No description available.

Myeloarchitecture is a prominent feature that can identify the primary motor and sensory areas in the cerebral cortex and is increasingly imaged in magnetic resonance imaging (MRI) studies of cortical parcellation in humans. However, MRI studies of cortical myeloarchitecture are technically difficult for two reasons: the cortex is only a few millimeters thick, and intracortical contrast due to myelin is much smaller than the overall anatomical contrast between cortical tissue and underlying white matter that is typically utilized in imaging. The research in this thesis thus presents specific MRI protocols to visualize intracortical myelin, image processing protocols to delineate the heavily myelinated cortex from the adjacent typical cortex and the application of these techniques in the precentral motor cortex to study morphology of the highly myelinated dorso-medial part, consisting of Brodmann area (BA) 4 and part of BA 6. Optimization of the MRI protocols involved determining the sequence parameters for a T1-weighted MRI sequence to obtain maximal intracortical contrast at 0.7 mm isotropic resolution in imaging time of 15 min, based on T1 differences between cortex that is myelinated (GMm) or unmyelinated (GM). As part of the optimization, T1 values were measured in the following brain tissues: GM, GMm and white matter (WM). The optimization was carried out by simulating the MRI signal for a 3D, magnetization prepared, gradient echo sequence, using the measured T1 values in the analytical signal equations. It was found that lengthening the time delay at the end of each inner phase encoding loop increased the intracortical contrast. The optimization of MRI protocols also included implementing techniques to reduce radio frequency field (B1) inhomogeneities. It was found that dividing the optimized, T1-weighted MRI with a predominantly proton density weighted image resulted in a ratio image with significantly reduced B1 inhomogeneities. The goal of the image processing protocols developed in this thesis was to visualize the variation of intracortical myelin across the precentral motor cortex and to delineate its well-myelinated dorso-medial part. The myeloarchitectonic feature that was selected to visualize the variation in intracortical myelination was the thickness of GMm in the deeper parts of the cortex relative to the cortical thickness, referred to as the proportional myelinated thickness (p). To measure p, the following processing steps were performed. The ratio image was segmented into four tissues: GM, GMm, WM and cerebrospinal fluid (CSF) using fuzzy C-means clustering technique. Using a level set approach, thickness of the cortex was determined as the distance between the outer boundaries of GM and WM and thickness of GMm or myelinated thickness (m) was determined as the distance between the outer boundaries of GMm and WM. The proportional myelinated thickness p, was calculated as follows: p= m/t. The well-myelinated dorso-medial part of the precentral cortex, referred to as Mm, was distinguishable from the adjacent cortex when the proportional myelinated thickness was projected on the outer cortical surface. The optimized MRI and image processing techniques developed in this thesis were used to investigate cortical plasticity in amputees. Two morphological features of the myeloarchitecture over Mm, the mean proportional myelinated thickness and area, were measured in four lower limb amputees and four matched controls. A comparison of these morphological features showed no statistically significant difference (p < 0.05) between the two groups. / Thesis / Doctor of Philosophy (PhD)

Introduction: Obsessive-compulsive disorder (OCD) is a complex disorder that is associated with significantly impaired functioning. The current prevailing model of OCD implicates dysfunction of the serotonergic neurotransmitter system and fronto-striatal neural networks, but challenges in replicating findings within OCD samples are often attributed to clinical heterogeneity. OCD symptoms that develop or worsen within the perinatal period appears to reflect a distinct subtype of the disorder, but the genetic and neurobiological factors that contributes to its presentation in women is poorly understood. In this dissertation, we aimed to review the literature on the genetic architecture of OCD, identify potential gene candidates for perinatal OCD and analyze one serotonin system gene according to OCD and possible subtypes using meta-analytic techniques. Based on these findings, we then tested the association of serotonergic candidate gene polymorphisms with the presence of infant-related obsessive-compulsive symptoms (OCS). Lastly, we investigated the cortical morphological features associated with perinatal OCD and OCS symptom severity in postpartum mothers. Results: From prior reports in the literature and our own meta-analytic investigation, polymorphic variants in genes coding for the serotonergic transporter and serotonin 2A receptor subtype (SLC6A4 and HTR2A, respectively) appear to be candidates for perinatal OCD due to their association in female samples. However, upon investigation in our perinatal sample (n=107), we found no evidence to support the association of the 5-HTTLPR polymorphism of SLC6A4 with perinatal-related OCS, but larger samples are needed to confirm this finding. Due to technical challenges, the HTR2A polymorphism remains to be tested. Our novel whole-brain explorations revealed distinct cortical morphology associated with symptom worsening across the perinatal period, irrespective of diagnosis. Cortical parameters were not able to differentiate mothers with and without OCD; however, OCD mothers displayed positive correlations between cortical surface area and symptom severity in widespread regions, including the frontal, parietal, temporal and occipital cortex. Conclusions: Overall, this body of work aimed to fill the gap in the literature by exploring the possible genetic and cortical correlates of perinatal-related OCS and OCD. While 5-HTTLPR or HTR2A are candidates for perinatal OCD, it is not yet clear whether they increase susceptibility for the development of infant-related OCS in the perinatal period. Distinct cortical alterations in surface area appeared alongside OCS exacerbation in the postpartum period in regions that extend beyond the frontoparietal network. This suggests that additional neural networks may be contributing to symptom severity and that the cortical plasticity that occurs across the perinatal period may predispose women for risk of OCD. Future studies should continue to use a multiple perspective approach, that utilizes genetic and neurobiological techniques, in order to provide greater insight into the etiology of perinatal OCD. / Dissertation / Doctor of Philosophy (PhD) / Women are at greater risk for the development of mental illness in the time surrounding pregnancy and postpartum, known as the perinatal period. In the case of perinatal obsessive-compulsive disorder (OCD), mothers may experience unique worries in regard to their parenting or fears that their baby may be harmed. While these worries are common, they can become disruptive when persistent and impact the mother’s mood and ability to bond with the infant. Our current understanding of OCD includes the influence of genetic factors and brain changes, but little is understood about what factors may increase risk for OCD in the perinatal period. In this thesis, we aimed to review whether certain alterations within DNA segments, known as gene variants, may be linked to the development of OCD in females and if these gene changes, as well as differences in brain structures in postpartum mothers, are associated with OCD symptoms during the perinatal period. The genes we examined are important for regulating a chemical signaling substance in the brain known as serotonin. Based on our results, we did not find a relationship between serotonin gene variants and OCD symptoms in perinatal women. We also found no differences when comparing the cortical brain structures between mothers with OCD and healthy mothers; however, we observed that measures of surface area across several cortical brain regions were related to symptom worsening from pregnancy to postpartum, and also with symptom severity in postpartum mothers with OCD. These results suggest that there are widespread brain changes during the postpartum period that may increase a mother’s risk for developing OCD. Overall, the work in this thesis provides the first glimpse into potential risk factors for perinatal OCD.