PILOT: THE IMPACT OF REPETITIVE MILD TBI BASED ON A CLOSED HEAD INJURY MODEL AND SERIAL FDG-MICROPET

Eighty percent of the 1.5 million brain injuries reported every year are classified as ¿mild¿ and a majority of these patients are likely to incur a second mild TBI. Early studies have shown that moderate to severe traumatic brain injury (TBI) in humans induces measurable metabolic changes via a neurochemical cascade. Within the first week after a severe brain injury, both regional and cerebral hyperglycolysis (increase in glucose utilization) has been documented in several patients. After peaking, cerebral glucose metabolism decreases to a broad minimum lasting up to one month followed by a slow increase lasting for months. A similar temporal change in glucose utilization has been observed in several rodent models, including lateral fluid percussion (LFP) and open or closed skull controlled cortical impact (CCI) injury in rats, with a metabolic depression lasting from 1 to 10 days. However, even though mild brain injury is the most clinically and militarily relevant injury, glucose metabolism changes have not been studied in mild TBI.A second injury sustained during this metabolically depressed period may result in worse damage compared to a second injury sustained after recovery. For example, the addition of a second injury, such as ischemia after LFP or multiple mild non-penetrating brain accelerations exacerbates ATP reduction. Worsened locomotor impairment and axonal damage have also been reported after brain injuries separated by 24 hours. This transient vulnerability was observed at injury time separations of 3 and 5 days but not at 7 days. These studies, however, did not correlate this transient conditioning with temporal glucose metabolic recovery or CBF transition. Nor has a study been done to quantify glucose metabolism changes after mild TBI in rodent models. Further, the time dependence of either a protective or a detrimental effect of a second injury is unclear. Therefore, we proposed to investigate the post-injury metabolism of injured rat brains using fluorodeoxyglucose (18F) (FDG)-microPET to determine the effect of different metabolic states on the outcome of a second brain injury.We hypothesized that FDGmicroPET could be used to visualize and quantify metabolic depression after a mild TBI, and that a second injury inflicted during hyperglycolysis, prior to the onset of the metabolic depression (< 6 hours), will have a protective ¿conditioning¿ effect, while an injury inflicted during the injury-induced metabolic depression will synergistically add to functional deficits.To investigate this hypothesis, we proposed two specific aims. Aim 1 would determine the temporal metabolic profile of the cortex and sub-cortex after mild TBI in rats. This aim utilized the LFP and closed head CCI TBI models, which result in mild functional deficits with diffuse axonal damage to investigate the temporal profile of glucose metabolism using 18FDG-microPET. Aim 2 would assess the motor and cognitive deficits of a second brain injury inflicted during periods of increased glucose metabolism, reduced glucose metabolism, and metabolic recovery.Utilizing the model in aim 1 that optimally results in a measurable glucose metabolism change, a second injury would be inflicted at the peak of hyperglycolysis, the peak of hypoglycosis, the middle of the metabolic depression, or after the metabolism returned to normal levels in order to determine the dependence of functional outcome after a second injury on the brain¿s metabolic state. The results from these studies will provide essential information on the role of metabolic recovery on brain vulnerability.