Brain stimulation has emerged as a novel treatment for stroke, a prevalent cause of death and disability worldwide. Studies in rodent models have shown that post-stroke electrical stimulation results in plasticity and neuroprotective benefits. However, techniques that were effective in rodents have rarely translated into clinically viable therapies in humans due to the significant differences in rodent and human neurophysiology and anatomy. Therefore, the goal of our study is to obtain clinically relevant outcomes that describe the mechanisms of stimulation induced plasticity in non-human primates. We combined electrophysiology and immunohistochemistry to investigate the degree of stimulation-induced plasticity and network dynamics after photothrombotic stroke in 4 macaques. We quantified the expression of two biomarkers, postsynaptic density-95 (PSD-95) and growth-associated protein-43 (GAP-43) in cells within ~10mm from the lesion penumbra. Since PSD-95 is important for the maturation of excitatory synapses and GAP-43 is involved in axonal branching and elongation, evaluating the expression of these two proteins around the lesion core allowed us to compare post-stroke synaptic and axonal plasticity in 2 control and 2 stimulated monkeys. Based on wide-field epifluorescence imaging, we identified the distance from the lesion penumbra at which there was a distinct difference in biomarker immunoreactivity in control and stimulated animals, and performed high-magnification confocal imaging to further investigate the structure of biomarker expression. Furthermore, analysis of the electrocorticography signal showed a largescale downregulation of neural activity following electrical stimulation, while Nissl staining revealed that stimulated monkeys had smaller lesion volumes than controls. These results indicate that stimulation elicits changes at both neurophysiological and cellular level, and may exert a neuroprotective effect on the post-stroke network by reducing metabolic energy consumption.. Therefore, this study investigates the effects of electrical stimulation on neuroplasticity and protection following injury, which may have a profound impact on future therapeutic interventions for stroke.

Non-human primate (NHP) research has become an essential step in the translation of medical technologies from animal models to clinical trials. This is especially so in neural research, as there is a large discrepancy between rodent and human brains in both anatomy and size. For some techniques such as optogenetics, which requires viral transduction of neurons, traditional diffusion-based viral infusion approaches are effective in rodent brains but are impractical for large NHP brains. Convection-enhanced delivery (CED), a large-scale infusion approach, currently lacks a practical quantitative bench-side infusion modeling method to guide neurosurgical preparation. To mitigate surgical risk, we have developed a gel model of the NHP brain and tested the validity of our model by monitoring the spread of the infusion through the gel and comparing the data with those from MRI scans of previous infusions in NHP. Since CED can behave differently depending on the location of infusion in the brain, we tested bench-side infusions at different depths to validate the versatility of our model and demonstrated that our model is applicable to these different depths. Additionally, we are developing methods of reducing tissue damage caused by the cannula insertion by testing the effectiveness of smaller cannula sizes with our bench-side model. We found that some cannula designs are able to maintain the same infusion results as our traditional, larger cannulas and we plan to perform CED infusions in rat brains with these new cannulas to quantify tissue damage reduction.