Magnetic Resonance Imaging Structural And Functional Study In Patients With Amyotrophic Lateral Sclerosis

PART I Gray matter volume changes over the whole brain in amyotrophic lateral sclerosis:A longitudinal voxel-based morphometry studyObjective Our purpose was to to study the structural changes of the whole brains in patients with amyotrophic lateral sclerosis (ALS). Materials and Methods Thirty patients with ALS and30the age-and sex-matched control subjects were enrolled in the study. Gray volume differences of the whole brain were assessed using SPM8to make voxel-based morphometry (VBM) comparison between patients and the control subjects. The model was designed to identify the brain regions attributing to the ALSFRS-R score, disease progression rate and disease duration. In addition, longitudinal analysis was performed in a subset of14patients who were able and willing to undergo a follow-up MRI scanning session. Results In our ALS patients, VBM revealed clusters of gray matter (GM) atrophy in the primary motor cortex and in motor-related areas of frontal and parietal lobes. Additional clusters of GM atrophy were observed in extra-motor cortices, namely temporal lobe and frontal pole (P<.001, uncorrected, k>701). In ALS, the positive correlation between gray matter value and ALSFRS-R score was found in the area of right premotor (P<.001, uncorrected, k≥76). Longitudinal cortical thinning was found in the area of bilateral frontal cortex (P<.001, uncorrected, k≥39). Conclusions Gray matter reductions in primary motor area observed with VBM in patients with ALS, which is a multisystem disorder, potentially can be as a structural markers to identify an extended motor cortical damage of ALS patients. PART Ⅱ Microstructural white matter involvement in amyotrophic lateral sclerosis:A longitudinal voxel-based whole brain diffusion tensor imaging studyObjective The present study aimed to detect white matter (WM) patterns of microstructural abnormalities to better investigate the pathologic process in amyotrophic lateral sclerosis (ALS) with magnetic resonance diffusion tensor imaging (DTI). Materials and Methods Thirty-three patients and30normal age-matched volunteers underwent DTI. In14of the33ALS patients, a second DTI was obtained after6months. Fractional anisotropy (FA) maps were processed using tract-based spatial statistics (TBSS) to make voxel-based comparison of DTI parameters in whole brain between the two groups. A volume of interest (VOI) analysis was then performed to analyze the TBSS results. Results Significant reductions in FA, increase in mean diffusivity (MD) and radial diffusivity (RD)(P<.05,TFCE corrected) in corpus callosum (CC), corticospinal tracts (CST) and superior longitudinal fasciculi (SLF) were found. Additionally, significant voxel-wise positive correlations between FA and the ALSFRS-R were detected in the WM tracts underneath the right primary motor cortex (P<.001, uncorrected) in patients with ALS. At the VOI level, mean FA values decreased, mean RD and MD values increased in the all the VOIs. Forthermore, mean FA values in the body of CC and SFL significantly correlated with ALSFRS-R (P<.05). With a direct comparison of baseline and follow-up dataset in ALS, significant reductions in FA, increase in MD, RD and AD were displayed in many WM, mainly along CC, CST and SLF (P<.05, TFCE corrected). Conclusions DTI detects changes in microstructural white matter that are regarded as prominent features of ALS and thus, shows promise in its function as a diagnostic biomarker. Using the technique herein, we could demonstrate DTI changes at follow-up which correlated well with clinical progression, which used to monitor the disease progression and observe the treatment response. PART III Altered cortical activation during action observation in amyotrophic lateral sclerosis patients:a functional MRI studyObjective The aim of this study was to investigate functional cerebral abnormalities in ALS patients with blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) during action observation. Furthermore, this study was to determine whether fMRI would be able to dissociate higher order motor control structures from motor system during action observation and whether disorders of the motor neuron such as ALS give rise to increased activation in these areas. Materials and Methods Thirty patients with ALS and30matched healthy controls were recruited. Subjects underwent BOLD-fMRI with an experimental paradigm while observing a video of repetitive flexion-extension of the fingers at three frequency levels (0.5,1and2Hz) or three complexity levels (repetitive flexion-extension of the fingers, four fingers all-to-thumb opposition, sequential finger-to-thumb opposition), alternated to epochs of static hand. The BOLD-fMRI scans using a block design, each4min8sec in length consisting of12pseudo-randomly presented blocks of20seconds. Statistical Parametric Mapping8(SPM8) software was used to analyze the BOLD-fMRI data. A parametric analysis was applied to determine the effects of each of both factors. Results Action observation activated similar neural networks as execution of action in ALS patients and healthy subjects in bilateral regions of the occipital and frontal lobes, the parietal lobe, and the supplementary motor area (SMA), which are core nodes of the mirror-neuron system (MNS). Amyotrophic lateral sclerosis patients presented that some of these regions, in particular the dorsal premotor cortex (dPMC), the inferior parietal lobule (IPL), and the SMA, were more activated compared to controls. Furthermore, increased activation within the primary motor cortex (M1), dPMC, inferior frontal gyrus (IFG) and superior parietal lobule (SPL) correlated mainly with hand movement frequency/complexity in the videos were seen in patients than controls. Conclusions The findings indicated an ongoing compensatory process within the higher order motor-processing system of ALS patients, probably to overcome loss of function. Our study suggested that action observation paradigm with BOLD-fMRI provided an objective task which activates motor networks without any voluntary movement, particularly for movement-impaired patients such as ALS. Changes in blood oxygenation level of fMRI associated with impaired movement indicate that fMRI may be a useful surrogate marker of clinical intervention and disability progression. Part IV Resting-state functional magnetic resonance imaging analysis in amyotrophic lateral sclerosisObjective To investigate the brain activity in resting state of patients with amyotrophic lateral sclerosis (ALS) by group independent component analysis (GICA) and ROI-based correlation analysis. Materials and Methods30patients with ALS and30normal age-matched volunteers as controls were scanned with3.0T MRI. All data were preprocessed with such software as SPM8and REST, followed by compare resting-state function network in whole brain between the two groups with software of GICA to detect changes that exist in brain functional networks. Additionally, by software of REST, we study the changed brain functional network with ROI-based correlation analysis. Results GICA analysis revealed5typical brain networks among which the sensorimotor network and the so-called default mode network showed distinct differences between patients and controls. The sensorimotor network showed less activation in patients in several regions including the right primary motor cortex, sensory area and supplementary motor area, and an increased activation of posterior cingulate cortex. The default mode network network showed group differences in the middle prefrontal cortex. In addition, the ROIs coupling in sensorimotor network showed significant intrahemispheric changes in connectivity of right primary motor cortex and supplementary motor area, and interhemispheric changes in connectivity of right primary motor cortex and left primary motor cortex. Conclusions We propose that resting state GICA analysis affords a new and simple means to assess ALS neurofunctional alterations in motor network and extra-motor network. And ROI-based correlation coefficient may be used to quantificate the brain function connectivity. The combination of GICA and ROI-based correlation analysis may provide a new insight into rest-state functional connectivity of ALS, and help us make better sense of the pathogenesis. Furthermore, the neuroimaging methodology may be utilized for those with "possible" or "suspected" ALS by identifying reliable neural biomarkers.