An observation technique for animal brain activity under freely moving conditions is important to understand brain functions because brain activity under an anesthetized condition is different from that under a nonanesthetized condition. We have developed an ultrasmall CMOS imaging device for brain activity observation under freely moving conditions. This device is composed of a CMOS image sensor chip and nine LEDs for illumination. It weighs only 0.02 g and its small size enables experiments to be performed without restricting animal movement. This feature is advantageous for brain imaging, particularly in freely moving situations. In this study, we have demonstrated blood-flow imaging using the device for the stable observation of brain activity over a long period. The blood flow can be observed without staining the brain during optical imaging. We have successfully estimated the blood-flow velocity under freely moving conditions.

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The application of the fluorescence imaging method to living animals, together with the use of genetically engineered animals and synthesized photo-responsive compounds, is a powerful method for investigating brain functions. Here, we report a fluorescence imaging method for the brain surface and deep brain tissue that uses compact and mass-producible semiconductor imaging devices based on complementary metal-oxide semiconductor (CMOS) technology. An image sensor chip was designed to be inserted into brain tissue, and its size was 1500 × 450 μm. Sample illumination is also a key issue for intravital fluorescence imaging. Hence, for the uniform illumination of the imaging area, we propose a new method involving the epi-illumination of living biological tissues, and we performed investigations using optical simulations and experimental evaluation.

Fluorescence imaging devices have been indispensable in elucidating the workings of the brain in living animals, including unrestrained, active ones. Various devices are available, each with their own strengths and weaknesses in terms of many factors. We have developed CMOS-based needle-type imaging devices that are small and lightweight enough to be doubly implanted in freely moving mice. The design also allowed angled implantations to avoid critical areas. We demonstrated the utility of the devices by using them on GCaMP6 mice in a formalin test experiment. Simultaneous implantations to the capsular-lateral central amygdala (CeLC) and dorsal raphe nucleus (DRN) were proven to be safe and did not hinder the execution of the study. Analysis of the collected calcium signaling data, supported by behavior data, showed increased activity in both regions as a result of pain stimulation. Thus, we have successfully demonstrated the various advantages of the device in its application in the pain experiment.

In this article, We demonstrated an image sensor for detecting changes in polarization with high sensitivity. For this purpose, we constructed an optical system with a two-layer structure, comprising an external polarizer and polarizers on a pixel array. An external polarizer is used to enhance the polarization rotation while reducing the intensity to avoid pixel saturation of the image sensor. Using a two-layer structure, the two polarizers can be arranged under optimal conditions and the image sensor can achieve high polarization-change detection performance. We fabricated the polarization image sensor using a 0.35-µm CMOS process and, by averaging 50 × 50 pixels and 96 frames, achieved a polarization rotation detection limit of 5.2 × 10 −4 • at a wavelength of 625 nm. We also demonstrated the applicability of electric-field distribution imaging using an electrooptic crystal (ZnTe) for weak-polarization-change distribution measurements.

A brain functional imaging technique over a long period is important to understand brain functions related to animal behavior. We have developed a small implantable CMOS imaging device for measuring brain activity in freely moving animals. This device is composed of a CMOS image sensor chip and LEDs for illumination. In this study, we demonstrated intrinsic signal imaging of blood flow using the device with a green LED light source at a peak wavelength of 535 nm, which corresponds to one of the absorption spectral peaks of blood cells. Brain activity increases regional blood flow. The device light weight of about 0.02 g makes it possible to stably measure brain activity through blood flow over a long period. The device has successfully measured the intrinsic signal related to sensory stimulation on the primary somatosensory cortex.

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In this study, a polarisation-analysing CMOS image sensor is fabricated for sensitive polarisation modulation detection. Although the image sensor with on-pixel polarisers can image the incident polarisation collectively, its sensitivity to a weak polarisation change is not high. With the proposed method, an external polariser is used to enhance the polarisation modulation sensitivity with a polarisation image sensor. The performance of this highly sensitive polarisation image sensor and imaging experiments are evaluated using a flow channel.