Human White Matter Research Articles

Principal-stretch-based constitutive neural networks autonomously discover a subclass of Ogden models for human brain tissue

The soft tissue of the brain deforms in response to external stimuli, which can lead to traumatic brain injury. Constitutive models relate the stress in the brain to its deformation and accurate constitutive modeling is critical in finite element simulations to estimate injury risk. Traditionally, researchers first choose a constitutive model and then fit the model parameters to tension, compression, or shear experiments. In contrast, constitutive artificial neural networks enable automated model discovery without having to choose a specific model before learning the model parameters. Here we reverse engineer a constitutive artificial neural network that uses the principal stretches, raised to a wide range of exponential powers, as activation functions. Upon training, the network autonomously discovers a subclass of models with multiple Ogden terms that outperform popular constitutive models including the neo Hooke, Blatz Ko, and Mooney Rivlin models. While invariant-based networks fail to capture the pronounced tension–compression asymmetry of brain tissue, our principal-stretch-based network can simultaneously explain tension, compression, and shear data for the cortex, basal ganglia, corona radiata, and corpus callosum. Without fixing the number of terms a priori, our model self-selects the best subset of terms out of more than a million possible combinations, while simultaneously discovering the best model parameters and best experiment to train itself. Eliminating user-guided model selection has the potential to induce a paradigm shift in soft tissue modeling and democratize brain injury simulations. Our source code, data, and examples are available at https://github.com/LivingMatterLab/CANN.Statement of Significance: Understanding the constitutive response of the brain is critical to estimate brain injury risk, design protective devices, and predict surgical intervention. The current gold standard in constitutive modeling, first choosing a constitutive model and then fitting its parameters to data, is largely biased by user experience and personal preference. Constitutive artificial neural networks eliminate the need for user-guided model selection and enable automated model discovery. Here we reverse-engineer a constitutive artificial neural network with custom-designed activation functions from principal stretches raised to a wide range of exponential powers. When trained with data from human gray and white matter tissue, our network autonomously discovers a subclass of models with multiple Ogden terms that outperform popular constitutive models including the neo Hooke, Blatz Ko, and Mooney Rivlin models. While these classical invariant-based networks fail to capture the pronounced tension-compression asymmetry of brain tissue, our discovered principal-stretch-based models can simultaneously explain tension, compression, and shear data from the human cortex, basal ganglia, corona radiata, and corpus callosum. Without fixing the number of model terms a priori, our network self-selects the best subset of terms out of more than a million possible combinations, while simultaneously discovering the best model parameters, for example, shear moduli of 1.47kPa, 0.68kPa, 0.69kPa, and 0.29kPa for these four brain regions. Our findings are significant in that they eliminate user-guided model selection and have the potential to make brain modeling more accessible to a wide group of scientists with diverse training and backgrounds towards the ultimate goal to democratize human brain simulations.

Periventricular and juxtacortical characterization of UManitoba-JHU functionally defined human white matter atlas networks.

The open-access UManitoba-JHU functionally defined human white matter (WM) atlas contains specific WM pathways and general WM regions underlying 12 functional brain networks in ICBM152 template space. However, it is not known whether any of these WM networks are disproportionately co-localized with periventricular and/or juxtacortical WM (PVWM and JCWM), which could potentially impact their ability to infer network-specific effects in future studies-particularly in patient populations expected to have disproportionate PVWM and/or JCWM damage. The current study therefore identified intersecting regions of PVWM and JCWM (defined as WM within 5 mm of the ventricular and cortical boundaries) and: (1) the ICBM152 global WM mask, and (2) all 12 UManitoba-JHU WM networks. Dice Similarity Coefficient (DSC), Jaccard Similarity Coefficient (JSC), and proportion of volume (POV) values between PVWM (and JCWM) and each functionally defined WM network were then compared to corresponding values between PVWM (and JCWM) and global WM. Between the 12 WM networks and PVWM, 8 had lower DSC, JSC, and POV; 1 had lower DSC and JSC, but higher POV; and 3 had higher DSC, JSC, and POV compared to global WM. For JCWM, all 12 WM networks had lower DSC, JSC, and POV compared to global WM. The majority of UManitoba-JHU functionally defined WM networks exhibited lower than average spatial similarity with PVWM, and all exhibited lower than average spatial similarity with JCWM. This suggests that they can be used to explore network-specific WM changes, even in patient populations with known predispositions toward PVWM and/or JCWM damage.

IL-17/CXCL5 signaling within the oligovascular niche mediates human and mouse white matter injury.

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment.

How do different parts of brain white matter develop after birth in humans?

Understanding human white matter development is vital to characterize typical brain organization and developmental neurocognitive disorders. In this issue of Neuron, Nazeri and colleagues1 identify different parts of white matter in the neonatal brain and show their maturational trajectories in line with microstructural feature development.

A Novel Stereospecific Bioluminescent Assay for Detection of Endogenous d-Cysteine.

The presence of endogenous d-stereoisomers of amino acids in mammals dispels a long-standing dogma about their existence. d-Serine and d-aspartate function as novel neurotransmitters in mammals. However, the stereoisomer with the fastest, spontaneous in vitro racemization rate, d-cysteine, has not been reported. We utilized a novel, stereospecific, bioluminescent assay to identify endogenous d-cysteine in substantial amounts in the eye, brain, and pancreas of mice. d-Cysteine is enriched in mice embryonic brains at day E9.5 (4.5 mM) and decreases progressively with development (μM levels). d-Cysteine is also present in significantly higher amounts in the human brain white matter compared with gray matter. In the luciferase assay, d-cysteine conjugates with cyano hydroxy benzothiazole in the presence of a base and reducing agent to form d-luciferin. d-Luciferin, subsequently, in the presence of firefly luciferase and ATP, emits bioluminescence proportional to the concentration of d-cysteine. The assay is stereospecific and allows the quantitative estimation of endogenous d-cysteine in tissues in addition to its specificity for d-cysteine. Future efforts aimed at bioluminescent in vivo imaging of d-cysteine may allow a more noninvasive means of its detection, thereby elucidating its function.

Glial progenitor cells of the adult human white and grey matter are contextually distinct.

Genomic analyses have revealed heterogeneity among glial progenitor cells (GPCs), but the compartment selectivity of human GPCs (hGPCs) is unclear. Here, we asked if GPCs of human grey and white brain matter are distinct in their architecture and associated gene expression. RNA profiling of NG2-defined hGPCs derived from adult human neocortex and white matter differed in their expression of genes involved in Wnt, NOTCH, BMP and TGFβ signaling, suggesting compartment-selective biases in fate and self-renewal. White matter hGPCs over-expressed the BMP antagonists BAMBI and CHRDL1, suggesting their tonic suppression of astrocytic fate relative to cortical hGPCs, whose relative enrichment of cytoskeletal genes presaged their greater morphological complexity. In human glial chimeric mice, cortical hGPCs assumed larger and more complex morphologies than white matter hGPCs, and both were more complex than their mouse counterparts. These findings suggest that human grey and white matter GPCs comprise context-specific pools with distinct functional biases.

A Novel Murine Multi-Hit Model of Perinatal Acute Diffuse White Matter Injury Recapitulates Major Features of Human Disease.

The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on animal models for insight into disease mechanisms. Improvements in obstetric and neonatal care in the past 20 years have caused the pathologic hallmarks of perinatal white matter injury (WMI) to evolve away from cystic necrotic lesions and toward diffuse regions of reactive gliosis and persistent myelin disruption. Therefore, updated animal models are needed that recapitulate the key features of contemporary disease. Here, we report a murine model of acute diffuse perinatal WMI induced through a two-hit inflammatory-hypoxic injury paradigm. Consistent with diffuse human perinatal white matter injury (dWMI), our model did not show the formation of cystic lesions. Corresponding to cellular outcomes of dWMI, our injury protocol produced reactive microgliosis and astrogliosis, disrupted oligodendrocyte maturation, and disrupted myelination.. Functionally, we observed sensorimotor and cognitive deficits in affected mice. In conclusion, we report a novel murine model of dWMI that induces a pattern of brain injury mirroring multiple key aspects of the contemporary human clinical disease scenario.

Neural Correlates of Sensory Eye Dominance in Human Visual White Matter Tracts.

A significant proportion of the human neurotypical population exhibits some degree of sensory eye dominance (SED), referring to the brain's preferential processing of one eye's input versus another. The neural substrates underlying this functional imbalance are not well known. Here, we investigated the relationship between visual white matter tract properties and SED in the human neurotypical population. Observers' performance on two commonly used dichoptic tasks were used to index SED, along with performance on a third task to address a functional implication of binocular imbalance: stereovision. We show that diffusivity metrics of the optic radiations (ORs) well predict behavioral SED metrics. We found no relationship between SED and stereosensitivity. Our data suggest that SED is not simply reflected by gray matter structural and functional alterations, as often suggested, but relates, at least in part to the microstructural properties of thalamocortical white matter.

Orientation dependence of R2 relaxation in the newborn brain

In MRI the transverse relaxation rate, R2 = 1/T2, shows dependence on the orientation of ordered tissue relative to the main magnetic field. In previous studies, orientation effects of R2 relaxation in the mature brain's white matter have been found to be described by a susceptibility-based model of diffusion through local magnetic field inhomogeneities created by the diamagnetic myelin sheaths. Orientation effects in human newborn white matter have not yet been investigated. The newborn brain is known to contain very little myelin and is therefore expected to exhibit a decrease in orientation dependence driven by susceptibility-based effects. We measured R2 orientation dependence in the white matter of human newborns. R2 data were acquired with a 3D Gradient and Spin Echo (GRASE) sequence and fiber orientation was mapped with diffusion tensor imaging (DTI). We found orientation dependence in newborn white matter that is not consistent with the susceptibility-based model and is best described by a model of residual dipolar coupling. In the near absence of myelin in the newborn brain, these findings suggest the presence of residual dipolar coupling between rotationally restricted water molecules. This has important implications for quantitative imaging methods such as myelin water imaging, and suggests orientation dependence of R2 as a potential marker in early brain development.

P11.62.A The link between gliomas infiltrationandwhite matter architecture investigated with electron microscopy and diffusion tensor imaging

Abstract Background Diffuse low-grade gliomas (DLGG) display different preferential locations in eloquent and secondary associative brain areas. The reason for this tendency is still unknown. We hypothesized that the intrinsic architecture and water diffusion properties of the white matter bundles in these regions may facilitate gliomas infiltration. Material and Methods Magnetic resonance imaging of sixty-seven diffuse low-grade gliomas patients were normalized to/and segmented in MNI space to create three probabilistic infiltration weighted gradient maps according to the molecular status of each tumor group (IDH mutated, IDH wild-type and IDH mutated/1p19q co-deleted). Diffusion tensor imaging (DTI)- based parameters were derived for five major white matter bundles, displaying regional differences in the grade of infiltration, averaged over 20 healthy individuals acquired from the Human connectome project (HCP) database. Transmission electron microscopy (TEM) was used to analyze fiber density, fiber diameter and g-ratio in 100 human white matter regions, sampled from cadaver specimens, reflecting areas with different gliomas infiltration in each white matter bundle. Histological results and DTI-based parameters were compared in anatomical regions of high- and low grade of infiltration (HIF and LIF) respectively. Results We detected differences in the white matter infiltration of five major white matter bundles in three groups. IDHm infiltrated left fronto-temporal subcortical areas. IDHwt were detected in the posterior-temporal and temporo-parietal regions bilaterally. IDHm/1p19q infiltrated anterior subcortical regions of the frontal lobes bilaterally. Regional differences within the same white matter bundles were detected by both TEM- and DTI analysis linked to different topographical variables. Our multimodal analysis showed that HIF regions, common to all the groups, displayed a smaller fiber diameter, lower FA and higher RD compared with LIF regions. Conclusion Our results suggest that the both morphological features and diffusion parameters of the white matter may be different in regions linked to the preferential location of DLGG.

Track density imaging using diffusion tensor imaging data from 1.5 T MRI scanner

Superresolution track density imaging (TDI) has recently been developed for achieving high resolution track density maps from low-resolution diffusion images acquired at 3 T. But, the utility of the approach is still unclear when applied to diffusion tensor imaging (DTI) data acquired at lower 1.5 T magnetic field strength and thus its advantages or disadvantages awaits for exploration. We implemented an algorithm to generate track density maps of human white matter using streamline tracking and tested its performance with data acquired from two healthy volunteers at 1.5 Tesla. The effects of number of diffusion directions and seed selections on the quality of the reconstructed TDI maps were investigated under a variety of settings. The results were visually evaluated by an anatomist and a radiologist, and statistically characterized using gray level cooccurance Matrices (GLCM). Producing high-quality maps with improved resolution required increasing the number of seeds per voxel. Statistical implications were consistent with visual inspection. Low signal-to-noise ratio in DTI data intrinsically yielded low SNR in the final TD map. Accurately defining the diffusion and thus fiber orientation within a voxel necessitated increasing the number of diffusion encoding directions. Our data suggests that TDI image with DTI data acquired at 1.5 T is possible using right trade-offs in data acquisition and processing and has the capability of delineating the substructures of the brain.

Hebbian activity-dependent plasticity in white matter.

SummarySynaptic plasticity is required for learning and follows Hebb’s rule, the computational principle underpinning associative learning. In recent years, a complementary type of brain plasticity has been identified in myelinated axons, which make up the majority of brain’s white matter. Like synaptic plasticity, myelin plasticity is required for learning, but it is unclear whether it is Hebbian or whether it follows different rules. Here, we provide evidence that white matter plasticity operates following Hebb’s rule in humans. Across two experiments, we find that co-stimulating cortical areas to induce Hebbian plasticity leads to relative increases in cortical excitability and associated increases in a myelin marker within the stimulated fiber bundle. We conclude that Hebbian plasticity extends beyond synaptic changes and can be observed in human white matter fibers.

Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice.

Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here, we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP, and SEPTIN8 correlates well with that in C57Bl/6N mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein 2 (PMP2), which was specific to human central nervous system myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes, including Pmp2, Tspan2, and Gjc3. A searchable web interface is accessible via www.mpinat.mpg.de/myelin. Species-dependent diversity of oligodendroglial mRNA expression and myelin protein composition can be informative when translating from mouse models to humans.

Single-nucleus transcriptome analysis reveals disease- and regeneration-associated endothelial cells in white matter vascular dementia.

BackgroundVascular dementia (VaD) is the accumulation of vascular lesions in the subcortical white matter of the brain. These lesions progress and there is no direct medical therapy.AimsTo determine the specific cellular responses in VaD so as to provide molecular targets for therapeutic development.Materials and MethodsSingle‐nucleus transcriptome analysis was performed in human periventricular white matter (PVWM) samples of VaD and normal control (NC) subjects.ResultsDifferential analysis shows that cell type‐specific transcriptomic changes in VaD are associated with the disruption of specific biological processes, including angiogenesis, immune activation, axonal injury and myelination. Each cell type in the neurovascular unit within white matter has a specific alteration in gene expression in VaD. In a central cell type for this disease, subcluster analysis of endothelial cells (EC) indicates that VaD contains a disease‐associated EC subcluster that expresses genes associated with programmed cell death and a response to protein folding. Two other subpopulations of EC in VaD express molecular systems associated with regenerative processes in angiogenesis, and in axonal sprouting and oligodendrocyte progenitor cell maturation.ConclusionThis comprehensive molecular profiling of brain samples from patients with VaD reveals previously unknown molecular changes in cells of the neurovascular niche, and an attempt at regeneration in injured white matter.

Preliminary Intermittent Hypoxia Training Alleviates the Damage of Sustained Normobaric Hypoxia on Human Hematological Indexes and Cerebral White Matter.

Zhang, Guangbo, Yanzhao Zhou, Zhengtao Cao, Xiang Cheng, Xiangpei Yue, Tong Zhao, Ming Zhao, Yongqi Zhao, Ming Fan, and Lingling Zhu. Preliminary intermittent hypoxia training alleviates the damage of sustained normobaric hypoxia on human hematological indexes and cerebral white matter. High Alt Med Biol. 23:273-283, 2022. Background: We aimed to examine the effects of preliminary intermittent hypoxia training (IHT) on human hematological indexes and cerebral white matter (WM) after exposure to a simulated altitude of 4,300 m. Methods: We recruited 20 young healthy volunteers. Participants were then randomized to either the IHT group (n = 10) or the control group (n = 10). We measured the physiological function of the control group at sea level and after exposure to a simulated altitude of 4,300 m, respectively. The IHT group performed the above tests at three time points: before and after hypoxia training, and after exposure to a simulated altitude of 4,300 m, respectively. Results: We found that mean SpO2 during day 10 of hypoxia training showed a significant increase compared with mean SpO2 on day 1 (88.3% ± 1.5% vs. 90.0% ± 1.6%, p < 0.05), and erythrocyte P50 of post-training was significantly increased compared with pretraining (37.8 ± 2.9 mmHg vs. 45.9 ± 6.4 mmHg, p < 0.05). Mean SpO2 measures after acute exposure to high altitude exhibited a significant difference, with the IHT group showing significantly greater SpO2 than the control group (73.8% ± 3.7% vs. 77.4% ± 3.2%, p < 0.05), and the Lake Louise Score was also lower than the control group (2.55 ± 2.1 vs. 6.67 ± 2.5, p < 0.05). After daily IHT, brain-derived neurotrophic factor plasma levels of participants in the IHT group did not change but significantly increased in response to high-altitude hypoxia (103.5% ± 70.4% vs. 29.7% ± 73.2%, p < 0.05). Interleukin-10 (IL-10) plasma level did not change before and after IHT in the IHT group, whereas the IL-10 plasma level of the control group after high-altitude exposure was significantly higher. Furthermore, we found that fractional anisotropy values in the left corticospinal tract and splenium of the corpus callosum in the IHT group were significantly higher than those in the control group after high-altitude hypoxia. Conclusions: These results demonstrate that IHT alleviates the damage of sustained normobaric hypoxia on human hematological indexes and cerebral WM.

Track-weighted imaging analysis of white matter microstructures in healthy children: Sex and hemispheric differences.

Structural substrates of sex differences in human function and behavior have been elucidated in previous studies. Diffusion weighted magnetic resonance imaging (DW-MRI) is a widely used non-invasive imaging technique in studying human brain white matter structural organization. While many DW-MRI studies reporting sex differences in WM structure are based on diffusion tensor imaging (DTI) measures, tract specific microstructural differences require further investigation. In this study, we aim to investigate sex differences and sex-specific hemispheric differences in white matter microstructural development in healthy 8-year-old children based on novel track weighted imaging (TWI) analysis. Average pathlength map (APM) is a TWI contrast in which the average length of fibers passing through a voxel is utilized. In this study, we employed tract specific APM measures to evaluate sex differences in WM microstructural development. A total of 37 WM tracts were analyzed including 7 commissural tracts, 9 bilateral association tracts and 6 bilateral projection tracts. APM maps were generated for each tract. Tract-wise group tests were done using the mean values of APM maps. Sex differences were tested using general linear model based group comparisons. Age and total brain volume were included as covariates in the group analysis. Sex specific hemispheric differences were performed for the 15 bilateral tracts. One sample t-tests were done independently for left>right and right>left cases and the APM measures were controlled for age and total cerebral hemispheric volume. P-values<0.05 were considered significant after correcting for multiple comparisons accounting for the total number of tracts. Significant sex differences were revealed in APM measures between boys and girls in 11 WM tracts including rostral body of corpus callosum (CC), left inferior fronto-occipital fasciculus (IFOF), right cingulum, bilateral first and second segments of superior longitudinal fasciculus (SLF), right middle longitudinal fasciculus (MLF), bilateral fronto-pontine (FPT) and right parieto-occipital pontine tracts (POPT). The sex differences showed higher APM values for these 11 tracts in boys as compared to that of girls. In hemispheric differences analysis for both boys and girls, 2 tracts, arcuate fasciculus and optic radiation showed higher APM in left tracts as compared right; 5 tracts, IFOF, MLF, third segment of SLF, FPT and superior thalamic radiation showed higher APM in right tracts as compared to left. This indicates that boys and girls possess similar lateral asymmetries in these 7 tracts. Additionally, anterior thalamic radiation (ATR) showed higher APM in left tract and 4 tracts, first segment of SLF, POPT, inferior longitudinal fasciculus and cortico-spinal tract showed higher APM in right for boys. In girls, second segment of SLF and uncinate fasciculus showed higher APM in right hemisphere. These results indicate different lateral asymmetries between boys and girls for 7 tracts. Overall, boys showed higher average fiber length in most of the tracts, even after controlling for total brain volume.

Optimized Load-Independent Hyperelastic Microcharacterization of Human Brain White Matter

Abstract A micromechanical methodology combined with genetic algorithm (GA) as a global optimization method is used to find the material properties of axons and extracellular matrix (ECM) in corpus callosum which is a part of human brain white matter. Studies have shown that axons are highly oriented in the ECM which enables us to approximate brain white matter as a unidirectional fibrous composite model. Using the one-term Ogden hyperelastic constitutive equations for the constituents and knowing the mechanical response of corpus callosum, GA optimization procedure is used in conjunction with finite element (FE) micromechanical analysis to find optimal material parameters for axon and ECM in three uniaxial loading scenarios of tension, compression, and simple shear. Moreover, by simultaneous fitting to the three loading modes' responses and applying Nelder–Mead simplex optimization method, best-fit parameters are found. The best-fit parameters can be used to approximate the behavior of axons and ECM in different uniaxial loading conditions with the minimum error and hence, can be interpreted as load-independent parameters. Micromechanical simulations by best-fit parameters show maximum stress increase of 2% and 29% for tension and shear and less than 1% reduction for compression mode compared to the case where optimal parameters are used. The findings and the methodology of this study can be employed for constitutive modeling of axonal fibers and its implementation in human head FE model where load-independent parameters are needed for simulating different loading scenarios.

Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types.

Neural epidermal growth factor-like like 2 (NELL2) is a cytoplasmic and secreted glycosylated protein with six epidermal growth factor-like domains. In animal models, NELL2 is predominantly expressed in neural tissues where it regulates neuronal differentiation, polarization, and axon guidance, but little is known about the role of NELL2 in human brain development. In this study, we show that rostral neural stem cells (rNSC) derived from human-induced pluripotent stem cell (hiPSC) exhibit particularly strong NELL2 expression and that NELL2 protein is enriched at the apical side of neural rosettes in hiPSC-derived brain organoids. Following differentiation of human rostral NSC into neurons, NELL2 remains robustly expressed but changes its subcellular localization from >20 small cytoplasmic foci in NSC to one–five large peri-nuclear puncta per neuron. Unexpectedly, we discovered that in human brain organoids, NELL2 is readily detectable in the oligodendroglia and that the number of NELL2 puncta increases as oligodendrocytes mature. Artificial intelligence-based machine learning further predicts a strong association of NELL2 with multiple human white matter diseases, suggesting that NELL2 may possess yet unexplored roles in regulating oligodendrogenesis and/or myelination during human cortical development and maturation.

Generalisation of continuous time random walk to anomalous diffusion MRI models with an age-related evaluation of human corpus callosum

Diffusion MRI measures of the human brain provide key insight into microstructural variations across individuals and into the impact of central nervous system diseases and disorders. One approach to extract information from diffusion signals has been to use biologically relevant analytical models to link millimetre scale diffusion MRI measures with microscale influences. The other approach has been to represent diffusion as an anomalous transport process and infer microstructural information from the different anomalous diffusion equation parameters. In this study, we investigated how parameters of various anomalous diffusion models vary with age in the human brain white matter, particularly focusing on the corpus callosum. We first unified several established anomalous diffusion models (the super-diffusion, sub-diffusion, quasi-diffusion and fractional Bloch-Torrey models) under the continuous time random walk modelling framework. This unification allows a consistent parameter fitting strategy to be applied from which meaningful model parameter comparisons can be made. We then provided a novel way to derive the diffusional kurtosis imaging (DKI) model, which is shown to be a degree two approximation of the sub-diffusion model. This link between the DKI and sub-diffusion models led to a new robust technique for generating maps of kurtosis and diffusivity using the sub-diffusion parameters βSUB and DSUB. Superior tissue contrast is achieved in kurtosis maps based on the sub-diffusion model. 7T diffusion weighted MRI data for 65 healthy participants in the age range 19–78 years was used in this study. Results revealed that anomalous diffusion model parameters α and β have shown consistent positive correlation with age in the corpus callosum, indicating α and β are sensitive to tissue microstructural changes in ageing.

Multispectral LEDs Eliminate Lipofuscin-Associated Autofluorescence for Immunohistochemistry and CD44 Variant Detection by in Situ Hybridization in Aging Human, non-Human Primate, and Murine Brain.

A major limitation of mechanistic studies in aging brains is the lack of routine methods to robustly visualize and discriminate the cellular distribution of tissue antigens using fluorescent immunohistochemical multi-labeling techniques. Although such approaches are routine in non-aging brains, they are not consistently feasible in the aging brain due to the progressive accumulation of autofluorescent pigments, particularly lipofuscin, which strongly excite and emit over a broad spectral range. Consequently, aging research has relied upon colorimetric antibody techniques, where discrimination of tissue antigens is often challenging. We report the application of a simple, reproducible, and affordable protocol using multispectral light-emitting diodes (mLEDs) exposure for the reduction/elimination of lipofuscin autofluorescence (LAF) in aging brain tissue from humans, non-human primates, and mice. The mLEDs lamp has a broad spectral range that spans from the UV to infrared range and includes spectra in the violet/blue and orange/red. After photo quenching, the LAF level was markedly reduced when the tissue background fluorescence before and after mLEDs exposure was compared (p < 0.0001) across the spectral range. LAF elimination was estimated at 95 ± 1%. This approach permitted robust specific fluorescent immunohistochemical co-visualization of commonly studied antigens in aging brains. We also successfully applied this method to specifically visualize CD44 variant expression in aging human cerebral white matter using RNAscope fluorescent in-situ hybridization. Photo quenching provides an attractive means to accelerate progress in aging research by increasing the number of molecules that can be topologically discriminated by fluorescence detection in brain tissue from normative or pathological aging.