La thèse explore trois questions méthodologiques en imagerie de diffusion (DTI) clinique du cerveau, dans le contexte d’une étude sur le VIH. La première question est comment améliorer la résolution du DTI. Le deuxième problème est comment créer un atlas multimodal spécifique à la population. La troisième question porte sur le calcul des statistiques pour comparer les zones de matière blanche entre les contrôles et patients. Les DTI cliniques ont une résolution spatiale et un rapport signal sur bruit faibles, ce qui rend difficile le calcul de statistiques significatives. Nous proposons un algorithme de super-résolution pour améliorer la résolution qui utilise un a priori spatial anisotrope. Cette méthode démontre une amélioration de l’anisotropie fractionnelle et de la tractographie. Pour normaliser spatialement les images du cerveau dans un système de coordonnées commun, nous proposons ensuite de construire un atlas multimodal spécifique á la population. Ceci permet de créer un atlas probabiliste de la matière blanche qui est consistant avec l’atlas anatomique. Cet atlas peut être utilisé pour des statistiques basées sur des régions d’intérêt ou pour le raffinement d’une segmentation. Enfin, nous améliorons les résultats de la méthode TBSS (Tract-Based Spatial Statistics) en utilisant le recalage des images DTI. Contrairement á la méthode TBSS traditionnelle, nous utilisons ici des statistiques multivariées. Nous montrons que ceci permet de détecter des différences dans les régions de matière blanche qui étaient non significatives auparavant, et de les corréler avec les scores des tests neuropsychologiques. / The thesis explores three major methodological questions in clinical brain DTI, in the context of a clinical study on HIV. The first question is how to improve the DTI resolution. The second problem addressed in the thesis is how to create a multimodal population specific atlas. The third question is on the computation of statistics to compare white matter (WM) regions among controls and HIV patients. Clinical DTIs have low spatial resolution and signal-to-noise ratio making it difficult to compute meaningful statistics. We propose a super-resolution (SRR) algorithm for improving DTI resolution. The SRR is achieved using anisotropic regularization prior. This method demonstrates improved fractional anisotropy and tractography. In order to spatially normalize all images in a consistent coordinate system, we create a multimodal population specific brain atlas using the T1 and DTI images from a HIV dataset. We also transfer WM labels from an existing white matter parcellation map to create probabilistic WM atlas. This atlas can be used for region of interest based statistics and refining manual segmentation. On the statistical analysis side, we improve the existing tract based spatial statistics (TBSS) by using DTI based registration for spatial normalization. Contrary to traditional TBSS routines, we use multivariate statistics for detecting changes in WM tracts. With the improved method it is possible to detect differences in WM regions and correlate it with the neuropschylogical test scores of the subjects.

This doctoral thesis investigated the role of the neuromodulator serotonin on four different value-based decision making tasks, using an acute tryptopahin intervention and an associative genetic approach - a naturally occuring variation in the promoter region of the serotonin transporter gene (5-HTTLPR). Additionally, structural (DTI) and functional aspects (BOLD-fMRI) of the brain were assessed using magnetic resonance imaging in relation to decision-making. Overall, we only found limited evidence for a serotonergic effect on decision-making that was restricted to a genetic association with risk-seeking for losses behaviour that could no be corroborated by differences in tonic serotonin levels or white matter microstructure. / In der vorliegenden Doktorarbeit wurde die Rolle des Neuromodulators Serotonin hinsichtlich vier verschiedener wertbasierter Entscheidungsfindungsaufgaben untersucht, wobei eine akute Tryptophanintervention und ein assoziativer genetischer Ansatz, eine natürlich vorkommende Variation in der Promoterregion des Serotonintransportergens (5-HTTLPR), zur Anwendung gekommen sind. Zusätzlich wurden strukturelle (DTI) und funktionelle Aspekte (BOLD-fMRI) des Gehirns mittels Magnetresonanztomographie in Bezug auf die Entscheidungsfindung erhoben. Insgesamt fanden wir nur eine begrenzte Evidenz eines serotonergen Effekts auf Entscheidungsverhalten, die sich auf eine genetische Assoziation mit risikofreudigem Verhalten bei Verlusten beschränkte. Diese Assoziation ließ sich nicht durch Unterschiede im tonischen Serotoninspiegel oder der Mikrostruktur der weißen Substanz erhärten.

Background. Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain’s largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. Method. Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. Results. Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. Conclusion. High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

MRI is used to produce images of tissue in the body. DTI, specifically, makes it possible to track the effects of nerves where they are in the brain. This project includes a shell script and a guide for using the FMRIB Software Library, followed by StarTrack and then Trackvis in order to track difficult areas in the brain. The focus is on the trigeminal nerve (CN V). The method can be used to compare nerves in the same patient, or as a comparison to a healthy brain.

Executive function describes high-level cognitive-abilities including planning, decision-making, set switching and response inhibition. Impairments of the executive functions in disease states may be subtle but can greatly reduce the quality of life and independence. The overarching theme of this project was to investigate the network of brain regions that are needed to support executive function. This was undertaken using a two-fold approach: one, to apply network analysis to resting state functional Magnetic Resonance Imaging (rs-fMRI) and Diffusion Tensor Imaging (DTI) data in order to describe how differences in morphometry and connectivity correlate to executive function differences of individuals with Mild Cognitive Impairment (MCI), and two, to describe the brain networks involved in one form of executive function, decision-making under uncertain conditions, in young, healthy individuals. Impaired decision-making can dramatically impact day-to-day functioning and understanding the underlying network of regions that support this task can provide a target for future intervention studies. Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used in the studies of MCI. Individuals were grouped by their executive abilities. A regions-of-interest approach was used to parcel and label various brain regions and a network of connections was constructed out of these regions. Differences between the networks were then compared between the MCI subjects with good and poor executive functions. Those with high executive abilities showed decreased functional network connectivity and increased structural network connectivity. The second arm of these studies was based an original decision-making paradigm that was used to compare of networks involved in decision-making at times of uncertainty in healthy young individuals using both electroencephalography (EEG) and task-based functional magnetic resonance imaging (fMRI). Overall we found greater network connectivity in the uncertain condition of the task than in the certain condition. This suggests that with increased uncertainty comes increased organized connectivity. Taken together, the results of this study re-iterate the notion that cognition depends upon the efficient communication between a network of brain regions rather than on isolated regions. They also highlight the importance of having a well-defined network of nodes and connections for optimal executive functioning.

Orofacial clefts are among the most common congenital defects in the United States, affecting roughly 1 in 600 births annually. A majority of these cases are considered to be “isolated” clefts of the lip and/or palate (ICLP). However the term “isolated” is somewhat of a misnomer, as functional deficits frequently accompany ICLP. One of the most problematic yet understudied of these deficits involves the high prevalence of reading disabilities in this population. It has been estimated that as high as 46% of children with ICLP will be diagnosed with a reading disability, particularly dyslexia. Despite this high prevalence and the well-established neurological basis of dyslexia, relatively little attention has been paid to the role that brain development plays in the reading problems in ICLP. Previous studies from our lab have demonstrated significant changes in brain structure in children with ICLP (that have importantly correlated with functional measures). However we have yet to combine both a structural and functional neuroimaging study with an in-depth analysis of reading dysfunction in this population. The current study examined boys with ICLP, age 8-12 (boys have a higher prevalence of ICLP and show more significant reading problems that girls with ICLP) compared to healthy control boys. Measures of cognitive functioning were obtained with an emphasis on reading and language skills. In addition MRI scans were obtained which included volumetric measures, diffusion-weighted measures (DWI; white matter), and connectivity measures (resting-state fMRI). Even after controlling for the effect of socioeconomic status, boys with ICLP showed significant decreases in reading and language skills (particularly reading fluency). Boys with ICLP did not show significant differences on phonlogical measures (the primary cause of dyslexia). In addition, phonological measures were not predictive of reading fluency, while object naming tasks were predictive of reading fluency in boys with ICLP. For white matter integrity, measures of fractional anisotropy (FA) were found to be increased in the right occipital lobe for boys with ICLP indicating more organized white matter in this region. This increase in right occipital FA was also predictive of better reading outcomes, particularly reading fluency. For more specific white matter tracts, only the fornix and the tapetum (both associated with the temporal lobes) showed a significant difference with a decrease in FA for boys with ICLP. The decrease in FA in the tapetum was also predictive of better reading outcomes in ICLP. When looking at resting-state networks, boys with ICLP showed an increase in connectivity within posterior and subcortical regions when compared to healthy control boys, indicating stronger network connections within the posterior language regions of the brain. Taken together, these results point to differences in both structural and functional connectivity in the brains boys with ICLP. Furthermore, this pattern is different than that found in children with developmental dyslexia as there appears to be no disruption of the posterior reading systems. Cognitive measures also indicate normal phonological awareness in this group, further distinguishing them from dyslexic children. Boys with ICLP instead may be over-relying on these posterior, more visually oriented reading systems as a compensatory mechanism to overcome problems with the development of the typical “lexical route” of reading.

Psychosocial problems are exceedingly common following moderate-to-severe traumatic brain injury (TBI), and are thought to be the major predictor of long-term functional outcome. However, current rehabilitation protocols have shown little success in improving interpersonal and social abilities of individuals with TBI, revealing a critical need for new and more effective treatments. Recent research has shown that neuro-modulatory treatments (e.g., non-invasive brain stimulation, lifestyle interventions) targeting the functionality of specific brain systems—as opposed to focusing on re-teaching individuals with TBI the impaired behaviors— hold the potential to succeed where past behavioral protocols have failed. However, in order to implement such treatments it is crucial to gain a better knowledge of the neural systems underlying social functioning secondary to TBI. It is well established that in TBI populations the inability to identify and interpret social cues, and in particular to engage in successful recognition of facial affects, is one of the factors driving impaired social functioning following TBI. The aims of the work here described were threefold: (1) to determine the degree of impairment in individuals with moderate-to-severe TBI on tasks measuring different sub-types of facial affect recognition skills, (2) to determine the relationship between white matter integrity and different facial affect recognition ability in individuals with TBI by using diffusion tensor imaging, and (3) to determine the patterns of brain activation associated with facial affect recognition ability in individuals with TBI by using task-related functional magnetic resonance imaging (MRI). Our results revealed that individuals with TBI are impaired at both perceptual and verbal categorization facial affect recognition tasks, although they are significantly more impaired in the latter. Moreover, performance on tasks tapping into different types of emotion recognition abilities showed different white-matter neural correlates, with more individuals with TBI showing more extensive damage in the left inferior fronto-occipital fasciculus, uncinate fasciculus and inferior longitudinal fasciculus more likely to perform poorly on verbal categorization tasks. Lastly, our functional MRI study suggests an involvement of left dorsolateral prefrontal regions in the disruption of more perceptual emotion recognition skills, and involvement on the fusiform gyrus and of the ventromedial prefrontal cortex in more interpretative facial affect recognition deficits. The findings here presented further out understanding of the neurobiological mechanisms underlying facial affect impairment following TBI, and have the potential to inform the development of new and more effective treatments.

The purpose of this study was to investigate the relationship between word reading and white matter (WM) integrity in the reading system and test a theory-based moderated mediation model such that relationship of WM integrity with word reading is mediated by processing speed and indirect effect is moderated by group. Thirty-seven adult survivors of childhood brain tumor and typically developing adults participated (mean age=24.19(4.51) years, 62% female). Tractography identified the WM tract for three reading system connections. Fractional anisotropy of the IFOF and PT-OT tracts were significantly correlated with word reading in survivors (r=.55, .46, respectively; p

Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.

Diffusion Tensor Imaging (DTI) can quantify tissue integrity in normal-appearing white matter (NAWM). NAWM abnormalities present at the earliest time point implicate neurodegeneration operative from the outset of multiple sclerosis (MS). DTI scans were obtained at first attacks from 6 children later diagnosed with MS and 6 children with monophasic demyelination, and from 6 controls, matched for age. DTI scans were also obtained from 22 children with established MS with clinical onset before age 12 years and compared to age-matched controls. Atlas- and tractography-based image processing methods were utilized. DTI metrics distinguished MS patients from patients with monophasic demyelination and from controls at the first attack. Differences in NAWM between children with established early-onset MS and controls were only notable when DTI was obtained in adolescence. DTI provides valuable insights into NAWM in children with MS, although in the youngest patients such changes may require time to develop.