Study of Human Cortical Microstructure Using Magnetization Transfer and T2* Mapping with Application in Multiple Sclerosis

RÉSUMÉ Description du problème: La sclérose en plaques (SEP) est une maladie dévastatrice touchant plus de 100.000 personnes au Canada (MS Society of Canada). Les déficits fonctionnels engendrés par la maladie peuvent se traduire en troubles moteurs, cognitifs et sensoriels ayant un grand impact sur les activités sociales et professionnelles des patients. Le coût socio-économique de la SEP est colossal. Premièrement, la qualité de vie des patients ainsi que celle de leur familles peut se voir considérablement altérée. Deuxièmement, les traitements diminuant les effets handicapant de la SEP sont extrêmement dispendieux, leur coût annuel est estimé à plusieurs milliards de dollars au Canada (Karampampa et al. 2012) ainsi qu’aux USA (Hartung et al. 2015). De nos jours, la SEP ne se soigne pas et les détails de sa pathophysiologie restent obscures. La SEP est une maladie du système nerveux central, chronique, inflammatoire et démyélinisante. Elle est caractérisé par la formation de lésions inflammatoires et démyélinisantes prenant place dans la moelle épinière et dans les matières blanche et grise du cerveau. Bien que l’Imagerie par Résonance Magnétique (IRM) soit resté l’outil principal de diagnostic de SEP, les lésions observées dans la matière blanche ne corrélaient que très peu avec les déficits fonctionnels observés. Récemment, il à été montré que la démyélinisation de la matière grise est un meilleur indice de l’aggravement fonctionnel (Mainero et al. 2015). Cependant, les techniques d’IRM classiques sont difficilement utilisables pour l’imagerie du cortex, en effet, son épaisseur est seulement 2 à 4 mm et la résolution spatiale d'une IRM standard est de l’ordre de grandeur de 1 mm, ce qui n’est pas suffisant pour examiner précisément la pathologies corticales. L’IRM à ultra-haut champ (7 Tesla) à été montré capable d’imager des détails microstructurels du cortex, grâce à un gain en résolution et en signal sur bruit. Récamment, il a été montré que la relaxation transverse (apellée T2*) acquise à 7 Tesla est un marqueur sensible de la progression de la pathologie corticale des patients polyscléreux, notamment, de la démyélinisation corticale (Pitt et al. 2010; Mainero et al. 2015; Cohen-Adad et al. 2011). Cependant, des effets confondants réduisent la spécificité qu’a le contraste T2* à quantifier la myéline (notamment, le contenu en fer, ou les vaisseaux sanguins) (Hwang et al. 2010; Lee et al. 2012). Une seconde mesure indépendante serait bénéfique pour augmenter la spécificité d’une potentielle estimation de quantitée de myéline. Le Ratio de Transfert de Magnétisation (MTR) à aussi été démontré sensible à la myéline dans le cortex (Derakhshan et al. 2014; Chen et al. 2013) et serait une excellent mesure----------ABSTRACT Problem description: Multiple Sclerosis (MS) is a devastating disease affecting around 100,000 people in Canada (MS Society of Canada). The functional deficits resulting from the disease include motor, cognitive and somatic troubles, affecting the social and professional activities of MS patients. The socio-economic cost of MS is colossal. Firstly, life quality of MS patients and those of their family members can be drastically hampered. Secondly, existing treatments that reduce handicapping effects of MS are expensive, with an annual cost estimated in billions of dollars in Canada (Karampampa et al. 2012) and in the USA (Hartung et al. 2015). To date, MS is not curable and its pathophysiological mechanisms are still obscure. MS is known to be a chronic, inflammatory, demyelinating disease of the central nervous system. It is characterized by the formation of inflammatory and demyelinating lesions in the spinal cord and in the brain’s white and gray matters. While Magnetic Resonance Imaging (MRI) has been the main tool for diagnosing MS, correlations of white matter lesions with functional deficits remain poor. Recently, it was shown that grey matter demyelination provides a more specific assessment of functional worsening (Mainero et al. 2015). However, it is difficult to image the grey matter with standard MRI methods because the cortex is only 2-4 mm thick and the spatial resolution of standard MRI system is on the order of 1 mm, which is not sufficient for proper examination of cortical pathology. Ultra-high field MRI (7 Tesla) was shown to reveal microstructural features thanks to an increase in signal to noise ratio and spatial resolution. Recently, transverse relaxation (characterized by a time constant: T2*) at 7 Tesla was shown to be a sensitive marker of pathology and disease progression associated with demyelination in the cortex of MS patients (Pitt et al. 2010; Mainero et al. 2015; Cohen-Adad et al. 2011). However, several confounds hamper the specificity of T2* measures (iron content, blood vessels) (Hwang et al. 2010; Lee et al. 2012). An independent measure would increase the specificity to the myelin content. Magnetization Transfer Ratio (MTR) imaging has been shown to be sensitive to myelin content (Derakhshan et al. 2014; Chen et al. 2013) and thus would be an excellent complementary measure because its underlying contrast mechanisms are different than that from T2*. However, mapping MTR and T2* in the cortex is challenging because the cortical ribbon is thin, highly convoluted and its geometry varies across individuals

Quantitative MRI provides markers of intra-, inter-regional, and age-related differences in young adult cortical microstructure

Measuring the structural composition of the cortex is critical to understanding typical development, yet few investigations in humans have charted markers in vivo that are sensitive to tissue microstructural attributes. Here, we used a well-validated quantitative MR protocol to measure four parameters (R1, MT, R2*, PD*) that differ in their sensitivity to facets of the tissue microstructural environment (R1, MT: myelin, macromolecular content; R2*: myelin, paramagnetic ions, i.e., iron; PD*: free water content). Mapping these parameters across cortical regions in a young adult cohort (18–39 years, N = 93) revealed expected patterns of increased macromolecular content as well as reduced tissue water content in primary and primary adjacent cortical regions. Mapping across cortical depth within regions showed decreased expression of myelin and related processes – but increased tissue water content – when progressing from the grey/white to the grey/pial boundary, in all regions. Charting developmental change in cortical microstructure cross-sectionally, we found that parameters with sensitivity to tissue myelin (R1 & MT) showed linear increases with age across frontal and parietal cortex (change 0.5–1.0% per year). Overlap of robust age effects for both parameters emerged in left inferior frontal, right parietal and bilateral pre-central regions. Our findings afford an improved understanding of ontogeny in early adulthood and offer normative quantitative MR data for inter- and intra-cortical composition, which may be used as benchmarks in further studies

Fractional order magnetic resonance fingerprinting in the human cerebral cortex

Mathematical models are becoming increasingly important in magnetic resonance imaging (MRI), as they provide a mechanistic approach for making a link between tissue microstructure and signals acquired using the medical imaging instrument. The Bloch equations, which describes spin and relaxation in a magnetic field, is a set of integer order differential equations with a solution exhibiting mono-exponential behaviour in time. Parameters of the model may be estimated using a non-linear solver, or by creating a dictionary of model parameters from which MRI signals are simulated and then matched with experiment. We have previously shown the potential efficacy of a magnetic resonance fingerprinting (MRF) approach, i.e. dictionary matching based on the classical Bloch equations, for parcellating the human cerebral cortex. However, this classical model is unable to describe in full the mm-scale MRI signal generated based on an heterogenous and complex tissue micro-environment. The time-fractional order Bloch equations has been shown to provide, as a function of time, a good fit of brain MRI signals. We replaced the integer order Bloch equations with the previously reported time-fractional counterpart within the MRF framework and performed experiments to parcellate human gray matter, which is cortical brain tissue with different cyto-architecture at different spatial locations. Our findings suggest that the time-fractional order parameters, {\alpha} and {\beta}, potentially associate with the effect of interareal architectonic variability, hypothetically leading to more accurate cortical parcellation

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics

Ultra‐high field MRI across the depth of the cortex has the potential to provide anatomically precise biomarkers and mechanistic insights into neurodegenerative disease like Huntington's disease that show layer‐selective vulnerability. Here we compare multi‐parametric mapping (MPM) measures across cortical depths for a 7T 500 μm whole brain acquisition to (a) layer‐specific cell measures from the von Economo histology atlas, (b) layer‐specific gene expression, using the Allen Human Brain atlas and (c) white matter connections using high‐fidelity diffusion tractography, at a 1.3 mm isotropic voxel resolution, from a 300mT/m Connectom MRI system. We show that R2*, but not R1, across cortical depths is highly correlated with layer‐specific cell number and layer‐specific gene expression. R1‐ and R2*‐weighted connectivity strength of cortico‐striatal and intra‐hemispheric cortical white matter connections was highly correlated with grey matter R1 and R2* across cortical depths. Limitations of the layer‐specific relationships demonstrated are at least in part related to the high cross‐correlations of von Economo atlas cell counts and layer‐specific gene expression across cortical layers. These findings demonstrate the potential and limitations of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics

Ultra-high field MRI across the depth of the cortex has the potential to provide ana- tomically precise biomarkers and mechanistic insights into neurodegenerative disease like Huntington's disease that show layer-selective vulnerability. Here we compare multi-parametric mapping (MPM) measures across cortical depths for a 7T 500 m whole brain acquisition to (a) layer-specific cell measures from the von Economo his- tology atlas, (b) layer-specific gene expression, using the Allen Human Brain atlas and (c) white matter connections using high-fidelity diffusion tractography, at a 1.3 mm isotropic voxel resolution, from a 300mT/m Connectom MRI system. We show that R2*, but not R1, across cortical depths is highly correlated with layer-specific cell number and layer-specific gene expression. R1- and R2*-weighted connectivity strength of cortico-striatal and intra-hemispheric cortical white matter connections was highly correlated with grey matter R1 and R2* across cortical depths. Limitations of the layer-specific relationships demonstrated are at least in part related to the high cross-correlations of von Economo atlas cell counts and layer-specific gene expres- sion across cortical layers. These findings demonstrate the potential and limitations of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease

High resolution quantitative and functional MRI indicate lower myelination of thin and thick stripes in human secondary visual cortex

The characterization of cortical myelination is essential for the study of structure-function relationships in the human brain. However, knowledge about cortical myelination is largely based on post mortem histology, which generally renders direct comparison to function impossible. The repeating pattern of pale-thin-pale-thick stripes of cytochrome oxidase (CO) activity in the primate secondary visual cortex (V2) is a prominent columnar system which is known to be differentiable by myelin content as well. However, depending on the applied histological method, higher myelination in both thin/thick and pale stripes were found, respectively. We used quantitative magnetic resonance imaging (qMRI) in conjunction with functional magnetic resonance imaging (fMRI) at ultra-high field strength (7T) to localize and study myelination of stripes in several humans at sub-millimeter resolution in vivo. Thin and thick stripes were functionally localized by exploiting their sensitivity to color and binocular disparity, respectively. Resulting functional activation maps showed robust stripe patterns in V2 which enabled further comparison of quantitative relaxation parameters between stripe types. Thereby, we found lower longitudinal relaxation rates (R1) of thin and thick stripes compared to surrounding gray matter in the order of 1-2%, indicating higher myelination of pale stripes. No differences for effective transverse relaxation rates (R2*) were found. The study demonstrates the feasibility to investigate structure-function relationships in living humans within one cortical area at the level of columnar systems using qMRI

Linking the cortical microstructure to oscillatory dynamics through in vivo imaging

Uncovering the intricate relationship between the brain’s structure and function remains a fundamental goal of the neuroscience field. Significantly, recent advancesin the neuroimaging field are now allowing for the investigation of this relationship at the microstructural level, opening up a wealth of new research possibilities. Of particular interest, is the ability to probe the myelin content of the cortex non- invasively and with high resolution. Notably a close relationship is known to exist between the cyto and myelo architecture of the brain and converging lines of evidence point to the potential existence of a relationship between myelination of the cortical grey matter and electrophysiological responses. Of particular interest in this regard are neural oscillations, which have been widely implicated in a variety of cognitive processes and clinical conditions. Thus, this thesis seeks to explore the possibility of investigating the relationship between a key aspect of the cortical microstructure, namely its myelin content and oscillatory dynamics in-vivo, through the use of highresolution 7T MRI in combination with MEG. Ultimately, the novel insights gained through this approach could have important implications for the understanding of brain structure-function relationships in both health and diseas