Alexandru V. Avram

Magnetic susceptibility anisotropy of human brain in vivo and its molecular underpinnings.

Frequency shift of gradient-echo MRI provides valuable information for assessing brain tissues. Recent studies suggest that the frequency and susceptibility contrast depend on white matter fiber orientation. However, the molecular underpinning of the orientation dependence is unclear. In this study, we investigated the orientation dependence of susceptibility of human brain in vivo and mouse brains ex vivo. The source of susceptibility anisotropy in white matter is likely to be myelin as evidenced by the loss of anisotropy in the dysmyelinating shiverer mouse brain. A biophysical model is developed to investigate the effect of the molecular susceptibility anisotropy of myelin components, especially myelin lipids, on the bulk anisotropy observed by MRI. This model provides a consistent interpretation of the orientation dependence of macroscopic magnetic susceptibility in normal mouse brain ex vivo and human brain in vivo and the microscopic origin of anisotropic susceptibility. It is predicted by the theoretical model and illustrated by the experimental data that the magnetic susceptibility of the white matter is least diamagnetic along the fiber direction. This relationship allows an efficient extraction of fiber orientation using susceptibility tensor imaging. These results suggest that anisotropy on the molecular level can be observed on the macroscopic level when the molecules are aligned in a highly ordered manner. Similar to the utilization of magnetic susceptibility anisotropy in elucidating molecular structures, imaging magnetic susceptibility anisotropy may also provide a useful tool for elucidating the microstructure of ordered biological tissues.

Integrated Laplacian-based phase unwrapping and background phase removal for quantitative susceptibility mapping

Quantitative susceptibility mapping (QSM) is a recently developed MRI technique that provides a quantitative measure of tissue magnetic susceptibility. To compute tissue magnetic susceptibilities based on gradient echoes, QSM requires reliable unwrapping of the measured phase images and removal of contributions caused by background susceptibilities. Typically, the two steps are performed separately. Here, we present a method that simultaneously performs phase unwrapping and HARmonic (background) PhasE REmovaL using the LAplacian operator (HARPERELLA). Both numerical simulations and in vivo human brain images show that HARPERELLA effectively removes both phase wraps and background phase, whilst preserving all low spatial frequency components originating from brain tissues. When compared with other QSM phase preprocessing techniques, such as path‐based phase unwrapping followed by background phase removal, HARPERELLA preserves the tissue phase signal in gray matter, white matter and cerebrospinal fluid with excellent robustness, providing a convenient and accurate solution for QSM. The proposed algorithm is provided, together with QSM and susceptibility tensor imaging (STI) tools, in a shared software package named ‘STI Suite’. Copyright

Fast and tissue-optimized mapping of magnetic susceptibility and T2* with multi-echo and multi-shot spirals

Gradient-echo MRI of resonance-frequency shift and T2* values exhibit unique tissue contrast and offer relevant physiological information. However, acquiring 3D-phase images and T2* maps with the standard spoiled gradient echo (SPGR) sequence is lengthy for routine imaging at high-spatial resolution and whole-brain coverage. In addition, with the standard SPGR sequence, optimal signal-to-noise ratio (SNR) cannot be achieved for every tissue type given their distributed resonance frequency and T2* value. To address these two issues, a SNR optimized multi-echo sequence with a stack-of-spiral acquisition is proposed and implemented for achieving fast and simultaneous acquisition of image phase and T2* maps. The analytical behavior of the phase SNR is derived as a function of resonance frequency, T2* and echo time. This relationship is utilized to achieve tissue optimized SNR by combining phase images with different echo times. Simulations and in vivo experiments were designed to verify the theoretical predictions. Using the multi-echo spiral acquisition, whole-brain coverage with 1 mm isotropic resolution can be achieved within 2.5 min, shortening the scan time by a factor of 8. The resulting multi-echo phase map shows similar SNR to that of the standard SPGR. The acquisition can be further accelerated with non-Cartesian parallel imaging. The technique can be readily extended to other multi-shot readout trajectories besides spiral. It may provide a practical acquisition strategy for high resolution and simultaneous 3D mapping of magnetic susceptibility and T2*.

In vivo detection of microscopic anisotropy using quadruple pulsed-field gradient (qPFG) diffusion MRI on a clinical scanner

We report our design and implementation of a quadruple pulsed-field gradient (qPFG) diffusion MRI pulse sequence on a whole-body clinical scanner and demonstrate its ability to non-invasively detect restriction-induced microscopic anisotropy in human brain tissue. The microstructural information measured using qPFG diffusion MRI in white matter complements that provided by diffusion tensor imaging (DTI) and exclusively characterizes diffusion of water trapped in microscopic compartments with unique measures of average cell geometry. We describe the effect of white matter fiber orientation on the expected MR signal and highlight the importance of incorporating such information in the axon diameter measurement using a suitable mathematical framework. Integration of qPFG diffusion-weighted images (DWI) with fiber orientations measured using high-resolution DTI allows the estimation of average axon diameters in the corpus callosum of healthy human volunteers. Maps of inter-hemispheric average axon diameters reveal an anterior-posterior variation in good topographical agreement with anatomical measurements reported in previous post-mortem studies. With further technical refinements and additional clinical validation, qPFG diffusion MRI could provide a quantitative whole-brain histological assessment of white and gray matter, enabling a wide range of neuroimaging applications for improved diagnosis of neurodegenerative pathologies, monitoring neurodevelopmental processes, and mapping brain connectivity.

Diffusion MRI properties of the human uncinate fasciculus correlate with the ability to learn visual associations

The uncinate fasciculus (UF) is a cortico-cortico white matter pathway that links the anterior temporal and the orbitofrontal cortex (OFC). In the monkey, transection of the UF causes significant impairments in learning conditional visual-visual associations, while object discrimination remains intact, suggesting an important role for the UF in mediating the learning of complex visual associations. Whether this functional role extends to the human UF has not been tested directly. Here, we used diffusion tensor magnetic resonance imaging (dMRI) and behavioral experiments to examine the relation between learning visual associations and the structural properties of the human UF. In a group of healthy adults, we segmented the UF and the inferior longitudinal fasciculus (ILF) and derived dMRI measures of the structural properties of the two pathways. We also used a behavioral experiment adapted from the monkey studies to characterize the ability of these individuals to learn to associate a persons face with a group of specific scenes (conditional visual-visual association). We then tested whether the variability in the dMRI measures of the two pathways correlated with variability in the ability to rapidly learn the face-place associations. Our study suggests that in the human, the left UF may be important for mediating the rapid learning of conditional visual-visual associations whereas the right UF may play an important role in the immediate retrieval of visual-visual associations. These results provide preliminary evidence suggesting similarities and differences in the functional role of the UF in monkeys compared to humans. The findings presented here contribute to our understanding of the functional role of the UF in humans and the functional neuroanatomy of the brain networks involved in visual cognition.

Myelin water weighted diffusion tensor imaging

In this study we describe our development and implementation of a magnetization transfer (MT) prepared stimulated-echo diffusion tensor imaging (DTI) technique that can be made sensitive to the microanatomy of myelin tissue. The short echo time (TE) enabled by the stimulated-echo acquisition preserves significant signal from the short T(2) component (myelin water), and the MT preparation further provides differentiating sensitization to this signal. It was found that this combined strategy could provide sufficient sensitivity in our first attempt to image myelin microstructure. Compared to the diffusion tensor derived from the conventional DTI technique, the myelin water weighted (MWW) tensor has the same principal diffusion direction but exhibits a significant increase in fractional anisotropy (FA), which is mainly due to a decrease in radial diffusivity. These findings are consistent with the microstructural organization of the myelin sheaths that wrap around the axons in the white matter and therefore hinder radial diffusion. Given that many white matter diseases (e.g. multiple sclerosis) begin with a degradation of myelin microanatomy but not a loss of myelin content (e.g. loosening of the myelin sheaths), our newly implemented MWW DTI has the potential to lead to improved assessment of myelin pathology and early detection of demyelination.

Two-dimensional phase cycled reconstruction for inherent correction of echo-planar imaging Nyquist artifacts.

The inconsistency of k‐space trajectories results in Nyquist artifacts in echo‐planar imaging (EPI). Traditional techniques often only correct for phase errors along the frequency‐encoding direction (one‐dimensional correction), which may leave significant residual artifacts, particularly for oblique‐plane EPI or in the presence of cross‐term eddy currents. As compared with one‐dimensional correction, two‐dimensional (2D) phase correction can be much more effective in suppressing Nyquist artifacts. However, most existing 2D correction methods require reference scans and may not be generally applicable to different imaging protocols. Furthermore, EPI reconstruction with these 2D phase correction methods is susceptible to error amplification due to subject motion. To address these limitations, we report an inherent and general 2D phase correction technique for EPI Nyquist removal. First, a series of images are generated from the original dataset, by cycling through different possible values of phase errors using a 2D reconstruction framework. Second, the image with the lowest artifact level is identified from images generated in the first step using criteria based on background energy in sorted and sigmoid‐weighted signals. In this report, we demonstrate the effectiveness of our new method in removing Nyquist ghosts in single‐shot, segmented and parallel EPI without acquiring additional reference scans and the subsequent error amplifications. Magn Reson Med, 2011.

Clinical feasibility of using mean apparent propagator (MAP) MRI to characterize brain tissue microstructure.

Diffusion tensor imaging (DTI) is the most widely used method for characterizing noninvasively structural and architectural features of brain tissues. However, the assumption of a Gaussian spin displacement distribution intrinsic to DTI weakens its ability to describe intricate tissue microanatomy. Consequently, the biological interpretation of microstructural parameters, such as fractional anisotropy or mean diffusivity, is often equivocal. We evaluate the clinical feasibility of assessing brain tissue microstructure with mean apparent propagator (MAP) MRI, a powerful analytical framework that efficiently measures the probability density function (PDF) of spin displacements and quantifies useful metrics of this PDF indicative of diffusion in complex microstructure (e.g., restrictions, multiple compartments). Rotation invariant and scalar parameters computed from the MAP show consistent variation across neuroanatomical brain regions and increased ability to differentiate tissues with distinct structural and architectural features compared with DTI-derived parameters. The return-to-origin probability (RTOP) appears to reflect cellularity and restrictions better than MD, while the non-Gaussianity (NG) measures diffusion heterogeneity by comprehensively quantifying the deviation between the spin displacement PDF and its Gaussian approximation. Both RTOP and NG can be decomposed in the local anatomical frame for reference determined by the orientation of the diffusion tensor and reveal additional information complementary to DTI. The propagator anisotropy (PA) shows high tissue contrast even in deep brain nuclei and cortical gray matter and is more uniform in white matter than the FA, which drops significantly in regions containing crossing fibers. Orientational profiles of the propagator computed analytically from the MAP MRI series coefficients allow separation of different fiber populations in regions of crossing white matter pathways, which in turn improves our ability to perform whole-brain fiber tractography. Reconstructions from subsampled data sets suggest that MAP MRI parameters can be computed from a relatively small number of DWIs acquired with high b-value and good signal-to-noise ratio in clinically achievable scan durations of less than 10min. The neuroanatomical consistency across healthy subjects and reproducibility in test-retest experiments of MAP MRI microstructural parameters further substantiate the robustness and clinical feasibility of this technique. The MAP MRI metrics could potentially provide more sensitive clinical biomarkers with increased pathophysiological specificity compared to microstructural measures derived using conventional diffusion MRI techniques.

Lorentz effect imaging of ionic currents in solution.

Current functional MRI techniques relying on hemodynamic modulations are inherently limited in their ability to accurately localize neural activity in space and time. To address these limitations, we previously proposed a novel technique based on the Lorentz effect and demonstrated its ability to directly image minute electrical activity with a millisecond temporal resolution in gel phantoms containing conductive wires as well as in the human median nerve in vivo. To better characterize its contrast mechanism and ultimately further improve its sensitivity for in vivo applications, we now apply this technique to image ionic currents in solution, which serve as a better model for neural conduction in biological systems than the electronic currents in conductive wires used in previous phantom studies. Our results demonstrate that ionic currents with durations and current densities on the same order of magnitude as those induced by neuroelectric activity in nerve fibers and in the brain can be detected.

Diffusion MRI and the detection of alterations following traumatic brain injury

This article provides a review of brain tissue alterations that may be detectable using diffusion magnetic resonance imaging MRI (dMRI) approaches and an overview and perspective on the modern dMRI toolkits for characterizing alterations that follow traumatic brain injury (TBI). Noninvasive imaging is a cornerstone of clinical treatment of TBI and has become increasingly used for preclinical and basic research studies. In particular, quantitative MRI methods have the potential to distinguish and evaluate the complex collection of neurobiological responses to TBI arising from pathology, neuroprotection, and recovery. dMRI provides unique information about the physical environment in tissue and can be used to probe physiological, architectural, and microstructural features. Although well‐established approaches such as diffusion tensor imaging are known to be highly sensitive to changes in the tissue environment, more advanced dMRI techniques have been developed that may offer increased specificity or new information for describing abnormalities. These tools are promising, but incompletely understood in the context of TBI. Furthermore, model dependencies and relative limitations may impact the implementation of these approaches and the interpretation of abnormalities in their metrics. The objective of this paper is to present a basic review and comparison across dMRI methods as they pertain to the detection of the most commonly observed tissue and cellular alterations following TBI.