The goal of this proposal is to better define the role of dopaminergic mechanisms in the memory deficits experienced by individuals after a traumatic brain injury. Many of the one to two million individuals who sustain a mild to moderate traumatic brain injury (MTBI) suffer deficits in working memory (WM) in the first several weeks following the injury. in fact, recent studies suggest that WM is one of the core deficits associated with MTBI. Although the majority of these individuals subsequently recover, a significant number, particularly those with moderate injuries, have persistent memory deficits. Both human and animal studies suggest that prefrontal and parietal cortical areas are important components of WM circuitry. These areas, particularly frontal cortex, are vulnerable to injury in TBI. The dopaminergic system plays a prominent role in the modulation of WM. Frontal dopaminergic systems appear to be important modulators of spatial WM in animals [Arnsten, 1998 #90]. Limited human studies suggest similar links between frontal dopaminergic systems and WM [Koechlin, 1999 #117; Muller, 1998 #88]. A recent study of TBI patients found improvement in some WM components following administration of a D2 receptor agonist (bromocriptine) [McDowell, 1998 #101; Whyte, 1997 #100; D'Esposito, 1998 #39]. Further, these TBI-related WM deficits are associated with abnormal frontal and parietal activation patterns seen with functional MRI fMRI)[McAllister, 1999 #165].
The aims of this project are to use neurocognitive and fMRI measures in two populations, one with normal WM capacity (healthy controls), and one with low WM capacity (individuals with MTBI).to: (1 ) characterize WM deficits in two domains (verbal and spatial) within one month of (MTBI), (2) to test the ability of dopaminergic agonists to ameliorate WM deficits in two domains (verbal and spatial) within one month of MTBI, and (3) to explore the differential roles of D1 and D2 receptors in the activation and modulation of two domains of WM. We propose to study 40 MTBI patients within one month of injury and 40 healthy controls in a prospective, double blind, placebo controlled design. MTBI subjects and controls will be randomly assigned to receive placebo and either pergolide (a D1/D2 agonist) or bromocriptine (a D2 agonist). Both groups will then be given a series of verbal and spatial WM tasks while undergoing fMRI, followed by further neurocognitive testing. Performance and fMRI visualized activation of WM circuitry will be characterized at baseline (on placebo) and following administration of a dopamine agonist.
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