O transtorno bipolar (TB) é uma das doenças psiquiátricas mais comuns e com altas taxas de morbimortalidade. Existe uma busca de um modelo neurofisiológico que poderia fornecer medidas objetivas para o diagnóstico desta doença, bem como fornecer parâmetros fisiológicos para monitorar a progressão, quantificar o dano causado pela mesma e prever a resposta ao tratamento na tentativa de direcionar a terapêutica adequada a cada estágio e evitar sua progressão. Kapczinski et al (2014) propôs um modelo de estadiamento do TB baseado em sintomas interepisódio, biomarcadores (inflamatórios e neuroplásticos) e dano cognitivo. Na última década, técnicas de neuroimagem e de genética proliferaram e vem se tornando promissoras ferramentas para se estabelecer a base de modelos neurofisiológicos do TB. Embora o prejuízo cognitivo já esteja bem descrito na literatura, o conhecimento sobre as alterações de conectividade em estudos de neuroimagem associadas a esta condição ainda é escasso. A atual pesquisa se propos a investigar os mecanismos fisiopatológicos do transtorno do humor bipolar com enfoque na substância branca (SB) cerebral. Primeiramente foi feita uma revisão sistemática da literatura internacional de estudos que correlacionaram o TB e estudo de tensor de difusão (DTI) por ressonância magnética (RM). Foram incluidos 18 trabalhos que fechavam com os critérios da pesquisa. Os trabalhos mostraram nas análises de DTI alterações na integridade da SB entre o os pacientes com TB em comparação com os controles normais. Essas alterações foram encontradas especialmente nos tratos de SB implicados em conectar uma ampla gama de redes neurais, incluindo as regiões estriatais ventrais e fronto-temporais. A maioria dos estudos mostrou valores de anisotropia fracionada (FA) reduzidos em tratos comissurais inter-hemisféricos e de associação frontolímbicos, com destaque para o corpo caloso que foi a estrutura mais acometida nos diferentes estudos. Estes achados são concordantes com a "síndrome de desconexão" que é encontrada em pacientes com TB. O segundo propósito desta tese foi fazer uma comparação dos volumes de substância branca total, do volume do corpo caloso e do volume total de substância cinzenta entre pacientes com TB em estagio inicial e avançado em relação aos seus respectivos controles normais pareados para sexo, idade, hemisfério dominante e nível de escolaridade. A análise de volumetria das estruturas corticais e subcorticais foi feita por meio de método de segmentação automatizada pelo software Freesurfer. Foram avaliados 55 sujeitos, sendo 29 pacientes com TB e 26 controles normais. A análise volumétrica encontrou redução da SB total e do volume do corpo caloso tanto em pacientes com TB no estagio inicial quanto tardio da doença. O volume de susbtância cinzenta (SC) total estava reduzido somente nos pacientes com TB em estágio tardio. Estes achados são inéditos na literatura e podem explicar a síndrome desconectiva dos pacientes com TB desde os estágios iniciais e o declínio cognitivo acentuado dos pacientes em estágios mais avançados da doença. Podem propor uma pista para achados de biomarcadores em populações em risco para desenvolver TB. / Bipolar disorder (BD) is one of the most common psychiatric disorders and with high morbidity and mortality rates. There is a search for a neurophysiological model that could provide objective measurements for diagnosis of this disease, as well as providing physiological parameters to monitor the progression, quantify the damage caused by it and predict response to treatment in an attempt to direct the appropriate therapy for each stage and prevent its progression. Kapczinski et al. (2014) proposed a staging BD model based on interepisode symptoms, biomarkers (inflammatory and neuroplastic) and cognitive impairment. In the last decade, techniques of neuroimaging and genetic proliferated and are becoming promising tools to settle the basis of neurophysiological models of BD. Although cognitive impairment is already well described in the literature, knowledge of the connectivity changes in neuroimaging studies associated with this condition is still scarce. Current research is proposed to investigate the pathophysiological mechanisms of bipolar disorder focusing on white matter (WM) brain. It was first made a systematic review of the literature studies that correlated the BD and diffusion tensor imaging (DTI). We found 18 published DTI studies that identified WM changes in subjects with bipolar disorder. The studies showed changes in the integrity of DTI WM between BD patients compared with normal controls. These changes were found especially in the treatment of WM connecting implicated in a wide range of neural networks, including ventral striatal regions and frontotemporal. Most studies showed reduced FA values in commissural inter-hemispheric and fronto-limbic association tracts, especially the corpus callosum which was the most affected structure in different studies. These findings are consistent with the "disconnection syndrome" which is found in patients with TB. The second purpose of this thesis was to compare the total white matter volume, the corpus callosum volume and total volume of gray matter in patients with BD in early and advanced stage in relation to their normal controls matched for sex, age, dominant hemisphere and education level. The volumetric analysis of cortical and subcortical structures was performed by automated segmentation method by FreeSurfer software. We evaluated 55 subjects, 29 BD patients and 26 normal controls. Volumetric analysis found reduced total WM and the corpus callosum volume both in BD patients at the early stage and late disease. The volume of total gray matter (GM) was reduced only in patients with late-stage BD. These findings are unprecedented in the literature and may explain the disconnection syndrome that is present in patients from the early stages and the marked cognitive decline of patients in more advanced stages of the disease. These findings may offer a clue to biomarker findings in populations at risk to develop BD.

Un des objectifs majeurs de la neuroimagerie moderne est l'identification de nouveaux marqueurs qui puissent aider au diagnostic et au suivi des pathologies neurologiques. L'imagerie par résonnance magnétique multimodale (IRMm) est une approche permettant l'évaluation de plusieurs biomarqueurs complémentaires au cours d'un seul examen d'IRM. Cette approche a montré son efficacité dans de nombreuses études récentes et notamment dans la maladie de Parkinson. A l'approche IRMm précédemment utilisée, nous avons introduit un nouveau biomarqueur i.e. les changements de forme des structures sous-corticales à partir d'images pondérées en T1. Ce dernier marqueur vient enrichir l'approche IRMm composée de la quantification de : (i) la volumétrie à partir d'images pondérées en T1 (ii) de l'intégrité et l'orientation microstructurales à partir des images pondérées en diffusion et (iii) des dépôts de métaux à partir de la relaxométrie T2*. Nous avons appliqué l'approche IRM multimodale à une autre maladie neurodégénérative, la maladie d'Alzheimer à un stade précoce. Les résultats de cette étude préliminaire nous ont permis de suggérer la présence de processus physiopathologiques différents à la phase prodromique de la maladie d'Alzheimer. En effet nous avons observé pour l'hippocampe et l'amygdale une atrophie avec modification de l'intégrité microstructurale alors que seule une atrophie a été observée pour le thalamus et le putamen. Ces résultats nous ont aussi permis de confirmer l'importance d'une approche multimodale pour les études portant sur les maladies neurodégénératives. Parmi les marqueurs de l'IRMm, la quantification du fer intracérébral par relaxométrie T2* est une des méthodes qui a été développé ces dernières années à l'unité Inserm U825. Le dérèglement du métabolisme du fer et son accumulation sont en effet impliqués dans la physiopathologie de nombreuses maladies neurodégénératives telles que la maladie de Parkinson. L'expérience acquise à travers les différentes validations cliniques de cette méthode ces dernières années nous a conduit à améliorer cette dernière. Nous avons dirigé nos travaux sur l'amélioration de la méthode de relaxométrie R2* en optimisant l'acquisition d'une part et le traitement des images d'autre part. Nous avons donc comparé différentes résolutions, antennes, facteurs d'accélération, et nombres d'acquisitions par temps d'écho afin de déterminer les paramètres permettant d'obtenir le plus haut rapport signal sur bruit. Pour la partie traitement des images nous avons comparé la méthode utilisée comme référence, la méthode des moindres carrés par algorithme de Levenberg-Marquardt, à une autre méthode, la décomposition en valeur singulière pour estimer avec le plus de justesse le taux relaxation R2*. Nous avons ainsi pu mettre au point une séquence de relaxométrie T2* optimisée que nous avons comparé à celle utilisée lors de la première étude, dans le modèle du vieillissement physiologique. Au final en plus de permettre la discrimination entre sujets âgés et jeunes, les résultats obtenus avec cette nouvelle séquence se sont révélés être beaucoup moins sensibles au bruit. / One of the main goals of modern neuroimaging is the identification of new markers that can help in the diagnosis and monitoring of neurological pathologies. Multimodal magnetic resonance imaging (MRIm), is an approach allowing the evaluation of several complementary biomarkers within one MRI. This approach has already demonstrated its efficiency in several recent studies, and in particular in Parkinson's disease. We added a new biomarker to the MRIm approach previously used i.e. shape changes of subcortical structures based on T1 images. This marker is now a part of our MRIm approach along with: (i) volumetry from T1 images, (ii) microstructural integrity and orientation from diffusion images and (iii) metal deposits from T2* relaxometry. We applied this multimodal MRI approach to an other neurodegenerative disease, the Alzheimer's disease at a prodromal stage. Results of this preliminary study gave us the opportunity to suggest the existence of two different physiopathological processes at the prodromal phase of the Alzheimer's disease. In fact we observed atrophy with modification of the microstructural integrity for the hippocampus and the amygdala, while only atrophy has been observed for the thalamus and the putamen. Those results also confirmed the necessity of studying neurodegenerative diseases in a multimodal way. Among MRIm markers, the T2* relaxometry for the quantification of intracerebral iron is one of the methods which has been developed lately at the Inserm U825. Dysregulation of iron metabolism and its accumulation are involved in the physiopathology of several neurodegenerative diseases like Parkinson's disease. The experience gained through the different clinical validation of this method in recent years has led us to improve it. Our work was to improve T2* relaxometry by optimizing the acquisition of the images on one hand, and the processing of the images on the other hand. We compared several resolutions, acquisition antennas, number of acquisition by echo time, to determine which parameters gave the higher signal to noise ratio. For the part about the process of the images, we compared the method used as a reference, the least square method using a Levenberg-Marquard algorithm, to an other method, the singular value decomposition to obtain the best estimation of the relaxation rate R2*. Then we were able to develop an optimized T2* relaxometry sequence, which we compared to the one used in the first study, but in the physiological ageing model. Finally in addition to allowing discrimination between elderly and young people, the results obtained with this new sequence were found to be much less sensitive to noise.

Thesis (M.Sc (Radiography))--Cape Peninsula University of Technology, 2016. / Multiple sclerosis (MS) affects the central nervous system (CNS) and is characterized by multiple demyelinating lesions. It is in this context that a need arises for reliable biomarkers such as Magnetic Resonance Imaging (MRI), which could lead to the early diagnosis and therapeutic intervention when maximum potential impact is possible. This study examines the impact of MRI as a marker and the sequences that give the best images to aid in evaluation of disease progression (which can indirectly be seen as disability) and the early diagnosis of MS which will, in turn, lead to more effective management of the disease. METHOD: Sixteen subjects underwent a neurological examination, the Expanded Disability Status Scale (EDSS), blood tests for iron parameters and a 3Tesla Magnetic Resonance Imaging (MRI) scan. In a study of MS, 11 had MRI data that could be analysed by using tract-based spatial statistics (TBSS). Subjects were divided according to the EDSS score (8 of the subjects had an EDSS score of ≤ 3 while 3 subjects had scores of ≥ 6). Diffusion tensor imaging (DTI), the fused Proton Density and Fluid Attenuation Recovery (FLAIR) was utilised to compute the lesion numbers and standard laboratory procedures were used to measure other biochemical markers (serum iron, % transferrin saturation, ferritin, haemoglobin) in subjects with disability and simultaneously assess the disease process. RESULTS: The FA of white matter tracts (WMTs) as a parameter of myelin integrity was lower in subjects with MS only in those who had high EDSS scores. An association between FA and iron parameters, especially percentage transferrin saturation (% Tf) sat were observed, which suggests that iron availability to the WM may be a requirement for optimal myelin functionality. CONCLUSION: The FA of WMTs as a parameter of myelin integrity was lower only in those MS subjects who had high EDSS scores. Subjects who had EDSS scores < 3 (i.e. who had a “benign” disease outcome) had FA values similar to control values and this finding was not related to their age or disease duration. The association found between FA and iron parameters, especially % Tf sat, suggests that iron availability to the WM may be a requirement for optimal myelin functionality. Results also suggest that serum iron concentration, ferritin and % Tf sat had an effect on myelination. The lack of association between FA and Hb suggests that the iron in this protein is not available for WM function.

O transtorno bipolar (TB) é uma das doenças psiquiátricas mais comuns e com altas taxas de morbimortalidade. Existe uma busca de um modelo neurofisiológico que poderia fornecer medidas objetivas para o diagnóstico desta doença, bem como fornecer parâmetros fisiológicos para monitorar a progressão, quantificar o dano causado pela mesma e prever a resposta ao tratamento na tentativa de direcionar a terapêutica adequada a cada estágio e evitar sua progressão. Kapczinski et al (2014) propôs um modelo de estadiamento do TB baseado em sintomas interepisódio, biomarcadores (inflamatórios e neuroplásticos) e dano cognitivo. Na última década, técnicas de neuroimagem e de genética proliferaram e vem se tornando promissoras ferramentas para se estabelecer a base de modelos neurofisiológicos do TB. Embora o prejuízo cognitivo já esteja bem descrito na literatura, o conhecimento sobre as alterações de conectividade em estudos de neuroimagem associadas a esta condição ainda é escasso. A atual pesquisa se propos a investigar os mecanismos fisiopatológicos do transtorno do humor bipolar com enfoque na substância branca (SB) cerebral. Primeiramente foi feita uma revisão sistemática da literatura internacional de estudos que correlacionaram o TB e estudo de tensor de difusão (DTI) por ressonância magnética (RM). Foram incluidos 18 trabalhos que fechavam com os critérios da pesquisa. Os trabalhos mostraram nas análises de DTI alterações na integridade da SB entre o os pacientes com TB em comparação com os controles normais. Essas alterações foram encontradas especialmente nos tratos de SB implicados em conectar uma ampla gama de redes neurais, incluindo as regiões estriatais ventrais e fronto-temporais. A maioria dos estudos mostrou valores de anisotropia fracionada (FA) reduzidos em tratos comissurais inter-hemisféricos e de associação frontolímbicos, com destaque para o corpo caloso que foi a estrutura mais acometida nos diferentes estudos. Estes achados são concordantes com a "síndrome de desconexão" que é encontrada em pacientes com TB. O segundo propósito desta tese foi fazer uma comparação dos volumes de substância branca total, do volume do corpo caloso e do volume total de substância cinzenta entre pacientes com TB em estagio inicial e avançado em relação aos seus respectivos controles normais pareados para sexo, idade, hemisfério dominante e nível de escolaridade. A análise de volumetria das estruturas corticais e subcorticais foi feita por meio de método de segmentação automatizada pelo software Freesurfer. Foram avaliados 55 sujeitos, sendo 29 pacientes com TB e 26 controles normais. A análise volumétrica encontrou redução da SB total e do volume do corpo caloso tanto em pacientes com TB no estagio inicial quanto tardio da doença. O volume de susbtância cinzenta (SC) total estava reduzido somente nos pacientes com TB em estágio tardio. Estes achados são inéditos na literatura e podem explicar a síndrome desconectiva dos pacientes com TB desde os estágios iniciais e o declínio cognitivo acentuado dos pacientes em estágios mais avançados da doença. Podem propor uma pista para achados de biomarcadores em populações em risco para desenvolver TB. / Bipolar disorder (BD) is one of the most common psychiatric disorders and with high morbidity and mortality rates. There is a search for a neurophysiological model that could provide objective measurements for diagnosis of this disease, as well as providing physiological parameters to monitor the progression, quantify the damage caused by it and predict response to treatment in an attempt to direct the appropriate therapy for each stage and prevent its progression. Kapczinski et al. (2014) proposed a staging BD model based on interepisode symptoms, biomarkers (inflammatory and neuroplastic) and cognitive impairment. In the last decade, techniques of neuroimaging and genetic proliferated and are becoming promising tools to settle the basis of neurophysiological models of BD. Although cognitive impairment is already well described in the literature, knowledge of the connectivity changes in neuroimaging studies associated with this condition is still scarce. Current research is proposed to investigate the pathophysiological mechanisms of bipolar disorder focusing on white matter (WM) brain. It was first made a systematic review of the literature studies that correlated the BD and diffusion tensor imaging (DTI). We found 18 published DTI studies that identified WM changes in subjects with bipolar disorder. The studies showed changes in the integrity of DTI WM between BD patients compared with normal controls. These changes were found especially in the treatment of WM connecting implicated in a wide range of neural networks, including ventral striatal regions and frontotemporal. Most studies showed reduced FA values in commissural inter-hemispheric and fronto-limbic association tracts, especially the corpus callosum which was the most affected structure in different studies. These findings are consistent with the "disconnection syndrome" which is found in patients with TB. The second purpose of this thesis was to compare the total white matter volume, the corpus callosum volume and total volume of gray matter in patients with BD in early and advanced stage in relation to their normal controls matched for sex, age, dominant hemisphere and education level. The volumetric analysis of cortical and subcortical structures was performed by automated segmentation method by FreeSurfer software. We evaluated 55 subjects, 29 BD patients and 26 normal controls. Volumetric analysis found reduced total WM and the corpus callosum volume both in BD patients at the early stage and late disease. The volume of total gray matter (GM) was reduced only in patients with late-stage BD. These findings are unprecedented in the literature and may explain the disconnection syndrome that is present in patients from the early stages and the marked cognitive decline of patients in more advanced stages of the disease. These findings may offer a clue to biomarker findings in populations at risk to develop BD.

Visuomotor behaviour – from handling simple objects to operating complex devices – is of fundamental importance in our everyday lives, yet there is relatively little evidence as to how healthy ageing affects these processes. A central role is played by the human capacity for reaching and grasping. Grasping an object requires complex visuomotor transformations, including processing of the object’s extrinsic features (it’s spatial location) and intrinsic features (such as size and shape). It has been documented that action relevant intrinsic object properties automatically facilitate specific motor actions despite being task-irrelevant, the so-called object affordance effect. These effects have been demonstrated for (1) grasp type (precision and power grips being facilitated by small and large objects) and (2) object-orientation (whereby right and left handed grasps are facilitated by object-orientation), and might underlie the effortlessness with which humans can interact with objects. Yet, these paradigms have not previously been employed in the study of healthy ageing, and little is known concerning how these processes change over the life span. Elucidating these changes is of particular importance as age-related degeneration of white matter integrity is well documented. Consequently, if successful visuomotor behaviour relies on white matter integrity, age-related reductions in affordance effects should be observed. This prediction was tested in a series of experiments. Experiment 1 investigated age-differences in object-size compatibility effects, and results corroborated our prediction of age-related reductions in object-size effects. Experiment 2 investigated age-differences in (1) spatial compatibility effects versus object-orientation effects, and (2) the locus of the effects (facilitation versus interference effects). Results revealed (1) some evidence of larger affordance than spatial effects in both age-groups, and (2) interference effects in the younger group and both facilitation and interference effects in the older group, showing a potential change in processing modes or strategies. Experiments 3 and 4 addressed the main competing account, the attention-directing hypothesis (according to which attentional shifts are responsible for the generation of automatic response codes, rather than the affects arising from afforded actions), by using a novel stimulus set in which such attentional differences can be ruled out. Results provided strong evidence in favour of the object-size affordance hypothesis. A final neuroimaging experiment investigated age-differences in the object-size effect and its neural correlates by combining behavioural, functional MRI and diffusion tensor imaging (DTI) data. Results revealed evidence of age-differences, both on the behavioural and functional level. For the DTI data, we investigated all four diffusion metrics (something which is not frequently reported in the healthy ageing literature), and found widespread age-related differences in white matter integrity. The empirical findings presented in this thesis offer a significant contribution to ageing research, by further elucidating the relationship between age-related neurophysiological changes and visuomotor behaviour. The overall picture which emerged from this series of experiments was consistent with our prediction of age-related reductions in affordance effects. Furthermore, it is likely that these age-differences may have, at least in part, a neurophysiological basis.

Obesity has been associated with accelerated cognitive decline during ageing and an increased risk for dementia (Fergenbaum et al., 2009; Fitzpatrick et al., 2009; Gustafson et al., 2009; Whitmer et al., 2008). However, recent discussions are questioning this detrimental relationship (Prickett et al., 2015). A protective effect of midlife obesity was found in a large epidemiologic study (Qizilbash et al., 2015), whereas a meta-analysis showed that midlife obesity increases the risk of dementia (Albanese et al., 2017). Methodological difference and reverse causation could be the reasons for such conflicting results (Gustafson, 2015; Kivimäki et al., 2018). For example, some studies used either body mass index (BMI) or waist-to-hip ratio (WHR); their results suggested abdominal or central obesity, which is measured by WHR or waist circumference, is more detrimental for cognitive decline than global obesity measured by BMI (Gustafson et al., 2009; Whitmer et al., 2008). Therefore, in order to assess the effect of body fat on cognitive function in a large group of community-dwelling healthy adults, we used both BMI and WHR as indicators for adiposity (Study 1). To better understand cognitive changes, it is important to investigate obesity-related brain changes. Regarding to brain structure, high body fat has been associated with decreased total brain volume and regional grey and white matter volume (Willette and Kapogiannis, 2015). However, the findings regarding white matter volume are inconsistent; obesity was found to be associated with decreased as well as increased white matter volumes (Bobb et al., 2014; Driscoll et al., 2012; Karlsson et al., 2013; Walther et al., 2010). Because of the inconsistency, diffusion-weighted imaging (DWI), which assesses the microstructural architecture, has been considered to have higher agreements among studies on obesity and decreased directional property of white matter (Willette and Kapogiannis, 2015). However, a recent study reported a positive association between obesity and white matter microstructure (Birdsill et al., 2017). The conflicting results may be explained by the relative small–medium sample size (n = 15– 268) among the studies and limited statistical power for data-driven whole brain voxel- wise analyses. Following the thought of increasing statistical power with bigger samples might be beneficial and more reliable, we investigated the link between body fat and white matter microstructure using a population-based sample of 1255 participants in Study 1. The obesity-related changes in the brain is considered to be a result of neuroinflammation. The neuroinflammation is likely caused by high fat intake- and excess adipose tissue-induced peripheral inflammation, which in turn leads to insulin resistance and hyperglycaemia; and these all together could also affect the hippocampus and result in memory inhibition (O’Brien et al., 2017; Pugazhenthi et al., 2016). A number of studies reported a negative association between obesity and hippocampal volume (Debette et al., 2011; Raji et al., 2010; Taki et al., 2008). However, others found a positive association (Widya et al., 2011) or no association (Bobb et al., 2014; Debette et al., 2011; Driscoll et al., 2012). This could be due to the fact that hippocampus comprises several subfields (cornu ammonis fields [CA1–4], the dentate gyrus [DG], and the subiculum), and these subfields have distinct functional properties (Deng et al., 2010; Strien et al., 2009; Yassa and Stark, 2011). It has also been reported that the hippocampal subfields are affected by ageing differently (Malykhin et al., 2017). Because the hippocampus is highly susceptible to degenerative processes (Pfefferbaum et al., 2013; Raz et al., 2010) and possesses neurogenesis ability in adults (Eriksson et al., 1998), it is often a key target in intervention studies. Several studies indicate that lifestyle interventions can be effective to combat obesity and to restore cognitive functions (Siervo et al., 2011). A double-blind randomised controlled trial of 1260 older individuals (aged 60–77 years) from the FINGER study showed that the intervention group obtained higher scores in a neuropsychological test battery compared to the control group after a 2-year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring) (Ngandu et al., 2015). Dietary nutrients that have anti-inflammatory or anti-oxidative effects, such as omega-3 fatty acids and polyphenols, have been associated with improved cognitive function and brain structural changes (Gómez-Pinilla, 2008; Huhn et al., 2015). Resveratrol is one type of polyphenols and occurs in variety of plants such as red grapes and blueberries (Baur et al., 2006). It has been reported to be associated with glucose metabolism and insulin sensitivity (Liu et al., 2014) as well as improved cognitive functions (Huhn et al., 2015; Marx et al., 2018). However, some studies reported no improvements in cognition after intervention (Köbe et al., 2017; Wightman et al., 2015). Besides the possibility that resveratrol does not affect cognition, another reason for these results could be that resveratrol is only effective in healthy ageing population (Evans et al., 2017; Witte et al., 2014) but not in young (Wightman et al., 2015) or patient population (Köbe et al., 2017). Therefore, replication studies with healthy older adults could help to evaluate whether there is an effect of resveratrol on cognitive function. Following this idea, we have conducted a double-blind randomised controlled trial (Study 2) with comprehensive neuropsychological test battery to assess the effect of resveratrol using 60 elderly subjects. In Study 1, we applied whole brain voxel-wise analysis to explore the correlations between overall obesity (measured by BMI) or abdominal obesity (WHR) and white matter microstructure. We found a negative correlation between BMI as well as WHR and fractional anisotropy (FA), a measure of microstructural architecture, in multiple white matter tracts independent of confounding factors. We further explored the indirect link of obesity and cognitive dysfunction using mediation analysis. In the mediation analysis, an indirect path through obesity-associated clusters was considered. We found that although obesity had no direct effect on executive functions and processing speed, it affected cognitive performance through lower FA in callosal and associative fibre tracts. We found the correlation between obesity and memory performance was not mediated by FA in the selected white matter tracts. In Study 2, we conducted a randomised trial for the effect of resveratrol on memory performance and hippocampal structure. We found that intake of resveratrol did not show any beneficial effect on either glucose metabolism or cognitive performance. Neither volume nor mean diffusivity (MD), another measure of microstructural architecture, showed changes after the intervention compared to the placebo group. However, subtle ageing- or lifestyle-related changes in the MD of the hippocampus were detected. This demonstrated that MD outperforms volumetric measures for detecting subtle changes of the hippocampus. The reason we could not observe any changes after resveratrol intake might be that this compound does not have an effect or that other lifestyle changes undermined the effect of resveratrol as neuroplasticity can be influenced by many factors. This thesis highlights that body fat is associated with lower FA in the white matter of the brain. This may indicate some widespread damage to the white matter; and mediation analysis indicates abdominal obesity is linked to poorer executive functions and processing speed through lower FA. Further this thesis shows that adding a dietary supplementation of resveratrol for six months does not improve memory or hippocampal structure in the present cohort of healthy adults with a large BMI range. Future studies should investigate longitudinal changes of body fat and brain structure in order to establish the causal relationship among obesity, white matter microstructure, and cognitive function. And more comprehensive lifestyle interventions combining diet, exercise, and cognitive training should be considered instead of one single approach to prevent and hopefully preserve obesity induced changes in cognition and in the brain.

No description available.

Early life stress has been found to be a strong predictor of depression severity, with genetic risk factors such as the serotonin transporter promotor (5-HTTLPR) and brain derived neurotrophic factor (BDNF) polymorphisms moderating depression development. Our investigation aims to extend these findings to examine the impact of depression severity, genetic risk factors, and childhood maltreatment on neuronal connectivity changes using tract based spatial statistics (TBSS) and probabilistic tractography. Fifty-five medication-free patients with major depressive disorder (MDD) [x̅ age: 36.4, M/F: 22/33] and 18 controls [x̅ age: 33.2, M/F: 8/10] underwent diffusion tensor imaging scanning, genotyping and completed the Childhood Trauma Questionairre. Corrected TBSS findings revealed trends toward significantly reduced FA in the right anterior internal capsule [p=0.051], fornix [p=0.085] and right anterior corona radiata [p=0.084] in the MDD group. Probabilistic tractography analysis examined fractional anisotropy (FA) in the cingulum bundle, uncinate fasciculus and superior longitudinal fasciculus. Individuals scoring high in depression severity and who experienced severe childhood physical neglect (PN) and emotional neglect (EN) had higher FA in the uncinate [PN: p=0.003, EN: p=0.029] and superior longitudinal fasciculus [PN: p=0.0748], with BDNF and 5-HTTLPR moderating these associations. BDNF polymorphisms also exhibited a stronger impact on uncinate FA in individuals with high depression severity, with val-BDNF exhibiting higher FA than met carriers [p=0.021]. In conclusion, MDD patients exhibit widespread decreases in FA across many neural regions. Furthermore, the impact that depression severity has on FA is considerably influenced by early life neglect. / Thesis / Master of Science (MSc)

The anterior cingulate has been implicated in a number of cognitive processes that are at risk following traumatic brain injury (TBI), such as executive function and emotional processing. While the cingulate is believed to play a role in the above-mentioned cognitive processes, the relative roles of gray and white matter in functional outcomes post-TBI are not fully understood. The current study investigated various quantifiable brain properties (e.g., cortical thickness and volume, volume of underlying white matter, and white matter integrity) of the caudal anterior cingulate (CAC) gyrus and their relationships with behavioral measures of cognitive control following pediatric TBI. Parent ratings at three months post-injury indicated that TBI children demonstrated greater difficulty inhibiting inappropriate behavior and effectively transitioning between tasks. Reductions of CAC white matter integrity were observed in TBI participants, in the absence of significant morphometric group differences in this region. Neither CAC morphometrics nor fractional anisotropy (FA) were associated with experimental measures of cognitive control. The current findings indicate that DTI metrics may be more sensitive to brain changes in the region of the CAC following TBI. While strong relationships were not observed between CAC properties and measures of cognitive control, it is possible that study limitations may have obscured potential findings.

Diffusion Magnetic Resonance Imaging (DMRI) is a class of Magnetic Resonance Imaging (MRI) techniques with broad medical applications ranging from characterization of tumors and brain damage to potential prediction of stroke. Gradient coil and signal-to- noise ratio (SNR) constraints limit spatial resolution, accuracy, and scan time in DMRI. Achieving high b-values (measures of a scan's sensitivity to diffusion) often require scans with long diffusion gradient pulses, leading to significant magnetic resonance (MR) signal decay before the signal can be sampled. This signal loss reduces the accuracy of diffusion parameter estimation. The ability to sample the MR signal sooner while maintaining the same b-value is restricted by the maximum amplitude and slew rate of gradient coils. A composite system utilizing body and high-powered insert gradient coils can achieve high b-values more quickly, enabling a shorter delay between excitation and signal sampling and improved accuracy of diffusion parameter estimation. Alternately, such a system can achieve higher b-values at an equivalent delay between excitation and signal sampling. This thesis describes the implementation of such a system, experiment design for evaluating the benefits of the system to DMRI, and design of a diffusion phantom. Also included are a characterization of a composite system's improvements to DMRI based on analysis of experimentally-obtained data and simulation results validating those findings. Finally, recommendations for further improvements to diffusion MRI are given.