Kevin A. White

The simultaneous measurement of biopotential and neurochemical signals provides a comprehensive view of the brain. Yet, most neural interfaces record solely biopotential or neurochemical activity. This work presents a complementary metal-oxide-semiconductor (CMOS) analog front-end (AFE) chip that integrates 32 biopotential amplifiers and 32 neurochemical amplifiers for parallel recording from 64 electrodes. The biopotential amplifier is a two-stage design providing a gain of 57.1 dB, a bandwidth of 0.4 Hz–6.2 kHz, and 6.7 µV_RMS input-referred noise (20 kHz sampling rate). The neurochemical amplifier is a rail-to-rail folded-cascode operational amplifier with selectable transimpedance gain (91.9 kΩ to 851.9 kΩ), a dynamic range of ±15 μA to ±2 μA, respectively, a bandwidth of 12.6 kHz, and input-referred noise as low as 46.3 pA_RMS (20 kHz sampling rate). The neurochemical amplifiers are designed for fast-scan cyclic voltammetry (FSCV) measurements. I/O complexity is minimized using a time-division multiplexing scheme for readout, enabling straightforward scalability. The chip is fabricated using a 0.35-µm CMOS process and occupies a 3.0 × 8.3 mm² area. In vitro recordings of catecholamines and neural spikes validate the chip’s function. The chip enables scalable, low-noise, bimodal neural recording, supporting investigations into the dynamics between neuronal biopotential activity and neurochemical signaling.

Electrochemical sensing arrays enable the spatial study of dopamine levels throughout brain slices, the diffusion of electroactive molecules, as well as neurotransmitter secretion from single cells. The integration of complementary metal-oxide semiconductor (CMOS) devices in the development of electrochemical sensing devices enables large-scale parallel recordings, providing beneficial high-throughput for drug screening studies, brain–machine interfaces, and single-cell electrophysiology. In this paper, an electrochemical sensor capable of recording at 40,000 frames per second using a CMOS sensor array with 1024 electrochemical detectors and a custom field-programmable gate array data acquisition system is detailed. A total of 1024 on-chip electrodes are monolithically integrated onto the designed CMOS chip through post-CMOS fabrication. Each electrode is paired with a dedicated transimpedance amplifier, providing 1024 parallel electrochemical sensors for high-throughput studies. To support the level of data generated by the electrochemical device, a powerful data acquisition system is designed to operate the sensor array as well as digitize and transmit the output of the CMOS chip. Using the presented electrochemical sensing system, both dopamine and hydrogen peroxide diffusions across the sensor array are successfully recorded at 40,000 frames per second across the 32 × 32 electrochemical detector array.

This study aims to develop a microelectrode array-based neural probe that can record dopamine activity with high stability and sensitivity. To mimic the high stability of the gold standard method (carbon fiber electrodes), the microfabricated platinum microelectrode is coated with carbon-based nanomaterials. Carboxyl-functionalized multi-walled carbon nanotubes (COOH-MWCNTs) and carbon quantum dots (CQDs) were selected for this purpose, while a conductive polymer like poly (3-4-ethylene dioxythiophene) (PEDOT) or polypyrrole (PPy) serves as a stable interface between the platinum of the electrode and the carbon-based nanomaterials through a co-electrodeposition process. Based on our comparison between different conducting polymers and the addition of CQD, the CNT–CQD–PPy modified microelectrode outperforms its counterparts: CNT–CQD–PEDOT, CNT–PPy, CNT–PEDOT, and bare Pt microelectrode. The CNT–CQD–PPy modified microelectrode has a higher conductivity, stability, and sensitivity while achieving a remarkable limit of detection (LOD) of 35.20 ± 0.77 nM. Using fast-scan cyclic voltammetry (FSCV), these modified electrodes successfully measured dopamine’s redox peaks while exhibiting consistent and reliable responses over extensive use. This electrode modification not only paves the way for real-time, precise dopamine sensing using microfabricated electrodes but also offers a novel electrochemical sensor for in vivo studies of neural network dynamics and neurological disorders.

Neurochemical recordings rely on electrochemical reactions of electroactive neurotransmitters such as dopamine, serotonin, and norepinephrine. This electrochemical technique allows for highly sensitive monitoring of neurotransmitters in the brain. Traditionally, single-channel carbon-fiber microelectrode recordings have been considered the gold standard method. However, an alternative approach involves the use of a microelectrode array, which enables high spatiotemporal resolution imaging of electroactive neurotransmitters. To enable neurochemical imaging using a microelectrode array, the development of a high-density current-sensing microchip is necessary. Here, a neurochemical microchip is introduced, featuring a 128-channel current sensing front-end capable of supporting 128 parallel neurochemical measurements. The designed amplifier array employs a highly scalable resistive feedback transimpedance amplifier design. This design allows for a large neurochemical dynamic range of ±5μA with a noise performance as low as 0.22nARMS. The presented current sensing front end is validated by electrochemical detection of dopamine, by fast-scan cyclic voltammetry at 400 V/s, using an external carbon-fiber electrode in an electrochemical flow cell.

Neurochemical recordings based on electrochemical reactions of electroactive neurotransmitters (e.g., dopamine, serotonin, and norepinephrine) are used for highly-sensitive monitoring of neurotransmitters in the brain. While single-channel carbon-fiber microelectrode recordings have been the gold standard method, a microelectrode array can be used to capture high spatiotemporal resolution imaging of electroactive neurotransmitters. To enable neurochemical imaging from a microelectrode array, a high-density current-sensing microchip must be developed to amplify and process redox signals. Here, a neurochemical microchip with a 128-ch current sensing front-end to support 128 parallel neurochemical measurements is presented. The designed amplifier array uses a highly scalable resistive feedback transimpedance amplifier design to provide a large neurochemical dynamic range (± 5 µA) with low noise performance (0.22 nARMs). This microchip will enable in vivo neurochemical imaging of dopamine with high spatiotemporal resolution.

Neurochemical recordings rely on electrochemical reactions of electroactive neurotransmitters such as dopamine, serotonin, and norepinephrine. This electrochemical technique allows for highly sensitive monitoring of neurotransmitters in the brain. Traditionally, single-channel carbon-fiber microelectrode recordings have been considered the gold standard method. However, an alternative approach involves the use of a microelectrode array, which enables high spatiotemporal resolution imaging of electroactive neurotransmitters. To enable neurochemical imaging using a microelectrode array, the development of a high-density current-sensing microchip is necessary. Here, a neurochemical microchip is introduced, featuring a 128-channel current sensing front-end capable of supporting 128 parallel neurochemical measurements. The designed amplifier array employs a highly scalable resistive feedback transimpedance amplifier design. This design allows for a large neurochemical dynamic range of ±5µA with a noise performance as low as 0.22nA _RMS . With the integration of this microchip, in vivo neurochemical imaging of dopamine can be achieved with high spatiotemporal resolution.

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.

Dopamine constitutes a significant portion of the catecholamine content in the brain and plays a distinct role in neuromodulation including directing motor control, motivation, reward, and cognitive function. For future neuroprobe technology, not only is simultaneous high-density neurochemical recording vital, temporal resolution plays a key part in the roles of the spatiotemporal distributions of catecholamines in the brain. In this work, we present a new probe design that contains a 256 microelectrode array with an integrated 256 transimpedance amplifier array capable of both amperometry and fast-scan cyclic voltammetry. Each amplifier in the array is capable of both modes of electrochemical detection with three gain settings for the voltammetry mode and occupies an area of 60 μm × 60 μm. The new probe enables a high-resolution spatiotemporal mapping of neurochemicals in the brain.

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.

Bio-inspired computing revolutionizes machine learning and artificial intelligence by mimicking efficient biological systems. Artificial neural networks (ANNs) are inspired by the brain, in which the synaptic connectivity between neurons resolves complex classification and data processing tasks. Although ANNs closely emulate biological neural networks (BNNs), the BNN relies heavily on neurochemical synaptic transmission which contributes to the stochastic computing of the brain. In biological synapses, membrane-bound neurotransmitters are released in quantal events to the extracellular space at synaptic clefts. Toward closely mimicking the biological system, we introduce a new biohybrid synapse that produces quantal neurotransmitter secretion to relay information to the artificial postsynaptic receptor. The presented neurochemical biohybrid synapse paves the way for a new generation of brain-inspired computing by enabling single biological cell to single artificial neuron connectivity. We also demonstrate the dynamic synaptic weighting in the biohybrid synapse which affects synaptic activities.