Cooperative Agreements

PROJECT SUMMARY Tourette syndrome (TS) is a continuous lifelong condition that is highly prevalent, socially disabling, and in some severe cases, physically injurious. DBS has emerged as a promising treatment option for addressing uncontrollable tics in medically resistant and severe cases of TS frequently involving self-injurious behavior. We have undertaken a major informatics initiative by establishing the International TS DBS Registry and Database, a multi-country consortium that has captured long term outcomes of 277 TS DBS patients representing 50-75% of all TS DBS cases worldwide.

Project Summary: High frequency oscillations (HFOs) of intracranial EEG (iEEG) have the potential to identify the surgical resection area/seizure onset zone (SOZ) in patients with drug resistant epilepsy. However, multiple reports indicate that HFOs can be generated not only by epileptic cerebral tissue but also by non-epileptic sites often including eloquent regions such as motor, visual and language cortices.

ABSTRACT The goal of this project is to significantly advance the field of acute and semichronic epilepsy monitoring using novel, high-resolution electrocorticography (ECoG) record/stimulate grids (4096/256 channels, respectively) and stereoelectroencephalography (sEEG) depth electrodes (120/8 micro/macro) with full wireless data and power transfer. This project builds on our previous success in conducting the first-ever human trials for acute mapping of eloquent brain tissue with multi-thousand channel microelectrode grids.

Project Summary To advance the development of next-generation personalized therapies for long-term seizure freedom, we urgently need technologies that improve seizure diagnostics while reducing risks associated with invasive neurosurgical procedures. Among the more than 1,000,000 Americans with uncontrolled focal epilepsy, many have poorly localized seizure foci. These individuals face the highest rates of ‘failure’ (i.e., ongoing seizures) after epilepsy surgery. That failure reflects the biology of their epilepsy as well as the overlap of seizure foci with essential cortical areas.

Limited recovery of function after stroke remains a major problem for millions. Disability persists in many, especially when hand function is limited. Existing therapies are limited and many have difficulties with activities of daily living, even after rehabilitation. Electrical stimulation of the brain has been proposed and used in early studies to try and aid recovery. In animals, stimulation delivered to the brain at precise times may improve the effect of stimulation.

PROJECT SUMMARY/ABSTRACT The ability to track electrical activity in genetically defined neurons deep in the brain has long been sought by neuroscientists to unravel the functions of neuronal circuits in health and disease. We seek to address this technical gap by developing genetically encoded voltage indicators (GEVIs), which are fluorescent proteins that report voltage dynamics as changes in brightness. GEVIs would be excellent completements to broadly-used indicators of calcium, another important information carrier in the brain.

Project summary The mammalian brain is remarkably dynamic and can quickly adjust its functional state in response to changes in the environment. For example, when a salient event occurs, the brain enters a mode that enhances memory formation. Such brain state changes occur too rapidly to be due to anatomical rewiring. Instead, they are thought to arise from the action of neuromodulators (NMs) and neuropeptides (NPs).

PROJECT SUMMARY / ABSTRACT Understanding how cognitively-relevant behavioral functions emerge from activity patterns of identified cell- types is predicated on the ability to record large-scale ensemble dynamics from genetically-identified and longitudinally-tracked neuronal populations across multiple brain regions and layers with high spatial and temporal resolution over behaviorally-relevant time-scales.

ABSTRACT Activity-sensitive fluorescent indicators and microscopy have proven valuable tools for measuring neuronal activity, but most forms of cellular microscopy can produce images of neurons only near the brain surface and generally only after removal of tissues overlying the brain surface, such as bone. Many neurons in neocortex are out of reach of cellular microscopy. Here we propose to optimize 3-photon (3P) excitation fluorescence imaging, a form of cellular microscopy, to enable deeper imaging into the brain.

1 Project Summary: The BRAIN 2025 Report, with the goal to “produce a dynamic picture of the functioning brain 2 by developing and applying improved methods for large-scale monitoring of neural activity” is directly 3 addressed by this application.