High density chronic optogenetic interface for primate brains

PROJECT SUMMARY 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 become a powerful tool for studying neural circuit function, but challenges remain in its application to NHPs. Large volume manipulations are essential in the large NHP brain in order to observe measurable electrophysiological or behavioral effects and understand the encoding of information across multiple brain areas. Under previous NIH BRAIN Initiative funding, an interdisciplinary team led by the University of Utah has developed and tested in vivo the Utah Optrode Array (UOA). This is a 10x10 array of penetrating transparent light guides, bonded to a µLED array, for large-volume, spatiotemporally patterned optogenetic modulation of neural circuits in large brains. In vivo testing of the UOA in NHP visual cortex demonstrated that the device allows for selective activation of deep cortical layers, as well as for both focal and large-scale photostimulation by simply varying the number of simultaneously activated µLEDs and/or their light irradiance These results establish the UOA as a powerful tool for studying local and large-volume targeted neuronal populations in large brains. Led by Blackrock Neurotech, the goal of this STTR is to transition the UOA into a commercializable device by combing the best features of its current ‘LED Stim’ optogenetic surface stimulation array with the UOA. Thus, the goal of Phase I is to engineer the first iteration of this new device, termed ‘OA2’ for development purposes: Aim 1: Integration of blue stimulation array, in which redesign, fabrication, and integration of the two-level stimulation device will be performed using independent 10×10 and 9×9 arrays of blue µLEDs for deep-layer and surface stimulation, respectively. Aim 2: Device encapsulation and packaging, in which robust encapsulation processes will be developed and tested, suitable for acute in vivo use. Aim 3: Development of matrix driver, in which a new driver and firmware will be developed in order to independently control the deep and surface stimulation arrays for spatially-multiplexed operation. The project includes a Go-NoGo to phase II paradigm which requires rt90% of the stimulation sites to remain active rt2.8 mW/mm2 following acute soak testing with 50% simultaneous operation at 10% duty cycle, artifact-free. Phase II will consist of four Aims: Aim 4: Device optimization for multi-color stimulation, in which the active µLED component will be modified to facilitate placement and hard encapsulation of µLEDs onto the topside of the device, allowing multi-color stimulation at each deep/surface site. Both single and two-color devices will be produced in Phase II. Aim 5: Device encapsulation and packaging, will build upon the work of Aim 2 to include hard encapsulation of the active components of the device in order to increase device in vivo reliability. Processes will be developed and tested suitable for chronic in vivo use. Aim 6: Development of dual-color matrix driver, in which the matrix driver will be updated to bipolar drive signals to enable multiplexed control of two µLEDs per stimulation site. Aim 7: In vivo testing in NHP, in which both acute and chronic testing of the OA2 device will be performed in macaque for periods up to 6 months.