Water Diffusion in the Live Human Brain is Gaussian at the Mesoscale.

Imaging the live human brain at the mesoscopic scale is a desideratum in basic and clinical neurosciences. Despite the promise of diffusion MRI, the lack of an accurate model relating the measured signal and the associated microstructure has hampered its success. The widely used diffusion tensor MRI (DTI) model assumes an anisotropic Gaussian diffusion process in each voxel, but lacks the ability to capture intravoxel heterogeneity. This study explores the extension of the DTI model to mesoscopic length scales by use of the diffusion tensor distribution (DTD) model, which assumes a Gaussian diffusion process in each subvoxel. DTD MRI has shown promise in addressing some limitations of DTI, particularly in distinguishing among different types of brain cancers and elucidating multiple fiber populations within a voxel. However, its validity in live brain tissue has never been established. Here, multiple diffusion-encoded (MDE) data were acquired in the living human brain using a 3 Tesla MRI scanner with large diffusion weighting factors. Two different diffusion times (Δ = 37, 74 ms) were employed, with other scanning parameters fixed to assess signal decay differences. In vivo diffusion-weighted signals in gray and white matter were nearly identical at the two diffusion times. Fitting the signals to the DTD model yielded indistinguishable results, except in the cerebrospinal fluid (CSF)-filled voxels likely due to pulsatile flow. Overall, the study supports the time invariance of water diffusion at the mesoscopic scale in live brain parenchyma, extending the validity of the anisotropic Gaussian diffusion model in clinical brain imaging.

The Subcortical Atlas of the Marmoset ("SAM") monkey based on high-resolution MRI and histology.

A comprehensive three-dimensional digital brain atlas of cortical and subcortical regions based on MRI and histology has a broad array of applications in anatomical, functional, and clinical studies. We first generated a Subcortical Atlas of the Marmoset, called the "SAM," from 251 delineated subcortical regions (e.g. thalamic subregions, etc.) derived from high-resolution Mean Apparent Propagator-MRI, T2W, and magnetization transfer ratio images ex vivo. We then confirmed the location and borders of these segmented regions in the MRI data using matched histological sections with multiple stains obtained from the same specimen. Finally, we estimated and confirmed the atlas-based areal boundaries of subcortical regions by registering this ex vivo atlas template to in vivo T1- or T2W MRI datasets of different age groups (single vs. multisubject population-based marmoset control adults) using a novel pipeline developed within Analysis of Functional NeuroImages software. Tracing and validating these important deep brain structures in 3D will improve neurosurgical planning, anatomical tract tracer injections, navigation of deep brain stimulation probes, functional MRI and brain connectivity studies, and our understanding of brain structure-function relationships. This new ex vivo template and atlas are available as volumes in standard NIFTI and GIFTI file formats and are intended for use as a reference standard for marmoset brain research.

"Tumor Treating Fields" delivered via electromagnetic induction have varied effects across glioma cell lines and electric field amplitudes.

Previous studies reported that alternating electric fields (EFs) in the intermediate frequency (100-300 kHz) and low intensity (1-3 V/cm) regime - termed "Tumor Treating Fields" (TTFields) - have a specific, anti-proliferative effect on glioblastoma multiforme (GBM) cells. However, the mechanism(s) of action remain(s) incompletely understood, hindering the clinical adoption of treatments based on TTFields. To advance the study of such treatment in vitro, we developed an inductive device to deliver EFs to cell cultures which improves thermal and osmolar regulation compared to prior devices. Using this inductive device, we applied continuous, 200 kHz electromagnetic fields (EMFs) with a radial EF amplitude profile spanning 0-6.5 V/cm to cultures of primary rat astrocytes and several human GBM cell lines - U87, U118, GSC827, and GSC923 - for a duration of 72 hours. Cell density was assessed via segmented pixel densities from GFP expression (U87, U118) or from staining (astrocytes, GSC827, GSC923). Further RNA-Seq analyses were performed on GSC827 and GSC923 cells. Treated cultures of all cell lines exhibited little to no change in proliferation at lower EF amplitudes (0-3 V/cm). At higher amplitudes (> 4 V/cm), different effects were observed. Apparent cell densities increased (U87), decreased (GSC827, GSC923), or showed little change (U118, astrocytes). RNA-Seq analyses on treated and untreated GSC827 and GSC923 cells revealed differentially expressed gene sets of interest, such as those related to cell cycle control. Up- and down-regulation, however, was not consistent across cell lines nor EF amplitudes. Our results indicate no consistent, anti-proliferative effect of 200 kHz EMFs across GBM cell lines and thus contradict previous in vitro findings. Rather, effects varied across different cell lines and EF amplitude regimes, highlighting the need to assess the effect(s) of TTFields and similar treatments on a per cell line basis.

Novel pore size-controlled, susceptibility matched, 3D-printed MRI phantoms.

PURPOSE: We report the design concept and fabrication of MRI phantoms, containing blocks of aligned microcapillaires that can be stacked into larger arrays to construct diameter distribution phantoms or fractured, to create a "powder-averaged" emulsion of randomly oriented blocks for vetting or calibrating advanced MRI methods, that is, diffusion tensor imaging, AxCaliber MRI, MAP-MRI, and multiple pulsed field gradient or double diffusion-encoded microstructure imaging methods. The goal was to create a susceptibility-matched microscopically anisotropic but macroscopically isotropic phantom with a ground truth diameter that could be used to vet advanced diffusion methods for diameter determination in fibrous tissues. METHODS: Two-photon polymerization, a novel three-dimensional printing method is used to fabricate blocks of capillaries. Double diffusion encoding methods were employed and analyzed to estimate the expected MRI diameter. RESULTS: Susceptibility-matched microcapillary blocks or modules that can be assembled into large-scale MRI phantoms have been fabricated and measured using advanced diffusion methods, resulting in microscopic anisotropy and random orientation. CONCLUSION: This phantom can vet and calibrate various advanced MRI methods and multiple pulsed field gradient or diffusion-encoded microstructure imaging methods. We demonstrated that two double diffusion encoding methods underestimated the ground truth diameter.

The Subcortical Atlas of the Marmoset ("SAM") monkey based on high-resolution MRI and histology.

A comprehensive three-dimensional digital brain atlas of cortical and subcortical regions based on MRI and histology has a broad array of applications for anatomical, functional, and clinical studies. We first generated a Subcortical Atlas of the Marmoset, called the "SAM," from 251 delineated subcortical regions (e.g., thalamic subregions, etc.) derived from the high-resolution MAP-MRI, T2W, and MTR images ex vivo. We then confirmed the location and borders of these segmented regions in MRI data using matched histological sections with multiple stains obtained from the same specimen. Finally, we estimated and confirmed the atlas-based areal boundaries of subcortical regions by registering this ex vivo atlas template to in vivo T1- or T2W MRI datasets of different age groups (single vs. multisubject population-based marmoset control adults) using a novel pipeline developed within AFNI. Tracing and validating these important deep brain structures in 3D improves neurosurgical planning, anatomical tract tracer injections, navigation of deep brain stimulation probes, fMRI and brain connectivity studies, and our understanding of brain structure-function relationships. This new ex vivo template and atlas are available as volumes in standard NIFTI and GIFTI file formats and are intended for use as a reference standard for marmoset brain research.

Mapping the individual human cortex using multidimensional MRI and unsupervised learning.

Human evolution has seen the development of higher-order cognitive and social capabilities in conjunction with the unique laminar cytoarchitecture of the human cortex. Moreover, early-life cortical maldevelopment has been associated with various neurodevelopmental diseases. Despite these connections, there is currently no noninvasive technique available for imaging the detailed cortical laminar structure. This study aims to address this scientific and clinical gap by introducing an approach for imaging human cortical lamina. This method combines diffusion-relaxation multidimensional MRI with a tailored unsupervised machine learning approach that introduces enhanced microstructural sensitivity. This new imaging method simultaneously encodes the microstructure, the local chemical composition and importantly their correlation within complex and heterogenous tissue. To validate our approach, we compared the intra-cortical layers obtained using our ex vivo MRI-based method with those derived from Nissl staining of postmortem human brain specimens. The integration of unsupervised learning with diffusion-relaxation correlation MRI generated maps that demonstrate sensitivity to areal differences in cytoarchitectonic features observed in histology. Significantly, our observations revealed layer-specific diffusion-relaxation signatures, showing reductions in both relaxation times and diffusivities at the deeper cortical levels. These findings suggest a radial decrease in myelin content and changes in cell size and anisotropy, reflecting variations in both cytoarchitecture and myeloarchitecture. Additionally, we demonstrated that 1D relaxation and high-order diffusion MRI scalar indices, even when aggregated and used jointly in a multimodal fashion, cannot disentangle the cortical layers. Looking ahead, our technique holds the potential to open new avenues of research in human neurodevelopment and the vast array of disorders caused by disruptions in neurodevelopment.

Correspondence of mean apparent propagator MRI metrics with phosphorylated tau and astrogliosis in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy is a neurodegenerative disease that is diagnosed and staged based on the localization and extent of phosphorylated tau pathology. Although its identification remains the primary diagnostic criteria to distinguish chronic traumatic encephalopathy from other tauopathies, the hyperphosphorylated tau that accumulates in neurofibrillary tangles in cortical grey matter and perivascular regions is often accompanied by concomitant pathology such as astrogliosis. Mean apparent propagator MRI is a clinically feasible diffusion MRI method that is suitable to characterize microstructure of complex biological media efficiently and comprehensively. We performed quantitative correlations between propagator metrics and underlying phosphorylated tau and astroglial pathology in a cross-sectional study of 10 ex vivo human tissue specimens with 'high chronic traumatic encephalopathy' at 0.25 mm isotropic voxels. Linear mixed effects analysis of regions of interest showed significant relationships of phosphorylated tau with propagator-estimated non-Gaussianity in cortical grey matter (P = 0.002) and of astrogliosis with propagator anisotropy in superficial cortical white matter (P = 0.0009). The positive correlation between phosphorylated tau and non-Gaussianity was found to be modest but significant (R2 = 0.44, P = 6.0 × 10-5) using linear regression. We developed an unsupervised clustering algorithm with non-Gaussianity and propagator anisotropy as inputs, which was able to identify voxels in superficial cortical white matter that corresponded to astrocytes that were accumulated at the grey-white matter interface. Our results suggest that mean apparent propagator MRI at high spatial resolution provides a means to not only identify phosphorylated tau pathology but also detect regions with astrocytic pathology and may therefore prove diagnostically valuable in the evaluation of concomitant pathology in cortical tissue with complex microstructure.

Optimizing Brain Health of United States Special Operations Forces.

United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life.

Multimodal anatomical mapping of subcortical regions in marmoset monkeys using high-resolution MRI and matched histology with multiple stains.

Subcortical nuclei and other deep brain structures play essential roles in regulating the central and peripheral nervous systems. However, many of these nuclei and their subregions are challenging to identify and delineate in conventional MRI due to their small size, hidden location, and often subtle contrasts compared to neighboring regions. To address these limitations, we scanned the whole brain of the marmoset monkeys in ex vivo using a clinically feasible diffusion MRI method, called the mean apparent propagator (MAP)-MRI, along with T2W and MTR (T1-like contrast) images acquired at 7 Tesla. Additionally, we registered these multimodal MRI volumes to the high-resolution images of matched whole-brain histology sections with seven different stains obtained from the same brain specimens. At high spatial resolution, the microstructural parameters and fiber orientation distribution functions derived with MAP-MRI can distinguish the subregions of many subcortical and deep brain structures, including fiber tracts of different sizes and orientations. The good correlation with multiple but distinct histological stains from the same brain serves as a thorough validation of the structures identified with MAP-MRI and other MRI parameters. Moreover, the anatomical details of deep brain structures found in the volumes of MAP-MRI parameters are not visible in conventional T1W or T2W images. The high-resolution mapping using novel MRI contrasts, combined and correlated with histology, can elucidate structures that were previously invisible radiologically. Thus, this multimodal approach offers a roadmap toward identifying salient brain areas in vivo in future neuroradiological studies. It also provides a useful anatomical standard reference for the region definition of subcortical targets and the generation of a 3D digital template atlas for the marmoset brain research (Saleem et al., 2023). Additionally, we conducted a cross-species comparison between marmoset and macaque monkeys using results from our previous studies (Saleem et al., 2021). We found that the two species had distinct patterns of iron distribution in subregions of the basal ganglia, red nucleus, and deep cerebellar nuclei, confirmed with T2W MRI and histology.

Ion-induced changes in DNA gels.

Small angle neutron scattering (SANS) measurements are reported for DNA gels under near physiological conditions in which the concentration of monovalent and divalent counter-ions and the pH are varied. The scattering intensity I(q) is described by a two-term equation, one due to osmotic concentration fluctuations and the other coming from static inhomogeneities frozen in by the cross-links. SANS in the low q range indicates the presence of large clusters and the size of which exceeds the resolution of the experiment. In the intermediate q-range, the intensity increases with the CaCl2 concentration and the slope approaches -1, corresponding to linear (rod-like) scatterers. In the highest q region, the scattering response is governed by the local chain geometry. Screening of electrostatic interactions by sodium chloride causes a moderate increase in the SANS intensity that is accompanied by an increase in the mesh size L of the network. Addition of calcium chloride, or a decrease in pH, produces similar trends, and ultimately leads to phase separation. The scattering intensity at q = 0, estimated from independent measurements of the osmotic pressure Π, is in excellent agreement with I(0) from the SANS measurements. Anomalous small angle X-ray scattering (ASAXS) measurements on the uncross-linked DNA show that the monovalent ion cloud is only weakly influenced by the addition of divalent ions. Conversely, the divalent counter-ion cloud tightly follows the contour of polymer chains.

Multimodal anatomical mapping of subcortical regions in Marmoset monkeys using high-resolution MRI and matched histology with multiple stains.

Subcortical nuclei and other deep brain structures play essential roles in regulating the central and peripheral nervous systems. However, many of these nuclei and their subregions are challenging to identify and delineate in conventional MRI due to their small size, hidden location, and often subtle contrasts compared to neighboring regions. To address these limitations, we scanned the whole brain of the marmoset monkeys in ex vivo using a clinically feasible diffusion MRI method, called the mean apparent propagator (MAP)-MRI, along with T2W and MTR (T1-like contrast) images acquired at 7 Tesla. Additionally, we registered these multimodal MRI volumes to the high-resolution images of matched whole-brain histology sections with seven different stains obtained from the same brain specimens. At high spatial resolution, the microstructural parameters and fiber orientation distribution functions derived with MAP-MRI can distinguish the subregions of many subcortical and deep brain structures, including fiber tracts of different sizes and orientations. The good correlation with multiple but distinct histological stains from the same brain serves as a thorough validation of the structures identified with MAP-MRI and other MRI parameters. Moreover, the anatomical details of deep brain structures found in the volumes of MAP-MRI parameters are not visible in conventional T1W or T2W images. The high-resolution mapping using novel MRI contrasts, combined and correlated with histology, can elucidate structures that were previously invisible radiologically. Thus, this multimodal approach offers a roadmap toward identifying salient brain areas in vivo in future neuroradiological studies. It also provides a useful anatomical standard reference for the region definition of subcortical targets and the generation of a 3D digital template atlas for the marmoset brain research (Saleem et al., 2023). Additionally, we conducted a cross-species comparison between marmoset and macaque monkeys using results from our previous studies (Saleem et al., 2021). We found that the two species had distinct patterns of iron distribution in subregions of the basal ganglia, red nucleus, and deep cerebellar nuclei, confirmed with T2W MRI and histology.

A novel framework for in-vivo diffusion tensor distribution MRI of the human brain.

Neural tissue microstructure plays an important role in developmental, physiological and pathophysiological processes. Diffusion tensor distribution (DTD) MRI helps probe subvoxel heterogeneity by describing water diffusion within a voxel using an ensemble of non-exchanging compartments characterized by a probability density function of diffusion tensors. In this study, we provide a new framework for acquiring multiple diffusion encoding (MDE) images and estimating DTD from them in the human brain in vivo. We interfused pulsed field gradients (iPFG) in a single spin echo to generate arbitrary b-tensors of rank one, two, or three without introducing concomitant gradient artifacts. Employing well-defined diffusion encoding parameters we show that iPFG retains salient features of a traditional multiple-PFG (mPFG/MDE) sequence while reducing the echo time and coherence pathway artifacts thereby extending its applications beyond DTD MRI. Our DTD is a maximum entropy tensor-variate normal distribution whose tensor random variables are constrained to be positive definite to ensure their physicality. In each voxel, the second-order mean and fourth-order covariance tensors of the DTD are estimated using a Monte Carlo method that synthesizes micro-diffusion tensors with corresponding size, shape, and orientation distributions to best fit the measured MDE images. From these tensors we obtain the spectrum of diffusion tensor ellipsoid sizes and shapes, and the microscopic orientation distribution function (µODF) and microscopic fractional anisotropy (µFA) that disentangle the underlying heterogeneity within a voxel. Using the DTD-derived µODF, we introduce a new method to perform fiber tractography capable of resolving complex fiber configurations. The results revealed microscopic anisotropy in various gray and white matter regions and skewed MD distributions in cerebellar gray matter not observed previously. DTD MRI tractography captured complex white matter fiber organization consistent with known anatomy. DTD MRI also resolved some degeneracies associated with diffusion tensor imaging (DTI) and elucidated the source of diffusion heterogeneity which may help improve the diagnosis of various neurological diseases and disorders.

Oligodendrocyte-mediated myelin plasticity and its role in neural synchronization.

Temporal synchrony of signals arriving from different neurons or brain regions is essential for proper neural processing. Nevertheless, it is not well understood how such synchrony is achieved and maintained in a complex network of time-delayed neural interactions. Myelin plasticity, accomplished by oligodendrocytes (OLs), has been suggested as an efficient mechanism for controlling timing in brain communications through adaptive changes of axonal conduction velocity and consequently conduction time delays, or latencies; however, local rules and feedback mechanisms that OLs use to achieve synchronization are not known. We propose a mathematical model of oligodendrocyte-mediated myelin plasticity (OMP) in which OLs play an active role in providing such feedback. This is achieved without using arrival times at the synapse or modulatory signaling from astrocytes; instead, it relies on the presence of global and transient OL responses to local action potentials in the axons they myelinate. While inspired by OL morphology, we provide the theoretical underpinnings that motivated the model and explore its performance for a wide range of its parameters. Our results indicate that when the characteristic time of OL's transient intracellular responses to neural spikes is between 10 and 40 ms and the firing rates in individual axons are relatively low (10 Hz), the OMP model efficiently synchronizes correlated and time-locked signals while latencies in axons carrying independent signals are unaffected. This suggests a novel form of selective synchronization in the CNS in which oligodendrocytes play an active role by modulating the conduction delays of correlated spike trains as they traverse to their targets.

Water exchange rates measure active transport and homeostasis in neural tissue.

For its size, the brain is the most metabolically active organ in the body. Most of its energy demand is used to maintain stable homeostatic physiological conditions. Altered homeostasis and active states are hallmarks of many diseases and disorders. Yet there is currently no direct and reliable method to assess homeostasis and absolute basal activity of cells in the tissue noninvasively without exogenous tracers or contrast agents. We propose a novel low-field, high-gradient diffusion exchange nuclear magnetic resonance (NMR) method capable of directly measuring cellular metabolic activity via the rate constant for water exchange across cell membranes. Exchange rates are 140 ± 16 s - 1 under normal conditions in viable ex vivo neonatal mouse spinal cords. High repeatability across samples suggest that values are absolute and intrinsic to the tissue. Using temperature and drug (ouabain) perturbations, we find that the majority of water exchange is metabolically active and coupled to active transport by the sodium-potassium pump. We show that this water exchange rate is sensitive primarily to tissue homeostasis and provides distinct functional information. In contrast, the apparent diffusion coefficient (ADC) measured with submillisecond diffusion times is sensitive primarily to tissue microstructure but not activity. Water exchange appears independently regulated from microstructural and oxygenation changes reported by ADC and T 1 relaxation measurements in an oxygen-glucose deprivation model of stroke; exchange rates remain stable for 30-40 min before dropping to levels similar to the effect of ouabain and never completely recovering when oxygen and glucose are restored.

"Tumor Treating Fields" delivered via electromagnetic induction have varied effects across glioma cell lines and electric field amplitudes.

Previous studies reported that alternating electric fields (EFs) in the intermediate frequency (100 - 300 kHz) and low intensity (1 - 3 V/cm) regime - termed "Tumor Treating Fields" (TTFields) - have a specific, anti-proliferative effect on glioblastoma multiforme (GBM) cells. However, the mechanism(s) of action remain(s) incompletely understood, hindering the clinical adoption of treatments based on TTFields. To advance the study of such treatment in vitro , we developed an inductive device to deliver EFs to cell cultures which improves thermal and osmolar regulation compared to prior devices. Using this inductive device, we applied continuous, 200 kHz electromagnetic fields (EMFs) with a radial EF amplitude profile spanning 0 - 6.5 V/cm to cultures of primary rat astrocytes and several human GBM cell lines - U87, U118, GSC827, and GSC923 - for a duration of 72 hours. Cell density was assessed via segmented pixel densities from GFP expression (U87, U118) or from staining (astrocytes, GSC827, GSC923). Further RNA-Seq analyses were performed on GSC827 and GSC923 cells. Treated cultures of all cell lines exhibited little to no change in proliferation at lower EF amplitudes (0 - 3 V/cm). At higher amplitudes (> 4 V/cm), different effects were observed. Apparent cell densities increased (U87), decreased (GSC827, GSC923), or showed little change (U118, astrocytes). RNA-Seq analyses on treated and untreated GSC827 and GSC923 cells revealed differentially expressed gene sets of interest, such as those related to cell cycle control. Up- and down-regulation, however, was not consistent across cell lines nor EF amplitudes. Our results indicate no consistent, anti-proliferative effect of 200 kHz EMFs across GBM cell lines and thus contradict previous in vitro findings. Rather, effects varied across different cell lines and EF amplitude regimes, highlighting the need to assess the effect(s) of TTFields and similar treatments on a per cell line basis.

Mapping astrogliosis in the individual human brain using multidimensional MRI.

There are currently no non-invasive imaging methods available for astrogliosis assessment or mapping in the central nervous system despite its essential role in the response to many disease states, such as infarcts, neurodegenerative conditions, traumatic brain injury and infection. Multidimensional MRI is an increasingly employed imaging modality that maximizes the amount of encoded chemical and microstructural information by probing relaxation (T1 and T2) and diffusion mechanisms simultaneously. Here, we harness the exquisite sensitivity of this imagining modality to derive a signature of astrogliosis and disentangle it from normative brain at the individual level using machine learning. We investigated ex vivo cerebral cortical tissue specimens derived from seven subjects who sustained blast-induced injuries, which resulted in scar-border forming astrogliosis without being accompanied by other types of neuropathological abnormality, and from seven control brain donors. By performing a combined post-mortem radiology and histopathology correlation study we found that astrogliosis induces microstructural and chemical changes that are robustly detected with multidimensional MRI, and which can be attributed to astrogliosis because no axonal damage, demyelination or tauopathy were histologically observed in any of the cases in the study. Importantly, we showed that no one-dimensional T1, T2 or diffusion MRI measurement can disentangle the microscopic alterations caused by this neuropathology. Based on these findings, we developed a within-subject anomaly detection procedure that generates MRI-based astrogliosis biomarker maps ex vivo, which were significantly and strongly correlated with co-registered histological images of increased glial fibrillary acidic protein deposition (r = 0.856, P < 0.0001; r = 0.789, P < 0.0001; r = 0.793, P < 0.0001, for diffusion-T2, diffusion-T1 and T1-T2 multidimensional data sets, respectively). Our findings elucidate the underpinning of MRI signal response from astrogliosis, and the demonstrated high spatial sensitivity and specificity in detecting reactive astrocytes at the individual level, and if reproduced in vivo, will significantly impact neuroimaging studies of injury, disease, repair and aging, in which astrogliosis has so far been an invisible process radiologically.

Prestressed Composite Polymer Gels as a Model of the Extracellular-Matrix of Cartilage.

Articular cartilage is a composite hydrogel found in animal and human joints, which exhibits unique load-bearing properties that have been challenging to reproduce in synthetic materials and model in molecular dynamics (MD) simulations. We computationally investigate a composite hydrogel that mimics key functional properties of articular cartilage as a potential biomimetic model to investigate its unique load-bearing properties. Specifically, we find that the emergence of prestress in composite gels derives primarily from the stiffness of the polymer matrix and the asymmetry in the enthalpic interactions of the embedded particles and polymer matrix. Our MD simulations of the development of prestress agree qualitatively with osmotic pressure measurements observed in our model composite hydrogel material.

High-resolution cortical MAP-MRI reveals areal borders and laminar substructures observed with histological staining.

The variations in cellular composition and tissue architecture measured with histology provide the biological basis for partitioning the brain into distinct cytoarchitectonic areas and for characterizing neuropathological tissue alterations. Clearly, there is an urgent need to develop whole-brain neuroradiological methods that can assess cortical cyto- and myeloarchitectonic features non-invasively. Mean apparent propagator (MAP) MRI is a clinically feasible diffusion MRI method that quantifies efficiently and comprehensively the net microscopic displacements of water molecules diffusing in tissues. We investigate the sensitivity of high-resolution MAP-MRI to detecting areal and laminar variations in cortical cytoarchitecture and compare our results with observations from corresponding histological sections in the entire brain of a rhesus macaque monkey. High-resolution images of MAP-derived parameters, in particular the propagator anisotropy (PA), non-gaussianity (NG), and the return-to-axis probability (RTAP) reveal cortical area-specific lamination patterns in good agreement with the corresponding histological stained sections. In a few regions, the MAP parameters provide superior contrast to the five histological stains used in this study, delineating more clearly boundaries and transition regions between cortical areas and laminar substructures. Throughout the cortex, various MAP parameters can be used to delineate transition regions between specific cortical areas observed with histology and to refine areal boundaries estimated using atlas registration-based cortical parcellation. Using surface-based analysis of MAP parameters we quantify the cortical depth dependence of diffusion propagators in multiple regions-of-interest in a consistent and rigorous manner that is largely independent of the cortical folding geometry. The ability to assess cortical cytoarchitectonic features efficiently and non-invasively, its clinical feasibility, and translatability make high-resolution MAP-MRI a promising 3D imaging tool for studying whole-brain cortical organization, characterizing abnormal cortical development, improving early diagnosis of neurodegenerative diseases, identifying targets for biopsies, and complementing neuropathological investigations.

Molecular dynamics study of the swelling and osmotic properties of compact nanogel particles.

Owing to their great importance in materials science and other fields, we investigate the solution and osmotic properties of uncharged compact nanogel particles over a wide range of solvent quality and particle concentration by molecular dynamics (MD) simulations. We characterize the osmotic pressure by estimating the second and third virial coefficients, and by extension, we identify the θ-point where the second virial coefficient vanishes. Calculations of the structure factor indicate that these particles are similar to macrogels in that the particle-like scattering profile disappears at moderate concentrations. We also find that improving the solvent quality enhances the spatial segmental uniformity, while significant heterogeneous structure arises near the θ-point. Well below the θ-point where the second osmotic virial coefficient vanishes, these heterogeneous structures become less prevalent as the particles tend to collapse. We also investigate the degree of swelling and structure of compact nanogel particles with a variable excluded volume interaction and gel particle concentration. The osmotic modulus and the scaling exponents in good and θ-point conditions of these gels are characteristic of interacting randomly branched polymers, i.e., "lattice animals".

Identifying transcranial magnetic stimulation induced EEG signatures of different neuronal elements in primary motor cortex.

OBJECTIVE: To investigate the neuronal elements involved in the activation of corticospinal neurons in the primary motor cortex (M1). METHODS: We studied 10 healthy subjects. Cortical evoked potentials with different components induced by monophasic transcranial magnetic stimulation (TMS) in anterior-posterior and posterior-anterior currents recorded with electroencephalography (EEG) were analyzed. RESULTS: EEG signatures with P25 and N45 components recorded at the C3 electrode with posterior-anterior current were larger than those with anterior-posterior current, while the signatures with P180 and N280 components recorded at the FC1 electrode with anterior-posterior current were larger than those with posterior-anterior current. The source localization analysis revealed that the cortical evoked potential with anterior-posterior current distributed both in the M1 and premotor cortex while that with posterior-anterior current only located in the M1. CONCLUSIONS: We conclude that the activation of corticospinal pyramidal neurons in the M1 is affected by various neuronal elements including the local intracortical circuits in the M1 and inputs from premotor cortex with different sensitivities to TMS in opposite current directions. SIGNIFICANCE: Our finding helped answer a longstanding question about how the corticospinal pathway from the M1 is functionally organized and activated.