The human brain is a complex and powerful organ, directing every aspect of life from somatosensory and motor function to visceral responses to higher order cognition. Neurological and psychiatric disorders often disrupt normal functioning. While the clinical symptoms of such disorders are known, their biological underpinnings are not as clearly characterized. Structural neuroimaging is a powerful, non-invasive tool that can play a critical role in finding biomarkers of these illnesses. Currently, variations in pre-processing techniques yield inconsistent and conflicting results. As neuroimaging is a nascent branch of medical research, gold standards in imaging methodologies have not yet been established. Quantitatively validating and optimizing the way these images are preprocessed is the first step towards standardization. Voxel-based morphometry (VBM) is one technique that is commonly used to compare whole-brain structural differences between groups. Statistical tests are used to compare intensities of voxels throughout all brain scans in each group. In order to ensure that comparable voxels are being tested, the images must be fitted into a common space, which is done through image preprocessing. Spatial normalization to templates is an early pre-processing step that is executed unreliably as many options for both templates and normalization algorithms exist. To determine the effect variations in template usage may cause, we utilized a VBM approach to detect simulated lesions. Template performance was analyzed by comparing the accuracy with which the lesion was detected.

Primary Progressive aphasia (PPA) is a disorder characterized by gradual decline in language functions, with relative sparing of other cognitive abilities. This behavioral profile results from neurodegenerative disease that preferentially affects language cortex. As is the case in aphasia resulting from stroke, any of several critical language processing domains may be affected in PPA, including syntax, semantics, phonology, and orthography. In stroke-induced aphasia, traditional lesion mapping approaches have provided important insight into the localization of cortical regions supporting these domains. Specifically, left perisylvian cortex has been implicated in syntactic and phonological aspects of language, whereas left extrasylvian cortical regions are associated with lexical-semantic and orthographic functions. The goal of the present study was to seek converging evidence for the role of left hemisphere cortical regions in language using a voxel-based imaging technique in individuals with PPA. Fifteen individuals with progressive aphasia and fifteen normal controls were given a comprehensive language battery comprising tasks in the domains of syntax, semantics, phonology, and orthography. A subset of patients and all normal controls underwent high-resolution structural MRI scanning. Voxel-based morphometry (VBM) was used to characterize patterns of regional cortical atrophy in the patients relative to controls and to correlate language tasks with gray matter volumes. Results confirm a key role for left perisylvian cortex in phonological and syntactic processes, and indicate that left temporal regions are critically involved in semantic processes. Findings shed light on the veracity of the "primary systems" hypothesis of written language, which posits that written language impairments arise from core cognitive deficits affecting semantic and phonological systems.

<div> <p> Essential tremor (ET) is one of the most common movement disorders, characterized by kinetic tremor in the upper extremities with additional cranial tremor often present in the neck or jaw. While it is well established that ET is primarily a cerebellar disorder, recent investigations have shown more widespread pathological effects throughout the brain. Furthermore, the neurodegenerative nature of ET is still disputed and requires additional investigation. Additionally, the link between ET and Parkinson’s disease (PD) is of special interest, as it can be challenging to clinically differentiate these diseases.</p> <p> While post-mortem studies have helped to further the pathological understanding of these diseases, non-invasive in-vivo techniques allow for more accurate diagnosis in the clinic. With a more accurate diagnosis comes a more targeted treatment, and hopefully an improved remediation of the disease. My thesis seeks to further investigate the neurodegenerative hypothesis of ET as well as explore magnetic resonance imaging (MRI) biomarkers for potential differences in ET and PD. </p> <p>These aims will be accomplished in three steps. First, gray matter volume loss in the cerebellum was investigated using voxel-based morphometry and the Spatially Unbiased Infra-Tentorial Template (SUIT) atlas on a lobule level. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls. The cerebellum was segmented into 34 lobules using the SUIT atlas. Percent gray matter was calculated as the ratio of lobule gray matter volume divided by total lobule volume. No significant differences were identified between ET cases and controls in any of the 34 lobules. However, nine lobules had significantly decreased percent gray matter in ET cases with head or jaw tremor (n = 27) compared to controls. Also, 11 lobules had significantly decreased percent gray matter in ET cases with voice tremor (n = 22) compared to controls. This result confirms, with increased regional accuracy, gray matter volume loss in the cerebellum of ET cases.</p> <p>Second, gray matter volume loss beyond the cerebellum, in the cerebrum, was investigated using voxel-based morphometry. High resolution 3D T1-weighted MRI images were acquired on 47 ET cases and 36 controls for processing in SPM12. The processing steps of SPM12 were updated to include a higher resolution atlas and set of tissue probability maps to optimize the segmentation and normalization of each subject image. After segmentation, normalization, and smoothing, a voxel-wise statistical analysis was performed to identify clusters of gray matter volume in ET cases compared to controls. ET cases showed decreased gray matter volume in the bilateral superior temporal region and the anterior and posterior cingulate cortex. These results, in combination with previous work provide support of wide-spread neurodegeneration in ET using optimized methodology.</p> <p>Third, we applied T2* mapping to determine relative iron concentrations in the substantia nigra (SN) and globus pallidus (GP) in ET and PD cases. Three separate studies were independently investigated to validate the reproducibility and detectability of group differences using T2* mapping. The first study (ET study) acquired T2* maps on 21 ET cases and 12 matched controls, the second study (PD study 1) acquired T2* maps on 10 PD cases and 7 controls, and the third study (PD study 2) acquired T2* maps on 21 PD cases and 17 controls. Regions of interest (ROIs) were manually placed in the SN and GP for each subject and group differences were calculated independently for each study using a linear regression model with age and sex as covariates. A significant decrease in T2* was found in PD study 1 and PD study 2 in the right SN in PD cases compared to their respective controls, indicating increased iron deposition. No significant difference was found in the ET group compared to their respective controls in the SN. No significant differences were found in any of the three studies in the GP. These results provide evidence for a difference in brain iron regulation in the pathology of ET and PD.</p> <p>Together, these thesis aims provide additional evidence in support of the neurodegenerative hypothesis of ET using updated methodology and present a quantitative imaging difference between groups of ET and PD cases. </p> </div> <br>

Prior research has suggested that any cortical volume (CV) abnormalities in Autism Spectrum Disorder (ASD) need to be further explored by examination of the two determinants of CV, that being cortical thickness (CT) and pial surface area (PSA; Murphy, Beecham, Craig, & Ecker, 2011). The current study suggests that the two determinants of CV should be explored even in the presence of null CV findings, if structure-function analyses are significant (i.e., bi-lateral precentral gyrus and neuropsychological motor test) as demonstrated in the current sample (see Duffield et al., 2013). The only significant anatomic finding was reduced CT in the left frontal motor regions (primarily left precentral gyrus), which also corresponded to the only significant relationship between a motor variable (i.e., grooved pegboard test) and motor region-of-interest (ROI) where ASD had a stronger relationship than typically developing controls (TDC; ASD > TDC). Left hemisphere biased CT group differences has been shown to have the highest classification accuracy (i.e., designation of ASD versus TDC) of morphological parameters (Ecker et al., 2010), yet PSA has been shown to have far greater modulation of CV abnormalities. This is particularly true for subthreshold PSA (Ecker et al., 2013). These prior findings are not only consistent with the current motor ROI findings, but also provide an explanatory framework for the functional neuroanatomy of a generally worse left handed performance (i.e., non-dominant hand) for ASD compared to controls in a generally right handed dominant sample (no significant group differences on handedness). The only significant motor ROI finding was in the left hemisphere (i.e., ipsilateral to worse left handed performance), but subthreshold PSA findings in the right precentral were found and likely provide explanatory power of motor performances in the aggregate, despite a lack of significant statistical differences in a specific motor ROI individually.

BACKGROUND: Migraine is a primary headache disorder that has a high prevalence and burden of disease throughout the world. Migraine symptoms include throbbing head pain, nausea, hypersensitivity to light, sound, and smell, and autonomic, cognitive, emotional, and motor disturbances. About a third of migraineurs have aura symptoms which are transient neurological symptoms with gradual onset before the migraine attack, visual disturbances, sensory loss, and/or communication impairment. The trigeminovascular system, central descending modulation, and brainstem descending modulation have been implicated in the pathophysiology of migraine. However, the exact neurovascular mechanism for migraine has not been determined. Several imaging techniques have been used to find structural and functional brain changes in migraineurs. OBJECTIVE: In order to further existing knowledge of migraine pathophysiology, structural brain differences were investigated using imaging between migraineurs and healthy individuals and differences within migraineurs. METHODS: Thirty-two patients with migraine (25 females) and 32 healthy control subjects (25 females) age-, ethnicity-, and gender-matched participated in our study. Magnetic resonance imaging (MRI) scans were collected from each participant. Then, voxel-based morphometry (VBM) was utilized to find any gray matter (GM) volume differences between migraine patients and controls. Also, VBM was performed in specific regions-of-interest (ROIs) to compare 11 migraine patients with aura (MA) and 11 migraine patients without aura (MO). RESULTS: A significant increase in regional gray matter volume difference was observed for migraine patients compared to control subjects in the intracalcarine gyrus of the visual cortex (corrected, p<0.05). In the VBM analysis of ROIs, the similarities between the MO and MA subjects included increases in the anterior cingulate cortex (ACC), hippocampus, insula, and intracalcarine cortex, along with decreases in the ACC and insula (uncorrected, p<0.05). MO subjects had decreases in the amygdala, hippocampus, intracalcarine cortex, and thalamus, but not in the MA subjects (uncorrected, p<0.05). The MA patients had increases in the amygdala and thalamus, but not in the MO patients (uncorrected, p<0.05). DISCUSSION: It can be concluded that the visual cortex is involved in the migraine mechanism since a large increase in GM volume difference was found in migraine, MO, and MA cohorts, as well as results from previous studies. Numerous GM volume changes in MO and MA cohorts reinforce evidence that particular brain regions are a part of migraine pathophysiology, but there were some regions that do not. Further research using imaging analysis and with larger study populations should be conducted to enhance our understanding of the migraine mechanism and differences that arise between migraine groups, so that diagnosis and treatment administration can be improved.

We aimed to assess whether frontal cortex-striatum-thalamus (FCST) pathway or other grey matter (GM) structures are associated with longitudinal patterns of fatigue, namely reversible (RF) versus sustained fatigue (SF). MS patients enrolled in our prospective cohort were grouped based on their longitudinal Modified Fatigue Impact Scale (MFIS) scores: 1. SF: MFIS≥38 at the two most recent yearly assessments; 2. RF: MFIS<38 at last assessment, but presence of at least one previous MFIS≥38; 3. Never Fatigued (NF): at least five MFIS<38. Accordingly, we selected 98 patients (30 SF, 31 RF, 37 NF; age-range:29-66, female/male:76/22, Extended Disability Status Scale (EDSS)6; 13 patients with secondary progressive (SP) MS and 85 with relapsing remitting (RR) MS in remission). Disability and depression were assessed using the EDSS and CES-D, respectively. 3T T1-weighted MRI was used for voxel based morphometry (VBM) to survey for GM atrophy associated with fatigue, controlling for age, sex and EDSS. Group-wise volumetric comparison was performed on deep GM structures identified by VBM, controlling for age, sex, EDSS and CES-D score. VBM showed significant inverse relation between the MFIS cognitive subscale score and areas within the bilateral fronto-medial and fronto-orbital cortices, anterior striata, thalami, temporal poles, insulae and left lateral occipital cortex (peak FWE-p value of 0.021), and between the MFIS physical subscale and areas within the bilateral frontal poles, and frontal medial cortices (peak FWE-p value of 0.043). Volumetric analysis showed significant atrophy in the putamen (RF<NF p<0.0004; SF<NF p<0.0085) and thalamus (RF<NF p<0.00048).

To characterize the relationship between dispersion-based intra-individual variability (IIVd) in neuropsychological test performance and brain volume among HIV seropositive and seronegative men and to determine the effects of cardiovascular risk and HIV infection on this relationship. Magnetic Resonance Imaging (MRI) was used to acquire high-resolution neuroanatomic data from 147 men age 50 and over, including 80 HIV seropositive (HIV+) and 67 seronegative controls (HIV-) in this cross-sectional cohort study. Voxel Based Morphometry was used to derive volumetric measurements at the level of the individual voxel. These brain structure maps were analyzed using Statistical Parametric Mapping (SPM2). IIVd was measured by computing intra-individual standard deviations (ISD’s) from the standardized performance scores of five neuropsychological tests: Wechsler Memory Scale-III Visual Reproduction I and II, Logical Memory I and II, Wechsler Adult Intelligence Scale-III Letter Number Sequencing. Total gray matter (GM) volume was inversely associated with IIVd. Among all subjects, IIVd -related GM atrophy was observed primarily in: 1) the inferior frontal gyrus bilaterally, the left inferior temporal gyrus extending to the supramarginal gyrus, spanning the lateral sulcus; 2) the right superior parietal lobule and intraparietal sulcus; and, 3) dorsal/ventral regions of the posterior section of the transverse temporal gyrus. HIV status, biological, and cardiovascular disease (CVD) variables were not linked to IIVd -related GM atrophy. IIVd in neuropsychological test performance may be a sensitive marker of cortical integrity in older adults, regardless of HIV infection status or CVD risk factors, and degree of intra-individual variability links with volume loss in specific cortical regions; independent of mean-level performance on neuropsychological tests.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13231号 / 論医博第2171号 / 新制||医||1036(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 高橋 淳, 教授 宮本 享, 教授 富樫 かおり / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

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