2009 — 2010 |
Adkins, Deanna L. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cognitive Neurorehabilitation to Enhance Recovery After Stroke @ University of Texas, Austin
DESCRIPTION (provided by applicant): The main objective of these studies is to determine if cognitive neurorehabilitation improves memory and induces neural plasticity in residual brain areas following stroke. There is a well-established model system to examine rehabilitation-induced motor recovery and plasticity following experimental strokes in rats. Motor recovery is thought to be a process of "relearning" in which motor functions are reacquired through functional compensation within spared brain regions. Several laboratories have demonstrated that such functional compensation is supported by synaptic plasticity within residual neural circuits that is driven by rehabilitation. However, it is unknown whether cognitive neurorehabilitative training will improve cognitive performance, such as improved memory. It seems possible that focused cognitive neurorehabilitation would improve specific areas of cognitive function and induce greater neural adaptive changes in spared brain regions that are relevant to the rehabilitated cognitive function. However, basic neurobiology research suggests that the neural basis of motor skills acquisition and performance is different from cognitive tasks such as episodic memory. Motor skills and cognitive functions involve different neural networks and thus the requirements of learning- induced neural plasticity in these networks are also likely different. This proposal is to systematically investigate how cognitive rehabilitative therapy after ischemic insult can improve cognitive ability, including the neural bases of the improvements and the efficacy of combining rehabilitation with pharmacological treatments. This will be investigated in a rat model of stroke (middle cerebral artery occlusion) using a combination of sensitive behavioral measures and manipulations of cognitive function and assays of neuronal and synaptic structural plasticity in the hippocampus. The aims of this project are to test the hypotheses that: 1) Post-stroke training in tasks requiring episodic memory will improve performance on tests of cognitive ability in an animal model of stroke compared to non- trained groups;2) Cognitive rehabilitative training that improves cognitive ability following stroke will result in restorative plasticity in the hippocampus compared to non-trained groups;3) Coupling cognitive neurorehabilitative training with an acetylcholinesterase inhibitor will enhance the efficacy of post-stroke cognitive neurorehabilitation. These investigations are expected to elucidate mechanisms involved in cognitive recovery after brain injury, with the potential of leading to better clinical treatment approaches. PUBLIC HEALTH RELEVANCE: Currently, there is not a well-developed rodent model of cognitive neurorehabilitation following neurological insult. We propose to develop a rat model of cognitive neurorehabilitative training that will provide knowledge regarding the effectiveness of task specific cognitive training and the neural mechanisms underlying its therapeutic efficacy following stroke. These investigations will serve as a foundation to test adjunctive therapies to optimize recovery from stroke.
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0.952 |
2011 — 2015 |
Adkins, Deanna L. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury @ University of Texas, Austin
DESCRIPTION (provided by applicant): The main objective of these studies is to determine if cortical stimulation combined with motor rehabilitative therapy will improve motor function following traumatic brain injury (TBI). Motor recovery is thought to be a process of "relearning" in which motor functions are reacquired through functional compensation within spared brain regions. Several laboratories have demonstrated that such functional compensation is supported by synaptic plasticity within residual neural circuits that are driven by rehabilitation. Previous studies in stroke models also strongly indicate that behavioral improvements and cortical plasticity are enhanced by administering cortical stimulation (CS) during motor rehabilitative training (RT). It is often assumed that motor impairments, and thus treatment strategies to alleviate them, are the same between TBI- and stroke-induced motor cortex damage. However, the optimal parameters used for treatment following ischemic stroke and contusion injury are almost certain to vary because they have very different patterns of cellular responses, time-line of behavioral recovery and responsiveness to rehabilitative training. Furthermore, because TBI appears to create an enduring resistance to experience-dependent neural plasticity, it may be that adjunctive treatments that overcome this resistance are especially critical to unleash the potential of behavioral interventions after this type of injury. We hypothesize that effective CS delivered over the contused sensorimotor cortex during rehabilitative training will induce greater behavioral improvements and that these improvements will be supported, at least in part, by enhancement of functionally relevant reorganization of remaining motor cortex. Our recent preliminary data in a rat model of controlled cortical impact (CCI) injury supports the likelihood that CS+RT can be used to improve motor performance after TBI and that this may be a result of its enhancement of motor cortical plasticity. However there is a need to better understand the parameters of CS treatment that maximize its effectiveness for promoting enduring improvements in motor function and to understand the neural basis of effective versus ineffective treatment. The proposed studies will 1) establish optimal stimulation parameters in a rat model of unilateral CCI;2) determine if effective CS enhances the motor cortical structural and functional responses to rehabilitative training and the necessity of the reorganized cortex for the behavioral improvements;3) investigate if there is a sensitive period for the effectiveness of CS-induced improvements;and 4) investigate if CS effects are enduring and if timing of treatment initiation affects CS endurance. We will use a combination of sensitive behavioral measures, quantitative light microscopy to assay changes in markers of neuronal structural plasticity, and intracortical microstimulation (ICMS) mapping to reveal the functional integrity and organization of motor cortex. These investigations are expected to provide support for a potentially powerful treatment option for survivors of traumatic brain injuries. PUBLIC HEALTH RELEVANCE: Cortical stimulation combined with motor rehabilitation may improve motor outcome after traumatic brain injury (TBI). Using an animal model, these studies will establish appropriate stimulation parameters to improve motor performance, test the persistence of improvements and quantify brain reorganization due to treatment. By revealing the neural mechanisms underlying effective versus ineffective CS treatment, these studies will facilitate the future development of assays of treatment efficacy as well as reveal new targets for therapeutic interventions, laying the foundation for future clinical trials using CS to improve motor recovery after TBI.
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1 |
2014 — 2015 |
Adkins, Deanna L. Jensen, Jens H [⬀] Jensen, Jens H [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Prediction of Motor Outcome After Acute Stroke Using Diffusional Kurtosis Imaging @ Medical University of South Carolina
DESCRIPTION (provided by applicant): Approximately one-third of all stroke patients endure persistent motor disability after their initial stroke. Rehabilitative interventions are crucial fo promoting motor recovery aimed at improving patients' ability to independently manage daily activities. Decisions regarding the design of specific rehabilitation protocols are governed by the clinical assessment of a patient's potential for motor recovery, among other factors. Diffusion tensor imaging (DTI) is a promising tool for quantifying stroke- related microstructural brain damage thought to be associated with eventual functional recovery. For chronic stroke, several DTI studies have demonstrated that poor motor function recovery is associated with low fractional anisotropy of water diffusion in the ipsilesional corticospinal tract. For acute stroke, however, corresponding DTI results have not been reliably demonstrated. Since delayed efforts for rehabilitation often lead to worse motor outcome, improved neuroimaging techniques for evaluating the potential for recovery during the acute stages of stroke would potentially be valuable for the planning of appropriate and timely rehabilitative intervention. In brain tissue, he presence of diffusion barriers, such as cellular membranes and organelles, causes water diffusion to be markedly non-Gaussian. Because DTI nonetheless assumes water diffusion to be Gaussian, its ability to characterize tissue microstructure is necessarily incomplete. To overcome this limitation, we have developed a clinically feasible diffusion MRI method that accounts for diffusional non-Gaussianity (i.e. kurtosis) called diffusional kurtosis imaging (DKI). Furthermore, diffusion metrics obtained from either DTI or DKI are bulk physical properties with no explicit link to tissue properties. To address this second limitation, we have developed a technique called cerebral microenvironment modeling (CMM) that provides estimates of specific tissue microstructural properties, such as neurite (i.e. axons and dendrites) density, orientation distribution and compartmental diffusion coefficients, by utilizing the diffusion metrics derived from DKI. Our overall hypothesis is that tissue properties obtained from our new CMM method are sensitive biomarkers of ischemic brain injury, which may be reliable prognostic indicators of motor function recovery after acute ischemic stroke. This hypothesis will be tested by the following Specific Aims: (1) to determine the relationship between CMM metrics and histologically defined brain cytoarchitecture after ischemic stroke; and (2) to investigate the association between CMM metrics and spontaneous and rehabilitation-induced motor recovery after stroke. Successful completion of this project will provide sensitive and biophysically interpretable biomarkers of spontaneous and rehabilitation-induced stroke recovery.
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1 |