Microelectrode Array Probe Research Articles

Flexible microelectrode array probe for simultaneous detection of neural discharge and dopamine in striatum of mice aversion system

Simultaneous detection of spike firing and neurotransmitters in mice is conducive to further understanding the mechanism of innate fear induced by aversive stimuli. As the key brain region of the dopamine aversion system, the synchronous changes of neural discharge and neurotransmitter concentration in the striatum under innate fear are less studied. This paper proposed a fabrication method for dual-mode high-sensitive flexible microelectrode array (MEA) probe based on Parylene. The microelectrode sites were modified with platinum black nanoparticles and conductive polymer PEDOT, which can realize single neuron action potential recording and dopamine concentration detection. The electrode sensitivity for dopamine detection can reach 162.3 pA/μM. We used this flexible MEA probe to simultaneously real-time detect electrophysiology activities and dopamine in the striatum of awake mice under aversive stimulation. The results showed that after fear, with the decrease of the mean activity of mice behavior, the action potential firing rate, local field potential (LFP) power in low-frequency (0–30 Hz), and dopamine concentration in the striatum of mice decreased synchronously. The spike firing rate decreased by about 32 %, and the dopamine concentration decreased by about 23.5 %. Our electrodes provide a powerful tool for multimodal neural information detection and our research provides new evidence for striatum involvement in the dopamine aversion system.

Method for MEA Data Analysis of Drug-treated Rat Primary Neurons and Human iPSC-derived Neurons to Evaluate the Risk of Drug-induced Seizures

Use of the microelectrode array (MEA) system to record spontaneous neuron activity from networks of cultured neurons has potential as a good risk evaluation method for drug-induced seizure events. Spontaneous electrical activity in neural networks consists of action potential spikes and organized patterns of action potential bursts. In both potentiated rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons, an epileptogenic response pattern manifests as a synchronized burst from spatially separated neurons. Here, we delineate how to perform MEA experiments using cultured neurons, and how to analyze the MEA data to detect drug-induced seizurogenic abnormalities. Usually, a drug's effects, as shown by MEA data, include changes in spike frequency, inter-spike intervals (ISI), burst frequency, burst duration, spikes in a burst, etc. Subsequently, seizurogenic events are evidenced by changes in synchronized burst phenotypes from spatially separated multiple channels in an MEA probe, such as a change in the cross correlation of the spike events from all channels in an MEA probe, or a change in histogram from the sum of ISI for all channels in a probe, etc. We attempted to depict an epileptogenic marker using a histogram of the sum of spikes for all channels in an MEA probe. Verification of these metrics for drug induced abnormalities is ongoing in various collaboration organizations, including the Consortium for Safety Assessment using Human iPS Cells (CSAHi), iPS Non-clinical Experiments for the Nervous System (iNCENS). Collaboration networks for the utilization of iPSC-derived cells during drug development are also summarized here.

Real-time simultaneous recording of electrophysiological activities and dopamine overflow in the deep brain nuclei of a non-human primate with Parkinson\u2019s disease using nano-based microelectrode arrays

Parkinson’s disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons. The precise mechanisms are still unknown. Since the neuronal communications are inherently electrical and chemical in nature, dual-mode detection of PD-related neuroelectrical and neurochemical information is essential for PD research. Subthalamic nucleus (STN) high-frequency stimulation (HFS) can improve most symptoms of PD patients and decrease the dosage of antiparkinsonian drugs. The mechanism of STN-HFS for PD still remains elusive. In this study, a silicon-based dual-mode microelectrode array (MEA) probe was designed and fabricated, and systematic dual-mode detection methods were established. The recording sites were modified using Pt nanoparticles and Nafion to improve the signal-to-noise (SNR) ratio. To evaluate its applicability to PD research, in vivo electrophysiological and electrochemical detection was performed in normal and hemiparkinsonian models, respectively. Through comparison of the dual-mode signals, we demonstrated the following in a PD monkey: (1) the maximum dopamine concentration in the striatum decreased by 90%; (2) the spike firing frequency increased significantly, especially in the region of the cortex; (3) the spectrogram analysis showed that much power existed in the 0–10 Hz frequency band; and (4) following repeated subthalamic nucleus high-frequency stimulation trials, the level of DA in the striatum increased by 16.5 μM, which led to a better elucidation of the mechanism of HFS. The dual-mode MEA probe was demonstrated to be an effective tool for the study of neurological disorders.

In Situ Real-Time Monitoring of Glutamate and Electrophysiology from Cortex to Hippocampus in Mice Based on a Microelectrode Array.

Changes in the structure and function of the hippocampus contribute to epilepsy, schizophrenia and other neurological or mental disorders of the brain. Since the function of the hippocampus depends heavily on the glutamate (Glu) signaling pathways, in situ real-time detection of Glu neurotransmitter release and electrophysiological signals in hippocampus is of great significance. To achieve the dual-mode detection in mouse hippocampus in vivo, a 16-channel implantable microelectrode array (MEA) was fabricated by micro-electromechanical system (MEMS) technology. Twelve microelectrode sites were modified with platinum black for electrophysiological recording and four sites were modified with glutamate oxidase (GluOx) and 1,3-phenylenediamine (mPD) for selective electrochemical detection of Glu. The MEA was implanted from cortex to hippocampus in mouse brain for in situ real-time monitoring of Glu and electrophysiological signals. It was found that the Glu concentration in hippocampus was roughly 50 μM higher than that in the cortex, and the firing rate of concurrently recorded spikes declined from 6.32 ± 4.35 spikes/s in cortex to 0.09 ± 0.06 spikes/s in hippocampus. The present results demonstrated that the dual-mode MEA probe was capable in neurological detections in vivo with high spatial resolution and dynamical response, which lays the foundation for further pathology studies in the hippocampus of mouse models with nervous or mental disorders.

An implantable microelectrode array for dopamine and electrophysiological recordings in response to L-dopa therapy for Parkinson's disease.

Dual-mode multielectrode recordings have become routine in rodent neuroscience research. However, robust and reliable application of acute, multielectrode recording methods in brain especially for in vivo research remains a challenge. In patients with Parkinson's disease (PD), the efficacy of L-dopa therapy depends on its ability to restore Dopamine (DA) neurotransmission in the striatum. In this paper, We describe a low cost thin film 16 sites implantable microelectrode array (MEA) chip fabricated by standard lithography technology for in vivo test. In urethane anesthetized rats, the MEA probes were implanted acutely for simultaneous recording of local field potentials, spikes, and L-dopa therapy evoked dopamine overflow on the same spatiotemporal scale. We present a detailed protocol for array fabrication, then show that the device can record Spikes, LFPs and dopamine variation in real time. Across any given microelectrode, spike amplitudes ranged from 80 to 300 μν peak to peak, with a mean signal-tonoise ratio of better than 5:1. Calibration results showed the MEA probe had high sensitivity and good selectivity for DA. Comparison with existing methods allow single mode recording, our neural probes would be useful for examining specific spatiotemporal relationships between electrical and chemical signaling in the brain.

A silicon based implantable microelectrode array for electrophysiological and dopamine recording from cortex to striatum in the non-human primate brain

Dual-mode, multielectrode recordings have become routine in rodent neuroscience research and have recently been adapted to the non-human primate. However, robust and reliable application of acute, multielectrode recording methods in monkeys especially for deep brain nucleus research remains a challenge. In this paper, We described a low cost silicon based 16-site implantable microelectrode array (MEA) chip fabricated by standard lithography technology for in vivo test. The array was 25mm long and designed to use in non-human primate models, for electrophysiological and electrochemical recording. We presented a detailed protocol for array fabrication, then showed that the device can record Spikes, LFPs and dopamine (DA) variation continuously from cortex to striatum in an esthetized monkey. Though our experiment, high-quality electrophysiological signals were obtained from the animal. Across any given microelectrode, spike amplitudes ranged from 70 to 300μV peak to peak, with a mean signal-to-noise ratio of better than 5:1. Calibration results showed the MEA probe had high sensitivity and good selectivity for DA. The DA concentration changed from 42.8 to 481.6μM when the MEA probe inserted from cortex into deep brain nucleus of striatum, which reflected the inhomogeneous distribution of DA in brains. Compared with existing methods allowing single mode (electrophysiology or electrochemistry) recording. This system is designed explicitly for dual-mode recording to meet the challenges of recording in non-human primates.

Simultaneous recording of brain extracellular glucose, spike and local field potential in real time using an implantable microelectrode array with nano-materials

Glucose is the main substrate for neurons in the central nervous system. In order to efficiently characterize the brain glucose mechanism, it is desirable to determine the extracellular glucose dynamics as well as the corresponding neuroelectrical activity in vivo. In the present study, we fabricated an implantable microelectrode array (MEA) probe composed of platinum electrochemical and electrophysiology microelectrodes by standard micro electromechanical system (MEMS) processes. The MEA probe was modified with nano-materials and implanted in a urethane-anesthetized rat for simultaneous recording of striatal extracellular glucose, local field potential (LFP) and spike on the same spatiotemporal scale when the rat was in normoglycemia, hypoglycemia and hyperglycemia. During these dual-mode recordings, we observed that increase of extracellular glucose enhanced the LFP power and spike firing rate, while decrease of glucose had an opposite effect. This dual mode MEA probe is capable of examining specific spatiotemporal relationships between electrical and chemical signaling in the brain, which will contribute significantly to improve our understanding of the neuron physiology.

Lithographic Microfabrication of a 16-Electrode Array on a Probe Tip for High Spatial Resolution Electrochemical Localization of Exocytosis.

We report the lithographic microfabrication of a movable thin film microelectrode array (MEA) probe consisting of 16 platinum band electrodes placed on top of a supporting borosilicate glass substrate. These 1.2 μm wide electrodes were tightly packed and positioned parallel in two opposite rows within a 20 μm × 25 μm square area and with a distance less than 10 μm from the edge of the glass substrate. We demonstrate the ability to control and place the probe in close proximity to the surface of adherent bovine chromaffin cells and to amperometrically record single exocytosis release events with high spatiotemporal resolution. The two-dimensional position of single exocytotic events occurring in the center gap area separating the two rows of MEA band electrodes and that were codetected by electrodes in both rows was determined by analysis of the fractional detection of catecholamine released between electrodes and exploiting random walk simulations. Hence, two-dimensional electrochemical imaging recording of exocytosis release between the electrodes within this area was achieved. Similarly, by modeling the current spikes codetected by parallel adjacent band electrodes positioned in the same electrode row, a one-dimensional imaging of exocytosis with submicrometer resolution was accomplished within the area. The one- and two-dimensional electrochemical imaging using the MEA probe allowed for high spatial resolution of exocytosis activity and revealed heterogeneous release of catecholamine at the chromaffin cell surface.

Microelectrode Array Probe for Simultaneous Detection of Glutamate and Local Field Potential during Brain Death

Abstract High extracellular potassium could induce depression-like depolarizations, elevations of extracellular glutamate and even neuronal death in brain. To investigate the contribution of high potassium in vivo , microelectrode arrays (MEAs) probe were fabricated and implanted in a rat brain for simultaneous record of striatal local field potential (LFP) and glutamate concentration. During these multi-modal recordings, the rat brain was exposed to a high potassium solution. It was observed that high potassium elevated extracellular glutamate while suppressing the LFP irreversibly. This is one of the first studies in which a dual-mode MEA probes is applied in vivo for neuronal death. It is concluded that the MEA probes are capable of examining specific spatiotemporal relationships between electrical and chemical signaling in the brain.

An implantable microelectrode array for simultaneous L-glutamate and electrophysiological recordings in vivo

L-glutamate, the most common excitatory neurotransmitter in the mammalian central nervous system (CNS), is associated with a wide range of neurological diseases. Because neurons in CNS communicate with each other both electrically and chemically, dual-mode (electric and chemical) analytical techniques with high spatiotemporal resolution are required to better understand glutamate function in vivo. In the present study, a silicon-based implantable microelectrode array (MEA) composed of both platinum electrochemical and electrophysiological microelectrodes was fabricated using micro-electromechanical system. In the MEA probe, the electrophysiological electrodes have a low impedance of 0.018 MΩ at 1 kHz, and the electrochemical electrodes show a sensitivity of 56 pA µM−1 to glutamate and have a detection limit of 0.5 µM. The MEA probe was used to monitor extracellular glutamate levels, spikes and local field potentials (LFPs) in the striatum of anaesthetised rats. To explore the potential of the MEA probe, the rats were administered to KCl via intraperitoneal injection. K+ significantly increases extracellular glutamate levels, LFP low-beta range (12–18 Hz) power and spike firing rates with a similar temporal profile, indicating that the MEA probe is capable of detecting dual-mode neuronal signals. It was concluded that the MEA probe can help reveal mechanisms of neural physiology and pathology in vivo. Abnormal transmission of L-glutamate can cause neurological disorders such as Parkinson's disease, stroke and epilepsy. In their search for effective treatments, researchers are deploying extensive efforts to understand this key neurotransmitter, which regulates receptors located at chemical synapses. However, their attempts often fail to analyze the syntrophic complexity of biochemical and electrical events occurring in neurons. Now, Xinxia Cai and co-workers from the Institute of Electronics, Chinese Academy of Sciences, Beijing, China, have developed a silicon-based probe that simultaneously measures L-glutamate levels and electrical activity at various locations in the brain with high spatial and temporal resolution. The implantable array combines electrochemical and electrophysiological microelectrodes created through MEMS and nanotechnology. The team expects it to provide insight into physiological and pathological pathways in live brain tissue, paving the way to new diagnostic and therapeutic approaches.

A Novel Microelectrode Array Probe Integrated with Electrophysiology Reference Electrode for Neural Recording

Nowadays, the study of brain function is advanced by implantable microelectrode arrays for they can simultaneously record signals from different groups of neurons regarding complex neural processes. This article presents the fabrication, characterization and use in vivo neural recording of an implantable microelectrode array probe which integrated with electrophysiology reference electrode. The probe was implemented on Silicon-On-Insulator (SOI) wafer using Micro-Electro-Mechanical-Systems (MEMS) methods, so the recording-site configurations and high-density electrode placement could be precisely defined. The 16 recording sites and the reference electrode were made of platinum. Double layers of platinum electrodes were used so that the width of the reference electrode was as small as 6 μm. The average impedance of the microelectrodes was 0.13 MΩ at 1 kHz. The probe has been employed to record the neural signals of rat, and the results showed that the signal-to-noise ratio (SNR) of the novel probe was as high as 10 and the ordinary probe was 3. Among the 16 recording sites, there are 9 effective sites having recorded useful signals for the probe with reference electrode and 6 for the ordinary probe.

A flexible perforated microelectrode array probe for action potential recording in nerve and muscle tissues

Flexible perforated microelectrode arrays probes for the simultaneous recording of electrophysiological activity between cells have been manufactured using photolithographic thin film techniques. Polyimide was used as the substrate. Gold was used as the active metal with titanium to adhere the gold to the substrate. A coating of silicon nitride improves the electrode isolation. Perforations in the substrate ensure the position of the electrode in tissue and improve the stability of recording during movement. These electrodes were used for extracellular recording in nerve and muscle tissues. The use of a flexible substrate alleviates the mechanical problems associated with local damage caused by rigid substrates during movement.