Distinct patterns of resting-state connectivity in U.S. service members with mild traumatic brain injury versus posttraumatic stress disorder.

Mild traumatic brain injury (mTBI) is highly prevalent in military populations, with many service members suffering from long-term symptoms. Posttraumatic stress disorder (PTSD) often co-occurs with mTBI and predicts worse clinical outcomes. Functional neuroimaging research suggests there are both overlapping and distinct patterns of resting-state functional connectivity (rsFC) in mTBI versus PTSD. However, few studies have directly compared rsFC of cortical networks in military service members with these two conditions. In the present study, U.S. service members (n = 137; ages 19-59; 120 male) underwent resting-state fMRI scans. Participants were divided into three study groups: mTBI only, PTSD only, and orthopedically injured (OI) controls. Analyses investigated group differences in rsFC for cortical networks: default mode (DMN), frontoparietal (FPN), salience, somatosensory, motor, auditory, and visual. Analyses were family-wise error (FWE) cluster-corrected and Bonferroni-corrected for number of network seeds regions at the whole brain level (pFWE < 0.002). Both mTBI and PTSD groups had reduced rsFC for DMN and FPN regions compared with OI controls. These group differences were largely driven by diminished connectivity in the PTSD group. rsFC with the middle frontal gyrus of the FPN was increased in mTBI, but decreased in PTSD. Overall, these results suggest that PTSD symptoms may have a more consistent signal than mTBI. Our novel findings of opposite patterns of connectivity with lateral prefrontal cortex highlight a potential biomarker that could be used to differentiate between these conditions.

Subcortical shape and neuropsychological function among U.S. service members with mild traumatic brain injury.

In a recent manuscript, our group demonstrated shape differences in the thalamus, nucleus accumbens, and amygdala in a cohort of U.S. Service Members with mild traumatic brain injury (mTBI). Given the significant role these structures play in cognitive function, this study directly examined the relationship between shape metrics and neuropsychological performance. The imaging and neuropsychological data from 135 post-deployed United States Service Members from two groups (mTBI and orthopedic injured) were examined. Two shape features modeling local deformations in thickness (RD) and surface area (JD) were defined vertex-wise on parametric mesh-representations of 7 bilateral subcortical gray matter structures. Linear regression was used to model associations between subcortical morphometry and neuropsychological performance as a function of either TBI status or, among TBI patients, subjective reporting of initial concussion severity (CS). Results demonstrated several significant group-by-cognition relationships with shape metrics across multiple cognitive domains including processing speed, memory, and executive function. Higher processing speed was robustly associated with more dilation of caudate surface area among patients with mTBI who reported more than one CS variables (loss of consciousness (LOC), alteration of consciousness (AOC), and/or post-traumatic amnesia (PTA)). These significant patterns indicate the importance of subcortical structures in cognitive performance and support a growing functional neuroanatomical literature in TBI and other neurologic disorders. However, prospective research will be required before exact directional evolution and progression of shape can be understood and utilized in predicting or tracking cognitive outcomes in this patient population.

ENIGMA MILITARY BRAIN INJURY: A COORDINATED META-ANALYSIS OF DIFFUSION MRI FROM MULTIPLE COHORTS.

Traumatic brain injury (TBI) is a significant cause of morbidity in military Veterans and Service Members. While most individuals recover fully from mild injuries within weeks, some continue to experience symptoms including headaches, disrupted sleep, and other cognitive, behavioral or physical symptoms. Diffusion magnetic resonance imaging (dMRI) shows promise in identifying areas of structural disruption and predicting outcomes. Although some studies suggest widespread structural disruption after brain injury, dMRI studies of military brain injury have yielded mixed results so far, perhaps due to the subtlety of mild injury, individual differences in injury location, severity and mechanism, and comorbidity with other disorders such as post-traumatic stress disorder (PTSD), depression, and substance abuse. We present preliminary dMRI results from the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) military brain injury working group. We found higher fractional anisotropy (FA) in participants with a history of TBI. Understanding the injury and recovery process, along with factors that influence these, will lead to improved diagnosis and treatment.

Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury.

OBJECTIVE: To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. PARTICIPANTS: Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High-dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. RESULTS: Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. CONCLUSION: Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population.

Susceptibility Weighted Imaging and White Matter Abnormality Findings in Service Members With Persistent Cognitive Symptoms Following Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is a major health concern among active duty service members and Veterans returning from combat operations, and it can result in variable clinical and cognitive outcomes. Identifying biomarkers that can improve diagnosis and prognostication has been at the forefront of recent research efforts. The purpose of this study was to compare the sensitivity and specificity of abnormalities identified using more traditional magnetic resonance imaging (MRI) sequences such as fluid attenuation inversion recovery (FLAIR) to more advanced MRI sequences such as susceptibility weighted imaging (SWI) among a cohort of active duty service members experiencing persistent cognitive symptoms after mTBI. One-hundred and fifty-two active duty service members (77 mTBI, 58 orthopedically injured [OI] only, 17 post-traumatic stress disorder [PTSD] only) underwent MRI and neuropsychological evaluation at a large military treatment facility. Results demonstrated that FLAIR white matter hyperintensities (WMHs) were present in all three groups at statistically similar rates (41% mTBI, 49% OI, and 29% PTSD). With the exception of a single OI participant showing a small discrete SWI lesion, SWI abnormalities were overwhelmingly present in mTBI patients (22% mTBI, 1% OI, and 0% PTSD). Functionally, mTBI participants with and without SWI abnormalities did not differ in demographics, symptom reporting, or cognitive performance. However, mTBI participants with and without WMH did differ for on measures of working memory with the mTBI participants with WMH having worse cognitive performance. No other significant differences were noted for those participants with and without imaging abnormalities for either the OI or PTSD only cohorts. These results appear to illustrate the sensitivity and specificity of SWI findings though these results did not have any significant functional impact in this cohort. In contrast, WMHs noted on FLAIR imaging were not sensitive or specific findings, but functionally relevant among mTBI participants. These findings emphasize the complexity of injury and functional outcome in mTBI patients that requires additional examination.

Comparing Two Processing Pipelines to Measure Subcortical and Cortical Volumes in Patients with and without Mild Traumatic Brain Injury.

PURPOSE: To compare volumetric results from NeuroQuant® and FreeSurfer in a service member setting. Since the advent of medical imaging, quantification of brain anatomy has been a major research and clinical effort. Rapid advancement of methods to automate quantification and to deploy this information into clinical practice has surfaced in recent years. NeuroQuant® is one such tool that has recently been used in clinical settings. Accurate volumetric data are useful in many clinical indications; therefore, it is important to assess the intermethod reliability and concurrent validity of similar volume quantifying tools. METHODS: Volumetric data from 148 U.S. service members across three different experimental groups participating in a study of mild traumatic brain injury (mTBI) were examined. Groups included mTBI (n = 71), posttraumatic stress disorder (n = 22), or a noncranial orthopedic injury (n = 55). Correlation coefficients and nonparametric group mean comparisons were used to assess reliability and concurrent validity, respectively. RESULTS: Comparison of these methods across our entire sample demonstrates generally fair to excellent reliability as evidenced by large intraclass correlation coefficients (ICC = .4 to .99), but little concurrent validity as evidenced by significantly different Mann-Whitney U comparisons for 26 of 30 brain structures measured. CONCLUSION: While reliability between the two segmenting tools is fair to excellent, volumetric outcomes are statistically different between the two methods. As suggested by both developers, structure segmentation should be visually verified prior to clinical use and rigor should be used when interpreting results generated by either method.

Volumetric and shape analyses of subcortical structures in United States service members with mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a significant health concern. The majority who sustain mTBI recover, although ~20 % continue to experience symptoms that can interfere with quality of life. Accordingly, there is a critical need to improve diagnosis, prognostic accuracy, and monitoring (recovery trajectory over time) of mTBI. Volumetric magnetic resonance imaging (MRI) has been successfully utilized to examine TBI. One promising improvement over standard volumetric approaches is to analyze high-dimensional shape characteristics of brain structures. In this study, subcortical shape and volume in 76 Service Members with mTBI was compared to 59 Service Members with orthopedic injury (OI) and 17 with post-traumatic stress disorder (PTSD) only. FreeSurfer was used to quantify structures from T1-weighted 3 T MRI data. Radial distance (RD) and Jacobian determinant (JD) were defined vertex-wise on parametric mesh-representations of subcortical structures. Linear regression was used to model associations between morphometry (volume and shape), TBI status, and time since injury (TSI) correcting for age, sex, intracranial volume, and level of education. Volumetric data was not significantly different between the groups. JD was significantly increased in the accumbens and caudate and significantly reduced in the thalamus of mTBI participants. Additional significant associations were noted between RD of the amygdala and TSI. Positive trend-level associations between TSI and the amygdala and accumbens were observed, while a negative association was observed for third ventricle. Our findings may aid in the initial diagnosis of mTBI, provide biological targets for functional examination, and elucidate regions that may continue remodeling after injury.