Neurochemical Challenge in Human Stroke Recovery

DESCRIPTION (provided by applicant): Most patients who have a stroke recover at least some degree of function. PET and fMRI studies have shown new regions of activation in the contralateral and ipsilateral cortex after infarction, even 1 day after stroke onset. The mechanisms by which such regions come to assume new roles in these patients are largely unknown. The long-term objective of this proposal is to determine the neurochemical systems that underlie functional recovery after cerebral vascular events in humans. In a novel baseline-sedation-postsedation design, our preliminary data have shown that a brief challenge with short-acting, commonly-used agents with specific neurochemical effects can unmask former deficits in patients whose syndromes had subsided/recovered after stroke or TIA. Midazolam, a GABAA agonist, was more effective in re-inducing motor dysfunction, and scopolamine, an anticholinergic agent, re-elicited aphasia. Over the 5-year project period, we propose to use this "induced dysfunction" model to prospectively study stroke and TIA patients at acute admission with a uniform series of aphasia, left hemineglect and motor tests, and to administer midazolam or scopolamine sedation challenges at prescribed intervals. For Specific Aim 1 we will recruit 160 patients at post-stroke Day 6 who have demonstrated a predefined increase in function in at last 1 of the 3 assessment spheres. Among the 80 patients in each drug group, there will be 40 patients in the hemiparesis group and 40 patients in the combined cognitive group comprised of 20 aphasic patients (with and without paresis) and 20 with left hemineglect (with and without paresis). After being randomized either to midazolam or scopolamine, each patient will undergo drug challenge on Days 7 and 90, during which all three spheres will be evaluated. There will also be 12 normal subjects, 6 in each drug group, to serve as controls. For Specific Aim 2, we will enroll 40 patients with a clinical history of TIA with a negative image who experienced brief aphasia (20 patients) and/or right-sided weakness (20 patients) into each of the midazolam and scopolamine groups. Drug challenges will take place on Days 4 and 90. Our hypothesis is that a GABAA agonist will more likely re-induce former motor deficits and that an anticholinergic agent will more likely unmask aphasia or hemineglect. T-tests will provide 80% power at the .05 level (2-tailed) to show a .45 SD difference in the mean change scores in function from baseline to sedation conditions. Functional magnetic resonance imaging will take place in Specific Aim 3 for a subset of patients and for all of the normal controls from Specific Aims 1 and 2 using the sedation-testing paradigm to determine whether there is a systematic change in activation following injury from stroke or TIA.