Stroke is a very common condition in the population, affecting nearly 800.000 new American every year. A third of stroke patients maintain long term motor deficits severe enough to be disabling, despite rehabilitative efforts. New therapies to improve motor outcomes after stroke are needed. The long-term goal of this line of investigation is to develop a neurorestorative therapy to enhance motor recovery for patients who have suffered cortico-subcortical strokes. The investigators have demonstrated previously that electrical stimulation of the lateral cerebellar (dentate) nucleus (LCN) produces sustained increment in cortical excitability and that chronic LCN stimulation enhance recovery of motor function in an established 3-vessel occlusion rodent model of ischemic stroke. The hypothesis was developed based on 1) prior evidence suggesting a role for the cerebello-thalamo-cortical pathway (a net disynaptic excitatory pathway) in modulating cerebral cortical excitability;2) evidence that cortical plasticity can be enhanced by augmenting cortical excitability;and 3) anatomical evidence that indicates the dentatothalamocortical pathway projects not only to the motor cortex but also to the premotor frontal and parietal cortical areas. These areas correspond to the perilesional zone in typical middle cerebral artery infarcts and are thought to be involved in local reorganization associated with motor recovery after stroke. Thus far, our results are promising and human translation is feasible given that the technology for deep brain stimulation (DBS) is already FDA approved for the treatment of movement disorders and has been proven safe in over 40,000 implants. This research proposal was designed to further develop this line of investigation with the goals of: a) identifying stimulation parameters that may drive motor recovery beyond the current results;b) addressing the question of optimal timing for stimulation onset and termination (i.e., therapeutic window), which will have a crucial impact in successful translation of this approach to humans and c) assessing a link between chronic LCN stimulation-induced motor recovery and perilesional cortical plasticity.

Public Health Relevance

The goal of this study is to explore a new therapy for improving rehabilitation of motor function after ischemic strokes. Strokes are very common in the population, affecting more than 500.000 Americans per year. Up to 30% of strokes cause permanent weakness. This therapy will be first tested in a rat model of strokes and then translated to humans. The equipment for use of this therapy is humans are already available and FDA approved for the treatment of patients with advanced Parkinson's disease and tremor. Hence translating this therapy for rats to humans will be simple. The connections between the brain hemispheres and the cerebellar hemispheres are well known. The cerebellum has excitatory input to the cerebral cortex on the opposite side, via the thalamus. The main connection goes through the dentatothalamocortical (DTC) pathway. In this study, we will assess how stimulation of a nucleus in the cerebellum (the origin of the DTC) will influence motor recovery.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Nitkin, Ralph M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Cooperrider, Jessica; Furmaga, Havan; Plow, Ela et al. (2014) Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model. J Neurosci 34:9040-50
Floden, Darlene; Cooper, Scott E; Griffith, Sandra D et al. (2014) Predicting quality of life outcomes after subthalamic nucleus deep brain stimulation. Neurology 83:1627-33
Plow, Ela B; Varnerin, Nicole; Cunningham, David A et al. (2014) Age-related weakness of proximal muscle studied with motor cortical mapping: a TMS study. PLoS One 9:e89371
Plow, Ela B; Machado, Andre (2014) Invasive neurostimulation in stroke rehabilitation. Neurotherapeutics 11:572-82
Machado, Andre G; Cooperrider, Jessica; Furmaga, Havan T et al. (2013) Chronic 30-Hz deep cerebellar stimulation coupled with training enhances post-ischemia motor recovery and peri-infarct synaptophysin expression in rodents. Neurosurgery 73:344-53; discussion 353
Cunningham, David A; Machado, Andre; Yue, Guang H et al. (2013) Functional somatotopy revealed across multiple cortical regions using a model of complex motor task. Brain Res 1531:25-36
Park, Hyun-Joo; Machado, Andre G; Cooperrider, Jessica et al. (2013) Semi-automated method for estimating lesion volumes. J Neurosci Methods 213:76-83