NOVEL PHANTOMS AND POST-PROCESSING FOR DIFFUSION SPECTRUM IMAGING

High Angular Resolution Diffusion Imaging (HARDI) techniques, including Diffusion Spectrum Imaging (DSI), have been proposed to resolve crossing and other complex fiber architecture in the human brain white matter. In these methods, directional information of diffusion is inferred from the peaks in the orientation distribution function (ODF). Extensive studies using histology on macaque brain, cat cerebellum, rat hippocampus and optic tracts, and bovine tongue are qualitatively in agreement with the DSI-derived ODFs and tractography. However, there are only two studies in the literature which validated the DSI results using physical phantoms and both these studies were not performed on a clinical MRI scanner. Also, the limited studies which optimized DSI in a clinical setting, did not involve a comparison against physical phantoms. Finally, there is lack of consensus on the necessary pre- and post-processing steps in DSI; and ground truth diffusion fiber phantoms are not yet standardized. Therefore, the aims of this dissertation were to design and construct novel diffusion phantoms, employ post-processing techniques in order to systematically validate and optimize (DSI)-derived fiber ODFs in the crossing regions on a clinical 3T MR scanner, and develop user-friendly software for DSI data reconstruction and analysis. Phantoms with a fixed crossing fiber configuration of two crossing fibers at 90° and 45° respectively along with a phantom with three crossing fibers at 60°, using novel hollow plastic capillaries and novel placeholders, were constructed. T2-weighted MRI results on these phantoms demonstrated high SNR, homogeneous signal, and absence of air bubbles. Also, a technique to deconvolve the response function of an individual peak from the overall ODF was implemented, in addition to other DSI post-processing steps. This technique greatly improved the angular resolution of the otherwise unresolvable peaks in a crossing fiber ODF. The effects of DSI acquisition parameters and SNR on the resultant angular accuracy of DSI on the clinical scanner were studied and quantified using the developed phantoms. With a high angular direction sampling and reasonable levels of SNR, quantification of a crossing region in the 90°, 45° and 60° phantoms resulted in a successful detection of angular information with mean ± SD of 86.93°±2.65°, 44.61°±1.6° and 60.03°±2.21° respectively, while simultaneously enhancing the ODFs in regions containing single fibers. For the applicability of these validated methodologies in DSI, improvement in ODFs and fiber tracking from known crossing fiber regions in normal human subjects were demonstrated; and an in-house software package in MATLAB which streamlines the data reconstruction and post-processing for DSI, with easy to use graphical user interface was developed. In conclusion, the phantoms developed in this dissertation offer a means of providing ground truth for validation of reconstruction and tractography algorithms of various diffusion models (including DSI). Also, the deconvolution methodology (when applied as an additional DSI post-processing step) significantly improved the angular accuracy of the ODFs obtained from DSI, and should be applicable to ODFs obtained from the other high angular resolution diffusion imaging techniques

Functional Organization of the Brain at Rest and During Complex Tasks Using fMRI

How and why functional connectivity (FC), which captures the correlations among brain regions and/or networks, differs in various brain states has been incompletely understood. I review high-level background on this problem and how it relates to 1) the contributions of task-evoked activity, 2) white-matter fMRI, and 3) disease states in Chapter 1. In Chapter 2, based on the notion that brain activity during a task reflects an unknown mixture of spontaneous activity and task-evoked responses, we uncovered that the difference in FC between a task state (a naturalistic movie) and resting state only marginally (3-15%) reflects task-evoked connectivity. Instead, these changes may reflect changes in spontaneously emerging networks. In Chapter 3, we were able to show subtle task-related differences in the white matter using fMRI, which has only rarely been used to study functions in this tissue type. In doing so, we also demonstrated that white matter independent components were also hierarchically organized into axonal fiber bundles, challenging the conventional practice of taking white-matter signals as noise or artifacts. Finally, in Chapter 4, we examined the utility of combining FC with task-activation studies in uncovering changes in brain activity during preclinical Alzheimer\u27s Disease (mild cognitive impairment (MCI) and subjective cognitive decline (SCD) populations), based on data collected at the Indiana University School of Medicine. We found a reduction in neural task-based activations and resting-state FC that appeared to be directly related to diagnostic severity. Taken together, the work presented in this dissertation paves the way for a novel framework for understanding neural dynamics in health and disease

Commissural white matter disconnectivity in normal ageing and Alzheimer’s disease

The network of commissural white matter fibres responsible for connecting the hemispheres of the brain is known as the corpus callosum (CC). Atrophy to the CC is evident in studies of aging and Alzheimer’s disease (AD), but patterns and functional implications of neurodegeneration are still somewhat unclear. In this thesis, neuroimaging methods were used to further examine how structural and functional CC properties are affected by normal ageing and AD. In Study 1, diffusion tensor imaging (DTI) was used to examine the posterior CC tract bundles in young and older adults. Parietal and temporal midsagittal CC segments were particularly impaired in older adults, while occipital tracts were relatively preserved. Study 2 applied this methodology to study Mild Cognitive Impairment (MCI) and AD. MCI patients exhibited reduced integrity in midsagittal parietal segments compared to controls. AD patients exhibited reductions in parietal and temporal segments, yielding high classification accuracy (95-98%) against controls. Study 3 assessed visual interhemispheric transfer in aging using electroencephalography (EEG). Transfer speed was elongated in older adults, but was driven by earlier activation of the input hemisphere rather than delayed activation of the receiving hemisphere. This was not interpreted as impairment in older age, in line with findings of preserved occipital tracts in Study 1. Study 5 examined EEG functional connectivity methodology. We showed that connectivity was strongest at the dominant EEG frequency, which experiences slowing in older age. Previous studies using conventional frequency bands may therefore be biased against older adults. Study 6 applied these findings to study interhemispheric functional connectivity in older adults, while controlling for age-related frequency slowing. Age-related disconnectivity between frontal sites was evident, reflecting typical anterior-posterior neurodegeneration in older adults (Bennett, Madden, Vaidya, Howard, & Howard, 2010). These studies provide novel spatial and methodological insight into the CC during ageing and AD

Brain effects of fetal growth restriction and their prevention in an animal model

[eng] BACKGROUND: Chronic hypoxia due to placental insufficiency and prenatal undernutrition are probably the two major causes worldwide of an adverse intrauterine environment having an impact on neurodevelopment. Clinically, both situations manifest as an intrauterine growth restriction (IUGR), a situation defined as a significant reduction in fetal growth resulting in a birth weight below the 10th percentile. This situation is a well-recognized cause of neurobehavioral and cognitive impairments extending beyond childhood and early adulthood period. Although all these evidence, the structural ground of these functional impairments and the pathophysiological mechanisms are not fully characterized. An improvement in these two aspects would allow us to propose different therapeutic strategies aiming to ameliorate and even revert the long-lasting consequences of the IUGR. HYPOTHESIS: We hypothesized that IUGR produces subtle structural brain changes that underlie the long-term neurobehavioral and cognitive impairments. The severity of the neurodevelopmental consequences might be related to the severity of the prenatal insult (reduction in nutrients with or without a reduction in oxygen). High-resolution brain imaging along with specific histological techniques focused on neuronal connectivity could evidence these structural brain changes. Additionally, we hypothesized that an early postnatal stimulation might ameliorate the structural and functional impairments that persist at the long-term period after IUGR. METHODS: Two animal models of IUGR were used in this thesis: i. A cohort of pregnant rabbits was randomized to reproduce an undernutrition model based on maternal food reduction intake, ii. Another cohort of pregnant rabbits was randomized to the placental insufficiency model based on the surgical ligation of 40-50% of the uteroplacental vessels that irrigate each gestational sac. After the delivery in both models, IUGR and controls animals were followed up to the 70th postnatal days. At the 30th postnatal days, a subgroup of IUGR animals was randomized to an environmental enrichment strategy. In all the groups at the neonatal period, general motor skills, reflexes, and olfactory sensitivity were evaluated. Similarly, at the 70th postnatal days, anxiety, memory, and learning were evaluated. Afterward, animals were sacrificed and brains were fixed and diffusion MRI was then performed. In a subset of animals, changes at the microstructural level and differences in the number of fibers in two specific brain circuits (anxiety and memory circuits) were performed by using a Voxel-Based approach (VBA) and Tractography analysis, respectively. Moreover, brain networks were obtained and evaluated by means of a Connectomics. Finally, a subgroup of animals was also histologically evaluated by means of dendritic spine and perineural nets evaluation in the Hippocampus. RESULTS: IUGR animals showed poorer functional performance in both moments, especially in the model of placental insufficiency. At the long-term period, IUGR animals presented an altered brain network architecture, being again these differences more pronounced in the placental insufficiency model. Moreover, VBA analysis and Tractography analysis evidenced microstructural brain changes mostly affecting gray matter and a decreased in the number of fibers involved in the anxiety and memory circuits in the IUGR animals in comparison to controls. At the cellular level, IUGR animals presented abnormal neuronal connectivity with changes in the dendritic spine density and in the perineural nets. In contrast, stimulated IUGR animals presented a functional and structural improvement in comparison to non-stimulated IUGR animals over the long-term period. CONCLUSIONS: This thesis adds to the previous evidence new insights regarding the pathophysiological mechanisms underlying IUGR and gives strong evidence linking IUGR with altered brain connectivity as the basis for the neurological sequelae associated with IUGR. Additionally, it gives preliminary evidence suggesting that a strategy based on physical, sensory, cognitive as well as social stimulation applied during early postnatal life, where brain plasticity is higher, might ameliorate the neurodevelopmental consequences of IUGR