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1.  Evaluating the effectiveness of reasoning training in military and civilian chronic traumatic brain injury patients: study protocol 
Trials  2013;14:29.
Individuals who sustain traumatic brain injuries (TBIs) often continue to experience significant impairment of cognitive functions mediated by the prefrontal cortex well into chronic stages of recovery. Traditional brain training programs that focus on improving specific skills fall short of addressing integrative functions that draw upon multiple higher-order processes critical for social and vocational integration. In the current study, we compare the effects of two short-term, intensive, group-based cognitive rehabilitation programs for individuals with chronic TBI. One program emphasizes learning about brain functions and influences on cognition, while the other program adopts a top-down approach to improve abstract reasoning abilities that are largely reliant on the prefrontal cortex. These treatment programs are evaluated in civilian and military veteran TBI populations.
One hundred individuals are being enrolled in this double-blinded clinical trial (all measures and data analyses will be conducted by blinded raters and analysts). Each individual is randomly assigned to one of two treatment conditions, with each condition run in groups of five to seven individuals. The primary anticipated outcomes are improvement in abstract reasoning and everyday life functioning, measured through behavioral tasks and questionnaires, and attention modulation, as measured by functional neuroimaging. Secondary expected outcomes include improvements in the cognitive processes of working memory, attention, and inhibitory control.
Results of this trial will determine whether cognitive rehabilitation aimed at teaching TBI-relevant information about the brain and cognition versus training in TBI-affected thinking abilities (e.g., memory, attention, and executive functioning) can improve outcomes in chronic military and civilian TBI patient populations. It should shed light on the nature of improvements and the characteristics of patients most likely to benefit. This trial will also provide information about the sustainability of treatment-related improvements 3 months post-training.
Trial registration Identifier: NCT01552473
PMCID: PMC3563488  PMID: 23363480
Cognitive rehabilitation; Traumatic brain injury; Neuroimaging; Neuropsychology; Reasoning; Memory; Attention
2.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
PMCID: PMC3465162  PMID: 20625067
4.  Assessing Spatial Relationships between Axonal Integrity, Regional Brain Volumes, and Neuropsychological Outcomes after Traumatic Axonal Injury 
Journal of Neurotrauma  2010;27(12):2121-2130.
Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearson's correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.
PMCID: PMC2996819  PMID: 20874032
atrophy; diffuse axonal injury; diffusion tensor imaging; traumatic brain injury; volumetric magnetic resonance imaging
5.  Cerebral Atrophy after Traumatic White Matter Injury: Correlation with Acute Neuroimaging and Outcome 
Journal of Neurotrauma  2008;25(12):1433-1440.
Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = −0.69, −0.59, −0.58, respectively; p < 0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = −0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = −0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.
PMCID: PMC2858299  PMID: 19072588
MR imaging; post-traumatic atrophy; TBI
6.  Brain MRI, Apoliprotein E Genotype, and Plasma Homocysteine in American Indian Alzheimer Disease Patients and Indian Controls 
Current Alzheimer research  2009;6(1):52-58.
We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61–89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5–13 years in the AD group and 12–16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 μmol/L vs. 9.8 μmol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eε4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).
PMCID: PMC2752625  PMID: 19199875
Alzheimer disease; American Indian; white matter hyperintensities; homocysteine; apolipoprotein E
NeuroRehabilitation  2009;24(1):75-85.
Neuropsychological evaluations conducted in the United States and abroad commonly include the use of tests translated from English to Spanish. The use of translated naming tests for evaluating predominately Spanish-speakers has recently been challenged on the grounds that translating test items may compromise a test’s construct validity. The Texas Spanish Naming Test (TNT) has been developed in Spanish specifically for use with Spanish-speakers; however, it is unlikely patients from diverse Spanish-speaking geographical regions will perform uniformly on a naming test. The present study evaluated and compared the internal consistency and patterns of item-difficulty and -discrimination for the TNT and two commonly used translated naming tests in three countries (i.e., United States, Colombia, Spain). Two hundred fifty two subjects (126 demented, 116 nondemented) across three countries were administered the TNT, Modified Boston Naming Test-Spanish, and the naming subtest from the CERAD. The TNT demonstrated superior internal consistency to its counterparts, a superior item difficulty pattern than the CERAD naming test, and a superior item discrimination pattern than the MBNT-S across countries. Overall, all three Spanish naming tests differentiated nondemented and moderately demented individuals, but the results suggest the items of the TNT are most appropriate to use with Spanish-speakers. Preliminary normative data for the three tests examined in each country are provided.
PMCID: PMC2666471  PMID: 19208960
8.  Impact of Age on Long-term Recovery From Traumatic Brain Injury 
To determine whether older persons are at increased risk for progressive functional decline after traumatic brain injury (TBI).
Longitudinal cohort study.
Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers.
Subjects enrolled in the TBIMS national dataset.
Not applicable.
Main Outcome Measures
Disability Rating Scale (DRS), FIM instrument cognitive items, and the Glasgow Outcome Scale–Extended.
Participants were separated into 3 age tertiles: youngest (16–26y), intermediate (27–39y), and oldest (≥40y). DRS scores were comparable across age groups at admission to a rehabilitation center. The oldest group was slightly more disabled at discharge from rehabilitation despite having less severe acute injury severity than the younger groups. While DRS scores for the 2 younger groups improved significantly from year 1 to year 5, the greatest magnitude of improvement in disability was seen among the youngest group. Additionally, after dividing patients into groups according to whether their DRS scores improved (13%), declined (10%), or remained stable (77%) over time, the likelihood of decline was found to be greater for the 2 older groups than for the youngest group. A multiple regression model demonstrated that age has a significant negative influence on DRS score 5 years post-TBI after accounting for the effects of covariates.
This study supported our primary hypothesis that older patients show greater decline over the first 5 years after TBI than younger patients. Additionally, the greatest amount of improvement in disability was observed among the youngest group of survivors. These results suggest TBI survivors, especially older patients, may be candidates for neuroprotective therapies after TBI.
PMCID: PMC2600417  PMID: 18452739
Brain injuries; Disabled persons; Rehabilitation

Results 1-8 (8)