Deep brain implantable microelectrode arrays for detection and functional localization of the subthalamic nucleus in rats with Parkinson’s disease

The subthalamic nucleus(STN)is considered the best target for deep brain stimulation treatments of Parkinson’s disease(PD).It is difficult to localize the STN due to its small size and deep location.Multichannel microelectrode arrays(MEAs)can rapidly and precisely locate the STN,which is important for precise stimulation.In this paper,16-channel MEAs modified with multiwalled carbon nanotube/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate)(MWCNT/PEDOT:PSS)nanocomposites were designed and fabricated,and the accurate and rapid identification of the STN in PD rats was performed using detection sites distributed at different brain depths.These results showed that nuclei in 6-hydroxydopamine hydrobromide(6-OHDA)-lesioned brains discharged more intensely than those in unlesioned brains.In addition,the MEA simultaneously acquired neural signals from both the STN and the upper or lower boundary nuclei of the STN.Moreover,higher values of spike firing rate,spike amplitude,local field potential(LFP)power,and beta oscillations were detected in the STN of the 6-OHDA-lesioned brain,and may therefore be biomarkers of STN localization.Compared with the STNs of unlesioned brains,the power spectral density of spikes and LFPs synchronously decreased in the delta band and increased in the beta band of 6-OHDA-lesioned brains.This may be a cause of sleep and motor disorders associated with PD.Overall,this work describes a new cellular-level localization and detection method and provides a tool for future studies of deep brain nuclei.

Simulation and fabrication of in vitro microfluidic microelectrode array chip for patterned culture and electrophysiological detection of neurons

To enable the detection and modulation of modularized neural networks in vitro,this study proposes a microfluidic microelectrode array chip for the cultivation,compartmentalization,and control of neural cells.The chip was designed based on the specific structure of neurons and the requirements for detection and modulation.Finite-element analysis of the chip’s flow field was conducted using the COMSOL Multiphysics software,and the simulation results show that the liquid within the chip can flow smoothly,ensuring stable flow fields that facilitate the uniform growth of neurons within the microfluidic channels.By employing MEMS technology in combination with nanomaterial modification techniques,the microfluidic microelectrode array chip was fabricated successfully.Primary hippocampal neurons were cultured on the chip,forming a well-defined neural network.Spontaneous electrical activity of the detected neurons was recorded,exhibiting a 23.7%increase in amplitude compared to neuronal discharges detected on an open-field microelectrode array.This study provides a platform for the precise detection and modulation of patterned neuronal growth in vitro,potentially serving as a novel tool in neuroscience research.

Microelectrode arrays for monitoring neural activity in neural stem cells with modulation by glutamate in vitro

In this study, a 60-channel microelectrode array(MEA) was fabricated and used to monitor the neural spikes and local field potentials(LFPs) of neurons differentiated from rat neural stem cells in vitro. The neurons were grown on the MEA surface to detect neural signals. Glutamate(Glu) was used to modulate neural activity during experiments. To enhance detection performance, platinum nanoparticles were modified onto the microelectrode site surface. Glutamate stimulated neural spikes and LFPs were recorded using the MEA. The average spike amplitude was approximately 70 μV in the normal state. The spike amplitude increased by 29% from 70 μV to 90 μV with Glu modulation. The firing rate increased by 69% from 4.01 Hz to 6.8 Hz with Glu modulation. The LFP power increased from 326 μW in the normal state to 617 μW with Glu modulation in the 0–10 Hz frequency band. Data analysis shows that neural activity stimulated by Glu modulation was recorded experimentally at high temporal-spatial resolution. These results may provide a new neuron detection method, as well as further understanding of neural stem cell spike firing and associated mechanisms.

Disposable Electrochemical Biosensor for Amperometric Measurement of β-hydroxybutyrate and Total Cholesterol

A new type of disposable thin-film amperometric biosensor has been developed for measurement ofβ-hydroxybutyrate and total cholesterol in serum.The biosensor consists of two plain gold electrodes mounted on a Polyethylene terephthalate (PET) substrate.The reagent solution contains bienzymes (cholesterol oxidase and cholesterol esterase for total cholesterol,β-hydroxybutyrate dehydrogenase and diaphorase forβ-hydroxybutyrate respectively) with mediator (ferricyanide) were absorption at the surface of electrodes coated by electrodepositing platinum black.The presence of the mediator lowers the applied potential and eliminates the interference from other oxidizable species enhancing the sensitivity and selectivity of the biosensor without modifying the dynamic parameters of the response.The enzymes stably retains in the matrices of platinum black film improving the performance of the mediated sensor.The linearity is observed in the concentration range from 1.0×10^(-4) to 1.0×10^(-2) mM and 1.0×10^(-4) mM to 4.99×10^(-3) mM with sensitivity of 1.958μA/mM and 2.447μA/mM respectively.The optimized biosensor exhibits excellent reproducibility and stability retaining more than 90% of its original activity over a period of one month.The simple operation of the biosensor mass-produced at low cost is expected to find clinical application and homecare.

Development of Enzyme Biosensor for Amperometric Measurement of Aspartate Aminotransferase

An enzyme biosensor for amperometric measurement of aspartate aminotransferase has been developed.The working electrode was modified with a thin-film of redox polymer,then glutamate oxidase,with the immobilized reagent cast and dried on the electrode.The biosensor responses to AST by detecting hydrogen peroxide were produced by enzymical reaction at-0.1 V with a response time of 120 seconds.The electrode gave a detection limit of 32.5 U/L with a linear concentration range of 32.5 U/L～2000 U/L in serum.Due to more sensitive and lower detection limit,the biosensor is expected mainly to be used for physiological identification and physical performance of athletes in the future.Extended application will also affect the practice of clinical medicine for the diagnosis of heart and liver disease.

Amperometric Enzyme Biosensor for the Determination of High Concentration Lactate in Whole Blood of Athletes

<正>Amperometric biosensor applied to the determination of high concentration lactate in serum and whole blood was described.The biosensor was constructed by gold electrode modified with nanoplatinum particles.Lactate oxidase (E.C.1.1.3.2) was immobilized at platinized activated gold electrode which was used for the determination of high concentration lactate at low potential (+0.2 V).The linear calibration graphs were obtained from 1 to 21 mmol·L~ (-1) lactate in serum and from 0.9 to 13.2 mmol.L~ (-1) lactate in whole blood.The correlation coefficients were 0.99 and 0.97,respectively at a steady-state response time of 50 s.

A Point-of-Care Test System for Biochemical Blood Analysis Based on ADUC824

A point-of-care test system has been studied in this paper.It was used to determine substances in blood such as Hemoglobin (HB),Aspartate Aminotransferase (AST),Creatine Kinase (CK) and so on.Based on the principle of amperometric determination,the research on detecting weak current signals was carried on.At the same time as to the weak signals (nA level),magnifying,sampling and processing the signals were also studied.Controlled by ADUC824 and assisted by other units, every substance could be determined automatically and rapidly integrated with the corresponding biosensor.In the experiment, the minimum detectable current of the instrument (YT2005-1) is 0.2 nA.With regard to the 1 nA which the experiment demanded,it could be up to the mustard.And the system can provide results in 180 s with a long term stability.

A NEW QUANTITATIVE DETECTION METHOD OF RECOMBINANT CFP10-ESAT6 AMALGAMATION PROTEINS FROM MYCOBACTERIUM TUBERCULOSIS BASED ON MICRO-MAGNETIC PROBES STRATEGY

A new rapid,specific and sensitive method for assay of recombinant CFP10-ESAT6 amalgamation proteins from Mycobacterium tuberculosis was proposed.The method used streptavidincoated magnetic beads to enrich the specific biotinylated anti-CFP10 antibody,then adopted a sandwich-type enzyme linked immunosorbent assay technology with two kinds of monoclonal antibodies:biotinylated anti-CFP10 antibody and HRP-labeled anti-CFP10 antibody to identify the target CFP10-ESAT6 proteins,and finally detected chemiluminescence intensity by a small home-made optical sensor.It was shown that,the corresponding chemiluminescence intensity had a good logarithmic linear response to the concentration of CFP10-ESAT6 proteins when ranging at 1~1000 ng/mL,and the correlation coefficient is 0.9937.The proposed method could detect the CFP10-ESAT6 proteins with low detection limit(1 ng/mL)and the detection time could be controlled within 45 min.Compared with commonly used detection methods of M.tuberculosis,this method was easy to operate,faster,and of higher sensitivity.The achievement of the quantitative detection of CFP10-ESAT6 proteins has important scientific significance and wide application prospects in tuberculosis control.

Wireless closed-loop deep brain stimulation using microelectrode array probes

Deep brain stimulation(DBS),including optical stimulation and electrical stimulation,has been demonstrated considerable value in exploring pathological brain activity and developing treatments for neural disorders.Advances in DBS microsystems based on implantable microelectrode array(MEA)probes have opened up new opportunities for closed-loop DBS(CL-DBS)in situ.This technology can be used to detect damaged brain circuits and test the therapeutic potential for modulating the output of these circuits in a variety of diseases simultaneously.Despite the success and rapid utilization of MEA probe-based CL-DBS microsystems,key challenges,including excessive wired communication,need to be urgently resolved.In this review,we considered recent advances in MEA probe-based wireless CL-DBS microsystems and outlined the major issues and promising prospects in this field.This technology has the potential to offer novel therapeutic options for psychiatric disorders in the future.

Impaired Spatial Firing Representations of Neurons in the Medial Entorhinal Cortex of the Epileptic Rat Using Microelectrode Arrays

Epilepsy severely impairs the cognitive behavior of patients.It remains unclear whether epilepsy-induced cognitive impairment is associated with neuronal activities in the medial entorhinal cortex(MEC),a region known for its involvement in spatial cognition.To explore this neural mechanism,we recorded the spikes and local field potentials from MEC neurons in lithium-pilocarpine-induced epileptic rats using self-designed microelectrode arrays.Through the open field test,we identified spatial cells exhibiting spatially selective firing properties and assessed their spatial representations in relation to the progression of epilepsy.Meanwhile,we analyzed theta oscillations and theta modulation in both excitatory and inhibitory neurons.Furthermore,we used a novel object recognition test to evaluate changes in spatial cognitive ability of epileptic rats.After the epilepsy modeling,the spatial tuning of various types of spatial cells had suffered a rapid and pronounced damage during the latent period(1 to 5 d).Subsequently,the firing characteristics and theta oscillations were impaired.In the chronic period(>10 d),the performance in the novel object experiment deteriorated.In conclusion,our study demonstrates the detrimental effect on spatial representations and electrophysiological properties of MEC neurons in the epileptic latency,suggesting the potential use of these changes as a"functional biomarker"for predicting cognitive impairment caused by epilepsy.

Nanomaterial-based microelectrode arrays for in vitro bidirectional brain–computer interfaces:a review

A bidirectional in vitro brain–computer interface(BCI)directly connects isolated brain cells with the surrounding environment,reads neural signals and inputs modulatory instructions.As a noninvasive BCI,it has clear advantages in understanding and exploiting advanced brain function due to the simplified structure and high controllability of ex vivo neural networks.However,the core of ex vivo BCIs,microelectrode arrays(MEAs),urgently need improvements in the strength of signal detection,precision of neural modulation and biocompatibility.Notably,nanomaterial-based MEAs cater to all the requirements by converging the multilevel neural signals and simultaneously applying stimuli at an excellent spatiotemporal resolution,as well as supporting long-term cultivation of neurons.This is enabled by the advantageous electrochemical characteristics of nanomaterials,such as their active atomic reactivity and outstanding charge conduction efficiency,improving the performance of MEAs.Here,we review the fabrication of nanomaterial-based MEAs applied to bidirectional in vitro BCIs from an interdisciplinary perspective.We also consider the decoding and coding of neural activity through the interface and highlight the various usages of MEAs coupled with the dissociated neural cultures to benefit future developments of BCIs.

Detection of neuronal defensive discharge information transmission and characteristics in periaqueductal gray double-subregions using PtNP/PEDOT:PSS modified microelectrode arrays

Threatened animals respond with appropriate defensive behaviors to survive.It has been accepted that midbrain periaqueductal gray(PAG)plays an essential role in the circuitry system and organizes defensive behavioral responses.However,the role and correlation of different PAG subregions in the expression of different defensive behaviors remain largely unexplored.Here,we designed and manufactured a microelectrode array(MEA)to simultaneously detect the activities of dPAG and vPAG neurons in freely behaving rats.To improve the detection performance of the MEAs,PtNP/PEDOT:PSS nanocomposites were modified onto the MEAs.Subsequently,the predator odor was used to induce the rat’s innate fear,and the changes and information transmission in neuronal activities were detected in the dPAG and vPAG.Our results showed that the dPAG and vPAG participated in innate fear,but the activation degree was distinct in different defense behaviors.During flight,neuronal responses were stronger and earlier in the dPAG than the vPAG,while vPAG neurons responded more strongly during freezing.By applying high-performance MEA,it was revealed that neural information spread from the activated dPAG to the weakly activated vPAG.Our research also revealed that dPAG and vPAG neurons exhibited different defensive discharge characteristics,and dPAG neurons participated in the regulation of defense responses with burst-firing patterns.The slow activation and continuous firing of vPAG neurons cooresponded with the regulation of long-term freezing responses.The results demonstrated the important role of PAG neuronal activities in controlling different aspects of defensive behaviors and provided novel insights for investigating defense from the electrophysiological perspective.

Recent advances and research progress on microsystems and bioeffects of terahertz neuromodulation

Terahertz waves can interact with the nervous system of organisms under certain conditions.Compared to common optical modulation methods,terahertz waves have the advantages of low photon energy and low risk;therefore,the use of terahertz waves to regulate the nervous system is a promising new method of neuromodulation.However,most of the research has focused on the use of terahertz technology for biodetection,while relatively little research has been carried out on the biological effects of terahertz radiation on the nervous system,and there are almost no review papers on this topic.In the present article,we begin by reviewing principles and objects of research regarding the biological effects of terahertz radiation and summarizing the current state of related research from a variety of aspects,including the bioeffects of terahertz radiation on neurons in vivo and in vitro,novel regulation and detection methods with terahertz radiation devices and neural microelectrode arrays,and theoretical simulations of neural information encoding and decoding.In addition,we discuss the main problems and their possible causes and give some recommendations on possible future breakthroughs.This paper will provide insight and assistance to researchers in the fields of neuroscience,terahertz technology and biomedicine.

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,dualmode(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 MΩat 1 kHz,and the electrochemical electrodes show a sensitivity of 56 pAμM^(−1) to glutamate and have a detection limit of 0.5μM.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.

Real-time simultaneous recording of electrophysiological activities and dopamine overflow in the deep brain nuclei of a non-human primate with Parkinson’s 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)highfrequency 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 16.5μM,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.

Low sample volume origami-paper-based graphene-modified aptasensors for label-free electrochemical detection of cancer biomarker-EGFR

In this work,an electrochemical paper-based aptasensor was fabricated for label-free and ultrasensitive detection of epidermal growth factor receptor(EGFR)by employing anti-EGFR aptamers as the bio-recognition element.The device used the concept of paper-folding,or origami,to serve as a valve between sample introduction and detection,so reducing sampling volumes and improving operation convenience.Amino-functionalized graphene(NH 2-GO)/thionine(THI)/gold particle(AuNP)nanocomposites were used to modify the working electrode not only to generate the electrochemical signals,but also to provide an environment conducive to aptamer immobilization.Electrochemical characterization revealed that the formation of an insulating aptamer–antigen immunocomplex would hinder electron transfer from the sample medium to the working electrode,thus resulting in a lower signal.The experimental results showed that the proposed aptasensor exhibited a linear range from 0.05 to 200 ngmL^(−1)(R^(2)=0.989)and a detection limit of 5pgmL^(−1) for EGFR.The analytical reliability of the proposed paper-based aptasensor was further investigated by analyzing serum samples,showing good agreement with the gold-standard enzyme-linked immunosorbent assay.

Grid cell remapping under three-dimensional object and social landmarks detected by implantable microelectrode arrays for the medial entorhinal cortex

Grid cells with stable hexagonal firing patterns in the medial entorhinal cortex(MEC)carry the vital function of serving as a metric for the surrounding environment.Whether this mechanism processes only spatial information or involves nonspatial information remains elusive.Here,we fabricated an MEC-shaped microelectrode array(MEA)to detect the variation in neural spikes and local field potentials of the MEC when rats forage in a square enclosure with a planar,three-dimensional object and social landmarks in sequence.The results showed that grid cells exhibited rate remapping under social conditions in which spike firing fields closer to the social landmark had a higher firing rate.Furthermore,global remapping showed that hexagonal firing patterns were rotated and scaled when the planar landmark was replaced with object and social landmarks.In addition,when grid cells were activated,the local field potentials were dominated by the theta band(5–8 Hz),and spike phase locking was observed at troughs of theta oscillations.Our results suggest the pattern separation mechanism of grid cells in which the spatial firing structure and firing rate respond to spatial and social information,respectively,which may provide new insights into how the brain creates a cognitive map.

A BFSK and OOK IF demodulation circuit with 2.8 μs settling time and re-configurable image rejection functions for MICS/BCC applications

A BFSK and OOK IF base-band circuit is provided to implement the low-IF RF receivers for a dualband MICS/BCC network controller. In order to transfer the massive vital data immediately, the IF circuit is comprised of the fast-settling feed-forward programmable gain amplifier（PGA）, a Gm-C complex filter, the fixed gain amplifier（FGA） and a 4-input ＂quadratic sum＂ demodulator. A novel auto-switched coarse gain-setting method is adopted in the PGA to enhance the reaction speed and narrow the output signal range. Also the PGA does not suffer the same stability constraint as open-loop topologies. The complex filter fulfills the function of image rejection,in which the center frequency and bandwidth can be adjusted individually. The FGA is used to ameliorate the linearity and the ＇quadratic sum＇ demodulator can reduce the overall power consumption. The designed IF circuit is fabricated with SMIC 0.18 μm CMOS process. The chip area is about 5.36 mm^2. Measurement results are given to verify the design goals.

Micro EEG/ECG signal's chopper-stabilization amplifying chip for novel drycontact electrode

Facing the body＇s EEG（electroencephalograph, 0.5–100 Hz, 5–100 μV） and ECG＇s（electrocardiogram,〈 100 Hz, 0.01–5 mV） micro signal detection requirement, this paper develops a pervasive application micro signal detection ASIC chip with the chopping modulation/demodulation method. The chopper-stabilization circuit with the RRL（ripple reduction loop） circuit is to suppress the ripple voltage, which locates at the single-stage amplifier＇s outputting terminal. The single-stage chopping core＇s noise has been suppressed too, and it is beneficial for suppressing noises of post-circuit. The chopping core circuit uses the PFB（positive feedback loop） to increase the inputting resistance, and the NFB（negative feedback loop） to stabilize the 40 dB intermediate frequency gain. The cascaded switch-capacitor sample/hold circuit has been used for deleting spike noises caused by non-ideal MOS switches, and the VGA/BPF（voltage gain amplifier/band pass filter） circuit is used to tune the chopper system＇s gain/bandwidth digitally. Assisted with the designed novel dry-electrode, the real test result of the chopping amplifying circuit gives some critical parameters： 8.1 μW/channel, 0.8 μVrms（@band-widthD100 Hz）, 4216–11220 times digitally tuning gain range, etc. The data capture system uses the NI CO＇s data capturing DAQmx interface,and the captured micro EEG/ECG＇s waves are real-time displayed with the PC-Labview. The proposed chopper system is a unified EEG/ECG signal＇s detection instrument and has a critical real application value.

Nanoliposome-encapsulated caged-GABA for modulating neural electrophysiological activity with simultaneous detection by microelectrode arrays

Effective and precise neural modulation with real-time detection in the brain is of great importance and represents a significant challenge.Nanoliposome-encapsulated light-sensitive compounds have excellent characteristics such as high temporal and spatial resolution,delayed drug clearance,and restricted drug biodistribution for neural modulation.In this study,we developed a nanoliposome-based delivery system for ruthenium-based caged GABA compounds(Nanolipo-Ru)to modulate neural activity and allow for real-time monitoring using the microelectrode arrays(MEAs).The Nanolipo-Ru nanoparticles had an average size of 134.10±4.30 nm and exhibited excellent stability for seven weeks.For the in vivo experiment in the rat,release of GABA by Nanolipo-Ru under blue light illumination resulted in an average firing rate reduction in interneurons and pyramidal neurons in the same brain region of 79.4%and 81.6%,respectively.Simultaneously,the average power of local field potentials in the 0–15 Hz range degraded from 4.34 to 0.85 mW.In addition,the Nanolipo-Ru nanoparticles have the potential to provide more flexible timing of modulation than unencapsulated RuBi-GABA in the experiments.These results indicated that Nanolipo-Ru could be an effective platform for regulating neuronal electrophysiology.Furthermore,nanoliposomes with appropriate modifications would render promising utilities for targeting of specific types of neurons in the future.