京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19931号 / 医博第4151号 / 新制||医||1017(附属図書館) / 33017 / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 髙橋 良輔, 教授 大森 孝一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Military personnel often experience mild traumatic brain injury (mTBI) from exposure to improvised explosive devices (IEDs). Soldiers typically endure blast trauma from the IED pressure wave as well as blunt trauma from ensuing head impacts. Researchers have not reached a consensus on whether the biomechanical response from blunt or blast trauma plays a more dominant role in mTBI because the specific biomechanical sources of injury are often undetermined. Consequently, the goal of this dissertation was to conduct three separate studies in order to characterize the mechanical behavior of the brain after exposure to mTBI conditions. For Study 1, mild blunt and blast trauma were induced in Sprague-Dawley rats using a custom-built device. In-house diffusion tensor imaging (DTI) software was used to make 3-D reconstructions of white matter fiber tracts before and after injury (1, 4, and 7 days). Axonal integrity was characterized by examining the fiber count, fiber length, and fractional anisotropy (FA). In-house image analysis software also quantified the microstructural variations in Hematoxylin and Eosin (H&E) stained brain sections, where significant differences in parameters such as the area fraction (AF) and nearest neighbor distance (NND) correlated to voids that formed after water diffused extracellularly from axons. Study 2 employed a computational approach involving the development of a finite element (FE) model for the rat head followed by the simulation of blunt and blast trauma, respectively. FE parameters such as von Mises stress, pressure, and maximum principal strain were analyzed at various locations including the skull, cerebral cortex, corpus callosum, and hypothalamus to compare injury cases. Study 3 involved interruption mechanical testing of porcine brain, a suitable animal surrogate of human brain. Compression, tension, and shear experiments were performed at a strain rate of 0.1 s-1 to examine the differential mechanical response. Microstructural changes in H&E stained brain sections were analyzed with in-house image analysis software to quantify differences among stress states at strains of 0.15, 0.30, and 0.40. Studies 1 and 2 confirmed that the brain behaves differently in response to blunt and blast trauma, respectively, while Study 3 further demonstrated the stress state dependent behavior of brain tissue.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24512号 / 医博第4954号 / 新制||医||1064(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 古川 壽亮, 教授 中本 裕士 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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This study investigates the in-vivo architecture of muscles in the lower leg using 2D ultrasound (US) and 3D diffusion tensor imaging (DTI) techniques. The muscle architecture of the gastrocnemius, posterior soleus and tibialis anterior were compared using US and DTI imaging. DTI and US differed on average by 17% in fascicle length (FL), 20% in muscle thickness (tm), and 36% in pennation angles (PA).The study furthermore examined the muscle morphology after stroke by comparing the muscles of the affected side to the less-affected side of five hemiplegic post-stroke patients. The morphology of eight muscle compartments in both legs of the patients was measured using only DTI. An, on average, 14% smaller muscle volume in the effected side was found, as well as a difference of 15% in FL, 11% PA, and 17% in physiological cross-sectional area (PCSA). However, changes in FL, PA and PCSA were not only observed between sides but also differed among muscle compartments. The parameter values were in general in the range of human subjects but no conclusive differences between sides could be found based on the acquired data. In conclusion, DTI and US both yielded results of muscle architecture parameters within a physiologically range but can differ substantially between methods and cannot be compared directly.

Youth football players ages 8-12 may incur hundreds of repeated head impacts (RHI) each season. Evidence suggests concussive brain injury during childhood may disrupt normal developmental processes resulting in long-term impairments. However, little research has investigated the long-term effects of incurring RHI during critical periods of neurodevelopment. Rapid myelination and cerebral blood flow rates, peaks in regional cortical thickness and volumes of specific structures, refinement of regional connectivity, and other neurodevelopmental changes occurring in the brain from ages 10-12 could create a window of vulnerability to RHI. The objective of this research was to determine the relationship between exposure to RHI prior to age 12, during a critical period of neurodevelopment, and later-life brain structure and function. Former National Football League (NFL) players ages 40-65 were divided into two groups based on their age of first exposure (AFE) to RHI through tackle football: AFE <12 and AFE ≥12. In the first study, we observed significantly lower scores on objective tests of executive functioning, memory, and estimated verbal IQ in those who began playing football prior to age 12 compared to those who began playing at age 12 or older. Next, we used diffusion tensor imaging (DTI) to examine the structural integrity of the corpus callosum (CC) and observed that the AFE <12 group had significantly lower fractional anisotropy (FA) as well as a greater decline in FA with age in anterior CC regions than the AFE ≥12 group. Lastly, we used advanced DTI tractography techniques to examine seven CC regions. Significant differences between AFE groups in associations between CC diffusion measures and cognition, mood, and behavior were found. The results of this research suggest that incurring RHI through tackle football during a critical neurodevelopmental period prior to age 12 may result in later-life structural and functional consequences, including cognitive, mood, and behavioral impairments; alterations in white matter structure; and greater vulnerability of white matter to the normal aging process. If replicated with longitudinal designs, larger samples, and athletes whose highest level of play was youth, high school, or college, these findings may have implications for safety recommendations for youth sports.

Each year in the United States, approximately 1.35 million people are a ected by mTBI (aka concussion) and subsequent cognitive impairment. Approximately 33% of mTBI cases results in persistent long-term cognitive de cits despite no abnormalities appearing on conventional neuroimaging scans. Therefore, an accurate and reliable imaging method is needed to determine injury location and extent of healing. The goal of this study was to characterize and quantify mTBI through DTI, an advanced MRI technique that encodes voxel-wise tissue water microstructural di usivity as a tensor, as well as QSM, which measures iron deposition within tissues. We hypothesized that personalizing the analysis of DTI and QSM will provide a better understanding of trauma-induced microstructural damage leading to improved diagnosis and prognosis accuracy. Through regression analysis, a preliminary comparison between DTI data to QSM measurements was performed to determine potential correlations between the two MRI techniques. Further, a large database of healthy pediatric brain DTI data was downloaded and each was warped into a standardized brain template to ultimately use for voxel-wise z-score analysis of individual mTBI patients (n=26). This allowed localization and quantitation of abnormal regions on a per-patient basis. Signi cant abnormalities were commonly observed in a number of regions including the longitudinal fasciculus, fronto-occipital fasciculus, and corticospinal tract, while unique abnormalities were localized in a host of other areas (due to the individuality of each childs injury). Further, through group-based Bonferroni corrected T-test analysis, the mTBI group was signi cantly di erent from controls in approximately 65% of regions analyzed. These results show that DTI is sensitive to the detection of microstructural changes caused by mTBI and has potential to be a useful tool for improving mTBI diagnosis accuracy / Thesis / Master of Applied Science (MASc) / Concussions affect over one million people in the United States each year. In a number of cases, these individuals must cope with persistent long-term cognitive impairment resulting from the injury. A current, significant problem is that concussion cannot be reliably diagnosed using conventional CT and MR imaging methods. Therefore, an accurate and reliable imaging method is needed to determine both injury location and severity, as well as to monitor healing. The goal of this study was to quantify concussion through MR imaging techniques known as Di ffusion Tensor Imaging and Quantitative Susceptibility Mapping, which accurately model the brain's mi- crostructure. Analysis utilizing these MRI methods found signifi cant abnormalities in a number of brain regions of concussed subjects relative to healthy individuals. These results suggest that DTI, in particular, is sensitive to microstructural changes caused by concussions and has the potential to be a useful tool for improving diagnosis accuracy.

In this thesis we were interested in combining functional connectivity (from functional Magnetic Resonance Imaging) and structural connectivity (from Diffusion Tensor Imaging) with a data fusion approach. While data fusion approaches provide an abundance of information they are underutilized due to their complexity. To solve this problem, we integrated the ease of a neuroimaging toolbox, known as the Functional And Tractographic Analysis Toolbox (FATCAT) with a data fusion approach known as the anatomically weighted functional connectivity (awFC) approach - to produce a practical and more efficient pipeline. We studied the connectivity within resting-state networks of different populations using this novel pipeline. We performed separate analyses with traditional structural and functional connectivity for comparison with the awFC findings - across all three projects. In the first study we evaluated the awFC of participants with major depressive disorder compared to controls. We observed significant connectivity differences in the default mode network (DMN) and the ventral attention network (VAN). In the second study we studied the awFC of MDD remitters compared to non-remitters at baseline and week-8 (post antidepressant), and evaluated awFC in remitters longitudinally from baseline to to week-8. We found significant group differences in the DMN, VAN, and frontoparietal network (FPN) for remitters and non-remitters at week-8. We also found significant awFC longitudinally from baseline to week-8 in the dorsal attention network (DAN) and FPN. We also tested the associations between connectivity strength and cognition. In the third study we studied the awFC in children exposed to pre- and postnatal adversity compared to controls. We observed significant differences in the DMN, FPN, VAN, DAN, and limbic network (LIM). We also assessed the association between connectivity strength in middle childhood and motor and behavioural scores at age 3. Therefore, the FATCAT-awFC pipeline, we designed was capable of identifying group differences in RSN in a practical and more efficient manner. / Thesis / Doctor of Philosophy (PhD)

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