Local diffusion in the extracellular space of the brain.

The brain extracellular space (ECS) is a vast interstitial reticulum of extreme morphological complexity, composed of narrow gaps separated by local expansions, enabling interconnected highways between neural cells. Constituting on average 20% of brain volume, the ECS is key for intercellular communication, and understanding its diffusional properties is of paramount importance for understanding the brain. Within the ECS, neuroactive substances travel predominantly by diffusion, spreading through the interstitial fluid and the extracellular matrix scaffold after being focally released. The nanoscale dimensions of the ECS render it unresolvable by conventional live tissue compatible imaging methods, and historically diffusion of tracers has been used to indirectly infer its structure. Novel nanoscopic imaging techniques now show that the ECS is a highly dynamic compartment, and that diffusivity in the ECS is more heterogeneous than anticipated, with great variability across brain regions and physiological states. Diffusion is defined primarily by the local ECS geometry, and secondarily by the viscosity of the interstitial fluid, including the obstructive and binding properties of the extracellular matrix. ECS volume fraction and tortuosity both strongly determine diffusivity, and each can be independently regulated e.g. through alterations in glial morphology and the extracellular matrix composition. Here we aim to provide an overview of our current understanding of the ECS and its diffusional properties. We highlight emerging technological advances to respectively interrogate and model diffusion through the ECS, and point out how these may contribute in resolving the remaining enigmas of the ECS.

Neuronal internalization of immunoglobulin G injected into the mouse brain by a novel absorption strategy to avoid unwanted interaction with immune complex using centrifugal filtration.

Monoclonal immunoglobulin-G (IgG) antibodies are now emerging as therapeutic tools to tackle various disorders, including those affecting the brain. However, little is known about how these IgG molecules behave in the brain. To better understand the potential behavior of IgG molecules in the brain, here we established a specific protocol to immunolocalize rat IgG injected into mouse striatum with an anti-rat IgG antibody. Using double immunolabeling, IgG-like immunoreactivity (IR) was mainly found in neurons but scarcely observed in glia 1 h after intrastriatal injection of IgG, whereas some surrounding glia contained IgG-like IR 24 h after injection. However, preabsorption with a large excess of rat IgG to confirm the authenticity of this labeling failed to eliminate this neuronal IgG-like IR but rather exhibited nuclear staining in glial cells. Because this unexpected nuclear staining escalated with increasing amount of absorbing IgG, we postulated that this nuclear staining is due to formation of immune complex IgG-anti-IgG, which can be removed by centrifugal filtration. As expected, this nuclear staining in glial cells was eliminated after centrifugal filtration of the IgG/anti-IgG mixture, and authentic IgG-like IR was chiefly detected in the cytoplasm of neurons around the injection channel. This study is the first demonstration of neuronal redistribution of injected IgG in the mouse brain. Neuronal internalization of exogenous IgG may be advantageous especially when the therapeutic targets of monoclonal IgG are intraneuronal such as neurofibrillary tangles or Lewy bodies.

Single-subject analysis of regional brain volumetric measures can be strongly influenced by the method for head size adjustment.

PURPOSE: Total intracranial volume (TIV) is often a nuisance covariate in MRI-based brain volumetry. This study compared two TIV adjustment methods with respect to their impact on z-scores in single subject analyses of regional brain volume estimates. METHODS: Brain parenchyma, hippocampus, thalamus, and TIV were segmented in a normal database comprising 5059 T1w images. Regional volume estimates were adjusted for TIV using the residual method or the proportion method. Age was taken into account by regression with both methods. TIV- and age-adjusted regional volumes were transformed to z-scores and then compared between the two adjustment methods. Their impact on the detection of thalamus atrophy was tested in 127 patients with multiple sclerosis. RESULTS: The residual method removed the association with TIV in all regions. The proportion method resulted in a switch of the direction without relevant change of the strength of the association. The reduction of physiological between-subject variability was larger with the residual method than with the proportion method. The difference between z-scores obtained with the residual method versus the proportion method was strongly correlated with TIV. It was larger than one z-score point in 5% of the subjects. The area under the ROC curve of the TIV- and age-adjusted thalamus volume for identification of multiple sclerosis patients was larger with the residual method than with the proportion method (0.84 versus 0.79). CONCLUSION: The residual method should be preferred for TIV and age adjustments of T1w-MRI-based brain volume estimates in single subject analyses.

IntraBrain Injector (IBI): A Stereotactic-Guided Device for Repeated Delivery of Therapeutic Agents Into the Brain Parenchyma.

BACKGROUND: To deliver therapeutics into the brain, it is imperative to overcome the issue of the blood-brain-barrier (BBB). One of the ways to circumvent the BBB is to administer therapeutics directly into the brain parenchyma. To enhance the treatment efficacy for chronic neurodegenerative disorders, repeated administration to the target location is required. However, this increases the number of operations that must be performed. In this study, we developed the IntraBrain Injector (IBI), a new implantable device to repeatedly deliver therapeutics into the brain parenchyma. METHODS: We designed and fabricated IBI with medical grade materials, and evaluated the efficacy and safety of IBI in 9 beagles. The trajectory of IBI to the hippocampus was simulated prior to surgery and the device was implanted using 3D-printed adaptor and surgical guides. Ferumoxytol-labeled mesenchymal stem cells (MSCs) were injected into the hippocampus via IBI, and magnetic resonance images were taken before and after the administration to analyze the accuracy of repeated injection. RESULTS: We compared the planned vs. insertion trajectory of IBI to the hippocampus. With a similarity of 0.990 ± 0.001 (mean ± standard deviation), precise targeting of IBI was confirmed by comparing planned vs. insertion trajectories of IBI. Multiple administrations of ferumoxytol-labeled MSCs into the hippocampus using IBI were both feasible and successful (success rate of 76.7%). Safety of initial IBI implantation, repeated administration of therapeutics, and long-term implantation have all been evaluated in this study. CONCLUSION: Precise and repeated delivery of therapeutics into the brain parenchyma can be done without performing additional surgeries via IBI implantation.

Promotion properties of TLR7 in pediatric meningitis via the NF-κB pathway.

Meningitis outcome is associated with the severity of inflammation in the subarachnoid space and that the outcome can be improved through anti-inflammation. However, a comprehensive understanding of the molecular basis underlying inflammatory responses in meningitis remains enigmatic. In the current study, we sought to determine the molecular mechanism of TLR7/NF-κB on the development of meningitis in children. Cerebrospinal fluid of patients with meningitis and children with simple febrile convulsions was collected, and meningitis mouse model was induced. TLR7 expression was determined in the serum of meningitis model mice and the cerebrospinal fluid of patients using RT-qPCR and Western blot. Afterwards, loss- and gain- function assays were conducted to determine the functional role of TLR7 in meningitis mouse model. The level of procalcitonin (PCT) and the number of bacterial colonies in the serum were analyzed. ELISA was used to detect the expression of inflammatory factors. Upregulated level of TLR7 was observed in patients and mice with meningitis. Inhibiting the expression of TLR7 inhibited the development of meningitis. Overexpressing TLR7 can activate the NF-κB signaling pathway and promote mouse meningitis. NF-κB signaling pathway inhibitor reversed promotion of meningitis caused by TLR7 activation. Our study provides evidence that TLR7 elevation can activate the NF-κB signaling pathway and promote meningitis in mice.

Evaluation of the Kinematic Biofidelity and Inter-Test Repeatability of Global Accelerations and Brain Parenchyma Pressure for a Head-Brain Physical Model.

Head surrogates are widely used in biomechanical research and headgear assessment. They are designed to approximate the inertial and mechanical properties of the head and are instrumented to measure global head kinematics. Due to the recent interest in studying disruption to the brain, some head models include internal fluid layers and brain tissue, and instrumentation to measure head intracranial biomechanics. However, it is unknown whether such models exhibit realistic human responses. Therefore, this study aims to assess the biofidelity and repeatability of a head model, the Blast Injury Protection Evaluation Device (BIPED), that can measure both global head kinematics and intraparenchymal pressure (IPP) for application in blunt impact, a common loading scenario in civilian life. Drop tests were conducted with the BIPED and the widely used Hybrid III headform. BIPED measures were compared to the Hybrid III data and published cadaveric data, and the biofidelity level of the global linear acceleration was quantified using CORrelation and Analysis (CORA) ratings. The repeatability of the acceleration and IPP measurements in multiple impact scenarios was evaluated via the coefficient of variation (COV) of the magnitudes and pulse durations. BIPED acceleration peaks were generally not significantly different from cadaver and Hybrid III data. The CORA ratings for the BIPED and Hybrid III accelerations ranged from 0.50 to 0.61 and 0.51 to 0.77, respectively. The COVs of acceleration and IPP were generally below 10%. This study is an important step toward a biofidelic head surrogate measuring both global kinematics and IPP in blunt impact.

Secondary parenchymal CNS involvement by lymphoma including rare types: Follicular and EBV-positive NK/T cell lymphoma, nasal type.

BACKGROUND: Secondary CNS involvement by systemic lymphomas (SCNSL) is uncommon, but when it occurs, is usually due to diffuse large B cell lymphoma (DLBCL). Three recent unusual cases serve to highlight diagnostic challenges. OBJECTIVE: To report SCNSL from DLBCL and two unusual lymphoma types: follicular lymphoma with high-grade transformation to DLBCL and NK/T cell lymphoma, nasal type (ENKL), nasal type. RESULTS: SCNSL in the DLBCL case occurred at 7-year interval from primary in a 54-year-old woman who presented with stroke-like symptoms and a right postcentral gyrus 2.6 × 2.9 × 2.6 cm. mass. The follicular lymphoma occurred at 6-month interval in a 69-year-old woman with 1 month of diplopia and 2 weeks of cognitive decline; multifocal lesions involved temporal lobe, subependymal periventricular areas, brainstem, cerebellum, hypothalamus, corpus callosum and gyrus rectus. The ENKL occurred at 25-month interval from nasal biopsy in a 45-year-old man with 1 week of altered mental status; multifocal cerebral and brainstem lesions were identified. Histological features in cases 1 and 3 were identical to the primary lymphoma, with high-grade transformation to DLBCL in the follicular lymphoma. CONCLUSION: Unusual features in our series include longer interval from primary to relapse in case 1 with DLBCL (usually <2 years of diagnosis), and SCNSL occurring from either follicular lymphoma or EKNL, nasal type (<6% of cases). Pathologists play an important role in excluding infectious, especially in cases with parenchymal lesions and characterizing the lymphoma type in SCNSL.

IgG4-Related Disease Complicated by Brain Parenchymal Lesions Successfully Treated with Corticosteroid Therapy: A Case Report.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is distinguished by the infiltration of IgG4-positive plasma cells in a variety of tissues and organs including the pancreas, salivary glands, retroperitoneal lesions, kidney, and lymph nodes with elevated serum IgG4 levels. Even so, central nervous system (CNS) lesions such as brain parenchymal lesions associated with IgG4-RD are scarce. So far, only six cases of IgG4-RD in relation with brain parenchymal lesions have been described, with its characteristics still being not clear. Here we have detailed a case of IgG4-RD with brain parenchymal lesions and reviewed previously-reported cases of IgG4-RD with brain parenchymal lesions. A 62-year-old Japanese male suffering from lung silicosis was admitted to our hospital for abdominal discomfort and altered consciousness. He has shown no major neurologic abnormalities except for drowsiness, urinary retention, and fecal incontinence. Brain magnetic resonance imaging has shown scattered hyperintense signals in the brain parenchyma. The serum IgG4 levels were elevated and systemic lymph nodes were enlarged. Biopsy from inguinal lymph nodes has shown massive infiltration of IgG4-positive plasma cells: the ratio of IgG4-positive/IgG-positive plasma cells was nearly 100%. Based on clinical courses, images, laboratory data, and pathological findings, a diagnosis of IgG4-RD that was complicated by brain parenchymal lesions and sacral nerve disturbance was confirmed. The patient was then given methylprednisolone pulse therapy (1g for 3 days) succeeding oral prednisolone (1 mg per body weight). The clinical and radiological improvements together with steroid therapy proposed IgG4-RD to be the cause of the lesions.

Regional and functional heterogeneity of antigen presenting cells in the mouse brain and meninges.

The central nervous system (CNS) is considered to be immune privileged, owing in part to the absence of major histocompatibility (MHC) class II+ cells in the healthy brain parenchyma. However, systemic inflammation can activate microglia to express MHC class II, suggesting that systemic inflammation may be sufficient to mature microglia into functional antigen presenting cells (APCs). We examined the effects of systemic lipopolysaccharide (LPS)-induced inflammation on the phenotype and function of putative APCs within the mouse brain parenchyma, as well as its supporting tissues-the choroid plexus and meninges. Microglia isolated from different regions of the brain demonstrated significant heterogeneity in their ability to present antigen to naïve OT-II CD4+ T cells following exposure to systemic LPS. Olfactory bulb microglia (but not cortical microglia) intimately interacted with T cells in vivo and stimulated T cell proliferation in vitro, albeit in the absence of co-stimulation. In contrast, myeloid cells within the choroid plexus and meninges were immunogenic and upregulated the co-stimulatory molecule CD80 following systemic inflammation. Dural APCs, which clustered around LYVE-1+ lymphatics, were more efficient at stimulating naïve T cell proliferation than choroid plexus APCs, suggesting that the dura may be an under-appreciated site for immune interactions. This study has highlighted the functional diversity of myeloid cells within the sub-compartments of the CNS and its supporting tissues. Furthermore, these findings demonstrate that systemic inflammation can mature selected microglia populations and choroid plexus/meningeal myeloid cells into functional APCs, which may contribute to the pathogenesis of neuroinflammation and neurodegenerative diseases.

Measurement of microvascular cerebral blood volume changes over the cardiac cycle with ferumoxytol-enhanced T2* MRI.

PURPOSE: This feasibility study investigates the non-invasive measurement of microvascular cerebral blood volume (BV) changes over the cardiac cycle using cardiac-gated, ferumoxytol-enhanced T2∗ MRI. METHODS: Institutional review board approval was obtained and all subjects provided written informed consent. Cardiac gated MR scans were prospectively acquired on a 3.0T scanner in 22 healthy subjects using T2∗ -weighted sequences with 2D-EPI and 3D spiral trajectories. Images were collected before and after the intravenous administration of 2 doses of ferumoxytol (1 mg FE/kg and 4 mg FE/kg). Cardiac cycle-induced R2∗ (1/ T2∗ ) changes (Δ R2∗ ) and BV changes (ΔBV) throughout the cardiac cycle in gray matter (GM) and white matter (WM) were quantified and differences assessed using ANOVA followed by post hoc analysis. RESULTS: Δ R2∗ was found to increase in a dose-dependent fashion. A significantly larger increase was observed in GM compared to WM in both 2D and 3D acquisitions (P < 0.050). In addition, Δ R2∗ increased significantly (P < 0.001) post versus pre-contrast injection in GM in both T2∗ MRI acquisitions. Mean GM Δ R2∗ derived from 2D-EPI images was 0.14 ± 0.06 s-1 pre-contrast and 0.33 ± 0.13 s-1 after 5 mg FE/kg. In WM, Δ R2∗ was 0.19 ± 0.06 s-1 pre-contrast, and 0.23 ± 0.06 s-1 after 5 mg FE/kg. The fractional changes in BV throughout the cardiac cycle were 0.031 ± 0.019% in GM and 0.011 ± 0.008% in WM (P < 0.001) after 5 mg FE/kg. CONCLUSION: Cardiac-gated, ferumoxytol-enhanced T2∗ MRI enables characterization of microvascular BV changes throughout the cardiac cycle in GM and WM tissue of healthy subjects.

Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice.

PURPOSE: To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. METHODS: L-[14C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. RESULTS: The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (Vmax = 0.051 nmoL/min and Km = 34.94 µM). CONCLUSIONS: A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.

[Importance of Virchow-Robin spaces]. / Bedeutung der Virchow-Robin-Räume.

Virchow-Robin spaces are perivascular fluid-filled cavities that surround perforating arteries and veins in the brain parenchyma. As a rule in healthy people they are approximately 5 mm in diameter. Typical localizations are brainstem ganglia, mesencephalon and the white matter of the brain. Morphological imaging characteristics of Virchow-Robin spaces are round or tubular, smoothly bordered areas which are hyperintense in T2-weighted sequences. Virchow-Robin spaces represent a physiological structure in normal brain parenchyma. It is assumed that they contain interstitial fluid filled with macrophages and play an important role in the drainage of interstitial fluid in the direction of the cervical lymph system. In many diseases, such as Alzheimer's disease, cerebrovascular diseases and traumatic brain injuries, an association with Virchow-Robin spaces is assumed. In the differential diagnostics lacunar infarcts, cystic space-occupying lesions, low-grade malignant tumors and arachnoid cysts must be considered. In individual studies an association with frequently occurring expanded perivascular spaces in patients with arterial hypertension and patients with CADASIL disease was established. Rarely, Virchow-Robin spaces are so expanded that they lead to compression of the aqueduct or the foramina of Monro with subsequent hydrocephalus.

Molecular insights into melanoma brain metastases.

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society.

Transcranial parenchymal sonography in patients with Chronic Disorders of Consciousness: Association with neuroimaging data, and beyond.

Differential diagnosis of patients with Chronic Disorders of Consciousness (DoC) is rather challenging, owing to the lack of objective approaches highlighting residual awareness. Sophisticated functional neuroimaging have provided high diagnostic value, but their application in the clinical setting is limited due to their relative complexity, cost, availability and poor collaboration of persons with DoC. By using a specific ultrasound-based methodology, namely Transcranial B-mode Parenchymal Sonography (TCS), it is possible to obtain images of the main parenchymal brain structures. We assessed the TCS abnormalities in three patients with DoC, demonstrating widespread alterations of brain parenchyma morphology that matched to MRI findings and were associated with the degree of consciousness disorders. Thus, TCS might represent a valuable tool for routine assessment and follow-up of brain structures functioning of patients with DoC, potentially helping in differential diagnosis and prognosis.

Temporal effects of vascular endothelial growth factor and 3,5-cyclic monophosphate on blood-brain barrier solute permeability in vivo.

To test the hypothesis that vascular endothelial growth factor (VEGF) can transiently increase the blood-brain barrier permeability, P, as for peripheral microvessels and that the elevation of 3,5-cyclic monophosphate (cAMP) levels can inhibit the VEGF-induced acute hyperpermeability, we employed multiphoton microscopy to quantify the cerebral microvessel permeability P to various-sized solutes under VEGF and cAMP treatments. The cerebral microcirculation was observed through a section of frontoparietal bone thinned with a microgrinder. Fluorescein (MW 376Da), fluorescein isothioyanate-dextran-20k (FITC-Dex-20k), FITC-Dex-70k, or Alexa Fluor 488-IgG in 1% bovine serum albumin mammalian Ringer's solution was injected into the cerebral circulation via the ipsilateral carotid artery with a syringe pump. Simultaneously, temporal images were collected from the brain parenchyma ∼100-200 µm below the pia mater. P was determined from the rate of tissue solute accumulation around individual microvessels. Exposure to 1 nM VEGF transiently increased P to 2.2, 10.5, 9.8, and 12.8 times control values, for fluorescein, Dex-20k, Dex-70k, and IgG, respectively, within 30 sec, and all returned to control levels within 2 min. After 20 min of pretreatment with 2 mM of the cAMP analog 8-bromo-cAMP, the initial increase by 1 nM VEGF was completely abolished in P of all solutes. The response pattern of P to VEGF and cAMP and the ratios of the peak to control values for rat cerebral microvessels are similar to those for rat mesenteric (peripheral) microvessels, except that the ratios are higher in P of cerebral microvessels for the intermediate and large solutes. These results imply a new approach for delivering large therapeutic agents to the brain.

Infantile Rosai-Dorfman Disease With Isolated Brain Lesions Disseminated to the Parenchyma and Intraventricular Ependyma, Alteration of Leukocytes as a Promotion Factor in Immune Defense, and New Proposals: A Case Report and Literature Review.

The patient is a one-year-old girl referred to the hospital for an enlarged head after a 1.5-month history of two falls, followed by polydipsia, polyuria, and slow movement and growth. Three subsequent magnetic resonance imaging (MRI) examinations of the brain revealed nodular lesions disseminated in the brain parenchyma and intraventricular ependyma, resulting in obstructive hydrocephalus. Thoracic and abdominopelvic sonography showed no additional lesions. The preliminary diagnosis was a primary or metastatic neoplasm or infection. A biopsy of a lesion in the right frontal lobe was taken. The histological examination revealed features of Rosai-Dorfman disease (RDD), consisting of limited perivascular lymphoplasma cell infiltration with intervening sheets of proliferated histiocytes, with some of the histiocytes showing endocytosis of a single intact lymphocyte (emperipolesis).

Transcranial brain parenchyma sonography in patients with juvenile myoclonic epilepsy.

INTRODUCTION: There are rising evidences that subcortical structures, including the basal ganglia, are affected in patients with epilepsy. These structures are thought to influence the modulation and phenotypic expression of epileptic seizures. Our study aimed to evaluate the presence of structural abnormalities in subcortical structures in patients with juvenile myoclonic epilepsy (JME). METHODS: This cross-sectional study included 51 patients who were diagnosed with JME and who were monitored on an outpatient basis at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade from January 1985 to October 2017. All patients underwent transcranial parenchymal sonography (TCS) from October 2015 to October 2017. Relation of clinical parameters (seizure control andcognitive functioning,) with TCS results was assessed. RESULTS: Hyperechogenicity of the substantia nigra (SN) was detected in 37.2% of JME subjects and it was significantly more common in patients with JME than in the control group. The marked echogenicity of the red nucleus (RN) was detected in 17.6% of cases, while 11.8% of subjects had hyperechogenic RN. The presence of hyperechogenic RN (both right and left) was significantly more frequent in the group of patients with JME compared to the control group. The third ventricle diameter was larger in patients with JME than in controls. CONCLUSION: Structural changes of certain subcortical structures, primarily SN and RN, detected in JME patients indicate additional non-lesional abnormalities of the basal ganglia and midbrain structures in these patients.

Neurosonographic Classification in Premature Infants Receiving Omega-3 Supplementation Using Convolutional Neural Networks.

This study focuses on developing a model for the precise determination of ultrasound image density and classification using convolutional neural networks (CNNs) for rapid, timely, and accurate identification of hypoxic-ischemic encephalopathy (HIE). Image density is measured by comparing two regions of interest on ultrasound images of the choroid plexus and brain parenchyma using the Delta E CIE76 value. These regions are then combined and serve as input to the CNN model for classification. The classification results of images into three groups (Normal, Moderate, and Intensive) demonstrate high model efficiency, with an overall accuracy of 88.56%, precision of 90% for Normal, 85% for Moderate, and 88% for Intensive. The overall F-measure is 88.40%, indicating a successful combination of accuracy and completeness in classification. This study is significant as it enables rapid and accurate identification of hypoxic-ischemic encephalopathy in newborns, which is crucial for the timely implementation of appropriate therapeutic measures and improving long-term outcomes for these patients. The application of such advanced techniques allows medical personnel to manage treatment more efficiently, reducing the risk of complications and improving the quality of care for newborns with HIE.

Using Multiphoton Intravital Microscopy to Study Neutrophil Transmigration and Blood-Brain Barrier Permeability in a Mouse Model of Herpes Simplex Virus Encephalitis.

Multiphoton intravital microscopy (MP-IVM) is an imaging technique used for the observation of living organisms at a microscopic resolution. The tissue of interest is exposed through a window allowing imaging of cells in real time. Using MP-IVM, the temporospatial kinetics of leukocyte transendothelial migration can be visualized and quantitated using reporter mice and cell-specific fluorophore-conjugated monoclonal antibodies to track the leukocytes within and outside of vascular beds. Here we describe a method used to study neutrophil transendothelial migration and blood-brain barrier permeability in a mouse model of herpes simplex virus I (HSV) encephalitis.

Fully automated measurement of intracranial CSF and brain parenchyma volumes in pediatric hydrocephalus by segmentation of clinical MRI studies.

BACKGROUND: Brain parenchyma (BP) and intracranial cerebrospinal fluid (iCSF) volumes measured by fully automated segmentation of clinical brain MRI studies may be useful for the diagnosis and follow-up of pediatric hydrocephalus. However, previously published segmentation techniques either rely on dedicated sequences, not routinely used in clinical practice, or on spatial normalization, which has limited accuracy when severe brain distortions, such as in hydrocephalic patients, are present. PURPOSE: We developed a fully automated method to measure BP and iCSF volumes from clinical brain MRI studies of pediatric hydrocephalus patients, exploiting the complementary information contained in T2- and T1-weighted images commonly used in clinical practice. METHODS: The proposed procedure, following skull-stripping of the combined volumes, performed using a multiparametric method to obtain a reliable definition of the inner skull profile, maximizes the CSF-to-parenchyma contrast by dividing the T2w- by the T1w- volume after full-scale dynamic rescaling, thus allowing separation of iCSF and BP through a simple thresholding routine. RESULTS: Validation against manual tracing on 23 studies (four controls and 19 hydrocephalic patients) showed excellent concordance (ICC > 0.98) and spatial overlap (Dice coefficients ranging from 77.2% for iCSF to 96.8% for intracranial volume). Accuracy was comparable to the intra-operator reproducibility of manual segmentation, as measured in 14 studies processed twice by the same experienced neuroradiologist. Results of the application of the algorithm to a dataset of 63 controls and 57 hydrocephalic patients (19 with parenchymal damage), measuring volumes' changes with normal development and in hydrocephalic patients, are also reported for demonstration purposes. CONCLUSIONS: The proposed approach allows fully automated segmentation of BP and iCSF in clinical studies, also in severely distorted brains, enabling to assess age- and disease-related changes in intracranial tissue volume with an accuracy comparable to expert manual segmentation.