Noninvasive Optogenetic Interventions for Epilepsy

In patients with epilepsy, central nervous system hyperexcitability and synchrony contribute to seizures and cognitive comorbidities. Systemic treatments with anticonvulsant drugs do not adequately control seizures and are often accompanied by severe side effects, where approximately 30-40% of the estimated 65 million epileptic patients worldwide are drug refractory. Consequently, new therapies are needed. Recent advances in optogenetics have demonstrated seizure suppression through precise cell type specific directional control of neural activity.

While closed-loop optogenetic interventions provide strategies to identify networks to curtail seizures, the use of implanted fiber optic waveguides and transgenic mice precludes usage as a therapeutic tool. To overcome challenges associated with optogenetics as a clinical modality, this proposal will test the hypothesis that recently discovered supersensitive and red-shifted Channelrhodopsins (ChRs) can enable transcranial and cell type specific termination of spontaneous, recurrent seizures. The hypothesis will be tested by developing noninvasive viral-targeting strategies to restrict expression of these new ChRs to therapeutically- relevant interneuron subtypes followed by transcranial closed-loop optogenetic control in mouse models of focal epilepsy in the cortex and hippocampus. Chronic seizure suppression will be performed to test the long- term stability of this approach in wild-type animals.

Further refining stimulation to specific projections will minimize off-target effects. By overcoming long standing hurdles of optogenetics, including invasiveness, viral- targeting of neural subpopulations, and scalability, this transcranial optogenetic platform will identify new opportunities for the treatment of epilepsy and may be extended to manage other neurological disorders. During the proposed research and career training plan, I will be mentored by an experienced team of experts in systems neuroscience, optogenetics, animal models of epilepsy and behavior, electrophysiology and computational analysis. This team will advise my research project and professional development through training in new techniques, manuscript and grant writing, public speaking, advising of mentees, and collaborations within the tremendous scientific environment at Stanford University, which offers several core facilities, career development centers, and formal coursework to support my work.

Upon completion of this mentored research project, I will gain a strong technical and conceptual foundation to bridge my background in engineering with systems neuroscience, which I will use to establish an independent research career to develop and apply methods to study the neural mechanisms that underly neurological disorders and to develop treatment concepts for them.

Grant Number: 5R00NS119784-05
NIH Institute/Center: NIH
Principal Investigator: Ritchie Chen