the brain. Prior morphometric studies have examined cortical atrophy in individuals with alcoholism; however, no previous studies have examined alcohol-associated atrophy using cortical thickness measurements to obtain regional mapping of tissue loss across the full cortical surface. METHODS: We compared cortical thickness measures from 31 abstinent individuals with a history of prior alcohol abuse to 34 healthy nonalcoholic control participants (total sample size = 65). Cortical surface models were created from high-resolution T1-weighted images, and cortical thickness was then estimated as the distance between the gray matter/white matter boundary and the outer cortical surface. RESULTS: Abstinent alcoholics showed reduced whole-brain thickness as compared to nonalcoholic participants. Decreases in thickness were found bilaterally in (i) superior frontal, (ii) precentral, (iii) postcentral, (iv) middle frontal, (v) middle/superior temporal, (vi) middle temporal, and (vii) lateral occipital cortical regions. Decreased cortical thickness in the alcoholic group was associated with severity of alcohol abuse. CONCLUSIONS: These findings demonstrate widespread reduction in cortical thickness as a consequence of chronic alcoholism, with most severe reductions in frontal and temporal brain regions.