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In the study of the brain, large and high-density microelectrode arrays have been widely used to study the behavior of neurotransmission. CMOS technology has facilitated these devices by enabling the integration of high-performance amplifiers directly on-chip. Usually, these large arrays measure only the voltage spikes resulting from action potentials traveling along firing neuronal cells. However, at synapses, communication between neurons occurs by the release of neurotransmitters, which cannot be measured on typical CMOS electrophysiology devices. Development of electrochemical amplifiers has resulted in the measurement of neurotransmitter exocytosis down to the level of a single vesicle. To effectively monitor the complete picture of neurotransmission, measurement of both action potentials and neurotransmitter activity is needed. Current efforts have not resulted in a device that is capable of the simultaneous measurement of action potential and neurotransmitter release at the same spatiotemporal resolution needed for a comprehensive study of neurotransmission. In this paper, we present a true dual-mode CMOS device that fully integrates 256-ch electrophysiology amplifiers and 256-ch electrochemical amplifiers, along with an on-chip 512 electrode microelectrode array capable of simultaneous measurement from all 512 channels. 

The electrical potential recordings using a large microelectrode array from neuronal cultures has been widely used to monitor neural spike activities and cellular activities. However, this approach does not monitor neurochemical release, and therefore only contains indirect information regarding synaptic neurotransmission. At the synapses, these action potentials instigate the secretion of neurotransmitters. Neurochemical recordings, based on electrochemical methods, enable the direct monitoring of synaptic transmissions with single-vesicle resolution as well as the excellent temporal resolution in the microsecond scale. The neural spike activities and the neurotransmitter secretions are related; however, one cannot be used to predict the other because of the complex vesicle trafficking and exocytosis processes. Here, we present a dual-mode amplifier array which integrates 256-ch transconductance amplifiers and 256-ch transimpedance amplifiers. The dual-mode amplifier array enables the simultaneous recordings of electrophysiology and neurochemical activities. Capturing both neurochemical and neural spike (action potential and local field potential) activities would provide comprehensive spatiotemporal images of the brain activities. 

A common problem in single-cell measurement is the low-throughput nature of measurements. Monolithic CMOS microsystems have enabled many parallel measurements to take place simultaneously to increase throughput due to the integration of electrodes and amplifiers into a single chip. This paper explores a CMOS chip containing an array of 1024 parallel transimpedance amplifiers that takes advantage of a “half-shared” operational amplifier architecture. This architecture splits a traditional 5-transistor operational amplifier into two, the inverting half and the non-inverting half. Splitting an amplifier into two allows for the non-inverting half to be “shared” with several inverting halves, reducing the die area required for each individual amplifier. This allows for an increased number of amplifiers to be embedded into the same chip; in this case, 32 amplifiers are able to fit in the same space as 17 traditional 5-transistor operational amplifiers. The amplifiers exhibit low mismatch of 1.65 mV across the entire 1024 amplifier array, as well as high linearity in transimpedance gain. The technique will enable larger arrays to be created in future designs to allow electrophysiologists, among others, access to even higher-throughput measurement tools. 

Fast electrochemical imaging enables the dynamic study of electroactive molecule diffusion in neurotransmitter release from single cells and dopamine mapping in brain slices. In this paper, we discuss the design of an electrochemical imaging sensor using a monolithic CMOS sensor array and a multifunctional data acquisition system. Using post-CMOS fabrication, the CMOS sensor integrates 1024 on-chip electrodes on the surface and contains 1024 low-noise amplifiers to simultaneous process parallel electrochemical recordings. Each electrochemical electrode and amplifier are optimized to operate at 10.38 kHz sampling rate. To support the operation of the high-throughput CMOS device, a multifunctional data acquisition device is developed to provide the required speed and accuracy. The high analog data rate of 10.63 MHz from all 1024 amplifiers is redundantly sampled by the custom-designed data acquisition system which can process up to 73.6 MHz with up to ~400 Mbytes/s data rate to a computer using USB 3.0 interface. To contain the liquid above the electrochemical sensors and prevent electronic and wire damage, we packaged the monolithic sensor using a 3D-printed well. Using the presented device, 32 pixel × 32 pixel electrochemical imaging of dopamine diffusion is successfully demonstrated at over 10,000 frames per second, the fastest reported to date. 

Neuroblastoma cells are often used as a cell model to study Parkinson's disease, which causes reduced dopamine release in substantia nigra, the midbrain that controls movements. In this paper, we developed a 1024-ch monolithic CMOS sensor array that has the spatiotemporal resolution as well as low-noise performance to monitor single vesicle release of dopamine from neuroblastoma cells. The CMOS device integrates 1024 on-chip electrodes with an individual size of 15 μm × 15 μm and 1024 transimpedance amplifiers for each electrode, which are each capable of measuring sub-pA current. Thus, this device can be used to study the detailed molecular dynamics of dopamine secretion at single vesicle resolution.