Fiber-Less, Large-Scale Opto-Electrophysiology Interface for Micro-Scale Interaction of Multiple Brain Regions.

Abstract

Recent neuroscientific research craves for understanding sophisticated brain networks formed by neuron ensembles across multiple regions. An ideal way to unveil the complex connectome is bidirectionally interacting (simultaneous recording and stimulation) with neurons at high spatiotemporal resolutions. Existing CMOS recording probes cannot provide micro-scale interactions with limited stimulation capability. Although optogenetics can achieve neuron-specific stimulation, conventional methods using optic fibers illuminate a large volume of tissue, resulting in unspecific perturbations. While our previous studies demonstrated micro-LED (μLED)-based optoelectrode for localized stimulation and recording, this work advances them into a fully integrated headstage combining the optoelectrode, CMOS IC, and flexible interposer for miniaturized implementation. The proposed system enables micro-scale interactions with high spatiotemporal precision through densely packed 256-neuron-size recording and 128-soma-size fiber-less opto-stimulation across multiple brain regions. Such high resolutions yet wide coverage is achieved by (1) advanced micromachining techniques integrating recording electrodes and μLEDs, (2) micro-second, independent 384-channel interaction via a low-power, area-efficient circuit, and (3) compact and reliable polyimide-cable-based hybrid assembly. A compact (23.8×28.8 mm2) and lightweight (3.5-gram) headstage achieved the highest reported channel density in area (0.56 channels/mm2) and weight (109.71 channels/gram). A single acute in vivo experiment on a transgenic mouse identified >160 isolated pyramidal neurons and narrow/wide interneurons in the dorsal hippocampus, with local and broad-range effects from focal optogenetic stimulation. We implemented the hybrid integrated, large-scale opto-electrophysiology interface prototype and verified its feasibility in vivo, representing the first fully integrated platform extending our μLED-based probes into a complete system.