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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040472-01
Application #
6193095
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Michel, Mary E
Project Start
2000-07-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$295,875
Indirect Cost
Name
Dartmouth College
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
McDonald, Brenna C; Saykin, Andrew J; McAllister, Thomas W (2012) Functional MRI of mild traumatic brain injury (mTBI): progress and perspectives from the first decade of studies. Brain Imaging Behav 6:193-207
McAllister, Thomas W; Flashman, Laura A; McDonald, Brenna C et al. (2011) Dopaminergic challenge with bromocriptine one month after mild traumatic brain injury: altered working memory and BOLD response. J Neuropsychiatry Clin Neurosci 23:277-86
McAllister, Thomas W; McDonald, Brenna C; Flashman, Laura A et al. (2011) Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: altered working memory and BOLD response. Int J Psychophysiol 82:107-14
Wishart, Heather A; Roth, Robert M; Saykin, Andrew J et al. (2011) COMT Val158Met Genotype and Individual Differences in Executive Function in Healthy Adults. J Int Neuropsychol Soc 17:174-80
Silver, Jonathan M; McAllister, Thomas W; Arciniegas, David B (2009) Depression and cognitive complaints following mild traumatic brain injury. Am J Psychiatry 166:653-61
McAllister, Thomas W (2009) Polymorphisms in genes modulating the dopamine system: do they inf luence outcome and response to medication after traumatic brain injury? J Head Trauma Rehabil 24:65-8
Arciniegas, David B; McAllister, Thomas W (2008) Neurobehavioral management of traumatic brain injury in the critical care setting. Crit Care Clin 24:737-65, viii
McAllister, Thomas W; Flashman, Laura A; McDonald, Brenna C et al. (2006) Mechanisms of working memory dysfunction after mild and moderate TBI: evidence from functional MRI and neurogenetics. J Neurotrauma 23:1450-67
McAllister, Thomas W; Rhodes, C Harker; Flashman, Laura A et al. (2005) Effect of the dopamine D2 receptor T allele on response latency after mild traumatic brain injury. Am J Psychiatry 162:1749-51
McAllister, Thomas W; Flashman, Laura A; Sparling, Molly B et al. (2004) Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment -- a review. Brain Inj 18:331-50

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