Title: Integration of neural optical recording and stimulation on minimally invasive, deep-brain implantable CMOS
Description: This thesis describes the development of a minimally invasive integrated platform for all-optical neural stimulation and measurement (OptoSAM). The OptoSAM platform is a single mixed-signal complementary metal-oxide semiconductor (CMOS) chip. After design, the chip is postprocessed to contain the necessary optical filters and emitters to enable both fluorescent detection and neural stimulation. Finally, the chip is packaged in a probe form factor for minimally-invasive implantation into neural tissue. The thesis describes how the OptoSAM is engineered for two applications: optical fluorescent imaging on one hand and optogenetic stimulation on the other. For either application, constraints and tradeoffs are described that guide design specifications. For fluorescent neural detection, this thesis focuses on improvements made in lens-less image reconstruction and optical filtering. It describes circuit design for the lens-less, filter-less fluorescent imaging subsystem and characterizes the resulting imaging performance.

The lack of on-chip filters precludes reliable imaging of fluorescent targets both in-vivo and ex-vivo. To address these limitations, the metal-insulator-metal angle sensitive pixel (MIMASP) is introduced, a novel nanophotonic structure that integrates lens-less imaging and optical filtering in an ultrathin (<5μm) frontend. The MIMASP offers three advantages over previously published angle sensitive pixels. First, it orthogonally modulates the detection light field for two arbitrary wavelengths, enabling the separation and detection of colors in the image. Secondly, each layer is constructed from optical long-pass filters, rejecting the blue excitation light. Third, an analytical framework is created that allows to optimize the ensemble image reconstruction resolution as a function of the available per-pixel geometries. The angle sensitive pixels are a promising lens-less imaging method for situations where both the number of pixels and the permitted device dimensions are extremely constrained.

Equipped with the MIMASP frontend, the imager is demonstrated in scattering media to successfully separate fluorescent targets based on color, fluorescent lifetime and even environmental pH. The experiments are extended to fluorescent detection in ex-vivo acute brain slices. For optogenetic stimulation, we equip the OptoSAM platform with organic light emitting diodes (OLEDs) as thin-film emitters. In-vivo results show how the OLED probe can evoke neural activity in a fully scalable fashion. Using synchronized groups of OLEDs, large neural populations can be synchronously activated. Simultaneously, single neurons can be manipulated by emission from single OLEDs at a 25μm pitch. We demonstrate single-unit manipulation and separation of both pyramidal and interneurons. A custom flexible, transparent multi-electrode array (MEA) provides the electrophysiological recording for cross-validation in the deep-brain. Measurements show how local field potentials (LFPs) are evoked at both 300μm and 1.2mm deep, and how the LFP magnitude roll-off proves locality of the induced activity.

Compared to previously published stateof- the-art, the OLED-on-CMOS approach provides a two orders of magnitude larger field of view (FoV) while improving resolution by 3×. Pixel pitch and count can be fully scaled to provide arbitrary fields of view and resolution. The OptoSAM platform proves a pathway towards behavioral studies in awake mice. These studies could address multiple brain regions independently with a single device insertion. This provides neuroscientists with the tools to study relationship between distant regions with single-neuron resolution. While the detection and stimulation are separately optimized and validated, the chip is a promising platform for future integration of both modalities. To this end, it proposes three future chip designs, each with their respective strengths. The proposals also provide potential solutions to the challenges associated with the design and fabrication. The thesis concludes with recommendations for future experiments, both for the OptoSAM platform and for future designs.