Electrical and Optogenetic Modulation of Cortical Activity to Promote Neuroprotection and Network Reorganization in Non-Human Primates

Abstract

Many debilitating neurological conditions arise from abnormal network dynamics and connectivity. Novel neuromodulation techniques, including electrical and optogenetic stimulation, aim to harness the brain's innate plasticity to reorganize neural connections, reduce tissue damage, and improve patient outcomes. To test the feasibility of these emerging neuromodulation approaches while improving their translational potential, my dissertation work applies advanced electrophysiology, histology, and computational tools in the brains of non-human primates (NHPs), evaluating the cortical response to different stimulation paradigms. Chapter 2 addresses the critical need for acute interventions in ischemic stroke, which can prevent irreversible tissue injury and improve functional outcomes. By inducing focal lesions in the sensorimotor cortex of NHPs while recording electrocorticography signals, we evaluated the impact of acute, theta-burst electrical stimulation delivered adjacent to the ischemic infarct. Early stimulation significantly reduced peri-infarct neuronal depolarization and microglial activation, leading to smaller lesion volumes. This study demonstrated the therapeutic potential of acute electrical stimulation to mitigate excitotoxicity, inflammation, and neural damage following ischemic injury, offering a promising strategy to enhance patient outcomes after stroke. Chapter 3 explores the use of optogenetic tools to modulate cortical network dynamics. By delivering patterned laser illumination to regions expressing an inhibitory opsin, we successfully disrupted functional connectivity in the posterior parietal cortex, reducing gamma-band coherence between targeted locations and the broader network. This selective decoupling highlights the potential of optogenetics to weaken pathological synchrony, complementing prior work using excitatory strategies to enhance connectivity and facilitate recovery. Together, these findings advance the development of targeted neuromodulation therapies aimed at restoring healthy network function in neurological disorders.