David Tate

Traumatic brain injury (TBI) is common among military personnel and is often followed by a heterogeneous array of clinical, cognitive, behavioral, mood, and neuroimaging changes. This inconsistent presentation makes it difficult to establish or validate biological and imaging markers that could help improve diagnostic and prognostic accuracy in this patient population. The purpose of this manuscript is to describe both the challenges and opportunities when conducting research with Service Members and Veterans and introduce the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Military Brain Injury working group. ENIGMA is a worldwide consortium focused on improving replicability and analytical power through data sharing and collaboration. In this paper, we discuss challenges affecting efforts to aggregate data in this patient group. In addition, we highlight how “big data” approaches might be used to understand better the role that each of these variables might play in ...

The global burden of mortality and morbidity caused by traumatic brain injury (TBI) is significant and the heterogeneity of TBI patients and the relatively small sample sizes of most current neuroimaging studies is a major challenge for scientific advances and clinical translation. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Adult moderate/severe TBI (AMS-TBI) working group aims to be a driving force for new discoveries in AMS-TBI by providing researchers world-wide with an effective framework and platform for large-scale cross-border collaboration and data sharing. Based on the principles of transparency, rigor, reproducibility and collaboration, we will facilitate the development and dissemination of multiscale and big data analysis pipelines for harmonized analyses in AMS-TBI using structural and functional neuroimaging in combination with nonimaging biomarkers, genetics, as well as clinical and behavioral measures. Ultimately, we will offer investigators a...

Investigate the relation of chronic pain interference to functional connectivity (FC) of brain regions and to cortical thickness in post-911 Veterans and Service Members (SMs) who sustained a mild traumatic brain injury (mTBI). This is an observational study with cross-sectional analyses. A sample of 65 enrollees completing initial evaluation at a single site of the Chronic Effects of Neurotrauma Consortium (CENC) reported pain interference ratings on the TBI QOL. Functional connectivity and cortical thickness were measured. Severity of pain interference was negatively related to FC of the default mode network (DMN), i.e., participants who reported more severe pain interference had less FC between mesial prefrontal cortex and posterior regions of the DMN including posterior cingulate cortex and precuneus. Cortical thickness of specific regions was positively related to severity of pain interference. The more that pain was perceived to interfere with daily life, the less the FC betwe...

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 anisot...

NeuroQuant (NQ) and FreeSurfer (FS) are commonly used computer-automated programs for measuring MRI brain volume. Previously they were reported to have high intermethod reliabilities but often large intermethod effect size differences. We hypothesized that linear transformations could be used to reduce the large effect sizes. This study was an extension of our previously reported study. We performed NQ and FS brain volume measurements on 60 subjects (including normal controls, patients with traumatic brain injury, and patients with Alzheimer's disease). We used two statistical approaches in parallel to develop methods for transforming FS volumes into NQ volumes: traditional linear regression, and Bayesian linear regression. For both methods, we used regression analyses to develop linear transformations of the FS volumes to make them more similar to the NQ volumes. The FS-to-NQ transformations based on traditional linear regression resulted in effect sizes which were small to mod...

Oxidative stress is a key mechanism of the aging process that can cause damage to brain white matter and cognitive functions. Polymorphisms in the superoxide dismutase 2 (SOD2) and catalase (CAT) genes have been associated with abnormalities in antioxidant enzyme activity in the aging brain, suggesting a risk for enhanced oxidative damage to white matter and cognition among older individuals with these genetic variants. The present study compared differences in white matter microstructure and cognition among 96 older adults with and without genetic risk factors of SOD2 (rs4880) and CAT (rs1001179). Results revealed higher radial diffusivity in the anterior thalamic radiation among SOD2 CC genotypes compared to CT/TT genotypes. Further, the CC genotype moderated the relationship between the hippocampal cingulum and processing speed, though this did not survive multiple test correction. The CAT polymorphism was not associated with brain outcomes in this cohort. These results suggest t...

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. 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...

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 wh...

An important component of the multicentre Chronic Effects of Neurotrauma Consortium (CENC) project is the development of improved quantitative magnetic resonance imaging (MRI) methods, including volumetric analysis. Although many studies routinely employ quality assurance (QA) procedures including MR and human phantoms to promote accuracy and monitor site differences, few studies perform rigorous direct comparisons of these data nor report findings that enable inference regarding site-to-site comparability. These gaps in evaluating cross-site differences are concerning, especially given the well-established differences that can occur between data acquired on scanners with different manufacturer, hardware or software. This study reports findings on (1) a series of studies utilizing two MR phantoms to interrogate machine-based variability using data collected on the same magnet, (2) a human phantom repeatedly imaged on the same scanner to investigate within-subject, within-site variab...

White matter hyperintensities (WMHs) are foci of abnormal signal intensity in white matter regions seen with magnetic resonance imaging (MRI). WMHs are associated with normal ageing and have shown prognostic value in neurological conditions such as traumatic brain injury (TBI). The impracticality of manually quantifying these lesions limits their clinical utility and motivates the utilization of machine learning techniques for automated segmentation workflows. This study develops a concatenated random forest framework with image features for segmenting WMHs in a TBI cohort. The framework is built upon the Advanced Normalization Tools (ANTs) and ANTsR toolkits. MR (3D FLAIR, T2- and T1-weighted) images from 24 service members and veterans scanned in the Chronic Effects of Neurotrauma Consortium's (CENC) observational study were acquired. Manual annotations were employed for both training and evaluation using a leave-one-out strategy. Performance measures include sensitivity, posi...

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 m...

Recent work using novel neuroimaging methods has revealed shorter white matter fiber bundle length (FBL) in older compared to younger adults. Shorter FBL also corresponds to poorer performance on cognitive measures sensitive to advanced age. However, it is unclear if individual factors such as cognitive reserve (CR) effectively moderate the relationship between FBL and cognitive performance. This study examined CR as a potential moderator of cognitive performance and brain integrity as defined by FBL. Sixty-three healthy adults underwent neuropsychological evaluation and 3T brain magnetic resonance imaging. Cognitive performance was measured using the Repeatable Battery of Assessment of Neuropsychological Status (RBANS). FBL was quantified from tractography tracings of white matter fiber bundles, derived from the diffusion tensor imaging. CR was determined by estimated premorbid IQ. Analyses revealed that lower scores on the RBANS were associated with shorter whole brain FBL (p = 0....

The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n = 27, ThrThr n = 27). Differences in subcortical hyperintensity (SH) volume were also examined between groups. Results indicated that the threonine variant was associated with significantly reduced integrity in the superior longitudinal fasciculus (SLF) and the cingulate gyrus segment of the cingulum bundle (cingulum CG) compared to...

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease confirmed at postmortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review, we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of inju...

Age-associated decline in gray matter brain volume and cognitive function in healthy adults has been reported in the literature. The goal of the current study is to examine the relationship between age-related changes in regional gray matter volumes and cognitive function in a large, cross-sectional sample of healthy adults across the lifespan. Magnetic resonance imaging and cognitive assessment were conducted on 148 adults aged 21-76 years. Multiple regression analyses examining the effect of age were performed on magnetic resonance image-derived gray matter brain volumes and standardized cognitive summary scores of attention and executive function. Regression was also performed to test the effect of age, gray matter volumes, and their interaction on the prediction of cognitive performance. Age significantly predicted performance on tests of attention (F [1, 146]=50.97, p <0.01, R2=0.26) and executive function (F [1, 146]=126.19, p <0.01, R2=0.46) and gray matter volumes for frontal subregions (lateral, medial, orbital), hippocampus, amygdala, and putamen (F [2, 145]=45.34-23.96, p…

There is a growing evidence that elevated body mass index (BMI) is associated with adverse neurocognitive outcome, though no study has examined whether morphometric differences are found in persons across the adult life span. We compared 201 healthy individuals in normal weight, overweight, and obese groups (aged 17-79). After correcting for demographic differences, obese individuals showed smaller whole brain and total gray matter volume than normal weight and overweight individuals. These findings support an independent relationship between BMI and brain structure and demonstrate that these differences are not limited to older adults.

Because of increased prevalence of macrocephaly in autism, head size must be controlled for in studies that examine volumetric findings of the temporal lobe in autistic subjects. We prospectively examined temporal lobe structures in individuals with autism who were normocephalic or macrocephalic (head circumference > 97th percentile) and in control subjects who were normocephalic or macrocephalic or who had a reading disorder (unselected for head size). The rationale for the reading disorder group was to have control subjects with potential temporal lobe anomalies, but who were not autistic. In individuals aged 7-31 years, autism was diagnosed on the basis of standardized interview and diagnostic criteria. Control subjects ranged in age from 7 to 22 years. All subjects were male. MR morphometrics of the major temporal lobe structures were based on ANALYZE segmentation routines, in which total brain volume and total intracranial volume (TICV) were calculated. Both group comparison...

We report on the utility of using a rapid, easy-to-use, visually based semi-quantitative neuroimaging atrophy rating scale in individuals with traumatic brain injury (TBI) and normal control subjects. Magnetic resonance (MR) scans were rated using a standardized semi-quantitative MR rating method. A four-point scale was used to rate each scan for atrophy in frontal, temporal, and parietal areas. Seventy-five TBI subjects (50 males, 25 females) and 75 age- and gender-matched control subjects were compared for atrophy ratings. Clinical atrophy ratings were also compared to a quantitative measure of atrophy, the ventricle-to-brain ratio, and with the TBI subjects' scores on standard neuropsychological tests. TBI patients had significantly higher clinical atrophy ratings in frontal and temporal lobe areas compared to controls. The clinical atrophy ratings significantly correlated with the ventricle-to-brain ratio, a quantitative measure of atrophy in the same TBI subjects. Higher clinical ratings of frontal and temporal atrophy correlated with deficits in memory and executive function. These findings indicate that clinical ratings of trauma-induced atrophy can be reliably performed and are associated with neuropsychological outcome and quantitative measures of cerebral atrophy.

Research in neuropsychology suggests that the etiology of a neurologic injury determines the neuropathological and neuropsychological changes. This study compared neuropsychological outcome in subjects who had traumatic brain injury (TBI) with subjects who had anoxic brain injury (ABI), who were matched for age, gender, and ventricle-to-brain ratio. There were no group differences for morphologic or neuropsychological measures. Both groups exhibited impaired memory, attention, and executive function, as well as slowed mental processing speed. Intelligence correlated with whole brain volume, and measures of memory correlated with hippocampal atrophy. There was no unique contribution of hippocampal atrophy on neuropsychological outcome between the groups. In the absence of localized lesions, the amount of neural tissue loss, rather than etiology, may be the critical factor in neuropsychological outcome.

An increased prevalence of macrocephaly defined by occipital-frontal circumference (OFC) is a consistent finding in autism. Several possible mechanisms have been proposed, the most compelling being early brain overgrowth. However, the proportion of non-neural tissues (NNT) that contribute to OFC has not been reported. Using quantitative magnetic resonance imaging (MRI) methods we analyzed the relationships between OFC and total brain (TBV), ventricular, surface cerebrospinal fluid (CSF)/meningeal, and NNT volumes in subjects with autism. Sixty male subjects (34 autistic; 26 controls) seven years of age and older were used in this study. Compared to other measures, NNT volume was most significantly related to OFC (r values > 0.8, p<or=0.001), though NNT volume did not differ between the groups. Ventricular volume was also uniformly related to OFC (r approximately 0.3, p> 0.06). In contrast, the OFC-TBV relationship was less robust in those with autism (r=0.25, p<or=0.09) and only significant in the controls (r=0.58, p<or=0.001). Conversely, subjects with autism had a more robust and significantly different relationship between subarachnoid CSF/meningeal volume than controls (r=0.53 and 0.24; p<or=0.001 and 0.12, respectively). Possible explanations for these findings are discussed in the context of potential OFC differences that may occur in accelerated early brain growth associated with autism.

We examined asymmetry of hippocampal volume as well as other temporal lobe structures (temporal lobe, temporal horn of the lateral ventricular system, parahippocampal and fusiform gyri) in 194 subjects from the Cache County, Utah study, with varying disorders [85 with Alzheimer's disease (AD), 59 with some cognitive or neuropsychiatric disorder—referenced as a Mixed Neuropsychiatric group, 30 with mild ambiguous/mild cognitive impairment (MA/MCI) and 20 controls] and APOE genotypes. Asymmetry was determined by subtracting left-side volume from the right corrected by total intracranial volume. No significant asymmetry was observed to be associated with presence of the ε4 allele. Since the AD-ε4 allele risk effect may be expressed early in the course of the disorder, we also examined asymmetry indices in AD, MA/MCI and Mixed Neuropsychiatric subjects early in the course of their disorder (2 years or less) to those with longer duration illness (greater than 2 years). We observed a ...

Traumatic brain injury (TBI) results in a variable degree of cerebral atrophy that is not always related to cognitive measures across studies. However, the use of different methods for examining atrophy may be a reason why differences exist. The purpose of this manuscript was to examine the predictive utility of seven magnetic resonance imaging (MRI) -derived brain volume or indices of atrophy for a large cohort of TBI patients (n = 65). The seven quantitative MRI (qMRI) measures included uncorrected whole brain volume, brain volume corrected by total intracranial volume, brain volume corrected by the ratio of the individual TICV by group TICV, a ventricle to brain ratio, total ventricular volume, ventricular volume corrected by TICV, and a direct measure of parenchymal volume loss. Results demonstrated that the various qMRI measures were highly interrelated and that corrected measures proved to be the most robust measures related to neuropsychological performance. Similar to an ear...

The authors performed quantitative and qualitative image analysis on a sample of the elderly population of Cache County, Utah, relating neuroimaging findings to Mini-Mental Status Examination (MMSE) scores and the presence of the apolipoprotein E epsilon4 allele. Neuroimaging measures included white, gray, and hippocampal volumes; a ventricle-to-brain ratio (VBR); and qualitative ratings of white matter lesions (WMLs) in the periventricular (PV) and centrum semiovale (CS) regions. Subjects included 85 persons with possible and probable Alzheimer disease (AD), 21 with vascular dementia (VaD), 30 with cognitive symptoms classified as mild/ambiguous (M/A), a heterogenous group of 39 non-AD or VaD subjects but diagnosed with some form of neuropsychiatric disorder ("Mixed Neuropsychiatric" group), and 20 normal control subjects aged 65 years or older. Controlling for age, sex, and length of disease, the authors found that AD and VaD subjects differed significantly from control subjects on WMLs, but only the VaD subjects significantly differed from M/A subjects. The two dementia groups also displayed, as expected, significant cerebral atrophy. The WMLs generally increased with age and severity of dementia. PV WMLs were significantly but only modestly associated with white matter volume loss and greater impairment on the MMSE. Modest correlations were also present between the quantitative measures of cerebral structure and MMSE performance. However, when degree of cerebral atrophy was controlled by using the VBR measure, WML effects on MMSE performance became nonsignificant, with the only significant relationship remaining being that between hippocampal volume and MMSE performance. There were no significant qualitative or quantitative findings related to presence of the epsilon4 allele and MMSE performance. The role of WMLs in aging and dementia is discussed.

Neuropsychological, qualitative, and quantitative magnetic resonance imaging findings were examined in subjects with Alzheimer's disease (AD), non-AD dementia or mixed neuropsychiatric disorder, subjects characterized as mild/ambiguous, and controls, all with known apolipoprotein E (APOE) genotype. Neuropsychological tasks included an expanded Consortium to Establish a Registery for Alzheimer's Disease (J. T. Tschanz et al., 2000; K. A. Welsh, J. M. Hoffman,

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 grou...

Although the cause of autism is undetermined, a general consensus has been that some type of early aberrant neural development underlies the disorder. Given the increased prevalence of macrocephaly in autism, one theory of abnormal neural development implicates early brain growth resulting in larger brain and head size in autism. Surface area measurements of the midsagittal section of the corpus callosum can be used as an index of neural development and white-matter integrity because the corpus callosum is the major white-matter structure that interconnects the two cerebral hemispheres. The purpose of this study was to obtain corpus callosum surface area, shape, and contour in a sample of non-mentally retarded autistic subjects with macrocephaly (n = 12) and compare them with those of matched (n = 8), typically developing control subjects with benign macrocephaly. No significant differences were found in surface area, shape, or contour between groups, nor did corpus callosum surface area relate to measures of IQ or picture vocabulary. These findings suggest no unique difference in overall regional corpus callosum surface area in autism with macrocephaly.

In the present study, we examined the relationships between whole brain volume (WBV), subcortical hyperintensities (SH), indices of cardiac disease and cognitive function in nondemented cardiac patients with evidence of mild cerebrovascular disease. A total of 27 ...

The purpose of this study was to examine the impact of age, sex, and education on category and letter verbal fluency task performance. A secondary goal was to examine whether resting EEG theta power in bilateral frontal and temporal lobes impacts age-associated decline in verbal fluency task performance. A large sample (N=471) of healthy, normal participants, age 21–82, was assessed for letter fluency (i.e., FAS), and for category fluency (i.e., Animal Naming), and with a 32-channel EEG system for ‘eyes-open’ resting theta power. The effects of age, sex, and education were examined using analyses of variance. Correlation analyses were used to test the impact of theta power on age and fluency performance by controlling for the effects of theta when examining the relationship between the other two variables. The results indicated that performance on both fluency tests declined linearly with age, but that the rate of decline was greater for category fluency. These age changes were not associated with education level, and there were no sex differences. While theta power was negatively associated with age and positively associated with Animal Naming performance, it did not moderate the relationship between the two. The differential age-associated decline between category and letter fluency suggests separate neurobiological substrates underlying the two domains of performance, which is not related to theta activity.

There have been many studies examining HIV-infection-related alterations of magnetic resonance imaging (MRI) diffusion metrics. However, examining scalar diffusion metrics ignores the orientation aspect of diffusion imaging, which can be captured with tractography. We examined five different tractography metrics obtained from global tractography maps (global tractography FA, average tube length, normalized number of streamtubes, normalized weighted streamtube length, and normalized total number of ...