Browsing by Author "Flashman, Laura A."
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Item Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury(Elsevier, 2016-09-06) Shee, Kevin; Lucas, Alexandra; Flashman, Laura A.; Nho, Kwangsik; Tsongalis, Gregory J.; McDonald, Brenna C.; Saykin, Andrew J.; McAllister, Thomas W.; Rhodes, C. Harker; Psychiatry, School of MedicineProblems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between α-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation.Item Apathy Is Associated With Ventral Striatum Volume in Schizophrenia Spectrum Disorder(American Psychiatric Association, 2016) Roth, Robert M.; Garlinghouse, Matthew A.; Flashman, Laura A.; Koven, Nancy S.; Pendergrass, J. Cara; Ford, James C.; McAllister, Thomas W.; Saykin, Andrew J.; Psychiatry, School of MedicineApathy is prevalent in schizophrenia, but its etiology has received little investigation. The ventral striatum (VS), a key brain region involved in motivated behavior, has been implicated in studies of apathy. We therefore evaluated whether apathy is associated with volume of the VS on MRI in 23 patients with schizophrenia using voxel-based morphometry. Results indicated that greater self-reported apathy severity was associated with smaller volume of the right VS even when controlling for age, gender, depression, and total gray matter volume. The finding suggests that apathy is related to abnormality of brain circuitry subserving motivated behavior in patients with schizophrenia.Item Associations between neuropsychiatric and health status outcomes in individuals with probable mTBI(Elsevier, 2019-02) Bomyea, Jessica; Flashman, Laura A.; Zafonte, Ross; Andaluz, Norberto; Coimbra, Raul; George, Mark S.; Grant, Gerald A.; Marx, Christine E.; McAllister, Thomas W.; Shutter, Lori; Lang, Ariel J.; Stein, Murray B.; Psychiatry, School of MedicineMild traumatic brain injury (mTBI) is a common occurrence, and may impact distal outcomes in a subgroup of individuals. Improved characterization of health outcomes and identification of factors associated with poor outcomes is needed to better understand the impact of mTBI, particularly in those with co-occurring posttraumatic stress disorder (PTSD). Participants in a data repository of the Injury and Traumatic Stress (INTRuST) Clinical Consortium (n = 625) completed functional disability [FD] and health-related quality of life [HRQOL] questionnaires, and a subset completed a neuropsychological assessment. FD and HRQOL were compared among participants with probable mTBI (mTBI), probable mTBI with PTSD (mTBI/PTSD), and health comparison participants (HC). Associations between symptoms, neuropsychological performance, and health outcomes were examined in those with probable mTBI with and without PTSD (n = 316). Individuals in the mTBI/PTSD group endorsed poorer health outcomes than those in the mTBI group, who endorsed poorer outcomes than those in the HC group. Individuals in either mTBI group performed worse than those in the HC on verbal learning and memory and psychomotor speed. Health outcomes were correlated with mental health and postconcussive symptoms, as well as neuropsychological variables. mTBI may adversely impact self-reported health, with the greatest effect observed in individuals with co-occurring mTBI/PTSD.Item Biomechanics of head impacts associated with diagnosed concussion in female collegiate ice hockey players(Elsevier, 2015-07-16) Wilcox, Bethany J.; Beckwith, Jonathan G.; Greenwald, Richard M.; Raukar, Neha P.; Chu, Jeffrey J.; McAllister, Thomas W.; Flashman, Laura A.; Maerlender, Arthur C.; Duhaime, Ann-Christine; Crisco, Joseph J.; Department of Psychiatry, IU School of MedicineEpidemiological evidence suggests that female athletes may be at a greater risk of concussion than their male counterparts. The purpose of this study was to examine the biomechanics of head impacts associated with diagnosed concussions in a cohort of female collegiate ice hockey players. Instrumented helmets were worn by 58 female ice hockey players from 2 NCAA programs over a three year period. Kinematic measures of single impacts associated with diagnosed concussion and head impact exposure on days with and without diagnosed concussion were evaluated. Nine concussions were diagnosed. Head impact exposure was greater in frequency and magnitude on days of diagnosed concussions than on days without diagnosed concussion for individual athletes. Peak linear accelerations of head impacts associated with diagnosed concussion in this study are substantially lower than those previously reported in male athletes, while peak rotational accelerations are comparable. Further research is warranted to determine the extent to which female athletes' biomechanical tolerance to concussion injuries differs from males.Item Comparison of Season-Long Diffusivity Measures in a Cohort of Non-Concussed Contact and Non-Contact Athletes(Taylor & Francis, 2020-10) Merz, Zachary C.; Flashman, Laura A.; Ford, James C.; McDonald, Brenna C.; McAllister, Thomas W.; Radiology and Imaging Sciences, School of MedicineIntroduction: Concern surrounding short- and long-term consequences of participation in contact sports has become a significant public health topic. Previous literature utilizing diffusion tensor imaging in sports-related concussion has exhibited notable variety of analysis methods and analyzed regions of interest, and largely focuses on acute effects of concussion. The current study aimed to compare diffusivity metrics across a single season within athlete cohorts with no history of concussion. Methods: A prospective cohort of 75 contact and 79 non-contact division I athletes were compared across diffusion tensor imaging metrics (i.e. TRACULA); examinations were also performed assessing the relationship between neuroimaging metrics, head impact exposure metrics (in-helmet accelerometer), and neurocognitive variables. Assessment occurred at pre-and post-season time points. Results: Seasonal changes in fractional anisotropy and mean diffusivity values did not differ between athlete cohorts, nor did they differ within cohort groups, across pre- and post-season scans. Specific to contact athletes, positive associations were found between uncinate fasciculus mean diffusivity values and season linear acceleration (p =.018), season rotational acceleration (p =.017), and season hit severity (p =.021). Conclusions: Results suggest an influence of impact frequency, type, and severity on white matter integrity in select brain regions in contact athletes. Current findings expand our knowledge of anatomical changes over the course of a single season, and underscore the importance of considering methodology when interpreting findings in this population, as differing image analysis techniques may lead to different conclusions regarding significant effects.Item Differential Effects of Pergolide and Bromocriptine on Working Memory Performance and Brain Activation after Mild Traumatic Brain Injury(Liebert, 2020) Flashman, Laura A.; McDonald, Brenna C.; Ford, James C.; Kenny, Rachel M.; Andrews, Katharine D.; Saykin, Andrew J.; McAllister, Thomas W.; Radiology and Imaging Sciences, School of MedicineDopamine D1 and D2 receptors differ with respect to patterns of regional brain distribution and behavioral effects. Pre-clinical work suggests that D1 agonists enhance working memory, but the absence of selective D1 agonists has constrained using this approach in humans. This study examines working memory performance in mild traumatic brain injury (mTBI) patients when given pergolide, a mixed D1/D2 agonist, compared with bromocriptine, a selective D2 agonist. Fifteen individuals were studied 1 month after mTBI and compared with 17 healthy controls. At separate visits, participants were administered 1.25 mg bromocriptine or 0.05 mg pergolide prior to functional magnetic resonance imaging (MRI) using a working memory task (visual-verbal n-back). Results indicated a significant group-by-drug interaction for mean performance across n-back task conditions, where the mTBI group showed better performance on pergolide relative to bromocriptine, whereas controls showed the opposite pattern. There was also a significant effect of diagnosis, where mTBI patients performed worse than controls, particularly while on bromocriptine, as shown in our prior work. Functional MRI activation during the most challenging task condition (3-back > 0-back contrast) showed a significant group-by-drug interaction, with the mTBI group showing increased activation relative to controls in working memory circuitry while on pergolide, including in the left inferior frontal gyrus. Across participants there was a positive correlation between change in activation in this region and change in performance between drug conditions. Results suggest that activation of the D1 receptor may improve working memory performance after mTBI. This has implications for the development of pharmacological strategies to treat cognitive deficits after mTBI.Item Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes(American Academy of Neurology, 2014-01-07) McAllister, Thomas W.; Ford, James C.; Flashman, Laura A.; Maerlender, Arthur; Greenwald, Richard M.; Beckwith, Jonathan G.; Bolander, Richard P.; Tosteson, Tor D.; Turco, John H.; Raman, Rema; Jain, Sonia; Department of Psychiatry, IU School of MedicineOBJECTIVE: To determine whether exposure to repetitive head impacts over a single season affects white matter diffusion measures in collegiate contact sport athletes. METHODS: A prospective cohort study at a Division I NCAA athletic program of 80 nonconcussed varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 79 non-contact sport athletes. Assessment occurred preseason and shortly after the season with diffusion tensor imaging and neurocognitive measures. RESULTS: There was a significant (p = 0.011) athlete-group difference for mean diffusivity (MD) in the corpus callosum. Postseason fractional anisotropy (FA) differed (p = 0.001) in the amygdala (0.238 vs 0.233). Measures of head impact exposure correlated with white matter diffusivity measures in several brain regions, including the corpus callosum, amygdala, cerebellar white matter, hippocampus, and thalamus. The magnitude of change in corpus callosum MD postseason was associated with poorer performance on a measure of verbal learning and memory. CONCLUSION: This study suggests a relationship between head impact exposure, white matter diffusion measures, and cognition over the course of a single season, even in the absence of diagnosed concussion, in a cohort of college athletes. Further work is needed to assess whether such effects are short term or persistent.Item Group-wise evaluation and comparison of white matter fiber strain and maximum principal strain in sports-related concussion(Mary Ann Liebert, 2015-04-01) Ji, Songbai; Zhao, Wei; Ford, James C.; Beckwith, Jonathan G.; Bolander, Richard P.; Greenwald, Richard M.; Flashman, Laura A.; Paulsen, Keith D.; McAllister, Thomas W.; Department of Psychiatry, IU School of MedicineSports-related concussion is a major public health problem in the United States and yet its biomechanical mechanisms remain unclear. In vitro studies demonstrate axonal elongation as a potential injury mechanism; however, current response-based injury predictors (e.g., maximum principal strain, ε(ep)) typically do not incorporate axonal orientations. We investigated the significance of white matter (WM) fiber orientation in strain estimation and compared fiber strain (ε(n)) with ε(ep) for 11 athletes with a clinical diagnosis of concussion. Geometrically accurate subject-specific head models with high mesh quality were created based on the Dartmouth Head Injury Model (DHIM), which was successfully validated (performance categorized as "good" to "excellent"). For WM regions estimated to be exposed to high strains using a range of injury thresholds (0.09-0.28), substantial differences existed between ε(n) and ε(ep) in both distribution (Dice coefficient of 0.13-0.33) and extent (∼ 5-10-fold differences), especially at higher threshold levels and higher rotational acceleration magnitudes. For example, an average of 3.2% vs. 29.8% of WM was predicted above an optimal threshold of 0.18 established from an in vivo animal study using ε(n) and ε(ep), respectively, with an average Dice coefficient of 0.14. The distribution of WM regions with high ε(n) was consistent with typical heterogeneous patterns of WM disruptions in diffuse axonal injury, and the group-wise extent at the optimal threshold matched well with the percentage of WM voxels experiencing significant longitudinal changes of fractional anisotropy and mean diffusivity (3.2% and 3.44%, respectively) found from a separate independent study. These results suggest the significance of incorporating WM microstructural anisotropy in future brain injury studies.Item Hybrid Diffusion Imaging in Mild Traumatic Brain Injury(Mary Ann Liebert, 2018-10-15) Wu, Yu-Chien; Mustafi, Sourajit M.; Harezlak, Jaroslaw; Kodiweera, Chandana; Flashman, Laura A.; McAllister, Thomas W.; Radiology and Imaging Sciences, School of MedicineMild traumatic brain injury (mTBI) is an important public health problem. Although conventional medical imaging techniques can detect moderate-to-severe injuries, they are relatively insensitive to mTBI. In this study, we used hybrid diffusion imaging (HYDI) to detect white matter alterations in 19 patients with mTBI and 23 other trauma control patients. Within 15 days (standard deviation = 10) of brain injury, all subjects underwent magnetic resonance HYDI and were assessed with a battery of neuropsychological tests of sustained attention, memory, and executive function. Tract-based spatial statistics (TBSS) was used for voxel-wise statistical analyses within the white matter skeleton to study between-group differences in diffusion metrics, within-group correlations between diffusion metrics and clinical outcomes, and between-group interaction effects. The advanced diffusion imaging techniques, including neurite orientation dispersion and density imaging (NODDI) and q-space analyses, appeared to be more sensitive then classic diffusion tensor imaging. Only NODDI-derived intra-axonal volume fraction (Vic) demonstrated significant group differences (i.e., 5-9% lower in the injured brain). Within the mTBI group, Vic and a q-space measure, P0, correlated with 6 of 10 neuropsychological tests, including measures of attention, memory, and executive function. In addition, the direction of correlations differed significantly between groups (R2 > 0.71 and pinteration < 0.03). Specifically, in the control group, higher Vic and P0 were associated with better performances on clinical assessments, whereas in the mTBI group, higher Vic and P0 were associated with worse performances with correlation coefficients >0.83. In summary, the NODDI-derived axonal density index and q-space measure for tissue restriction demonstrated superior sensitivity to white matter changes shortly after mTBI. These techniques hold promise as a neuroimaging biomarker for mTBI.Item Hybrid Diffusion Imaging to Detect Acute White Matter Injury after Mild TBI(Office of the Vice Chancellor for Research, 2016-04-08) Mustafi, Sourajit M.; Kodiweera, Chandana; Flashman, Laura A.; McAllister, Thomas W.; Wu, Yu-ChienIntroduction: In the present study we used multi-shell Hybrid Diffusion Imaging (HYDI) to study white matter changes in the acute stage of mild traumatic brain injury (mTBI). Non-parametric diffusion analysis, q-space imaging as well as parametric analyses including conventional DTI and novel neurite orientation dispersion and density imaging (NODDI) were used to analyze the HYDI data. Method: Nineteen mTBI patients and 23 trauma-controlled subjects were recruited from the Emergency Department. Participants received T1W SPGR and HYDI in a Philips 3T Achieve TX scanner with 8-channel head coil and SENSE parallel imaging. The diffusion-weighting (DW) pulse sequence scan-time was about 24 min similar to (1). Results: Forty-eight WM ROIs were defined in the standard MNI space by intersecting subjects’ mean WM skeleton with WM atlas of Johns Hopkins University (JHU) ICBM-DTI-81(2). Linear model analysis was used to test the significance of diffusion metrics between mTBI and trauma-controlled groups with gender and age as covariates (model 3 in Table 1). Maps of DTI, q-space and NODDI diffusion metrics of an mTBI subject are shown in Figure 1. Among various diffusion metrics, only the NODDI derived parenchymal axonal density (Vic) was sensitive to mTBI with significant decreases in 60% of WM ROIs (Table 1). The mTBI subjects had an approximately 4% decrease in Vic. The affected WM tracts concentrated on pyramidal tracts and its cortical projections (bilateral corona radiatae). Most of the cerebella related tracts and hippocampal tracts are spared. Conclusion: HYDI and its diffusion metrics provide insights about microstructural changes of WM in the acute stage of mTBI and may prove useful as a marker of injury.