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Using diffusion imaging to explore the anatomical nature of early course schizophrenia
Using diffusion imaging to explore the anatomical nature of early course schizophrenia
Schizophrenia (SCZ) is a serious brain disorder that affects around 1% of the world population. Despite a long history of research in diagnosis and treatment of SCZ, we are still far from being able to explain the origin of the disease and the interindividual differences in the trajectory of the disease. The neurodevelopmental hypothesis states that SCZ is caused by early maturational abnormalities, which interact with later brain development. Neuroimaging provides a noninvasive opportunity to study this theory in vivo. Traditionally, Magnetic resonance imaging (MRI) has been used to examine macrostructural gray matter features such as gray matter volume or cortical thickness and SCZ has been established as a brain disorder hereinafter. Diffusion tensor imaging (DTI) allows to investigate the microstructure of brain tissue. It measures the magnitude and direction of water molecule`s diffusion and is highly sensitive to alterations of gray and white matter organization. Gray matter contains the neurons and the white matter contains myelinated axons and provides long and middle range connectivity between cortical neurons. White matter alterations observed in SCZ, therefore, support the disconnection theory stating that SCZ is a brain disorder with disrupted integration of different brain systems. Finally, while early imaging research focused on chronic states of SCZ a shift of the field towards studying early stages can be observed in more recent years. Understanding early course SCZ raises the hope to improve diagnosis and subsequently prevention and intervention. In line with this research the aim of the presented studies is to characterize microstructural white and gray matter alterations in early course SCZ using diffusion MRI combined with advanced post-processing techniques, which are sufficiently sensitive to detect subtle brain conspicuities. Implications of and associations with neuropsychological and clinical symptoms and diagnosis of SCZ will be discussed subsequently. Paper 1 The purpose of the first project is to characterize white matter organization in patients with early course SCZ. To my knowledge this is the first study investigating five main intra-hemispheric corti-cocortical white matter tracts using manual guided tractography in early course SCZ. The tracts were selected based on previous findings: uncinate fasciculus (UF), cingulum bundle (CB), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and arcuate fasciculus (AF). Diffusion parameters (fractional anisotropy [FA], trace, axial diffusivity [AD] and radial diffusivity [RD]) were computed for each tract and compared between patients with early course SCZ (number [n]=30) and healthy controls (HC) (n=30). The association of the diffusion parameters of the tracts with clinical symptoms, memory performance, and processing speed was examined afterwards. A significant group effect, represented by reduced FA and increased RD and trace in the patients’ group compared to HC was observed for the right AF (FA [F=5.94, df=1, p=.016]; RD [F=5.60, df=1, p=.020]), CB (FA [F=9.35, df=1, p=.003]; RD [F=11.55, df=1, p=.0010] and ILF (FA [F=14.77, df=1, p=.004]; RD [F=13.25, df=1, p<.0001]). The pattern of lower FA and higher RD is indicative for myelin abnormalities. Structural alterations were correlated with positive symptoms (ILF, AF), and cognitive performance (CB), which points to the clinical relevance of the observed white matter conspicuities. Paper 2 In the past, DTI has mainly been used to study white mater, because technical challenges limited the use of DTI for the characterization of gray matter organization. However, as an extension of the classical disconnection theory one would not only expect dysconnectivity in white matter, but also a disruption of gray matter organization. The aim of this study therefore is to use novel DTI method- heterogeneity- to study the microstructural gray matter organization over the course of SCZ. In comparison to traditional diffusion indices, which focus on intra-voxel diffusion properties, heterogeneity captures the microstructural organization of a larger cortical area. After applying a free water correc-tion to control for partial volume effects, T1 and diffusion images were registered to each other and the variability (=heterogeneity) of diffusion parameters within the four brain lobes defined by auto-matic parcellation method was calculated. Patients with chronic SCZ (n=27) did not show differences of cortical organization when compared to HC (n=22). However, patients with early course SCZ (n=19) showed increased heterogeneity in the frontal lobe when compared to HC (n=15) (F=10.68, df=1, p<.0030). This indicates a lower grade of cortical organization in patients than in HC. It is suggested that this can be explained by neurodevelopmental abnormalities, plausibly caused by abnormal synaptic reorganization and pruning during adolescence and early adulthood in SCZ.
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Seitz, Johanna
2020
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Seitz, Johanna (2020): Using diffusion imaging to explore the anatomical nature of early course schizophrenia. Dissertation, LMU München: Faculty of Medicine
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Abstract

Schizophrenia (SCZ) is a serious brain disorder that affects around 1% of the world population. Despite a long history of research in diagnosis and treatment of SCZ, we are still far from being able to explain the origin of the disease and the interindividual differences in the trajectory of the disease. The neurodevelopmental hypothesis states that SCZ is caused by early maturational abnormalities, which interact with later brain development. Neuroimaging provides a noninvasive opportunity to study this theory in vivo. Traditionally, Magnetic resonance imaging (MRI) has been used to examine macrostructural gray matter features such as gray matter volume or cortical thickness and SCZ has been established as a brain disorder hereinafter. Diffusion tensor imaging (DTI) allows to investigate the microstructure of brain tissue. It measures the magnitude and direction of water molecule`s diffusion and is highly sensitive to alterations of gray and white matter organization. Gray matter contains the neurons and the white matter contains myelinated axons and provides long and middle range connectivity between cortical neurons. White matter alterations observed in SCZ, therefore, support the disconnection theory stating that SCZ is a brain disorder with disrupted integration of different brain systems. Finally, while early imaging research focused on chronic states of SCZ a shift of the field towards studying early stages can be observed in more recent years. Understanding early course SCZ raises the hope to improve diagnosis and subsequently prevention and intervention. In line with this research the aim of the presented studies is to characterize microstructural white and gray matter alterations in early course SCZ using diffusion MRI combined with advanced post-processing techniques, which are sufficiently sensitive to detect subtle brain conspicuities. Implications of and associations with neuropsychological and clinical symptoms and diagnosis of SCZ will be discussed subsequently. Paper 1 The purpose of the first project is to characterize white matter organization in patients with early course SCZ. To my knowledge this is the first study investigating five main intra-hemispheric corti-cocortical white matter tracts using manual guided tractography in early course SCZ. The tracts were selected based on previous findings: uncinate fasciculus (UF), cingulum bundle (CB), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and arcuate fasciculus (AF). Diffusion parameters (fractional anisotropy [FA], trace, axial diffusivity [AD] and radial diffusivity [RD]) were computed for each tract and compared between patients with early course SCZ (number [n]=30) and healthy controls (HC) (n=30). The association of the diffusion parameters of the tracts with clinical symptoms, memory performance, and processing speed was examined afterwards. A significant group effect, represented by reduced FA and increased RD and trace in the patients’ group compared to HC was observed for the right AF (FA [F=5.94, df=1, p=.016]; RD [F=5.60, df=1, p=.020]), CB (FA [F=9.35, df=1, p=.003]; RD [F=11.55, df=1, p=.0010] and ILF (FA [F=14.77, df=1, p=.004]; RD [F=13.25, df=1, p<.0001]). The pattern of lower FA and higher RD is indicative for myelin abnormalities. Structural alterations were correlated with positive symptoms (ILF, AF), and cognitive performance (CB), which points to the clinical relevance of the observed white matter conspicuities. Paper 2 In the past, DTI has mainly been used to study white mater, because technical challenges limited the use of DTI for the characterization of gray matter organization. However, as an extension of the classical disconnection theory one would not only expect dysconnectivity in white matter, but also a disruption of gray matter organization. The aim of this study therefore is to use novel DTI method- heterogeneity- to study the microstructural gray matter organization over the course of SCZ. In comparison to traditional diffusion indices, which focus on intra-voxel diffusion properties, heterogeneity captures the microstructural organization of a larger cortical area. After applying a free water correc-tion to control for partial volume effects, T1 and diffusion images were registered to each other and the variability (=heterogeneity) of diffusion parameters within the four brain lobes defined by auto-matic parcellation method was calculated. Patients with chronic SCZ (n=27) did not show differences of cortical organization when compared to HC (n=22). However, patients with early course SCZ (n=19) showed increased heterogeneity in the frontal lobe when compared to HC (n=15) (F=10.68, df=1, p<.0030). This indicates a lower grade of cortical organization in patients than in HC. It is suggested that this can be explained by neurodevelopmental abnormalities, plausibly caused by abnormal synaptic reorganization and pruning during adolescence and early adulthood in SCZ.