Jeffrey A. Kleim - US grants

The majority of stroke survivors display limb weakness and motor impairments, but will show some measurable recovery of function over time. Regaining some impaired function may be explained by brain plasticity and this holds promise for therapeutic and rehabilitative treatments. A possible strategy for improving functional recovery following cerebral strokes in humans involves augmenting brain plasticity by combining rehabilitative training with mild focal electrical stimulation of peri-infarct cortical areas. The long-term objective is to enhance recovery from stoke by activating and teaching cortical neuronal networks by using cortical stimulation in combination with rehabilitative training. This project has two aims; 1) determine the optimal electrical stimulation parameters (frequency, amplitude, and temporal pattern) on behavioral efficacy, and 2) determine the optimal electrode configuration, duration of therapy and persistence of the enhanced recovery. The effect of the stimulation parameters on movement and seizure thresholds will also be determined in both the lesioned and intact hemisphere. In order to achieve these aims we use a rodent model of stroke. The rats are initially trained on skilled behavioral tasks, undergo a focal ischemic infarct (stroke), receive cortical stimulation with rehabilitative training and are assessed on their recovery. Furthermore, we will determine the stimulation parameters that markedly improve behavioral recovery but minimize unwanted side effects (a maximal therapeutic index). The results from the studies above will then be used to guide the development of clinical applications of the technique in humans that have had strokes.

[unreadable] DESCRIPTION (provided by applicant): Stroke the third largest cause of death and is a leading cause of serious, long-term disability in the United States and worldwide. Of the 700,000 Americans who will survive a stroke this year, 70% receive some form of motor rehabilitation. However, the efficacy of current motor rehabilitation interventions is highly variable and reflects our lack of understanding of the neural and behavioral signals driving functional recovery. Motor recovery is supported by functional compensation within residual motor areas including primary motor cortex. The neural mechanisms underlying functional reorganization within motor cortex involve synaptic plasticity within cortical circuitry that is driven by specific neural signaling pathways. We hypothesize that some of the variability in the efficacy of motor rehabilitation interventions is due to inherent differences in the capacity for experience-dependent plasticity. Specifically, polymorphisms within genes that govern the activity of neural signaling pathways mediating synaptic plasticity can influence the rate and level of motor recovery after stroke. The goals of the proposed set of experiments are to characterize the relationship between genotype, cortical plasticity and motor performance. The studies will use blood genotyping, transcranial magnetic stimulation and extensive motor training/testing to examine determine how naturally occurring polymorphisms in the Brain Derived Neurotrophic Factor (BDNF) gene, known to be involved in mediating cortical plasticity, influence the capacity for cortical plasticity, age related decrements in motor performance and capacity for motor recovery after stroke. The experiments will be conducted in both young and old subjects with or without the polymorphism. We hypothesize that age related decrements in motor status and motor impairments after stroke will be exacerbated in polymorphic individuals and that this represents a compromised capacity for compensation that occurs in response to age and stroke related declines in neural function. This process is particularly important for stroke victims receiving rehabilitation to improve motor function. The short term goal of these experiments is to establish the baseline role of these different genotypes in experience-dependent plasticity in the intact brain. The long term goal of this research program is to determine how genotype may influence the capacity for motor recovery after stroke Using transcranial magnetic stimulation we will examine changes in corticospinal output in response to motor training in young, middle aged and old subjects with three variants of the BDNF genotype. We will further examine the relationship between experience- dependent cortical plasticity, motor function and age. Finally we will examine how the capacity for rehabilitation-dependent motor recovery in stroke patients varies as a function of BDNF genotype. [unreadable] [unreadable] [unreadable] [unreadable]