Faculty Bibliography

PURPOSE/OBJECTIVE:Inhomogeneous magnetization transfer (ihMT) MRI is uniquely sensitive to myelin with lipids as a primary source of its contrast. In this study, we investigated whether ihMT can detect white matter structures in the hypomyelinated shiverer mouse brain, a model of dysmyelination. METHODS:control and shiverer mouse brains at 7T using previously reported optimized saturation parameters. RESULTS:ihMT ratio (ihMTR) maps revealed hypomyelinated corpus callosum in the shiverer mouse brain, whereas conventional MT ratio (MTR) maps showed no clear contrast. The ihMTR values of the corpus callosum in the shiverer mice were reduced by approximately 40% compared to controls, but remained significantly higher than the ihMTR values of the cortex. CONCLUSION/CONCLUSIONS:The finding further confirms ihMT's high myelin specificity and suggests its use as a marker to detect early myelination or myelin repair.

The embryonic mouse brain undergoes drastic changes in establishing basic anatomical compartments and laying out major axonal connections of the developing brain. Correlating anatomical changes with gene-expression patterns is an essential step toward understanding the mechanisms regulating brain development. Traditionally, this is done in a cross-sectional manner, but the dynamic nature of development calls for probing gene-neuroanatomy interactions in a combined spatiotemporal domain. Here, we present a four-dimensional (4D) spatiotemporal continuum of the embryonic mouse brain from E10.5 to E15.5 reconstructed from diffusion magnetic resonance microscopy (dMRM) data. This study achieved unprecedented high-definition dMRM at 30- to 35-µm isotropic resolution, and together with computational neuroanatomy techniques, we revealed both morphological and microscopic changes in the developing brain. We transformed selected gene-expression data to this continuum and correlated them with the dMRM-based neuroanatomical changes in embryonic brains. Within the continuum, we identified distinct developmental modes comprising regional clusters that shared developmental trajectories and similar gene-expression profiles. Our results demonstrate how this 4D continuum can be used to examine spatiotemporal gene-neuroanatomical interactions by connecting upstream genetic events with anatomical changes that emerge later in development. This approach would be useful for large-scale analysis of the cooperative roles of key genes in shaping the developing brain.

PURPOSE/OBJECTIVE:To develop a deep learning-based reconstruction framework for ultrafast and robust diffusion tensor imaging and fiber tractography. METHODS:SuperDTI was developed to learn the nonlinear relationship between DWIs and the corresponding diffusion tensor parameter maps. It bypasses the tensor fitting procedure, which is highly susceptible to noises and motions in DWIs. The network was trained and tested using data sets from the Human Connectome Project and patients with ischemic stroke. Results from SuperDTI were compared against widely used methods for tensor parameter estimation and fiber tracking. RESULTS:Using training and testing data acquired using the same protocol and scanner, SuperDTI was shown to generate fractional anisotropy and mean diffusivity maps, as well as fiber tractography, from as few as six raw DWIs, with a quantification error of less than 5% in all white-matter and gray-matter regions of interest. It was robust to noises and motions in the testing data. Furthermore, the network trained using healthy volunteer data showed no apparent reduction in lesion detectability when directly applied to stroke patient data. CONCLUSIONS:Our results demonstrate the feasibility of superfast DTI and fiber tractography using deep learning with as few as six DWIs directly, bypassing tensor fitting. Such a significant reduction in scan time may allow the inclusion of DTI into the clinical routine for many potential applications.

Translational work in rodents elucidates basic mechanisms that drive complex behaviors relevant to psychiatric and neurological conditions. Nonetheless, numerous promising studies in rodents later fail in clinical trials, highlighting the need for improving the translational utility of preclinical studies in rodents. Imaging of small rodents provides an important strategy to address this challenge, as it enables a whole-brain unbiased search for structural and dynamic changes that can be directly compared to human imaging. The functional significance of structural changes identified using imaging can then be further investigated using molecular and genetic tools available for the mouse. Here, we describe a pipeline for unbiased search and characterization of structural changes and network properties, based on diffusion MRI data covering the entire mouse brain at an isotropic resolution of 100 µm. We first used unbiased whole-brain voxel-based analyses to identify volumetric and microstructural alterations in the brain of adult mice exposed to unpredictable postnatal stress (UPS), which is a mouse model of complex early life stress (ELS). Brain regions showing structural abnormalities were used as nodes to generate a grid for assessing structural connectivity and network properties based on graph theory. The technique described here can be broadly applied to understand brain connectivity in other mouse models of human disorders, as well as in genetically modified mouse strains. Graphic abstract: Pipeline for characterizing structural connectome in the mouse brain using diffusion magnetic resonance imaging. Scale bar = 1 mm.

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.

It is currently unclear whether early life stress (ELS) affects males and females differently. However, a growing body of work has shown that sex moderates responses to stress and injury, with important insights into sex-specific mechanisms provided by work in rodents. Unfortunately, most of the ELS studies in rodents were conducted only in males, a bias that is particularly notable in translational work that has used human imaging. Here we examine the effects of unpredictable postnatal stress (UPS), a mouse model of complex ELS, using high resolution diffusion magnetic resonance imaging. We show that UPS induces several neuroanatomical alterations that were seen in both sexes and resemble those reported in humans. In contrast, exposure to UPS induced fronto-limbic hyper-connectivity in males, but either no change or hypoconnectivity in females. Moderated-mediation analysis found that these sex-specific changes are likely to alter contextual freezing behavior in males but not in females.

BACKGROUND:Diffusion MRI is routinely used to evaluate brain injury in neonatal encephalopathy. Although abnormal mean diffusivity (MD) is often attributed to cytotoxic edema, the specific contribution from neuronal pathology is unclear. PURPOSE:To determine whether MD from high-resolution diffusion tensor imaging (DTI) can detect variable degrees of neuronal degeneration and pathology in piglets with brain injury induced by excitotoxicity or global hypoxia-ischemia (HI) with or without overt infarction. STUDY TYPE:Prospective. ANIMAL MODEL:Excitotoxic brain injury was induced in six neonatal piglets by intrastriatal stereotaxic injection of the glutamate receptor agonist quinolinic acid (QA). Three piglets underwent global HI or a sham procedure. Piglets recovered for 20-96 hours before undergoing MRI (n = 9). FIELD STRENGTH/SEQUENCE:-weighted imaging. ASSESSMENT:injury were assessed in the putamen and caudate. The cell bodies of normal neurons, degenerating neurons (excitotoxic necrosis, ischemic necrosis, or necrosis-apoptosis cell death continuum), and injured neurons with equivocal degeneration were counted by histopathology. STATISTICAL TESTS:injury and neuron counts were evaluated by descriptive analysis. RESULTS:-weighted MRI. DATA CONCLUSION:MD is more accurate than FA for detecting neuronal degeneration and loss during acute recovery from neonatal excitotoxic and HI brain injury. MD does not reliably detect nonfulminant, nascent, and potentially reversible neuronal injury. EVIDENCE LEVEL:1 TECHNICAL EFFICACY: Stage 2 J. Magn. Reson. Imaging 2020;52:1216-1226.

Diffusion-time- (t_d) dependent diffusion MRI (dMRI) extends our ability to characterize brain microstructure by measuring dMRI signals at varying t_d. The use of oscillating gradient (OG) is essential for accessing short t_d but is technically challenging on clinical MRI systems. This study aims to investigate the clinical feasibility and value of t_d-dependent dMRI in neonatal hypoxic-ischemic encephalopathy (HIE). Eighteen HIE neonates and six normal term-born neonates were scanned on a 3 T scanner, with OG-dMRI at an oscillating frequency of 33 Hz (equivalent t_d ≈ 7.5 ms) and pulsed gradient (PG)-dMRI at a t_d of 82.8 ms and b-value of 700 s/mm². The t_d-dependence, as quantified by the difference in apparent diffusivity coefficients between OG- and PG-dMRI (ΔADC), was observed in the normal neonatal brains, and the ΔADC was higher in the subcortical white matter than the deep grey matter. In HIE neonates with severe and moderate injury, ΔADC significantly increased in the basal ganglia (BG) compared to the controls (23.7% and 10.6%, respectively). In contrast, the conventional PG-ADC showed a 12.6% reduction only in the severe HIE group. White matter edema regions also demonstrated increased ΔADC, where PG-ADC did not show apparent changes. Our result demonstrated that t_d-dependent dMRI provided high sensitivity in detecting moderate-to-severe HIE.