Uncontrolled brain swelling and subsequent rise in ICP is one of the most perplexing problems in neurosurgical management of the head injured patient. One factor contributing to this problem is that the fluid compartment, responsible for the swelling has not been identified. Both vascular engorgement and brain edema have been implicated but their relative contribution to the swelling process remains unknown. This project, by virtue of unique non-invasive methods developed at our institution, will finally resolve this issue by quantitatively measuring changes in water content using magnetic resonance imaging and changes in blood volume using special computerized tomographic methods in severely head injured patients.
The specific aims deal with first identifying the relative contribution of each compartment to test the hypothesis that edema is primarily responsible for increased tissue volume. Secondly, with knowledge of the BBB opening to Gadolinium coupled with cerebral blood flow measures we will help characterize the type of edema the role of vasogenic vs neurotoxic processes. Finally, as the consequences of swelling is raised ICP, we will dissect the contribution of increased cerebrovenous pressure measured in the jugular bulb in patients with brain swelling thereby testing the hypothesis that increased sagittal sinus pressure contributes to raised ICP. P01NS125870017 Human traumatic brain injury (TBI) and laboratory models of TBI produce significant morbidity including deficits in motor and cognitive function. The long-term objectives of this research are to investigate mechanisms by which TBI induces altered neuronal function and subsequent morbidity. Laboratory studies have demonstrated that receptor-mediated excitotoxic processes significantly contribute to TBI morbidity. Recent evidence demonstrates that glutamate- and carbachol-stimulated inositol phosphate (IP)( production is significantly enhanced and induction of long term potentiation (LTP) is significantly altered in rat hippocampus following fluid percussion TBI. Our central hypothesis states that TBI-induced excessive stimulation of phospholipase C (PLC)-linked neurotransmitter receptors at the time of impact will initiate pathological cascades that contribute to long-term behavioral morbidity. These cascades involve alterations in neuronal signaling produced in part by modifications in receptor-effector response coupling. PLC-linked receptors may be important contributors to TBI pathophysiological processes since the hydrolysis of phosphoinositide (PI) can increase intracellular Ca++ through the production of the second messengers, diacylglycerol and inositol 1,4,5-trisphosphate. We will examine the effects of fluid percussion TBI in the rat on agonist-induced IP production and receptor binding acutely (1 hr) and at time points after injury that correspond to maximal motor deficits (24 hr) and memory deficits (15 days). We will then examine the effects of acute pharmacological manipulation of PI-linked muscarinic and glutamate receptors in injured rats by measuring at later time points (24 hr and 15 days): 1) agonist-induced IP production, 2) hippocampal LTP, and 3) sensory-motor and cognitive indices of behavioral morbidity. This research will provide important mechanistic information about relationships between TBI, altered neuronal signaling, and behavioral morbidity. This research will also provide clinically relevant information about potential pharmacological agents for the acute treatment of human head injury.
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