Cornelia Laule

Neurofilaments are neuronal-specific proteins involved in neuroaxonal functions like determining axonal diameter and transporting organelles and other proteins. After neuronal tissue damage, neurofilaments are detectable in the cerebrospinal fluid and blood in many neurological diseases including multiple sclerosis (MS). Metrics derived from quantitative magnetic resonance imaging (MRI) techniques specific to myelin content and axonal integrity have been proposed as potential biomarkers of MS disease processes. While there have been studies associating higher neurofilament levels, particularly the light chain (NfL), in blood with disease progression, greater lesion volume, and atrophy, few studies have examined the relationship between NfL and advanced imaging measures in MS. In this thesis, linear regressions were used to assess the relationship between serum NfL and MRI measures in the whole brain, normal appearing white matter, and lesions. 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting MS, 30 secondary progressive MS, 20 primary progressive MS) underwent 3T MRI to obtain the measures myelin water fraction (MWF), water content, high angular resolution diffusion imaging (HARDI) derived axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA), diffusion basis spectrum imaging (DBSI) derived AD, RD, FA, water, fiber, restricted, and hindered ratios, T1, geometric mean T2 (GMT2), normalized brain, lesion, thalamic, and deep grey matter (GM) volumes, and cortical thickness. Blood was collected on the same day as MR experiments and quantified using single molecule array (SIMOA) technology (Quanterix). Some measures were transformed for normality and multiple comparison correction was applied. Higher serum NfL levels were associated with lower brain structure volumes (thalamus, deep GM, normalized brain volume) and cortical thickness as well as higher lesion volume. Furthermore, increasing serum NfL levels were seen with increasing metrics of myelin damage (MWF decrease, RD increase), axonal damage (FA decrease, AD increase), edema and inflammation (T1, GMT2 increase), and decreasing metrics for cellularity (restricted ratio). The results show that myelin and axonal health are strongly coupled where there is a cascade of damage occurring in the MS brain causing NfL release. Serum NfL may be a useful biomarker that reflects not only axonal loss, but also myelin damage and brain volume changes.

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Transcranial magnetic stimulation (TMS) is an increasingly popular treatment for psychiatric diseases including depression, the most common cause of psychiatric disability worldwide. TMS is an effective treatment for depression even in patients where conventional pharmacological and therapeutic treatments for the disease have been unsuccessful. As the mechanism of TMS relies on electromagnetic induction, it is a completely noninvasive treatment.While TMS is known to be effective in treating depression, exactly how TMS affects the brain is an active area of research. To properly study the effects of TMS in vivo, non-invasive methods are required. As such, magnetic resonance (MR) modalities present an attractive option due to their non-invasive nature. There is interest in studying the effects of TMS using MR concurrently with TMS, however, concurrent TMS/MR is challenging due to TMS-related distortions to the MR scanners magnetic field. MR Spectroscopy (MRS) is ideal for TMS/MR applications as not only does MRS provide information about brain chemicals thought to change during TMS, it also is sensitive enough to characterize distortions that are present in other MR images but not as easy to recognize.In this thesis, non-water-suppressed MRS experiments were performed concurrently with TMS to characterize distortions to the MRS water signal. Phantom experiments were performed under a wide range of experimental conditions, varying MRS voxel positioning and parameters related to TMS pulsing. Distortions investigated included signal-noise ratio, free induction decay spikes, B0 inhomogeneity, eddy currents, and frequency modulation sidebands. As a proof of concept, concurrent TMS/MRS results from a human experiment are presented.The dominant source of signal distortion was found to be related to the presence of the TMS coil itself, and the magnitude of the distortions depended most strongly on the position of the MRS voxel relative to the TMS coil. To a lesser extent, TMS pulses further distorted MRS signal, particularly at higher pulse amplitudes and when there was a smaller time delay between the TMS pulse and 90◦ radiofrequency pulse.This work presents results from the first concurrent TMS/MRS experiments reported. It is intended that these results provide guidance for future research using concurrent TMS/MRS.

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Magnetic resonance spectroscopy (MRS) measures relative signals arising from spins on different metabolites, e.g. N-Acetyl aspartate (NAA). To improve the interpretability of changes caused by disease, it is optimal to convert these relative signals to absolute concentrations e.g. by referencing it to the MR signal of water. Segmentation of high-resolution qualitative magnetic resonance images (MRI) is an accessible and easy-to-use method to estimate the properties of tissue water in the spectroscopic volume of interest (VOI), including water content, [H₂O], and relaxation properties (T₁, T₂) with pre-determined literature values. However, these tissue properties can change in disease and with age. Therefore, we proposed the use of a quantitative MRI approach to reference metabolite concentrations by measuring subject-specific T₁ and T₂ relaxation as well as water content maps. The approach was first validated by measuring a range of biologically relevant water contents and metabolite concentrations in vitro. [H₂O] was overestimated by 4.8% on average, while NAA concentrations were underestimated by 9.9%. In a study of ten healthy controls comparing the traditional segmentation quantification with the novel quantitative MRI method, we observed larger variabilities for subject-specific water properties, which did not propagate to the variability of the absolute metabolite concentrations of the neurochemicals (p > 0.37). Metabolite concentrations were lower with the quantitative MRI approach by -5.4% (p=0.002) in a white matter volume of interest (VOI) and -2.4% (p=0.002) in a grey matter VOI compared to the segmentation-based quantification.The quantitative MRI method for calculating absolute metabolite concentrations in MRS showed promising results, offering a potential alternative for the currently widely used segmentation approach.

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