The overall goal of this project is to determine the physiological bases for neurochernical markers of brain injury seen with proton Magnetic Resonance Spectroscopy (IH-MRS) in TBI patients with a long-term goal of improving the treatment of TBI patients. TBI has widespread economic and social impact, and yet prognostication based on clinical data is still unreliable. The investigators have shown in human studies that neurochemical markers of brain injury, metabolic depression, and inflammation measured with (1)H-MRS are highly predictive of cognitive outcome. However, the underlying physiological events that link cell loss and metabolic abnormalities to MRS changes are poorly understood. Using a well-established contusion model of TBI in the rat, they will measure the time courses of changes in N-acetylaspartate (NAA, an amino acid found at concentrations similar to glutamate in the neuron and which is highly sensitive to neuronal injury) and choline (Cho -a marker of membrane injury and inflammation) during the acute phase (about one hr) up to the chronic phase of 28 days post TBI in a longitudinal study. The relative contributions of cerebral blood flow (CBF) changes, cell death and metabolic depression to NAA signals will be determined by comparing the MRS signals with the 3D images of CBF changes to be measured with perfusion MR, cell death to be determined histologically and metabolic depression to be determined with the cytochrome oxidase technique. The reduction and eventual recovery in NAA level expected after a TBI will be also related to cellular physiological measures in order to determine functional bases for the ability of NAA to predict cognitive outcome, by measuring intrinsic and network neuronal excitability with voltage-sensitive dyes, and by measuring the intracellular regulation of Ca2+ with fluorescence techniques at different time points ranging from four hrs to 28 days. The measurements will be carried out initially on in vitro slice preparations obtained from the animals after performing MRS measurements. In later studies, the study will be done in vivo with a two-photon scanning laser microscope. The changes in Cho and MRS-visible lipids will be related to macrophage/microglia digestion of membranes and to edema. They anticipate that the combination of approaches will provide important new information about the cellular basis for MRS profiles after TBI. This should be eventually valuable in patient management and the development of new intervention for treatment of TBI.
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