Deficits within the brain microcirculation contribute to poor patient outcome following aneurysmal subarachnoid hemorrhage (SAH). However, the underlying pathophysiology is not well understood. Intra-cerebral (parenchymal) arterioles are encased by specialized glial processes, called astrocyte endfeet. Ca2+ signals in the endfeet, driven by the ongoing pattern of neuronal activity, regulate parenchymal arteriolar diameter and thereby influence local cerebral blood flow. In the healthy brain, this phenomenon, called neurovascular coupling (NVC), matches focal increases in neuronal activity with local arteriolar dilation. This ensures adequate delivery of oxygen and other nutrients to areas of the brain with increased metabolic demand. Recently, we demonstrated inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from SAH model animals. This pathological change, which would restrict blood flow to active brain regions, was accompanied by an increase in the amplitude of spontaneous Ca2+ events in astrocyte endfeet. It is possible that the emergence of higher amplitude endfoot Ca2+ events shifts the polarity of NVC after SAH by elevating levels of vasoactive agents (e.g. K+ ions) within the perivascular space. In the first aim of this dissertation we tested whether altered endfoot Ca2+ signaling underlies the inversion of NVC after SAH. Brain injury is often associated with increased levels of extracellular purine nucleotides (e.g. ATP). A recent study found that ATP levels in the cerebrospinal fluid of aneurysmal SAH patients were roughly 400-fold higher than that of non-SAH controls. Astrocytes express a variety of purinergic (P2) receptors that, when activated, could trigger a spike in intra-cellular Ca2+. It is possible that enhanced signaling via astrocyte P2 receptors underlies the change in endfoot Ca2+ signaling after SAH. In the second aim of this dissertation we determined the role of purinergic signaling in the generation of high-amplitude spontaneous endfoot Ca2+ events after SAH. Parenchymal arteriolar diameter and endfoot Ca2+ dynamics were recorded simultaneously in fluo-4-loaded rat brain slices using combined infrared-differential interference contrast and multi-photon fluorescence microscopy. We report that SAH led to a time-dependent emergence of spontaneous endfoot high-amplitude Ca2+ signals (eHACSs) that were only present in brain slices exhibiting inversion of NVC. Depletion of intracellular Ca2+ stores abolished spontaneous endfoot Ca2+ signals, including eHACSs, and restored arteriolar dilation in SAH brain slices to two downstream elements in the NVC signaling cascade, (1) increased endfoot Ca2+ and (2) elevated extracellular K+. We next tested the role of purinergic signaling in the generation of SAH-induced eHACSs by recording endfoot activity before and after treatment with the broad-spectrum purinergic receptor antagonist, suramin. Remarkably, suramin selectively abolished eHACSs and restored vasodilatory NVC in SAH brain slices. Desensitization of Ca2+-permeable ionotropic purinergic (P2X) receptors had no effect on eHACSs after SAH. However, eHACSs were selectively blocked using a cocktail of inhibitors targeting Gq-coupled purinergic (P2Y) receptors. Collectively, our results support a model in which SAH leads to an emergence of P2Y receptor-mediated eHACSs that cause inversion of NVC. Further, we identify the FDA-approved drug, suramin, as a potential therapy to be used in the treatment of aneurysmal SAH.

Traumatic brain injury (TBI) remains a significant source of death and permanent disability, contributing to nearly one-third of all injury related deaths in the United States and exacting a profound personal and economic toll. Despite the increased resources that have recently been brought to bear to improve our understanding of TBI, the developme

This book contains articles presented at the 12th International Conference on Cerebral Vasospasm, held in Lucerne, Switzerland, in July 2013. The included papers represent a balanced cross-section of the enormous progress achieved in basic and clinical research on aneurysmal subarachnoid hemorrhage and its sequelae, including early neurovascular events and delayed cerebral vasospasm. The section on basic research covers a broad range of aspects, with a special focus on animal models for the study of acute events after experimental subarachnoid hemorrhage. The section on clinical topics encompasses imaging and endovascular management, surgical innovations and techniques, management and monitoring in neurocritical care, the status of clinical trials, and factors involved in aneurysm formation. This edition is of interest not only for basic researchers but also for clinicians who wish to apply state-of-the-art knowledge to the research and management of this devastating condition.

No detailed description available for "Timing of Aneurysm Surgery".

More than 40 articles provide an extensive coverage of clinical and basic science advances over the last three years of research on subarachnoid hemorrhage-induced brain injuries. Early brain injury, the new frontier of subarachnoid research, which may be a key contributor to the high mortality and morbidity, promotes collaborative efforts from neurosurgery, neurology, neuro-ICU into other interrelated fields and basic neurosciences. For the first time, subarachnoid hermorrhage research is almost equally divided by early brain injury and cerebral vasospasm, mechanistic investigations and therapeutic approaches, demonstrating a translational feature of the future direction.

Primer on Cerebrovascular Diseases is a handy reference source for scientists, students, and physicians needing reliable, up-to-date information on basic mechanisms, physiology, pathophysiology, and medical issues related to brain vasculature. The book consists of short, specific chapters written by international experts on cerebral vasculature, and presents the information in a comprehensive and easily accessible manner. The book also contains valuable information on practical applications of basic research. Presents topics in a comprehensive and accessible format Written by international authorities on cerebral vasculature Provides practical applications for researchers

With the contribution from more than one hundred CNS neurotrauma experts, this book provides a comprehensive and up-to-date account on the latest developments in the area of neurotrauma including biomarker studies, experimental models, diagnostic methods, and neurotherapeutic intervention strategies in brain injury research. It discusses neurotrauma mechanisms, biomarker discovery, and neurocognitive and neurobehavioral deficits. Also included are medical interventions and recent neurotherapeutics used in the area of brain injury that have been translated to the area of rehabilitation research. In addition, a section is devoted to models of milder CNS injury, including sports injuries.