Cooperative Agreements

 DESCRIPTION (provided by applicant): Approximately 1/3 of people living with epilepsy (PWE) continue to have seizures despite anti-epileptic drugs (AEDs). Recent trials using therapeutic brain stimulation show reductions in seizures, but rarely provide seizure free outcomes. Although seizures occupy a small fraction of their life, as little as 0.01%, PWE take anti-epileptic drugs (AED) daily, suffer AED related side effects, and spend their lives dreading when the next seizure will strike. The apparent randomness of seizures is associated with significant psychological consequences.

 DESCRIPTION (provided by applicant): Neurologic disorders including cervical spinal cord injury, brainstem stroke, and amyotrophic lateral sclerosis can lead to severe paralysis of all fou limbs. More than 100,000 people in the US have tetraplegia from these and other disorders, which in their most extreme forms can lead to loss of all voluntary movement and the loss of speech (locked-in syndrome).

 DESCRIPTION (provided by applicant): Severe to moderate traumatic brain injury (smTBI) annually afflicts many hundreds of thousands of Americans producing chronic cognitive disabilities that lack effective treatments. The present proposal will develop a critical first-in-an early clinical feasibility study to support a next generation device to provide central thalamic deep brain stimulation (CT-DBS).

Attaining effective optical modulation and readout of neuronal circuit activities has been a longstanding goal in neuroscience and is a key near-term aim of the BRAIN Initiative.

We propose to develop a revolutionary tool for simultaneous intracellular recording from hundreds of single neurons in the freely-moving animal. In order to link neural activity and behavior it is essential to record the electrical activity of many individual neurons simultaneously for long periods of time. Current methods allow recording of multiple neurons only at the spike level, losing the crucial details that are available in subthreshold synaptic activity.

To understand brain function in health and disease it is essential to rapidly monitor signaling in neural circuits. Two-photon microscopy is a core tool for neuroscience research because it enables neuronal activity to be monitored at high spatial resolution deep within brain tissue. However, the mechanical scanning and focusing of conventional designs severely limits the temporal resolution of 30 imaging and brain movement complicates recordings.

This proposal aims to develop better tools for analyzing brain cells and circuits and for large-scale recordings of brain activity. The currently available tools are relatively primitive in terms of sensitivity and speed. One major function of a neuron is to process electrical signals. Thus a tool that is of particular significance is high speed membrane potential imaging. Genetically encoded fluorescent protein voltage indicators (GEVI's) are a obvious strategic approach for “visualizing the brain in action”.

The ability to reliably and chronically introduce electrical signals directly into the brain is crucial for a host of efforts to create neural prostheses as well as for basic research to understand brain function. Our goal is to further these efforts by developing a novel micro-coil based magnetic stimulation device suitable for implantation into cortex or into other regions of the CNS. Magnetic stimulation from micro-coils offers some important advantages over conventional electric stimulation.

Understanding the function of neural circuits in the cerebral cortex of the non-human primate (NHP), the model system closest to human, is crucial to understanding normal cortical function and the circuit-level basis of human brain disorders. Optogenetics has emerged as a powerful tool for studying neural circuit function, by using light to perturb the activity of specific cell types genetically modified to express light-activated microbial opsins, and assessing the consequences of this perturbation on network activity and behavior.

Implantable neural electrodes have enjoyed decades of development but the ability to record resolvable neuronal activities is often reduced or completely lost over time. This is true regardless of species with recording lifetimes of months to at best a few years in animal; although select neural probes have been successfully implemented in human, the recording lifetimes are short (