Alternative Neuropsychological and Magnetic Resonance Imaging Measures in Multiple Sclerosis: Exploring the relation between brain lesion measured by diffusion tensor magnetic resonance imaging and interhemispheric communication and processing speed in multiple sclerosis

Multiple sclerosis (MS) is a chronic neurological disease of the central nerve system that affects young adults with a higher prevalence in women (ratio 3:2). The neuropathology of the disease is characterised by demyelination of the white matter in the brain and central cord. MS may involve degeneration of white matter throughout the nervous system, with a predilection for specific target zones that includes the corpus callosum. The pathologic process may lead to motor problems, but halve of the patients has cognitive problems associated with MS. In this thesis, we focus on the cognitive problems and the relation with neuropathological brain damage. One of the brain areas preferentially involved in MS, is the corpus callosum. This brain structure is the largest white matter tract connecting both hemispheres. Research in callosotomy patients, acallosal patients and callosal section patients indicates that robust callosal damage may lead to interhemispheric transfer dysfunctions. In the first part of this thesis callosal problems in MS are explored. Damage to the corpus callosum in this patient group is subtler than in callosotomy patients. Moreover, the callosal damage strongly varies from patient to patient. In this thesis the redundancy gain paradigm, a behavioural measure to investigate interhemispheric communication is used. In this task, flashes of light are presented to the left, right or bilateral (left and right simultaneously) visual hemifield while the subject fixates to the middle of the screen. As soon as the subject detects a flash, he presses the response button with the left or right hand (detection task). An effect that is typically observed in healthy subjects is that reaction times to bilateral stimuli are faster than to unilateral stimuli. This effect is referred to as the redundancy gain effect. Previous research shows that the redundancy gain effect is enlarged in patients with callosal problems (acallosal patients or patients with callosal section). The results in this thesis show, in analogy with the results in patients with robust callosal damage, an enlarged redundancy gain effect for MS patients. These results demonstrate the sensitiveness of the redundancy gain paradigm to investigate callosal problems in MS. To explore the effect of the amount of callosal brain damage on the redundancy gain effect, the callosal damage needs to be quantified. For this purpose diffusion tensor imaging was used. With this technique, water diffusion in the white matter can be investigated. Water in the brain spreads preferentially along the direction of the axonal fibers. Intact myelin sheets are effective barriers for the water. Demyelination, an important pathological aspect of MS, leads to decreased delineation of the tracts along which the water spreads. This results in changed diffusion derived measures. Fractional anisotropy is an important diffusion derived measure for inter- and intravoxel fiber coherence. Previous research shows that fractional anisotropy is decreased in MS patients compared to healthy controls. To calculate the fractional anisotropy, diffusion measures along three directions are defined, more specific along the principal direction, along the direction of minimal diffusion and along a third Alternative Neuropsychological and MRI Measures in MS 89 Summary direction that is orthogonal to the previous two. With this information, the longitudinal and transverse diffusivity can be calculated. Longitudinal diffusivity is the diffusion eigenvalue along the principal direction, whereas the transverse diffusivity is the mean of the eigenvalues along the other two directions. Recent research shows that demyelination and axonal loss, specific for MS pathology, is characterised by increased transverse diffusivity. Hence, transverse diffusivity is a unique marker for MS. The results of this thesis confirm this and show that transverse diffusivity is significantly more increased than longitudinal diffusivity in MS patients compared to healthy matched controls. Thirdly, a correlation between the behavioural results, the redundancy gain effect, and the brain imaging measures, the diffusion derived measures, was found: the larger the transverse diffusivity, or in other words, the MS related callosal damage, the larger the redundancy gain effect in MS patients. Moreover, neither longitudinal diffusivity, nor callosal lesion load as defined on conventional T2 images were additional factors in explaining this correlation. The results of the first part of this thesis show a) that the redundancy gain paradigm is a sensitive measure to investigate callosal brain damage in MS, b) that diffusion derived parameters are subtle measures to indicate MS related brain damage and c) that a significant correlation between callosal brain damage and the redundancy gain effect could be found in MS patients. In the second part of this thesis the focus was on the relation between cerebral brain damage as defined by diffusion derived measures and information processing speed in MS. Information processing speed is a cognitive measure tested by the Paced Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), two commonly used neuropsychological tests in MS. A significant correlation between the performance on the SDMT and transverse diffusivity in the whole brain was found in MS patients, indicating that demyelination and axonal damage, characteristic for MS pathology, are important factors for explaining the slowed information processing speed in MS. No correlation was found with the performance on the PASAT, which can be explained by the weaker psychometric qualities of the PASAT compared to the SDMT. First of all, the results of this thesis corroborate the heterogeneous pathological condition in MS. Research on callosal problems in MS can not be done without considering these individual differences. Based on our results, diffusion weighted imaging seems to offer a promising technique to determine cerebral damage in MS. Transverse diffusivity, considered to be a unique benchmark of white matter demyelination as seen in MS, is of special interest. Moreover, this diffusion derived measures correlate with cognitive (dys)function in MS, a correlation not consistently found for conventional imaging (lesion load on T2 of T1 images)

Assessing Functional Deficits at Optic Neuritis Onset in EAE Mice Using Manganese-Enhanced MRI (MEMRI) and Diffusion fMRI

Optic neuritis: ON) is frequently a first sign of multiple sclerosis: MS), which is an inflammatory demyelinative disease of the central nerve system: CNS), including brain, optic nerve, and spinal cord. Investigating ON provides an approach to improve MS diagnosis and treatment monitoring. Experimental autoimmune encephalomyelitis: EAE) is a widely used animal model of MS and exhibits pathologies similar to the human disease. Magnetic resonance imaging: MRI) is a non-invasive tool to detect disease progress and as a standard diagnose procedure for MS in the clinic. In biological samples, the hydrogen nuclei are used to produce the MR signal due to its abundance in water and fat. As a result of tissue microstructural differences, 1H nuclei exhibit tissue-specific and pathology-specific relaxation and diffusion properties, which are reflected in the resulting MR image contrast. Therefore, the pathologies of MS, such as inflammation, demyelination, and axonal injury can be detected using different MR-related tools, including T1- and T2-weighted imaging, diffusion-weighted imaging, and diffusion tensor imaging, and so on. Importantly, direct non-invasive assessment of functional deficits could be important for understanding pathology mechanisms or provide a useful bio-index to validate treatment strategies. In this dissertation, manganese-enhanced MRI: MEMRI) and diffusion fMRI were introduced to explore the functional deficits, including axonal transport disruption and axon-activity dysfunction, at optic neuritis onset in EAE mice

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

Longitudinal assessment of white matter pathology in the injured mouse spinal cord through ultra-high field (16.4T) in vivo diffusion tensor imaging

This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 70 mu m in-plane resolution, 1 mm slice thickness) to evaluate the spatiotemporal development of severe mid-thoracic contusive spinal cord injury (SCI) in mice. In vivo imaging was performed prior to SCI, then again at 2 h, 1 day, 3 days, 7 days, and 30 days post-SCI using a Bruker 16.4 T small animal nuclear magnetic resonance spectrometer. Cross-sectional spinal cord areas were measured in axial slices and various DTI parameters, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(parallel to)) and radial diffusivity (lambda(perpendicular to)), were calculated for the total spared white matter (WM), ventral funiculi (VF), lateral funiculi (LF) and dorsal columns (DCs) and then correlated with histopathology. Cross-sectional area measurements revealed significant atrophy (32% reduction) of the injured spinal cord at the lesion epicentre in the chronic phase of injury. Analysis of diffusion tensor parameters further showed that tissue integrity was most severely affected in the DCs, i.e. the site of immediate impact, which demonstrated a rapid and permanent decrease in FA and lambda(parallel to). In contrast, DTI parameters for the ventrolateral white matter changed more gradually with time, suggesting that these regions are undergoing more delayed degeneration in a manner that may be amenable to therapeutic intervention. Of all the DTI parameters, lambda(perpendicular to) was most closely correlated to myelin content whereas changes in FA and lambda(parallel to) appeared more indicative of axonal integrity, Wallerian degeneration and associated presence of macrophages. We conclude that longitudinal DTI at 16.4 T provides a clinically relevant, objective measure for assessing white matter pathology following contusive SCI in mice that may aid the translation of putative neuroprotective strategies into the clinic. (C) 2013 Elsevier Inc. All rights reserved

Correlation of Diffusion and Metabolic Alterations in Different Clinical Forms of Multiple Sclerosis

Diffusion tensor imaging (DTI) and MR spectroscopic imaging (MRSI) provide greater sensitivity than conventional MRI to detect diffuse alterations in normal appearing white matter (NAWM) of Multiple Sclerosis (MS) patients with different clinical forms. Therefore, the goal of this study is to combine DTI and MRSI measurements to analyze the relation between diffusion and metabolic markers, T2-weighted lesion load (T2-LL) and the patients clinical status. The sensitivity and specificity of both methods were then compared in terms of MS clinical forms differentiation. MR examination was performed on 71 MS patients (27 relapsing remitting (RR), 26 secondary progressive (SP) and 18 primary progressive (PP)) and 24 control subjects. DTI and MRSI measurements were obtained from two identical regions of interest selected in left and right centrum semioval (CSO) WM. DTI metrics and metabolic contents were significantly altered in MS patients with the exception of N-acetyl-aspartate (NAA) and NAA/Choline (Cho) ratio in RR patients. Significant correlations were observed between diffusion and metabolic measures to various degrees in every MS patients group. Most DTI metrics were significantly correlated with the T2-LL while only NAA/Cr ratio was correlated in RR patients. A comparison analysis of MR methods efficiency demonstrated a better sensitivity/specificity of DTI over MRSI. Nevertheless, NAA/Cr ratio could distinguish all MS and SP patients groups from controls, while NAA/Cho ratio differentiated PP patients from controls. This study demonstrated that diffusivity changes related to microstructural alterations were correlated with metabolic changes and provided a better sensitivity to detect early changes, particularly in RR patients who are more subject to inflammatory processes. In contrast, the better specificity of metabolic ratios to detect axonal damage and demyelination may provide a better index for identification of PP patients

Diffusion Tensor Imaging Based Tractography of Human Brain Fiber Bundles

Tractography is a non-invasive process for reconstruction, modeling and visualization of neural fibers in the white matter (WM) of human brain. It has emerged as a major breakthrough for neuroscience research due to its usefulness in clinical applications. Two types of tractography approaches: deterministic and probabilistic have been investigated to evaluate their performances on tracking fiber bundles using diffusion tensor imaging (DTI). The images are taken by applying pulsed magnetic fields in multiple gradient directions. After removing the non-brain areas from the images, the diffusion tensor indices for each image voxel are calculated. White matter connectivity of the brain, i.e. tractography, is primarily based upon streamline algorithms where the local tract direction is defined by the principle direction of the diffusion tensor. Simulations are performed using three approaches: fiber assignment by continuous tracking (FACT), probability index of connectivity (PICo) and Gibbs tracking (GT). Simulation results show that probabilistic tractography i.e. PICo and GT can reconstruct longer length of fibers compared to the deterministic approach-FACT but with a cost of high computation time. Moreover, GT handles the more complex fiber configurations of crossing and kissing fibers, more effectively and provides the best reconstruction of fibers. In addition, diffusion tensor indices: fractional anisotropy (FA) and mean diffusivity (MD) for a region of interest can be quantified and used to assess several brain diseases. Prospective investigation of DTI based tractography can reveal useful information on WM architecture in normal and diseased brain which will speed up the detection and treatment of various brain diseases

Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats

Blocking the action of inhibitory molecules at sites of central nervous system injury has been proposed as a strategy to promote axonal regeneration and functional recovery. We have previously shown that genetic deletion or competitive antagonism of EphA4 receptor activity promotes axonal regeneration and functional recovery in a mouse model of lateral hemisection spinal cord injury. Here we have assessed the effect of blocking EphA4 activation using the competitive antagonist EphA4-Fc in a rat model of thoracic contusive spinal cord injury. Using a ledged tapered balance beam and open-field testing, we observed significant improvements in recovery of locomotor function after EphA4-Fc treatment. Consistent with functional improvement, using high-resolution ex vivo magnetic resonance imaging at 16.4T, we found that rats treated with EphA4-Fc had a significantly increased cross-sectional area of the dorsal funiculus caudal to the injury epicenter compared with controls. Our findings indicate that EphA4-Fc promotes functional recovery following contusive spinal cord injury and provides further support for the therapeutic benefit of treatment with the competitive antagonist in acute cases of spinal cord injury

Development of Advanced, Clinically Feasible Neuroimaging Methodology with Diffusional Kurtosis Imaging

Diffusion MRI (dMRI) is a powerful, non-invasive tool for probing the structural organization of the human brain. Quantitative dMRI analyses provide unique capabilities for the characterization of tissue microstructure as well as imaging contrast that is not available to other modalities. White matter tractography relies on dMRI and is currently the only non-invasive technique for mapping structural connections in the human brain. In this chapter, we will describe diffusional kurtosis imaging, an effective and versatile dMRI technique, and discuss a clinical problem in temporal lobe epilepsy (TLE) which is insurmountable with current diagnostic approaches. Subsequent chapters will further develop the capabilities of DKI and demonstrate how it may be particularly well suited to overcome current barriers to care in the clinical management of TLE