We have been studying impaired memory and attention in prospective, controlled longitudinal experiments funded by NIDRR and the NINDS that have focused on individuals one month and one year after TBI. The aim of this work has been to characterize the nature of cognitive deficits after TBI, and to understand the neural mechanisms underlying these deficits. More recently we have started to characterize the relationship between cognitive function and polymorphisms of specific candidate genes, and to use fMRI to characterize the neural mechanisms underlying these interactions. We plan to use this understanding to develop effective treatment interventions for individuals with disabling cognitive impairments after TBI.

A major focus of our work has been to use functional MRI (fMRI) to assess the relationship between subjective cognitive complaints and observed deficits in attention and memory.

1. Studies of Verbal WM Load (The 2-Back)
Tasks/Methods: We have used the auditory "n-back" task to probe working memory (WM). Three conditions were presented that have increasing WM processing demands: the 0-back, 1-back, and 2-back. The number of correct and incorrect responses is recorded. Results: As shown in Fig. 1, controls showed increased activation in regions involved in WM from the 0-back to the 1-back condition, with minimal further increases from the 1-back to the 2-back condition. By contrast, MTBI patients showed less activation than controls in the 0-back to 1-back comparison, but showed extensive activation as WM load increased from 1-back to 2-back. Also noteworthy is the highly focal nature of the increase from 1-back to 2-back in the controls compared to the extensive frontal and parietal increases seen in the MTBI group. Comment: These results suggest that individuals with MTBI, studied within one month of their injury, have demonstrable differences in the ability to activate, allocate, and modulate WM processing resources. Although the controls and the MTBI participants differed on few individual tests of the neuropsychological battery, these subjects reported many more symptoms, particularly difficulties with attention and memory. One explanation is that the MTBI patients perceive the change in their ability to engage WM efficiently and experience this change as "memory problems", feeling that they have to work harder to maintain performance. This may account for the discrepancy between the severity of complaints voiced by many MTBI patients and the relatively minor performance deficits often found on individual tests of cognitive function in these individuals. Subsequent to the above work, we have used similar methods to demonstrate:

(1)	Higher WM processing loads (3-back) result in some drop off in performance, another significant increase in extent of activation in controls but not in individuals with MTBI (see McAllister et al. 2001).
(2)	WM performance and cerebral activation patterns improve one year after even mild injury, but performance and activation pattern remain different from that seen in healthy controls. Improved performance correlates with increased activation in regions of WM circuitry (McAllister et al. 2002).
(3)	Evidence of reduced brain activation associated with both memory encoding and retrieval processes (in addition to the already described WM deficits) in individuals shortly after mild and moderate TBI (McAllister et al. 2001).

2. Catecholaminergic Augmentation Strategies: Effects on Attention and Memory Performance and fMRI Activation Patterns (see McAllister et al. 2003): Overview: Given the evidence that central catecholaminergic systems, particularly dopaminergic (DA) and alpha-2 adrenergic (A2A) systems play key roles in attention and WM, we wondered if (1) injury-induced alterations in these neurotransmitter systems played a role in the observed abnormalities in our fMRI and WM studies, and (2) catecholaminergic agonists could be used to enhance memory and attention performance in healthy controls (those with presumably normal catecholaminergic function) and individuals with MTBI (putative catecholaminergic dysfunction). Tasks/Methods: To address these questions we developed a psychopharmacological challenge paradigm to use in combination with fMRI. We have been studying the effects of the three different catecholaminergic agonists; bromocriptine, pergolide, and guanfacine. This work is ongoing, but preliminary results suggest that individuals studied one month after MTBI do differ from healthy controls in their cognitive response to catecholamine agonists, and that these performance differences are associated with differences in patterns of activation of WM circuitry. Furthermore, there appear to be differences between response to dopaminergic and alpha-2 adrenergic agonists (McAllister et al. 2003, 2004).

3. Role of Genetic Polymorphisms in TBI and Other Neuropsychiatric Disorders: One of the hypotheses of our work in TBI and other neuropsychiatric disorders has been that polymorphisms in key genes impacting on cognitive function would play a role in outcome from neurotrauma of varying types, and that fMRI could be useful in characterizing the underlying mechanisms of these effects. We have been banking DNA from consenting individuals in our various protocols. Our efforts to date have focused on the role of two alleles of the catechol-o-methyl transferase (COMT) gene in frontal executive function following TBI, the e4 allele of apolipoprotein E (a gene involved in neuronal repair and lipid transport), and the DRD2 Taq1 A1 allele. This work is ongoing.

4. Summary: The work cited and described above indicates the following:

a.	Memory/attention are important sources of disability for individuals with TBI both acutely and chronically.
b.	fMRI can be used to characterize the neural mechanisms underlying the subjective cognitive complaints and observed cognitive deficits.
c.	Catecholaminergic (both DA and A2A) and cholinergic systems are disrupted after TBI.
d.	Polymorphisms in key genes affecting central catecholaminergic and cholinergic function modulate memory/attention performance in healthy controls and individuals with TBI and other brain disorders.
e.	fMRI can be used to characterize the neural mechanisms underlying the influence of genetic polymorphisms on cognitive functions including memory and attention.
f.	The combination of functional imaging, neurocognitive assessment, and molecular genetics can be applied to individuals with TBI to explain the mechanisms underlying deficits in memory/attention and ultimately to design treatment interventions based on this knowledge.