On connectivity in the central nervous systeem : a magnetic resonance imaging study

Brain function has long been the realm of philosophy, psychology and psychiatry and since the mid 1800s, of histopathology. Through the advent of magnetic imaging in the end of the last century, an in vivo visualization of the human brain became available. This thesis describes the development of two unique techniques, imaging of diffusion of water protons and manganese enhanced imaging, that both allow for the depiction of white matter tracts. The reported studies show, that these techniques can be used for a three-dimensional depiction of fiber bundles and that quantitative measures reflecting fiber integrity and neuronal function can be extracted from such data. In clinical applications, the potential use of the developed methods is illustrated in human gliomas, as measure for fiber infiltration, and in spinal cord injury, to monitor potential neuroprotective and __regenerative medication.UBL - phd migration 201

Quantitative Susceptibility Imaging of Tissue Microstructure Using Ultra-High Field MRI

This thesis has used ultra-high field (UHF) magnetic resonance imaging (MRI) to investigate the fundamental relationships between tissue microstructure and such susceptibility-based contrast parameters as the apparent transverse relaxation rate (R2*), the local Larmor frequency shift (LFS) and quantitative volume magnetic susceptibility (QS). The interaction of magnetic fields with biological tissues results in shifts in the LFS which can be used to distinguish underlying cellular architecture. The LFS is also linked to the relaxation properties of tissues in a gradient echo MRI sequence. Equally relevant, histological analysis has identified iron and myelin as two major sources of the LFS. As a result, computation of LFS and the associated volume magnetic susceptibility from MRI phase data may serve as a significant method for in vivo monitoring of changes in iron and myelin associated with normal, healthy aging, as well as neurological disease processes. In this research, the cellular level underpinnings of the R2* and LFS signals were examined in a model rat brain system using 9.4 T MRI. The study was carried out using biophysical modeling and correlation with quantitative histology. For the first time, multiple biophysical modeling schemes were compared in both gray and white matter of excised rat brain tissue. Suprisingly, R2* dependence on tissue orientation has not been fully understood. Accordingly, scaling relations were derived for calculating the reversible, mesoscopic magnetic field component, R2\u27, of the apparent transverse relaxation rate from the orientation dependence in gray and white matter. Our results demonstrate that the orientation dependence of R2* and LFS in both white and cortical gray matter has a sinusoidal dependence on tissue orientation and a linear dependence on the volume fraction of myelin in the tissue. A susceptibility processing pipeline was also developed and applied to the calculation of phase-combined LFS and QS maps. The processing pipeline was subsequently used to monitor myelin and iron changes in multiple sclerosis (MS) patients compared to healthy, age and gender-matched controls. With the use of QS and R2* mapping, evidence of statistically significant increases in iron deposition in sub-cortical gray matter, as well as myelin degeneration along the white matter skeleton, were identified in MS patients. The magnetic susceptibility-based MRI methods were then employed as potential clinical biomarkers for disease severity monitoring of MS. It was demonstrated that the combined use of R2* and QS, obtained from multi-echo gradient echo MRI, could serve as an improved metric for monitoring both gray and white matter changes in early MS

Evaluation of Upper Motor Neuron Pathology in Amyotrophic Lateral Sclerosis by Mri;Towards Identifying Noninvasive Biomarkers of the Disease

Amyotrophic lateral sclerosis (ALS) is the commonest adult motor neuron disease (MND) which causes progressive muscle paralysis and death usually within 5 years of symptom onset. As a result, only ̃30,000 individuals in the United States are afflicted at any one time even though 5,000 or more individuals are diagnosed yearly. The diagnosis of ALS requires evidence of degeneration in upper motor neurons (UMNs) in the brain and in lower motor neurons (LMNs) that exit the brainstem and spinal cord to innervate skeletal muscles. Diagnosis can be incorrect or delayed when disease is early or atypical because non-invasive objective tests of UMN involvement do not exist, unlike electromyography to assess the LMN. Although magnetic resonance imaging (MRI) of brain and spinal cord is used primarily to identify conditions which mimic ALS, novel MRI sequences and post-processing techniques can identify macroscopic and even sub-macroscopic changes in ALS brain related to neuronoaxonal degeneration (e.g., in corticospinal motor tracts). MRI-based techniques like diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (1H-MRS), as well as nuclear medicine modalities like positron emission tomography (PET) and single photon emission tomography (SPECT) are being used to study brains of patients with ALS. Many previous MRI studies of ALS brain are limited either in methodology or information obtained being primarily qualitative, i.e. changes visible to the naked eye (macroscopic). This study employed both routine and novel MRI sequences to objectively assess gray and white matter pathology of the brain in ALS patients, including T2 relaxometry, DTI, and voxel based morphometry (VBM) of 3D high resolution T1-weighted images. DTI metrics showed significant (p\u3c 0.05) changes in rostral extent of corticospinal tract (CST) in ALS patients with predominantly UMN symptoms and signs, and the ALS-dementia patients, whereas more caudal involvement was observed in ALS patients with classic findings of UMN and LMN

Microstructural MRI basis of the cognitive functions in patients with Spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter (WM) bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar WM microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that WM diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Moving beyond DTI: non-gaussian diffusion in the brain and skeletal muscle

Diffusion Magnetic Resonance Imaging (dMRI) is a diagnostic technique able to provide in- vivo measures that are related to the microstructure of tissues. Thanks to the sensitivity to microstructural tissue changes, Diffusion Weighted Imaging (DWI) and derived metrics, as the Apparent Diffusion Coefficient (ADC) , became the gold standard for the detection of strokes and ischemia since the early 90‟s. In 1994 Basser and colleagues introduced Diffusion Tensor Imaging (DTI), the first quantification approach able to capture the anisotropy of the diffusion process in in-vivo biological tissues. Chapter II shows the results we obtained applying DTI to investigate white matter alterations of a population affected by Friedreich‟s Ataxia. After more than 20 years from its introduction, DTI is still widely applied. However, concerns about the limitations of the technique have been increasingly risen over-time, with particular reference to the lack of specificity of the model and the coexistence of tissues with multiple architectures. Additionally, the tensor model can be applied only to a range of “moderate” diffusion sensitizations, after which the presence of biological membranes becomes non-negligible and gives origin to phenomena of “non-Gaussian diffusion”, that violate the assumptions of the model. Chapter III and Chapter IV deal specifically with these limitations, addressing the problem with two different approaches and applications. Another popular technique to investigate the dMRI signal is Spherical Deconvolution (SD), that in Chapter IV is presented in a tissue specific formulation and applied to derive diffusivity metrics specific to white matter, gray matter and cerebrospinal fluid, both in healthy controls and in a patient affected by MS. Since the early days of dMRI, experiments have been performed not only in the brain but in several body districts, including the skeletal muscle. Back in 1986 Le Bihan et al. observed that the water flowing in the micro vascular network and in the vessels was contributing to the acquisition of data at very low diffusion sensitization, and proposed the “Intra- Voxel Incoherent Motion” (IVIM) model. IVIM can be seen either as a model to obtain measures of pseudo-diffusion, or as a technique to obtain perfusion free ADC measures, thus recognizing it as an artifact. Although dMRI and DTI were applied to the skeletal muscle since its early days, later evolutions as Diffusion Kurtosis Imaging have only recently been applied to the skeletal muscle to fit dMRI data acquired at strong diffusion sensitization. The concepts of IVIM and DKI are developed in Chapter V, where the effects of the first on DTI and DKI, as well as the relation between DTI and DKI metrics are investigated through simulations and MRI data of the calf. In line with the current dMRI literature, the first 5 chapters of this thesis depict the diffusion signal as a complex measure arising from multiple tissue components. Chapter VI investigates a multi-compartment pseudo-continuous deconvolution approach, a technique that does not require explicit modeling of the tissues. Finally, Chapter VII presents an overview of other research topics I have work on during the PhD

Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study

Background: Our understanding of the effect of ataxia-telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography