Regulation of the proton concentration (pH) in the brain is important for maintaining normal brain function. In the brain of healthy individuals, intracellular pH is maintained at 6.8-7.0, while extracellular pH is maintained at 7.2-7.4. While the homeostatic importance of pH regulation has long been recognized, recent studies have shown that protons may also be directly involved in neurotransmission. This suggests an additional dimension to the relevance of pH changes to brain function under both physiological and pathological conditions. Double-barrel and concentric microelectrodes can only measure pH at a single point, limiting their utility for correlating proton changes with globalized brain activity during seizures and ischemia. In contrast, magnetic resonance imaging (MRI) can simultaneously measure the distribution of protons throughout the brain and thus detect regional variations in pH. However, to further investigate regional and neural activity-dependent proton dynamics in the brain, the development of a device with both wide area detectability and high temporal-spatial resolution is necessary. Therefore, we have developed a novel image sensor with high spatio-temporal resolution specifically designed for in vivo proton measurements. Here, we show that spatially distinct neural stimulation by visual stimulation induces distinct patterns of proton changes in the visual cortex. This result indicates that our biosensor can detect micrometer- and millisecond-scale changes in protons over a large area. To our knowledge, this is the first report showing that a CMOS-based proton image sensor with high spatial and temporal precision can be used to detect pH changes associated with biological events. In this symposium, we will also report on the application of our sensor to pathological models, the development of a multi-ion image sensor, and its miniaturization to enable ion imaging under free-moving conditions.