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.
| Dunn, Lauren E; Schweber, Adam B; Manson, Daniel K et al. (2016) Variability in Motor and Language Recovery during the Acute Stroke Period. Cerebrovasc Dis Extra 6:12-21 |
| Lazar, Ronald M; Minzer, Brandon; Antoniello, Daniel et al. (2010) Improvement in aphasia scores after stroke is well predicted by initial severity. Stroke 41:1485-8 |
| Dhamoon, M S; Lazar, R M; Marshall, R S (2010) Impairment versus activity limitation after incident ischaemic stroke. Int J Stroke 5:132-3 |
| Lazar, Ronald M; Berman, Mitchell F; Festa, Joanne R et al. (2010) GABAergic but not anti-cholinergic agents re-induce clinical deficits after stroke. J Neurol Sci 292:72-6 |
| Chmayssani, Mohamad; Lazar, Ronald M; Hirsch, Joy et al. (2009) Reperfusion normalizes motor activation patterns in large-vessel disease. Ann Neurol 65:203-8 |
| Lazar, Ronald M; Antoniello, Daniel (2008) Variability in recovery from aphasia. Curr Neurol Neurosci Rep 8:497-502 |
| Lazar, R M; Speizer, A E; Festa, J R et al. (2008) Variability in language recovery after first-time stroke. J Neurol Neurosurg Psychiatry 79:530-4 |
| Prabhakaran, Shyam; Zarahn, Eric; Riley, Claire et al. (2008) Inter-individual variability in the capacity for motor recovery after ischemic stroke. Neurorehabil Neural Repair 22:64-71 |
| Noskin, O; Krakauer, J W; Lazar, R M et al. (2008) Ipsilateral motor dysfunction from unilateral stroke: implications for the functional neuroanatomy of hemiparesis. J Neurol Neurosurg Psychiatry 79:401-6 |
| Lazar, Ronald M; Festa, Joanne R; Geller, Allison E et al. (2007) Multitasking disorder from right temporoparietal stroke. Cogn Behav Neurol 20:157-62 |
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