La sclérose latérale amyotrophique [SLA] est une pathologie idiopathique à issue fatale caractérisée par la dégénérescence progressive et sélective des motoneurones du système nerveux central et périphérique. La SLA n’est pas exclusivement identifiée comme une maladie de la voie pyramidale, mais considérée plus largement comme une pathologie neurodégénérative multisystème. L’étude des mécanismes posturaux dans cette population n’a pas fait l’objet d’une grande attention. Dans ce travail de thèse, une exploration en imagerie cérébrale multimodale (imagerie en tenseur de diffusion [DTI] et morphométrie basée sur le voxel [VBM]) est proposée chez des patients SLA avec instabilité posturale [AIP] et stables [SIP] en vue de vérifier l’intégrité morphologique et structurelle des régions corticales et sous-corticales posturales. La comparaison entre les sujets contrôles et les patients SLA a démontré une augmentation significative du volume de la substance grise au niveau du noyau caudé chez les patients stables (SIP vs contrôle p<0,001 ; SIP vs AIP p<0,01). L’évaluation structurelle a révélé une diminution de la fraction d’anisotropie [FA] au niveau de l’aire motrice supplémentaire [AMS] dans les deux groupes de patients par rapport aux contrôles (contrôle vs SIP p<0,05 ; contrôle vs AIP p<0,001). Au niveau du noyau caudé, le groupe AIP a présenté une diminution de la valeur de la FA par rapport aux sujets contrôles (p<0,001) et aux sujets SIP (p<0,05). Ainsi, ces résultats contribuent à une meilleure caractérisation et compréhension des atteintes corticales et sous corticales des régions qui interviennent dans la posture chez les patients SLA. / The Amyotrophic Lateral Sclerosis [ALS] is an idiopathic pathology with a fatal outcome. It is characterized by a progressive and selective degeneration of motor neurons in the central and peripheral nervous system. ALS is no longer exclusively identified as a disease of the pyramidal pathway, but it is considered more broadly as multisystem neurodegenerative pathology. However, the analysis of postural processes in these patients has not been well studied in the literature. Multimodal brain imaging (Diffusion Tensor Imaging [DTI] and Voxel Based Morphometry [VBM]) exploration was performed for ALS patients with postural instability [AIP] and without postural instability [SIP] to test the morphometric and structural integrity of postural cortical and subcortical regions. A significant increase of gray matter in caudate nucleus volume has been noticed for stable patients (SIP vs controls p<0.001, SIP vs AIP p<0.01). The structural evaluation revealed a decrease of the Fractional Anisotropy [FA] at the Supplementary Motor Area [SMA] level in both groups of patients compared to controls (controls vs SIP p<0.05, controls vs. AIP p<0.001). At the caudate nucleus, the AIP group showed FA value decrease compared to controls (p<0.001) and SIP subjects (p<0.05). Thus, these results would contribute to a better characterization and understanding of the cortical and subcortical impairments of the postural regions in ALS patients.

Adult survivors of childhood posterior fossa tumors can experience reading difficulties related to white matter integrity. Previously, reading was shown to be related to cortical white matter tracts, however information transfer across the corpus callosum (CC) may also play a role in reading. The current study used both macro- and microstructural measures of the WM structure of the corpus callosum. The current study examined how white matter volume and fractional anisotropy (FA) in five divisions of the CC was related to degree of neurological risk and reading skill, and tested two mediation models predicting reading. Participants included 20 adult survivors of childhood posterior fossa tumor and 23 healthy controls. Volume and FA were measured in five divisions of the mid-sagittal corpus callosum. Total intracranial vault was used as a covariate in volume analyses. FA was reduced in CC1 and volume was reduced in each subregion in survivors. Volume but not FA was related to degree of neurological risk. Results identified that reduced volume in CC1 and CC5, and FA in CC5 appear to be specifically related to reading skill in line with the cortical reading regions that connect in these subregions of the CC. Mediation models indicate that processing speed is the mechanism by which volume is related to reading skill. These findings have implications for addressing processing speed in reading interventions in survivors and provide insight into the interhemispheric connections in the reading network.

Diffusion Tensor Magnetic Resonance Imaging (DTI) is a recently-developed technique that can image in vivo the white matter pathways of the central nervous system. This study used 12-direction diffusion-weighted MRI data from nine stroke patients acquired as part of a three-year stroke rehabilitation study coordinated by the Movement Neuroscience Laboratory at the University of Auckland. DTI was used to investigate corticospinal connectivity. From the FA maps, it is found that in those patients whose motor connectivity has been compromised by the stroke to the extent that no motor evoked potential (MEP) can be elicited from a selected affected muscle group, the asymmetry in mean FA values in the posterior limbs of the internal capsules (PLICs) is correlated with functional recovery as measured by the Fugl-Meyer clinical score. Using probabilistic tractography in the contralesional hemisphere produced CST location and somatotopy results that were consistent with those of previous studies. However, in the ipsilesional hemisphere, connectivity results were highly variable. A measure of change in symmetry of mean connectivity is found to correlate with functional recovery as measured by change in FM score. This supports previous work which has correlated CST integrity and functional improvement and it supports the theory that functional recovery after stroke depends on the extent to which motor CNS symmetry can be regained in the new post-stroke architecture. It also suggests that the movement of the fMRI activations occurs in such a way as to make the most of the preserved white matter connectivity.

Introduction: Preterm birth is increasing worldwide and is a major cause of neonatal death. Survivors are at increased risk of neurodisability, cognitive, social and psychiatric disorders in later life. Alterations to the white matter can be assessed using diffusion tensor imaging (DTI) MRI and are associated with poor neurodevelopmental outcome. The pathogenesis of white matter injury is multifactorial and several clinical risk and resilience factors have been identified. DNA methylation (DNAm) is an epigenetic process which links stressful early life experience to later life disease and is associated with normal brain development, neuronal processes and neurological disease. Several studies have shown DNAm is altered by the perinatal environment, however its role in preterm white mater injury is yet to be investigated. Aims: 1. To examine the relationship between preterm birth and white matter integrity 2. To investigate the effect of neuroprotective treatments and deleterious clinical states on white matter integrity in preterm infants 3. To assess the best DTI method of quantifying white matter integrity in a neonatal population 4. To investigate the effect of preterm birth on DNA methylation and 5. To determine the clinical and imaging factors that contribute to the variance in DNA Methylation caused by preterm birth Methods: DTI data was acquired from preterm infants (< 32 weeks' gestation or < 1500 grams at birth) at term equivalent age (TEA) and term controls (> 37 weeks' gestation at birth). Region-of-interests (ROI) and tract-averaged methods of DTI analysis were performed to obtain measurements of fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum, posterior limb of internal capsule and centrum semiovale. Clinical data was collected for all infants and the effect of prematurity, neuroprotective agents and clinical risk factors on white matter integrity were analysed. 8 major white matter tracts were segmented using probabilistic neighbourhood tractography (PNT), a tract-averaged technique which also allowed the calculation of tract shape. The two DTI techniques were compared to evaluate agreement between results. DNA was collected from preterm infants and term controls at TEA, and a genome-wide analysis of DNAm was performed. DTI parameters from probabilistic neighborhood tractography (PNT) methodology and clinical risk and resilience factors were used to inform a principal components analysis to investigate the contribution of white matter integrity and clinical variables to variance in DNAm. Results: FA and MD were significantly affected by preterm birth on ROI analysis. In addition, DTI parameters were affected by clinical factors that included antenatal magnesium sulphate, histological chorioamnionitis and bronchopulmonary dysplasia. Evaluation of DTI methodology revealed good accuracy in repeated ROI measurements but limited agreement with tract-averaged values. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants, compared with controls. 10 of these genes have a documented association with neural function or neurological disease. Differences detected in the array were validated with pyrosequencing which captured additional differentially methylated CpGs. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Conclusions: Preterm birth is associated with alterations in white matter integrity which is modifiable by clinical risk factors and neuroprotective agents. ROI analysis may not provide sufficient representation of white matter tracts in their entirety. Prematurity is related to alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for future work and contributed to the understanding of the pathogenesis of preterm brain injury.

Cognitive performance declines in depression and increases with physical activity. These changes may in part be due to changes in the level of neurogenesis (the generation and survival of adult-born neurons), which decreases with depression and increases with physical activity. Pattern separation (the formation of distinct neural representations of incoming information through orthogonalizing similar patterns of activation) has also been linked to neurogenesis. This project explores pattern separation within these two populations through three experiments.Experiment 1. Previous research has found impaired pattern separation among individuals with higher depression scores, but who have not been diagnosed with Major Depressive Disorder (MDD). This experiment sought to expand these findings and evaluated behavioral differences during the performance of a continuous recognition pattern separation task among women with MDD and age- and education-matched controls. It was hypothesized that clinically depressed participants would have lower pattern separation scores and would be more likely to incorrectly identify lure stimuli as "old". Contrary to this prediction, clinically depressed participants had higher pattern separation scores, while controls were more likely to misidentify lure items as "old".Experiment 2. While there are many known benefits of regular physical activity, the majority of individuals in the United States do not engage in the recommended levels of fitness training. Furthermore, there have only been a limited number of studies evaluating the effect physical activity may have on cognitive abilities and neurological components and none have evaluated what effect the recommended levels of fitness may have on these areas. The second experiment evaluated differences between individuals with varying levels of physical activity using functional magnetic resonance imaging (fMRI) during the performance of a continuous recognition pattern separation task. It was hypothesized that participants with self-reported higher levels of physical activity would have greater activation in the CA3/dentate gyrus subregions of the hippocampus than those with lower fitness levels and sedentary individuals. Surprisingly, there were no activation differences across groups. Experiment 3. The final experiment explored diffusion tensor imaging (DTI) differences in physical activity levels with the same sample used in Experiment 2. It was hypothesized that participants with self-reported higher levels of physical activity would have indications of increased white matter integrity compared to those with lower fitness levels and sedentary individuals. There were significant differences across groups in DTI measures of white matter integrity (axial diffusivity or AD) in bilateral cingulum, the left temporal middle gyrus, and the right uncinate fasciculus.

Gilles de la Tourette syndrome (GTS) is a chronic neuropsychiatric disorder characterized by multiple motor and vocal tics, affecting approximately 1% of the population. The precise neuropathology of GTS has not yet been delineated, but current models implicate subcortical and cortical areas - the cortico-striato-thalamo-cortical (CSTC) circuit. The majority of studies in the literature have either dealt with GTS with comorbid conditions and/or children with GTS. As these factors are known to affect brain structure and function, it unknown what the neurobiological underpinnings of pure adult GTS are. The objective of this body of work was to use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize differences in brain function and structure in pure adult GTS patients versus age- and sex-matched controls. I employed a series of three distinct analyses for this purpose, based upon current models of CSTC circuit-related dysfunction in GTS. In the first, GTS patients and control participants executed three finger-tapping paradigms that varied in both complexity and memory requirements. These finger-tapping tasks were modeled after previous studies that showed CSTC circuit-related activity in healthy individuals. Using a multivariate statistical technique to assess task-related patterns of activation across the whole brain, I found that, while there was much overlap in brain activation patterns between groups, sensorimotor cortical regions were differentially recruited by GTS patients compared to controls. In the second fMRI analysis, I measured low-frequency spontaneous fluctuations of the blood oxygen level dependent signal during rest, and found that GTS patients exhibited greater resting state functional connectivity with the left putamen compared to controls. In the final analysis, DTI was used to provide a whole-brain assessment of regional diffusion anisotropy in GTS patients and healthy volunteers and to investigate the fractional anisotropy in predetermined ROIs. This analysis found no differences between GTS patients and controls. Overall, my findings indicated that several CSTC-related regions shown to be atypical in GTS patients previously, are also atypical in pure adult GTS, and that sensorimotor cortical regions and the putamen may be regions of functional disturbance in pure adult GTS.

Gilles de la Tourette syndrome (GTS) is a chronic neuropsychiatric disorder characterized by multiple motor and vocal tics, affecting approximately 1% of the population. The precise neuropathology of GTS has not yet been delineated, but current models implicate subcortical and cortical areas - the cortico-striato-thalamo-cortical (CSTC) circuit. The majority of studies in the literature have either dealt with GTS with comorbid conditions and/or children with GTS. As these factors are known to affect brain structure and function, it unknown what the neurobiological underpinnings of pure adult GTS are. The objective of this body of work was to use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize differences in brain function and structure in pure adult GTS patients versus age- and sex-matched controls. I employed a series of three distinct analyses for this purpose, based upon current models of CSTC circuit-related dysfunction in GTS. In the first, GTS patients and control participants executed three finger-tapping paradigms that varied in both complexity and memory requirements. These finger-tapping tasks were modeled after previous studies that showed CSTC circuit-related activity in healthy individuals. Using a multivariate statistical technique to assess task-related patterns of activation across the whole brain, I found that, while there was much overlap in brain activation patterns between groups, sensorimotor cortical regions were differentially recruited by GTS patients compared to controls. In the second fMRI analysis, I measured low-frequency spontaneous fluctuations of the blood oxygen level dependent signal during rest, and found that GTS patients exhibited greater resting state functional connectivity with the left putamen compared to controls. In the final analysis, DTI was used to provide a whole-brain assessment of regional diffusion anisotropy in GTS patients and healthy volunteers and to investigate the fractional anisotropy in predetermined ROIs. This analysis found no differences between GTS patients and controls. Overall, my findings indicated that several CSTC-related regions shown to be atypical in GTS patients previously, are also atypical in pure adult GTS, and that sensorimotor cortical regions and the putamen may be regions of functional disturbance in pure adult GTS.

Diffusion Tensor Magnetic Resonance Imaging (DTI) is a recently-developed technique that can image in vivo the white matter pathways of the central nervous system. This study used 12-direction diffusion-weighted MRI data from nine stroke patients acquired as part of a three-year stroke rehabilitation study coordinated by the Movement Neuroscience Laboratory at the University of Auckland. DTI was used to investigate corticospinal connectivity. From the FA maps, it is found that in those patients whose motor connectivity has been compromised by the stroke to the extent that no motor evoked potential (MEP) can be elicited from a selected affected muscle group, the asymmetry in mean FA values in the posterior limbs of the internal capsules (PLICs) is correlated with functional recovery as measured by the Fugl-Meyer clinical score. Using probabilistic tractography in the contralesional hemisphere produced CST location and somatotopy results that were consistent with those of previous studies. However, in the ipsilesional hemisphere, connectivity results were highly variable. A measure of change in symmetry of mean connectivity is found to correlate with functional recovery as measured by change in FM score. This supports previous work which has correlated CST integrity and functional improvement and it supports the theory that functional recovery after stroke depends on the extent to which motor CNS symmetry can be regained in the new post-stroke architecture. It also suggests that the movement of the fMRI activations occurs in such a way as to make the most of the preserved white matter connectivity.

Background: Heading is an important part of soccer, yet recent research has indicated that cumulative effects of repetitive heading may cause sub-concussive injury (Koerte et al., 2015). Objective: The current study aimed to prospectively investigate the effects of repetitive, intentional heading in soccer practice on brain structure and cognitive function using a within-subjects design. Methods: Participants included 11 soccer players (M=20.09, SD=2.88) that were examined immediately pre and post heading practice. Magnetic resonance imaging data were acquired on a 3T GE Scanner with diffusion tensor imaging (DTI). Behavioural measures were also completed pre and post soccer heading and included the Sideline Concussion Assessment Tool 3 (SCAT-3) and several short-computerized executive function tasks. An accelerometer was used to measure the force of the impact during soccer heading. Heart-rate data was collected on Polar Monitors. DTI analyses were completed using FSL’s Tract Based Spatial Statistics to examine changes in both fractional anisotropy (FA) and mean diffusivity (MD) due to heading the soccer ball. The current study investigated microstructural changes and behavioural performance in young soccer players. Heart rate variability data were not available for analyses due to technical difficulties. Results: Heading impacts were not greater than 10g. At this level of impact, there were no significant pre-post heading differences in either FA or MD. There were no significant differences between pre and post heading in the three behavioural tasks. Additionally, there were no significant differences in SCAT-3 scores between groups. Some practice effects were demonstrated in one behavioural task and a section of the SCAT-3. Conclusion: The current work shows initial evidence that repetitive heading in soccer in a practice setting does not cause changes in brain structure or cognitive function. Future research should investigate heading in games and sex differences with a greater sample size. / Graduate

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are two neurodevelopmental disorders with distinct diagnostic criteria that often co-occur. Although both ASD and ADHD are associated with structural and functional brain abnormalities when compared to typically developing (TD) populations, it is necessary to disentangle the shared and specific abnormalities between these disorders, potentially underlying similarities and differences in their clinical and neurocognitive profiles. The aim of this thesis was to explore the shared and disorder specific functional and structural brain abnormalities between ASD and ADHD. For this purpose, the neural underpinnings of a group of children with ADHD, a group of children with ASD and a group of TD children aged 8 to 12 years old were compared using different neuroimaging techniques. In Chapter 2, the experimental sample included in this thesis was described using multiple clinical and neurocognitive measures. In the first study (Chapter 3), total and regional brain volumes were compared between groups, using voxel-based morphometry. The results of this study showed larger grey matter volume (GMV) in the left precuneus and decreased GMV in the right thalamus in the ADHD group compared to either the TD or the ASD groups, and increased GMV in the right precentral gyrus in the ASD group compared to either the ADHD or the TD groups. In the second study (Chapter 4), white matter microstructure was compared between groups using diffusion tensor imaging derived indices (fractional anisotropy [FA] and mean diffusivity [MD]). Reduced FA (i.e. reduced diffusion directionality) in the genu of the corpus callosum (CC) was found in the ASD group compared to either children with ADHD or TD children, whereas lower FA in the body of the CC was a shared feature between the ADHD and ASD groups. Finally, in the last study (Chapter 5), inhibition-related brain activation was compared between groups during the execution of an inhibition stop-signal task. In children with ADHD, successful inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared to the ADHD or the TD groups. Taken together, our findings provide further evidence contributing to disentangle the shared and specific brain structural and functional abnormalities between ASD and ADHD. / Doctorat en Sciences psychologiques et de l'éducation / info:eu-repo/semantics/nonPublished