Functional MRI (fMRI) is a primary tool in the study of brain function. The primary cause of data corruption in fMRI is head motion while scanning. This problem is compounded by the fact that subjects are asked to perform behavioural tasks, which can promote head motion. Random and/or large head motions are often not handled well in post-processing correction algorithms. This thesis investigates the use of an alternate method: an MRI simulator to help reduce head motion in subjects through training. A simulator environment was developed where subjects could be trained to reduce their head motion through closed loop visual feedback. The effect of simulator training was investigated in young, old and stroke subjects. Performance of subjects with respect to head motion was investigated prior, during and after feedback training, including subsequent fMRI scans. This research helps improve fMRI image quality by reducing head motion prior to scanning.

Functional MRI (fMRI) is a primary tool in the study of brain function. The primary cause of data corruption in fMRI is head motion while scanning. This problem is compounded by the fact that subjects are asked to perform behavioural tasks, which can promote head motion. Random and/or large head motions are often not handled well in post-processing correction algorithms. This thesis investigates the use of an alternate method: an MRI simulator to help reduce head motion in subjects through training. A simulator environment was developed where subjects could be trained to reduce their head motion through closed loop visual feedback. The effect of simulator training was investigated in young, old and stroke subjects. Performance of subjects with respect to head motion was investigated prior, during and after feedback training, including subsequent fMRI scans. This research helps improve fMRI image quality by reducing head motion prior to scanning.

This study presented six typically developing children between the ages of five to eight with familiarization (baseline) in a mock scanner after which behavioural intervention ensued, in a non-concurrent multiple baseline design. The behavioural intervention included reinforcement for the contingency of lying motionless, and response cost (the removal of desirable stimuli) as a punishment contingency for movement. During baseline, all children showed a fair amount of head motion in the mock scanner. During intervention, small to large reductions in head motion were observed for five of the six participants. Therefore, use of the mock scanner and the reinforcement/punishment contingencies, may be an aid used prior to actual MRI/fMRI scans for children between the ages of five to eight: it is cost effective, may require only a session or two of intervention to be effective, and the potentially dangerous side effects and/or disabilities of sedation/anaesthesia can be avoided.

Cognitive fatigue (CF) presents a considerable challenge for individuals with multiple sclerosis (MS) often negatively impacting quality of life. CF can be defined as a decrease in, or inability to sustain, optimal task performance throughout the duration of a continuous cognitive task. The following dissertation presents three original research reports which evaluate CF in MS in three distinct ways using a multidimensional approach. The objective of this dissertation was to comprehensively evaluate and quantify this frequently misunderstood symptom of the disease. The first report examines four theoretical models of CF in MS which evaluate the interrelatedness of disease severity, fatigue, depression, and sleep quality in order to determine their predictive roles with regard to CF. The second report assesses CF longitudinally by examining whether or not the ability to perform optimally on a continuous cognitive task changes as the disease progresses across a three-year time interval. The final report objectively quantifies CF in MS by evaluating changes in global and regional cerebral blood flow during a task of sustained attention using arterial spin labeling perfusion fMRI. Results of all three reports are further discussed in terms of clinical and research implications. CF is a symptom of MS not readily apparent to outside observers but presents a very real burden for people with the disease that negatively impacts their ability to lead active and productive lives. These individuals may be discriminated against because CF has thus far been a largely unverifiable subjective experience. The totality of these three studies allows for a multidimensional quantification of CF. By providing objective support to the self-reports of individuals with MS, not only can they achieve much needed validation, but this can also lead to interventions that may provide further direct benefit to their health-related quality of life.

With the rapid and alarming rise in the obesity epidemic that continues to plague both developed and developing nations, increasing efforts are being directed toward solving this pressing issue that is associated with multiple metabolic complications. Research efforts continue to target this population for greater insight as to causes, preventative measures and treatment options that may provide health benefits to those suffering from the physical and psychological manifestations of this newly classified neurobiological disease, in addition to cut down on excruciating obesity-related costs affecting the current health care budget. Alongside an emphasis on physical activity and proper nutrition to both prevent and ameliorate the effects of obesity, pharmacological treatment has garnered an appreciable appeal as an additional interventional approach in an urgency to slow the progression of this widespread problem. The introduction of lorcaserin (Belviq®), a serotonin (5-hydroxytryptamine, 5-HT) agonist that selectively targets the 5-HT receptor subtype 2C (5-HT2C), has already exhibited great potential for combating the obesity epidemic since it was approved by the Food and Drug Administration (FDA) in 2012. With its ability to decrease appetite and enhance weight loss with few side effects, lorcaserin is a promising treatment option. However, the mechanisms behind the drug are still not fully known. Determining the exact role that lorcaserin plays in appetite control would provide valuable insight into appetite regulation and could illustrate the medication's potential for reversing the health-impairing effects of obesity on our current populations. This study examined, through the use of functional magnetic resonance imaging (fMRI), the effects of lorcaserin on the centers of the brain that control appetite and food intake, in addition to areas of cognition that are thought to be affected by obesity. Due to the nature of the double-blind trial, only baseline characteristics were obtained and analyzed. However, observed correlations from these data largely confirm previously established relationships seen in obese populations providing support for the validity of this study. These correlations were also important to obtain to set the stage for assessing any short-term or long-term neuroimaging changes and neurocognitive effects of lorcaserin on brain responses to high and low calorie food imagery.

archives@tulane.edu / With the rapid development of precision medicine across almost all areas of medicine, the Research Domain Criteria (RDoC) project has been initiated to develop data-driven matrices toward precision medicine for mental disorder by integrating multilevel information including genomics, molecules, circuits, and behaviors. This thesis, under the guidance of the RDoC framework, aims to gain a more complete understanding of the role of oscillatory behavior and network connectivity in normal/abnormal brain functioning and cognitive development. Two specific topics were involved: 1. Understand the complex mechanism for mental disorder through multiomics data; 2. Study the development of FC from childhood to adulthood using multi-paradigm brain images. We intend to identify new and reliable biomarkers for the purpose of precise diagnosis and can potentially provide an enormous impetus for drug discovery through the comparison of normal and abnormal brains and the investigation of dynamic changes. This thesis proposes several new analytic graphical models (directed and undirected) to assess brain functional connectivity (FC), each targeting a specific problem in the biomedical applications: the psi-learning method to resolve the high dimensionality for networks on voxel level, the latent Gaussian copula model for mix data distributions, the joint Bayesian incorporating estimation to address heterogeneities in undirected graphical models; the psi-LiNGAM and BiLiNGAM for the situations of small sample size and heterogeneities in directed acyclic graphs, respectively. The proposed methods are validated through a series of simulation studies and large genomic and neuroimaging datasets, where they confirm results from previous studies and lead to new biological insights. In addition, we put extra efforts on promoting reproducible research and make the proposed methods widely available to the scientific community by the release of free and open-source codes. / 1 / Aiying Zhang

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18887号 / 医博第3998号 / 新制||医||1009(附属図書館) / 31838 / 京都大学大学院医学研究科医学専攻 / (主査)教授 河野 憲二, 教授 渡邉 大, 教授 大森 治紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Concussion management is changing. Recent years have marked a sea change, with the former rest-is-best approach being supplanted by an exercise-is-medicine mindset. Despite this, important questions remain unanswered in the pediatric exercise-concussion literature. The overarching aim of this thesis was to examine the effects of exercise on outcomes beyond concussion symptoms, and build our understanding of the relationship between pediatric concussion and physical activity. Four studies were performed to this end. First, per a systematic review, we found that randomized trials on the effects of exercise on neuroimaging and cognitive outcomes remain limited. Studies suggest that exercise may improve brain structure and function post-concussion, while data with respect to cognitive outcome were mixed. Second, we provided the first evidence that the functional neuropathology of pediatric concussion differs by sex at 1 month post-injury, with females demonstrating impairment not observed in males. Namely, only females with concussion showed patterns of both hyper-connectivity (between the lateral pre-frontal cortex & inferior frontal gyrus, lateral pre-frontal cortex & lateral occipital cortex, and the posterior cingulate cortex & cerebellum; all p-corrected <0.05) and hypo-connectivity (between the anterior cingulate cortex & precuneus, anterior cingulate cortex & cingulate gyrus, and posterior cingulate cortex & paracingulate gyrus; all p-corrected <0.05). Third, we provided the first accelerometer-based characterization of physical activity and sedentary time in children with concussion in comparison to 1:1 matched healthy controls. Relative to healthy controls, children with concussion were more sedentary, with a mean difference [MD] of 38.3 minutes/day (95% confidence interval [CI] 11.2 to 65.4, p<0.01), and they also performed less light (MD -19.5 minutes/day, CI -5.3 to -33.7, p<0.01), moderate (MD -9.8 minutes/day, CI -5.7 to -13.8, p<0.001) and vigorous physical activity (MD -12.0, CI -6.9 to -17.2, p<0.001); greater physical activity deficits were observed in females with concussion. Fourth, per the first study to employ both accelerometry and functional neuroimaging in pediatric concussion, we found that intra-network connectivity of the default mode network was associated with subsequent accelerometer-measured light (F(2, 11) = 7.053, p = 0.011, Ra2 = 0.562; β = 0.469), moderate (F(2, 11) = 6.159, p = 0.016, Ra2 = 0.528; β = 0.725), and vigorous (F(2, 11) = 10.855, p = 0.002, Ra2 = 0.664; β = 0.792) physical activity. This study provides the insight into a potential link between brain activity and physical activity in pediatric concussion. The next wave of exercise and physical activity research in concussion needs to move beyond symptom studies, employ sex-specific analyses, understand the impact of exercise on brain function, and consider interventions that increase habitual physical activity. Doing so is necessary for exercise to become medicine for concussion patients. / Thesis / Doctor of Philosophy (PhD) / Until a few years ago, the advice children received after a concussion (or mild brain injury) was to rest until they no longer had symptoms. But the way concussions are being treated is changing. Scientists have found that exercising soon after a concussion can lessen symptoms. It is no longer thought that rest-is-best. Instead, it is now believed that exercise-is-medicine. But there are still important questions about the role of exercise after a concussion that have not been answered. The four studies in this thesis had the goal of answering some of those questions. In the first study, we found that while exercise improves symptoms after a concussion, we know less about how it impacts the brain and our ability to think. From the second study, we learned that a concussion impacts the brains of boys and girls in different ways, and that girls may have longer lasting brain changes after a concussion than boys. Our third study showed that after a concussion, girls take part in less physical activity than boys throughout the day. The fourth study suggests that there may be a link between brain activity and physical activity in children with a concussion. This thesis adds to our knowledge of the role of exercise in concussion. It also raises some important questions that should be answered by new studies in the near future.

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