Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

Characterization of Laser-Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy.

Background and objectivesPort wine stain (PWS) is a congenital vascular malformation of the human skin. Laser is the treatment of choice for PWS. Laser-resistant PWS is one crucial factor accounting for inadequate treatment outcome, which needs to be fully characterized. This study aims to quantitatively characterize the morphology of laser-resistant PWS blood vessels in the upper papillary dermis using in vivo reflectance confocal microscopy (RCM).Study design/materials and methodsA total of 42 PWS subjects receiving laser treatment from August 2016 through July 2018 were enrolled into this study. Thirty-three subjects had facial PWS; nine had extremity PWS. All subject's PWS received multiplex 585/1,064 nm laser treatment. RCM images were taken before and after treatment. The density, diameter, blood flow, and depth of PWS blood vessels were analyzed.ResultsWe found 44.4% PWS on the extremities (four out of nine subjects) were laser-resistant, which was significantly higher (P < 0.001) when compared with those PWS on the face (15.2%, 5 out of 33 subjects). The laser-resistant facial PWS blood vessels had significantly higher blood flow (1.35 ± 0.26 U vs. 0.89 ± 0.22 U, P < 0.001), larger blood vessel diameters (109.60 ± 18.24 µm vs. 84.36 ± 24.04 µm, P = 0.033) and were located deeper in the skin (106.01 ± 13.87 µm vs. 87.82 ± 12.57 µm, P < 0.001) in the skin when compared with laser-responsive PWS on the face. The average PWS blood vessel density (17.01 ± 4.63/mm2 vs. 16.61 ± 4.44/mm2 , P = 0.857) was not correlated to the laser resistance.ConclusionsLaser-resistant PWS blood vessels had significantly higher blood flow, larger diameters, and were located deeper in the skin. RCM can be a valuable tool for a prognostic evaluation on laser-resistant lesions before treatment, thereby providing guidance for tailored laser treatment protocols, which may improve the therapeutic outcome. The limitations for this study include relative small sample size and acquisitions of different blood vessels before and after 2 months of treatment. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc

VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis

Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF-A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin-Tie2 system in the thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity. Notably, blockade of VEGF-A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin-responsive genes in goitrogen-fed thyroids. Collectively, these findings establish follicular VEGF-Avascular VEGFR2 axis as a main regulator for thyrotropindependent thyroid angiofollicular remodeling and goitrogenesis.Peer reviewe

Multiscale modelling of tumour growth and therapy: the influence of vessel normalisation on chemotherapy

Following the poor clinical results of antiangiogenic drugs, particularly when applied in isolation, tumour biologists and clinicians are now turning to combinations of therapies in order to obtain better results. One of these involves vessel normalisation strategies. In this paper, we investigate the effects on tumour growth of combinations of antiangiogenic and standard cytotoxic drugs, taking into account vessel normalisation. An existing multiscale framework is extended to include new elements such as tumour-induced vessel dematuration. Detailed simulations of our multiscale framework allow us to suggest one possible mechanism for the observed vessel normalisation-induced improvement in the efficacy of cytotoxic drugs: vessel dematuration produces extensive regions occupied by quiescent (oxygen-starved) cells which the cytotoxic drug fails to kill. Vessel normalisation reduces the size of these regions, thereby allowing the chemotherapeutic agent to act on a greater number of cells

MRI Visualization of Whole Brain Macro- and Microvascular Remodeling in a Rat Model of Ischemic Stroke: A Pilot Study

Using superparamagnetic iron oxide nanoparticles (SPION) as a single contrast agent, we investigated dual contrast cerebrovascular magnetic resonance imaging (MRI) for simultaneously monitoring macro- and microvasculature and their association with ischemic edema status (via apparent diffusion coefficient [ADC]) in transient middle cerebral artery occlusion (tMCAO) rat models. High-resolution T1-contrast based ultra-short echo time MR angiography (UTE-MRA) visualized size remodeling of pial arteries and veins whose mutual association with cortical ischemic edema status is rarely reported. ??R2?????R2*-MRI-derived vessel size index (VSI) and density indices (Q and MVD) mapped morphological changes of microvessels occurring in subcortical ischemic edema lesions. In cortical ischemic edema lesions, significantly dilated pial veins (p???=???0.0051) and thinned pial arteries (p???=???0.0096) of ipsilateral brains compared to those of contralateral brains were observed from UTE-MRAs. In subcortical regions, ischemic edema lesions had a significantly decreased Q and MVD values (p???<???0.001), as well as increased VSI values (p???<???0.001) than normal subcortical tissues in contralateral brains. This pilot study suggests that MR-based morphological vessel changes, including but not limited to venous blood vessels, are directly related to corresponding tissue edema status in ischemic stroke rat models

Real-time, label-free, intraoperative visualization of peripheral nerves and microvasculatures using multimodal optical imaging techniques

Accurate, real-time identification and display of critical anatomic structures, such as the nerve and vasculature structures, are critical for reducing complications and improving surgical outcomes. Human vision is frequently limited in clearly distinguishing and contrasting these structures. We present a novel imaging system, which enables noninvasive visualization of critical anatomic structures during surgical dissection. Peripheral nerves are visualized by a snapshot polarimetry that calculates the anisotropic optical properties. Vascular structures, both venous and arterial, are identified and monitored in real-time using a near-infrared laser-speckle-contrast imaging. We evaluate the system by performing in vivo animal studies with qualitative comparison by contrast-agent-aided fluorescence imaging

Vascular responses and wound repair in mice exposed to moderate and severe hypoxia

Vascular responses and wound repair in mice exposed to moderate and severe hypoxi

Vasculature-driven stem cell population coordinates tissue scaling in dynamic organs

Stem cell (SC) proliferation and differentiation organize tissue homeostasis. However, how SCs regulate coordinate tissue scaling in dynamic organs remain unknown. Here, we delineate SC regulations in dynamic skin. We found that interfollicular epidermal SCs (IFESCs) shape basal epidermal proliferating clusters (EPCs) in expanding abdominal epidermis of pregnant mice and proliferating plantar epidermis. EPCs consist of IFESC-derived Tbx3⁺–basal cells (Tbx3⁺-BCs) and their neighboring cells where Adam8–extracellular signal–regulated kinase signaling is activated. Clonal lineage tracing revealed that Tbx3⁺-BC clones emerge in the abdominal epidermis during pregnancy, followed by differentiation after parturition. In the plantar epidermis, Tbx3⁺-BCs are sustained as long-lived SCs to maintain EPCs invariably. We showed that Tbx3⁺-BCs are vasculature-dependent IFESCs and identified mechanical stretch as an external cue for the vasculature-driven EPC formation. Our results uncover vasculature-mediated IFESC regulations, which explain how the epidermis adjusts its size in orchestration with dermal constituents in dynamic skin

Perivascular waste metabolites clearance in central nervous system (cns)

Efficient clearance of interstitial waste metabolites is essential for normal brain homeostasis. Such effective clearance is hampered by the lack of a lymphatic system in the brain, and the cerebrospinal fluid (CSF) is unable to clear large size waste metabolites in the brain. Here, a novel idea that brain arterial endothelium and smooth muscle cells reactivity regulates the clearance of these water-insoluble large size waste metabolites through the perivascular dynamic exchange, and that low dose ethanol promotes this perivascular clearance is proposed. In Aim 1, the biodistribution of a large size waste metabolite (Amyloid-β protein mimic) in rat perivascular space as a proof-of-concept is examined. Then the effects of low dose alcohol (ethanol) for promoting perivascular clearance path are evaluated. The result shows that ethanol increases perivascular clearance by enhancing the dilative reactivity of arterial endothelial cells (ECs) and alpha-smooth muscle cells (α-SMCs) via the activation of endothelial specific nitric oxide synthase (eNOS) and nitric oxide (NO) production. In Aim 2, the underlying molecular mechanisms of low dose ethanol on the perivascular clearance of waste metabolites is examined. The result shows that low dose ethanol specifically activates eNOS in arterial wall and generates physiological favorable level of NO without affecting the integrity of the Blood-Brain Barrier (BBB). This vasodilator NO stimulates the dilative reactivity of ECs- α-SMCs, which promotes the diffusive movement of waste metabolites from interstitial space/CSF to perivascular-perivenous drainage path. Decrease in phosphorylation of myosin light chain in α-SMCs and increase in arterial vessel diameter validates α-SMCs reactivity and movement of waste metabolites towards perivascular space. In Aim 3, the contrast effects of chronic moderate alcohol intake on perivascular clearance of waste metabolites is assessed. The result reveals that chronic alcohol intake switches the induction of eNOS to inducible nitric oxide synthase (iNOS), thereby generating high level of NO. This continuous production of NO by iNOS in chronic alcohol exposure causes oxidative damage of the arterial endothelial-smooth muscle layers, and reduces dilative reactivity. Decrease in tight junction protein levels validates the BBB dysfunction, and increase in phosphorylation of myosin light chain in α-SMCs validates the impairment of α-SMCs reactivity, that are closely correlated with decrease in waste metabolites movement towards perivascular clearance path. The current work affords huge clinical relevance since aggregation of large size waste metabolites like Ab protein around the perivascular space is a hallmark of Alzheimer\u27s disease. As such, the findings suggest new strategies for prevention and treatment of neurological diseases that are associated with clearance of entangled proteins