MAPPING LOW-FREQUENCY FIELD POTENTIALS IN BRAIN CIRCUITS WITH HIGH-RESOLUTION CMOS ELECTRODE ARRAY RECORDINGS

Neurotechnologies based on microelectronic active electrode array devices are on the way to provide the capability to record electrophysiological neural activity from a thousands of closely spaced microelectrodes. This generates increasing volumes of experimental data to be analyzed, but also offers the unprecedented opportunity to observe bioelectrical signals at high spatial and temporal resolutions in large portions of brain circuits. The overall aim of this PhD was to study the application of high-resolution CMOS-based electrode arrays (CMOS-MEAs) for electrophysiological experiments and to investigate computational methods adapted to the analysis of the electrophysiological data generated by these devices. A large part of my work was carried out on cortico-hippocampal brain slices by focusing on the hippocampal circuit. In the history of neuroscience, a major technological advance for hippocampal research, and also for the field of neurobiology, was the development of the in vitro hippocampal slice preparation. Neurobiological principles that have been discovered from work on in vitro hippocampal preparations include, for instance, the identification of excitatory and inhibitory synapses and their localization, the characterization of transmitters and receptors, the discovery of long-term potentiation (LTP) and long-term depression (LTD) and the study of oscillations in neuronal networks. In this context, an initial aim of my work was to optimize the preparation and maintenance of acute cortico-hippocampal brain slices on planar CMOS-MEAs. At first, I focused on experimental methods and computational data analysis tools for drug-screening applications based on LTP quantifications. Although the majority of standard protocols still use two electrodes platforms for quantifying LTP, in my PhD I investigate the potential advantages of recording the electrical activity from many electrodes to spatiotemporally characterized electrically induced responses. This work also involved the collaboration with 3Brain AG and a CRO involved in drug-testing, and led to a software tool that was licensed for developing its exploitation. In a second part of my work I focused on exploiting the recording resolution of planar CMOS-MEAs to study the generation of sharp wave ripples (SPW-Rs) in the hippocampal circuit. This research activity was carried out also by visiting the laboratory of Prof. A. Sirota (Ludwig Maximilians University, Munich). In addition to set-up the experimental conditions to record SPW-Rs from planar CMOS-MEAs integrating 4096 microelectrodes, I also explored the implementation of a data analysis pipeline to identify spatiotemporal features that might characterize different type of in-vitro generated SPW-R events. Finally, I also contributed to the initial implementation of high-density implantable CMOS-probes for in-vivo electrophysiology with the aim of evaluating in vivo the algorithms that I developed and investigated on brain slices. With this aim, in the last period of my PhD I worked on the development of a Graphical User Interface for controlling active dense CMOS probes (or SiNAPS probes) under development in our laboratory. I participated to preliminary experimental recordings using 4-shank CMOS-probes featuring 1024 simultaneously recording electrodes and I contributed to the development of a software interface for executing these experiments.