Insight into the fundamental trade-offs of diffusion MRI from polarization-sensitive optical coherence tomography in ex vivo human brain

In the first study comparing high angular resolution diffusion MRI (dMRI) in the human brain to axonal orientation measurements from polarization-sensitive optical coherence tomography (PSOCT), we compare the accuracy of orientation estimates from various dMRI sampling schemes and reconstruction methods. We find that, if the reconstruction approach is chosen carefully, single-shell dMRI data can yield the same accuracy as multi-shell data, and only moderately lower accuracy than a full Cartesian-grid sampling scheme. Our results suggest that current dMRI reconstruction approaches do not benefit substantially from ultra-high b-values or from very large numbers of diffusion-encoding directions. We also show that accuracy remains stable across dMRI voxel sizes of 1 ​mm or smaller but degrades at 2 ​mm, particularly in areas of complex white-matter architecture. We also show that, as the spatial resolution is reduced, axonal configurations in a dMRI voxel can no longer be modeled as a small set of distinct axon populations, violating an assumption that is sometimes made by dMRI reconstruction techniques. Our findings have implications for in vivo studies and illustrate the value of PSOCT as a source of ground-truth measurements of white-matter organization that does not suffer from the distortions typical of histological techniques.Published versio

Cortical lamina-dependent blood volume changes in human brain at 7T

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6 mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans

Neural Representations of Visual Motion Processing in the Human Brain Using Laminar Imaging at 9.4 Tesla

During natural behavior, much of the motion signal falling into our eyes is due to our own movements. Therefore, in order to correctly perceive motion in our environment, it is important to parse visual motion signals into those caused by self-motion such as eye- or head-movements and those caused by external motion. Neural mechanisms underlying this task, which are also required to allow for a stable perception of the world during pursuit eye movements, are not fully understood. Both, perceptual stability as well as perception of real-world (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. The central aim of this thesis is to examine whether different levels of cortical depth or distinct columnar structures of visual motion regions are differentially involved in disentangling signals related to self-motion, objective, or object motion. Based on previous studies reporting segregated populations of voxels in high level visual areas such as V3A, V6, and MST responding predominantly to either retinal or extra- retinal (‘real’) motion, we speculated such voxels to reside within laminar or columnar functional units. We used ultra-high field (9.4T) fMRI along with an experimental paradigm that independently manipulated retinal and extra-retinal motion signals (smooth pursuit) while controlling for effects of eye-movements, to investigate whether processing of real world motion in human V5/MT, putative MST (pMST), and V1 is associated to differential laminar signal intensities. We also examined motion integration across cortical depths in human motion areas V3A and V6 that have strong objective motion responses. We found a unique, condition specific laminar profile in human area V6, showing reduced mid-layer responses for retinal motion only, suggestive of an inhibitory retinal contribution to motion integration in mid layers or alternatively an excitatory contribution in deep and superficial layers. We also found evidence indicating that in V5/MT and pMST, processing related to retinal, objective, and pursuit motion are either integrated or colocalized at the scale of our resolution. In contrast, in V1, independent functional processes seem to be driving the response to retinal and objective motion on the one hand, and to pursuit signals on the other. The lack of differential signals across depth in these regions suggests either that a columnar rather than laminar segregation governs these functions in these areas, or that the methods used were unable to detect differential neural laminar processing. Furthermore, the thesis provides a thorough analysis of the relevant technical modalities used for data acquisition and data analysis at ultra-high field in the context of laminar fMRI. Relying on our technical implementations we were able to conduct two high-resolution fMRI experiments that helped us to further investigate the laminar organization of self-induced and externally induced motion cues in human high-level visual areas and to form speculations about the site and the mechanisms of their integration

High-Field Functional MRI from the Perspective of Single Vessels in Rats and Humans

Functional MRI (fMRI) has been employed to map brain activity and connectivity based on the neurovascular coupled hemodynamic signal. However, in most cases of fMRI studies, the cerebral vascular hemodynamic signal has been imaged in a spatially smoothed manner due to the limit of spatial resolution. There is a need to improve the spatiotemporal resolution of fMRI to map dynamic signal from individual venule or individual arteriole directly. Here, the thesis aims to provide a vascular-specific view of hemodynamic response during active state or resting state. To better characterize the temporal features of task-related fMRI signal from different vascular compartments, we implemented a line-scanning method to acquire vessel-specific blood-oxygen-level-dependent (BOLD) / cerebral-blood-volume (CBV) fMRI signal at 100-ms temporal resolution with sensory or optogenetic stimulation. Furthermore, we extended the line-scanning method with multi-echo scheme to provide vessel-specific fMRI with the higher contrast-to-noise ratio (CNR), which allowed us to directly map the distinct evoked hemodynamic signal from arterioles and venules at different echo time (TE) from 3 ms to 30 ms. The line-scanning fMRI methods acquire single k-space line per TR under a reshuffled k space acquisition scheme which has the limitation of sampling the fMRI signal in real-time for resting-state fMRI studies. To overcome this, we implemented a balanced Steady-state free precession (SSFP) to map task-related and resting-state fMRI (rsfMRI) with high spatial resolution in anesthetized rats. We reveal venule-dominated functional connectivity for BOLD fMRI and arteriole-dominated functional connectivity for CBV fMRI. The BOLD signal from individual venules and CBV signal from individual arterioles show correlations at an ultra-slow frequency (< 0.1 Hz), which are correlated with the intracellular calcium signal measured in neighboring neurons. In complementary data from awake human subjects, the BOLD signal is spatially correlated among sulcus veins and specified intracortical veins of the visual cortex at similar ultra-slow rhythms. This work provides a high-resolution fMRI approach to resolve brain activation and functional connectivity at the level of single vessels, which opened a new avenue to investigate brian functional connectivity at the scale of vessels

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

In vivo Structural Imaging of the Cerebellum, the Contribution of Ultra-High Fields

This review covers some of the contributions to date from cerebellar imaging studies performed at ultra-high magnetic fields. A short overview of the general advantages and drawbacks of the use of such high field systems for imaging is given. One of the biggest advantages of imaging at high magnetic fields is the improved spatial resolution, achievable thanks to the increased available signal-to-noise ratio. This high spatial resolution better matches the dimensions of the cerebellar substructures, allowing a better definition of such structures in the images. The implications of the use of high field systems is discussed for several imaging sequences and image contrast mechanisms. This review covers studies which were performed in vivo in both rodents and humans, with a special focus on studies that were directed towards the observation of the different cerebellar layer