Capturing alterations of intracellular-extracellular lactate distribution in the brain using diffusion-weighted MR spectroscopy in vivo.

While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to noninvasively probe lactate in intracellular and extracellular spaces. Here, we show that, by measuring the diffusion of lactate with diffusion-weighted magnetic resonance (MR) spectroscopy in vivo and comparing it to the diffusion of purely intracellular metabolites, noninvasive quantification of extracellular and intracellular lactate fractions becomes possible. More specifically, we detect alterations of lactate diffusion in the APP/PS1 mouse model of Alzheimer's disease. Data modeling allows quantifying decreased extracellular lactate fraction in APP/PS1 mice as compared to controls, which is quantitatively confirmed with implanted enzyme-microelectrodes. The capability of diffusion-weighted MR spectroscopy to quantify extracellular-intracellular lactate fractions opens a window into brain metabolism, including in Alzheimer's disease.

Merged magnetic resonance and light sheet microscopy of the whole mouse brain.

We have developed workflows to align 3D magnetic resonance histology (MRH) of the mouse brain with light sheet microscopy (LSM) and 3D delineations of the same specimen. We start with MRH of the brain in the skull with gradient echo and diffusion tensor imaging (DTI) at 15 µm isotropic resolution which is ~ 1,000 times higher than that of most preclinical MRI. Connectomes are generated with superresolution tract density images of ~5 µm. Brains are cleared, stained for selected proteins, and imaged by LSM at 1.8 µm/pixel. LSM data are registered into the reference MRH space with labels derived from the ABA common coordinate framework. The result is a high-dimensional integrated volume with registration (HiDiver) with alignment precision better than 50 µm. Throughput is sufficiently high that HiDiver is being used in quantitative studies of the impact of gene variants and aging on mouse brain cytoarchitecture and connectomics.

Diffusion MRI of the Hippocampus.

The hippocampus is a brain structure that plays key roles in a variety of cognitive processes. Critically, a wide range of neurological disorders are associated with degeneration of the hippocampal microstructure, defined as neurons, dendrites, glial cells, and more. Thus, the hippocampus is a key target for methods that are sensitive to these microscale properties. Diffusion MRI is one such method, which can noninvasively probe neural architecture. Here we review the extensive use of diffusion MRI to capture hippocampal microstructure in both health and disease. The results of these studies indicate that (1) diffusion tensor imaging is sensitive but not specific to the hippocampal microstructure; (2) biophysical modeling of diffusion MRI signals is a promising avenue to capture more specific aspects of the hippocampal microstructure; (3) use of ultra-short diffusion times have shown unique laminar-specific microstructure and response to hippocampal injury; (4) dispersion of microstructure is likely abundant in the hippocampus; and (5) the angular richness of the diffusion MRI signal can be leveraged to improve delineation of the internal hippocampal circuitry. Overall, extant findings suggest that diffusion MRI offers a promising avenue for characterizing hippocampal microstructure.

Development of the Fetal Brain Corticocortical Structural Network during the Second-to-Third Trimester Based on Diffusion MRI.

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the interwired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and postmortem fetal brains, the in utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in utero dMRI data from human fetuses of both sexes between 26 and 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intrahemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for Wernicke's area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development.

Diffusion-Weighted Imaging Fluid-Attenuated Inversion Recovery Mismatch on Portable, Low-Field Magnetic Resonance Imaging Among Acute Stroke Patients.

OBJECTIVE: For stroke patients with unknown time of onset, mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) can guide thrombolytic intervention. However, access to MRI for hyperacute stroke is limited. Here, we sought to evaluate whether a portable, low-field (LF)-MRI scanner can identify DWI-FLAIR mismatch in acute ischemic stroke. METHODS: Eligible patients with a diagnosis of acute ischemic stroke underwent LF-MRI acquisition on a 0.064-T scanner within 24 h of last known well. Qualitative and quantitative metrics were evaluated. Two trained assessors determined the visibility of stroke lesions on LF-FLAIR. An image coregistration pipeline was developed, and the LF-FLAIR signal intensity ratio (SIR) was derived. RESULTS: The study included 71 patients aged 71 ± 14 years and a National Institutes of Health Stroke Scale of 6 (interquartile range 3-14). The interobserver agreement for identifying visible FLAIR hyperintensities was high (κ = 0.85, 95% CI 0.70-0.99). Visual DWI-FLAIR mismatch had a 60% sensitivity and 82% specificity for stroke patients <4.5 h, with a negative predictive value of 93%. LF-FLAIR SIR had a mean value of 1.18 ± 0.18 <4.5 h, 1.24 ± 0.39 4.5-6 h, and 1.40 ± 0.23 >6 h of stroke onset. The optimal cut-point for LF-FLAIR SIR was 1.15, with 85% sensitivity and 70% specificity. A cut-point of 6.6 h was established for a FLAIR SIR <1.15, with an 89% sensitivity and 62% specificity. INTERPRETATION: A 0.064-T portable LF-MRI can identify DWI-FLAIR mismatch among patients with acute ischemic stroke. Future research is needed to prospectively validate thresholds and evaluate a role of LF-MRI in guiding thrombolysis among stroke patients with uncertain time of onset. ANN NEUROL 2024;96:321-331.

Age of onset of obsessive-compulsive disorder differentially affects white matter microstructure.

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation -particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)-and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD.

Microstructural associations between locus coeruleus, cortical, and subcortical regions are modulated by astrocyte reactivity: a 7T MRI adult lifespan study.

The locus coeruleus-norepinephrine system plays a key role in supporting brain health along the lifespan, notably through its modulatory effects on neuroinflammation. Using ultra-high field diffusion magnetic resonance imaging, we examined whether microstructural properties (neurite density index and orientation dispersion index) in the locus coeruleus were related to those in cortical and subcortical regions, and whether this was modulated by plasma glial fibrillary acidic protein levels, as a proxy of astrocyte reactivity. In our cohort of 60 healthy individuals (30 to 85 yr, 50% female), higher glial fibrillary acidic protein correlated with lower neurite density index in frontal cortical regions, the hippocampus, and the amygdala. Furthermore, under higher levels of glial fibrillary acidic protein (above ~ 150 pg/mL for cortical and ~ 145 pg/mL for subcortical regions), lower locus coeruleus orientation dispersion index was associated with lower orientation dispersion index in frontotemporal cortical regions and in subcortical regions. Interestingly, individuals with higher locus coeruleus orientation dispersion index exhibited higher orientation dispersion index in these (sub)cortical regions, despite having higher glial fibrillary acidic protein levels. Together, these results suggest that the interaction between locus coeruleus-norepinephrine cells and astrocytes can signal a detrimental or neuroprotective pathway for brain integrity and support the importance of maintaining locus coeruleus neuronal health in aging and in the prevention of age-related neurodegenerative diseases.

Dynamical differential covariance recovers directional network structure in multiscale neural systems.

Investigating neural interactions is essential to understanding the neural basis of behavior. Many statistical methods have been used for analyzing neural activity, but estimating the direction of network interactions correctly and efficiently remains a difficult problem. Here, we derive dynamical differential covariance (DDC), a method based on dynamical network models that detects directional interactions with low bias and high noise tolerance under nonstationarity conditions. Moreover, DDC scales well with the number of recording sites and the computation required is comparable to that needed for covariance. DDC was validated and compared favorably with other methods on networks with false positive motifs and multiscale neural simulations where the ground-truth connectivity was known. When applied to recordings of resting-state functional magnetic resonance imaging (rs-fMRI), DDC consistently detected regional interactions with strong structural connectivity in over 1,000 individual subjects obtained by diffusion MRI (dMRI). DDC is a promising family of methods for estimating connectivity that can be generalized to a wide range of dynamical models and recording techniques and to other applications where system identification is needed.

Changes in Cortical Microstructure of the Human Brain Resulting from Long-Term Motor Learning.

The mechanisms subserving motor skill acquisition and learning in the intact human brain are not fully understood. Previous studies in animals have demonstrated a causal relationship between motor learning and structural rearrangements of synaptic connections, raising the question of whether neurite-specific changes are also observable in humans. Here, we use advanced diffusion magnetic resonance imaging (MRI), sensitive to dendritic and axonal processes, to investigate neuroplasticity in response to long-term motor learning. We recruited healthy male and female human participants (age range 19-29) who learned a challenging dynamic balancing task (DBT) over four consecutive weeks. Diffusion MRI signals were fitted using Neurite Orientation Dispersion and Density Imaging (NODDI), a theory-driven biophysical model of diffusion, yielding measures of tissue volume, neurite density and the organizational complexity of neurites. While NODDI indices were unchanged and reliable during the control period, neurite orientation dispersion increased significantly during the learning period mainly in primary sensorimotor, prefrontal, premotor, supplementary, and cingulate motor areas. Importantly, reorganization of cortical microstructure during the learning phase predicted concurrent behavioral changes, whereas there was no relationship between microstructural changes during the control phase and learning. Changes in neurite complexity were independent of alterations in tissue density, cortical thickness, and intracortical myelin. Our results are in line with the notion that structural modulation of neurites is a key mechanism supporting complex motor learning in humans.SIGNIFICANCE STATEMENT The structural correlates of motor learning in the human brain are not fully understood. Results from animal studies suggest that synaptic remodeling (e.g., reorganization of dendritic spines) in sensorimotor-related brain areas is a crucial mechanism for the formation of motor memory. Using state-of-the-art diffusion magnetic resonance imaging (MRI), we found a behaviorally relevant increase in the organizational complexity of neocortical microstructure, mainly in primary sensorimotor, prefrontal, premotor, supplementary, and cingulate motor regions, following training of a challenging dynamic balancing task (DBT). Follow-up analyses suggested structural modulation of synapses as a plausible mechanism driving this increase, while colocalized changes in cortical thickness, tissue density, and intracortical myelin could not be detected. These results advance our knowledge about the neurobiological basis of motor learning in humans.

Fast and robust quantification of uncertainty in non-linear diffusion MRI models.

Diffusion MRI (dMRI) allows for non-invasive investigation of brain tissue microstructure. By fitting a model to the dMRI signal, various quantitative measures can be derived from the data, such as fractional anisotropy, neurite density and axonal radii maps. We investigate the Fisher Information Matrix (FIM) and uncertainty propagation as a generally applicable method for quantifying the parameter uncertainties in linear and non-linear diffusion MRI models. In direct comparison with Markov Chain Monte Carlo (MCMC) sampling, the FIM produces similar uncertainty estimates at much lower computational cost. Using acquired and simulated data, we then list several characteristics that influence the parameter variances, including data complexity and signal-to-noise ratio. For practical purposes we investigate a possible use of uncertainty estimates in decreasing intra-group variance in group statistics by uncertainty-weighted group estimates. This has potential use cases for detection and suppression of imaging artifacts.

Sex matters: The MouseX DW-ALLEN Atlas for mice diffusion-weighted MR imaging.

Overcoming sex bias in preclinical research requires not only including animals of both sexes in the experiments, but also developing proper tools to handle such data. Recent work revealed sensitivity of diffusion-weighted MRI to glia morphological changes in response to inflammatory stimuli, opening up exciting possibilities to characterize inflammation in a variety of preclinical models of pathologies, the great majority of them available in mice. However, there are limited resources dedicated to mouse imaging, like those required for the data processing and analysis. To fill this gap, we build a mouse MRI template of both structural and diffusion contrasts, with anatomical annotation according to the Allen Mouse Brain Atlas, the most detailed public resource for mouse brain investigation. To achieve a standardized resource, we use a large cohort of animals in vivo, and include animals of both sexes. To prove the utility of this resource to integrate imaging and molecular data, we demonstrate significant association between the mean diffusivity from MRI and gene expression-based glia density. To demonstrate the need of equitable sex representation, we compared across sexes the warp fields needed to match a male-based template, and our template built with both sexes. Then, we use both templates for analysing mice imaging data obtained in animals of different ages, demonstrating that using a male-based template creates spurious significant sex effects, not present otherwise. All in all, our MouseX DW-ALLEN Atlas will be a widely useful resource getting us one step closer to equitable healthcare.

A unified filtering method for estimating asymmetric orientation distribution functions.

Numerous filtering methods have been proposed for estimating asymmetric orientation distribution functions (ODFs) for diffusion magnetic resonance imaging (dMRI). It can be hard to make sense of all these different methods, which share similar features and result in similar outputs. In this work, we disentangle these many filtering methods proposed in the past and combine them into a novel, unified filtering equation. We also propose a self-supervised data-driven approach for calibrating the filtering parameter values. Our equation is implemented in an open-source GPU-accelerated python software to facilitate its integration into any existing dMRI processing pipeline. Our method is applied on multi-shell multi-tissue fiber ODFs from the Human Connectome Project dataset (1.25 mm3 native resolution) and on single-shell single-tissue fiber ODFs from the Bilingualism and the Brain dataset (2.0 mm3 isotropic resolution) to evaluate the occurrence of asymmetric patterns on different spatial resolutions, representing cutting-edge and "clinical" research data. Asymmetry measures such as the asymmetric index (ASI) and our novel number of fiber directions (NuFiD) are then used to explain the behaviour of our method in these images. The contributions of this work are: (i) the disentanglement and unification of filtering methods for estimating asymmetric ODFs; (ii) a calibration method for automatically fixing the parameters governing the filtering; (iii) an open-source, efficient implementation of our unified filtering method for estimating asymmetric ODFs; (iv) a novel number of fiber directions (NuFiD) index for explaining asymmetric fiber configurations; and (v) a novel template of asymmetries, revealing that our filtering method estimates asymmetric configurations in at least 50% of the brain voxels (∼31% of the white matter and ∼63% of the gray matter).

Developing an AI-empowered head-only ultra-high-performance gradient MRI system for high spatiotemporal neuroimaging.

Recent advances in neuroscience requires high-resolution MRI to decipher the structural and functional details of the brain. Developing a high-performance gradient system is an ongoing effort in the field to facilitate high spatial and temporal encoding. Here, we proposed a head-only gradient system NeuroFrontier, dedicated for neuroimaging with an ultra-high gradient strength of 650 mT/m and 600 T/m/s. The proposed system features in 1) ultra-high power of 7MW achieved by running two gradient power amplifiers using a novel paralleling method; 2) a force/torque balanced gradient coil design with a two-step mechanical structure that allows high-efficiency and flexible optimization of the peripheral nerve stimulation; 3) a high-density integrated RF system that is miniaturized and customized for the head-only system; 4) an AI-empowered compressed sensing technique that enables ultra-fast acquisition of high-resolution images and AI-based acceleration in q-t space for diffusion MRI (dMRI); and 5) a prospective head motion correction technique that effectively corrects motion artifacts in real-time with 3D optical tracking. We demonstrated the potential advantages of the proposed system in imaging resolution, speed, and signal-to-noise ratio for 3D structural MRI (sMRI), functional MRI (fMRI) and dMRI in neuroscience applications of submillimeter layer-specific fMRI and dMRI. We also illustrated the unique strength of this system for dMRI-based microstructural mapping, e.g., enhanced lesion contrast at short diffusion-times or high b-values, and improved estimation accuracy for cellular microstructures using diffusion-time-dependent dMRI or for neurite microstructures using q-space approaches.

High-fidelity intravoxel incoherent motion parameter mapping using locally low-rank and subspace modeling.

PURPOSE: Intravoxel incoherent motion (IVIM) is a quantitative magnetic resonance imaging (MRI) method used to quantify perfusion properties of tissue non-invasively without contrast. However, clinical applications are limited by unreliable parameter estimates, particularly for the perfusion fraction (f) and pseudodiffusion coefficient (D*). This study aims to develop a high-fidelity reconstruction for reliable estimation of IVIM parameters. The proposed method is versatile and amenable to various acquisition schemes and fitting methods. METHODS: To address current challenges with IVIM, we adapted several advanced reconstruction techniques. We used a low-rank approximation of IVIM images and temporal subspace modeling to constrain the magnetization dynamics of the bi-exponential diffusion signal decay. In addition, motion-induced phase variations were corrected between diffusion directions and b-values, facilitating the use of high SNR real-valued diffusion data. The proposed method was evaluated in simulations and in vivo brain acquisitions in six healthy subjects and six individuals with a history of SARS-CoV-2 infection and compared with the conventionally reconstructed magnitude data. Following reconstruction, IVIM parameters were estimated voxel-wise. RESULTS: Our proposed method reduced noise contamination in simulations, resulting in a 60%, 58.9%, and 83.9% reduction in the NRMSE for D, f, and D*, respectively, compared to the conventional reconstruction. In vivo, anisotropic properties of D, f, and D* were preserved with the proposed method, highlighting microvascular differences in gray matter between individuals with a history of COVID-19 and those without (p = 0.0210), which wasn't observed with the conventional reconstruction. CONCLUSION: The proposed method yielded a more reliable estimation of IVIM parameters with less noise than the conventional reconstruction. Further, the proposed method preserved anisotropic properties of IVIM parameter estimates and demonstrated differences in microvascular perfusion in COVID-affected subjects, which weren't observed with conventional reconstruction methods.

Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities.

A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.

Latent diffusion model-based MRI superresolution enhances mild cognitive impairment prognostication and Alzheimer's disease classification.

INTRODUCTION: Timely diagnosis and prognostication of Alzheimer's disease (AD) and mild cognitive impairment (MCI) are pivotal for effective intervention. Artificial intelligence (AI) in neuroradiology may aid in such appropriate diagnosis and prognostication. This study aimed to evaluate the potential of novel diffusion model-based AI for enhancing AD and MCI diagnosis through superresolution (SR) of brain magnetic resonance (MR) images. METHODS: 1.5T brain MR scans of patients with AD or MCI and healthy controls (NC) from Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) were superresolved to 3T using a novel diffusion model-based generative AI (d3T*) and a convolutional neural network-based model (c3T*). Comparisons of image quality to actual 1.5T and 3T MRI were conducted based on signal-to-noise ratio (SNR), naturalness image quality evaluator (NIQE), and Blind/Referenceless Image Spatial Quality Evaluator (BRISQUE). Voxel-based volumetric analysis was then conducted to study whether 3T* images offered more accurate volumetry than 1.5T images. Binary and multiclass classifications of AD, MCI, and NC were conducted to evaluate whether 3T* images offered superior AD classification performance compared to actual 1.5T MRI. Moreover, CNN-based classifiers were used to predict conversion of MCI to AD, to evaluate the prognostication performance of 3T* images. The classification performances were evaluated using accuracy, sensitivity, specificity, F1 score, Matthews correlation coefficient (MCC), and area under the receiver-operating curves (AUROC). RESULTS: Analysis of variance (ANOVA) detected significant differences in image quality among the 1.5T, c3T*, d3T*, and 3T groups across all metrics. Both c3T* and d3T* showed superior image quality compared to 1.5T MRI in NIQE and BRISQUE with statistical significance. While the hippocampal volumes measured in 3T* and 3T images were not significantly different, the hippocampal volume measured in 1.5T images showed significant difference. 3T*-based AD classifications showed superior performance across all performance metrics compared to 1.5T-based AD classification. Classification performance between d3T* and actual 3T was not significantly different. 3T* images offered superior accuracy in predicting the conversion of MCI to AD than 1.5T images did. CONCLUSIONS: The diffusion model-based MRI SR enhances the resolution of brain MR images, significantly improving diagnostic and prognostic accuracy for AD and MCI. Superresolved 3T* images closely matched actual 3T MRIs in quality and volumetric accuracy, and notably improved the prediction performance of conversion from MCI to AD.

Anatomically constrained tractography of the fetal brain.

Diffusion-weighted Magnetic Resonance Imaging (dMRI) is increasingly used to study the fetal brain in utero. An important computation enabled by dMRI is streamline tractography, which has unique applications such as tract-specific analysis of the brain white matter and structural connectivity assessment. However, due to the low fetal dMRI data quality and the challenging nature of tractography, existing methods tend to produce highly inaccurate results. They generate many false streamlines while failing to reconstruct the streamlines that constitute the major white matter tracts. In this paper, we advocate for anatomically constrained tractography based on an accurate segmentation of the fetal brain tissue directly in the dMRI space. We develop a deep learning method to compute the segmentation automatically. Experiments on independent test data show that this method can accurately segment the fetal brain tissue and drastically improve the tractography results. It enables the reconstruction of highly curved tracts such as optic radiations. Importantly, our method infers the tissue segmentation and streamline propagation direction from a diffusion tensor fit to the dMRI data, making it applicable to routine fetal dMRI scans. The proposed method can facilitate the study of fetal brain white matter tracts with dMRI.

High-resolution diffusion magnetic resonance imaging and spatial-transcriptomic in developing mouse brain.

Brain development is a highly complex process regulated by numerous genes at the molecular and cellular levels. Brain tissue exhibits serial microstructural changes during the development process. High-resolution diffusion magnetic resonance imaging (dMRI) affords a unique opportunity to probe these changes in the developing brain non-destructively. In this study, we acquired multi-shell dMRI datasets at 32 µm isotropic resolution to investigate the tissue microstructure alterations, which we believe to be the highest spatial resolution dMRI datasets obtained for postnatal mouse brains. We adapted the Allen Developing Mouse Brain Atlas (ADMBA) to integrate quantitative MRI metrics and spatial transcriptomics. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI) metrics were used to quantify brain development at different postnatal days. We demonstrated that the differential evolutions of fiber orientation distributions contribute to the distinct development patterns in white matter (WM) and gray matter (GM). Furthermore, the genes enriched in the nervous system that regulate brain structure and function were expressed in spatial correlation with age-matched dMRI. This study is the first one providing high-resolution dMRI, including DTI, DKI, and NODDI models, to trace mouse brain microstructural changes in WM and GM during postnatal development. This study also highlighted the genotype-phenotype correlation of spatial transcriptomics and dMRI, which may improve our understanding of brain microstructure changes at the molecular level.

Quantitative characterization of breast lesions and normal fibroglandular tissue using compartmentalized diffusion-weighted model: comparison of intravoxel incoherent motion and restriction spectrum imaging.

BACKGROUND: To compare the compartmentalized diffusion-weighted models, intravoxel incoherent motion (IVIM) and restriction spectrum imaging (RSI), in characterizing breast lesions and normal fibroglandular tissue. METHODS: This prospective study enrolled 152 patients with 157 histopathologically verified breast lesions (41 benign and 116 malignant). All patients underwent a full-protocol preoperative breast MRI, including a multi-b-value DWI sequence. The diffusion parameters derived from the mono-exponential model (ADC), IVIM model (Dt, Dp, f), and RSI model (C1, C2, C3, C1C2, F1, F2, F3, F1F2) were quantitatively measured and then compared among malignant lesions, benign lesions and normal fibroglandular tissues using Kruskal-Wallis test. The Mann-Whitney U-test was used for the pairwise comparisons. Diagnostic models were built by logistic regression analysis. The ROC analysis was performed using five-fold cross-validation and the mean AUC values were calculated and compared to evaluate the discriminative ability of each parameter or model. RESULTS: Almost all quantitative diffusion parameters showed significant differences in distinguishing malignant breast lesions from both benign lesions (other than C2) and normal fibroglandular tissue (all parameters) (all P < 0.0167). In terms of the comparisons of benign lesions and normal fibroglandular tissues, the parameters derived from IVIM (Dp, f) and RSI (C1, C2, C1C2, F1, F2, F3) showed significant differences (all P < 0.005). When using individual parameters, RSI-derived parameters-F1, C1C2, and C2 values yielded the highest AUCs for the comparisons of malignant vs. benign, malignant vs. normal tissue and benign vs. normal tissue (AUCs = 0.871, 0.982, and 0.863, respectively). Furthermore, the combined diagnostic model (IVIM + RSI) exhibited the highest diagnostic efficacy for the pairwise discriminations (AUCs = 0.893, 0.991, and 0.928, respectively). CONCLUSIONS: Quantitative parameters derived from the three-compartment RSI model have great promise as imaging indicators for the differential diagnosis of breast lesions compared with the bi-exponential IVIM model. Additionally, the combined model of IVIM and RSI achieves superior diagnostic performance in characterizing breast lesions.

Altered thalamocortical tract trajectory growth with undisrupted thalamic parcellation pattern in human lissencephaly brain at mid-gestational stage.

Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage.