Implantable Microelectrode Research Articles

Applications of Implantable Microelectrodes in Brain-Computer Interfaces

Implantable microelectrodes represent a crucial advancement in Brain-Computer Interfaces (BCIs), enabling a wide array of applications across neuroscience and clinical domains. This paper presents a comprehensive overview of implantable microelectrodes, and three kinds of microelectrode arrays are explained in detail. The paper also deals with the integration of microelectrodes with BCI, with an emphasis on critical areas such as neuromodulation, including deep brain stimulation and neural feedback control, motor recovery, and three varieties of clinical applications in people with Parkinson's disease, epilepsy and amputees. Additionally, this work delves into the advanced hardware enhancing application of Implantable microelectrodes. This includes the development of microelectrode arrays, closed-loop systems, and the latest materials and microfabrication techniques. Despite the challenges in data processing, managing immune responses, and optimizing electrode-tissue interfaces, implantable micro-electrodes offer tremendous potential for advances in neuroscience, medicine, and rehabilitation engineering, paving the way for enhanced understanding and treatment of neurological disorders.

PEDOT: PSS-Modified Organic Flexible and Implantable Microelectrode for Internal Bi-Directional Electrophysiology of Three-Dimensional Cardiomyocyte Spheroid.

Three-dimensional (3D) cardiomyocyte spheroids are essential models to replicate cardiac structural and functional features in vitro. However, conventional planar and rigid microelectrode arrays (MEAs) suffer from low-quality electrophysiological recording of 3D cultures, due to limited contact areas and weak coupling between cells and MEA chips. Herein, we developed a PEDOT: PSS-modified organic flexible and implantable MEA (OFI-MEA) coupled with a self-developed integrated biosensing platform to achieve high-throughput, long-term, and stable bidirectional internal electrophysiology in 3D cardiomyocyte spheroids. Electrostimulation enhanced the functional performance of the 3D cardiomyocytes, causing a remarkable 2.69-fold increase in frequency. Furthermore, time-frequency analysis of the multisite electrophysiological signals to highlight diverse cell activity patterns in the spheroids. It provides a powerful tool to record electrophysiological signals of 3D cardiomyocyte spheroids, allowing continuing evaluation of cardiac dynamics and regulation of electrical signals, providing a novel evaluation strategy for cardiac disease model construction, drug screening, and cardiological research.

Dynamic changes in the structure and function of brain mural cells around chronically implanted microelectrodes

Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring at the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

Mapping cognitive activity from electrocorticography field potentials in humans performing NBack task

Objective. Advancements in data science and assistive technologies have made invasive brain-computer interfaces (iBCIs) increasingly viable for enhancing the quality of life in physically disabled individuals. Intracortical microelectrode implants are a common choice for such a communication system due to their fine temporal and spatial resolution. The small size of these implants makes the implantation plan critical for the successful exfiltration of information, particularly when targeting representations of task goals that lack robust anatomical correlates. Approach. Working memory processes including encoding, retrieval, and maintenance are observed in many areas of the brain. Using human electrocorticography (ECoG) recordings during a working memory experiment, we provide proof that it is possible to localize cognitive activity associated with the task and to identify key locations involved with executive memory functions. Results. From the analysis, we could propose an optimal iBCI implant location with the desired features. The general approach is not limited to working memory but could also be used to map other goal-encoding factors such as movement intentions, decision-making, and visual-spatial attention. Significance. Deciphering the intended action of a BCI user is a complex challenge that involves the extraction and integration of cognitive factors such as movement planning, working memory, visual-spatial attention, and the decision state. Examining field potentials from ECoG electrodes while participants engaged in tailored cognitive tasks can pinpoint location with valuable information related to anticipated actions. This manuscript demonstrates the feasibility of identifying electrodes involved in cognitive activity related to working memory during user engagement in the NBack task. Devoting time in meticulous preparation to identify the optimal brain regions for BCI implant locations will increase the likelihood of rich signal outcomes, thereby improving the overall BCI user experience.

A Function-integrated Neurosurgical Robot for Distributed Implantation of Microelectrodes

A Function-integrated Neurosurgical Robot for Distributed Implantation of Microelectrodes

Brain–computer interface for simultaneous dual‐region spatial coding in hippocampal and somatosensory cortex of freely behaving rats

AbstractDecoding of spatial information from place cells is currently limited to individual brain regions, severely constraining the understanding of the brain's spatial navigation mechanisms. In this study, synchronized detection of dual‐brain region spatial encoding was conducted using brain–computer interface (BCI). Therefore, an implantable microelectrode array (MEA) was developed tailored for the simultaneous detection of neuronal activities in the CA1 of the hippocampus and the Barrel Cortex (BC) of the somatosensory cortex in rats as BCI. The MEA was improved by modifying the nanocomposite PtNP/PEDOT:PSS to improve their electrical properties (reducing impedance from 1.82 ± 0.17 MΩ to 3.4 ± 0.3 kΩ), facilitating neural recordings in freely behaving rats. The neural activities were obtained from the CA1 and the BC simultaneously and validated the existence of place cells in both brain regions. This study highlighted the potential of PtNP/PEDOT:PSS‐modified MEA as BCI in concurrently detecting neural activity associated with spatial encoding in two brain regions, offering novel perspectives on the processing of tactile stimuli and the formation of cognitive maps for navigation.

Intraoperative assessment of microimplantation-induced acute brain inflammation with titanium oxynitride-based plasmonic biosensor

Implantable devices for brain-machine interfaces and managing neurological disorders have experienced rapid growth in recent years. Although functional implants offer significant benefits, issues related to transient trauma and long-term biocompatibility and safety are of significant concern. Acute inflammatory reaction in the brain tissue caused by microimplants is known to be an issue but remains poorly studied. This study presents the use of titanium oxynitride (TiNO) nanofilm with defined surface plasmon resonance (SPR) properties for point-of-care characterizing of acute inflammatory responses during robot-controlled micro-neuro-implantation. By leveraging surface-enriched oxynitride, TiNO nanofilms can be biomolecular-functionalized through silanization. This label-free TiNO-SPR biosensor exhibits a high sensitivity toward the inflammatory cytokine interleukin-6 with a detection limit down to 6.3 fg ml−1 and a short assay time of 25 min. Additionally, intraoperative monitoring of acute inflammatory responses during microelectrode implantation in the mice brain has been accomplished using the TiNO-SPR biosensors. Through intraoperative cerebrospinal fluid sampling and point-of-care plasmonic biosensing, the rhythm of acute inflammatory responses induced by the robot-controlled brain microelectrodes implantation has been successfully depicted, offering insights into intraoperative safety assessment of invasive brain-machine interfaces.

Machine learning-based rapid analysis of the failure progress of thin-film electrodes from electric impedance spectroscopy (EIS) data

Abstract Parylene C is a common substrate and encapsulation material used in implantable microelectrodes. Its reliability and failure are of great significance in the research and application of microelectrodes. In this study, three different failure stages of Parylene C thin-film electrodes were modeled using equivalent circuits, and the electric impedance spectroscopy of the electrodes were rapidly analyzed 9 different machine learning algorithms to identify the failure stages. The results showed that the three equivalent circuit models can represent the dynamics of the three failure stages of the Parylene C thin-film electrodes. The support vector machine (SVM) algorithm achieves more than 93% accuracy in identifying the equivalent circuit models from electric impedance spectroscopy data with an average time of 0.0273s. The SVM algorithm has great potential in fast analysis of electric impedance spectroscopy for the endurability study and application of implantable microelectrodes.

Comprehensive proteomic analysis of the differential expression of 62 proteins following intracortical microelectrode implantation

Intracortical microelectrodes (IMEs) are devices designed to be implanted into the cerebral cortex for various neuroscience and neuro-engineering applications. A critical feature of IMEs is their ability to detect neural activity from individual neurons. Currently, IMEs are limited by chronic failure, largely considered to be caused by the prolonged neuroinflammatory response to the implanted devices. Over the past few years, the characterization of the neuroinflammatory response has grown in sophistication, with the most recent advances focusing on mRNA expression following IME implantation. While gene expression studies increase our broad understanding of the relationship between IMEs and cortical tissue, advanced proteomic techniques have not been reported. Proteomic evaluation is necessary to describe the diverse changes in protein expression specific to neuroinflammation, neurodegeneration, or tissue and cellular viability, which could lead to the further development of targeted intervention strategies designed to improve IME functionality. In this study, we have characterized the expression of 62 proteins within 180 μm of the IME implant site at 4-, 8-, and 16-weeks post-implantation. We identified potential targets for immunotherapies, as well as key pathways that contribute to neuronal dieback around the IME implant.

Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation

Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes.

Dynamic changes in structure and function of brain mural cells around chronically implanted microelectrodes.

Integration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

Neuronal functional connectivity is impaired in a layer dependent manner near chronically implanted intracortical microelectrodes in C57BL6 wildtype mice

Objective. This study aims to reveal longitudinal changes in functional network connectivity within and across different brain structures near chronically implanted microelectrodes. While it is well established that the foreign-body response (FBR) contributes to the gradual decline of the signals recorded from brain implants over time, how the FBR affects the functional stability of neural circuits near implanted brain–computer interfaces (BCIs) remains unknown. This research aims to illuminate how the chronic FBR can alter local neural circuit function and the implications for BCI decoders. Approach. This study utilized single-shank, 16-channel,100 µm site-spacing Michigan-style microelectrodes (3 mm length, 703 µm2 site area) that span all cortical layers and the hippocampal CA1 region. Sex balanced C57BL6 wildtype mice (11–13 weeks old) received perpendicularly implanted microelectrode in left primary visual cortex. Electrophysiological recordings were performed during both spontaneous activity and visual sensory stimulation. Alterations in neuronal activity near the microelectrode were tested assessing cross-frequency synchronization of local field potential (LFP) and spike entrainment to LFP oscillatory activity throughout 16 weeks after microelectrode implantation. Main results. The study found that cortical layer 4, the input-receiving layer, maintained activity over the implantation time. However, layers 2/3 rapidly experienced severe impairment, leading to a loss of proper intralaminar connectivity in the downstream output layers 5/6. Furthermore, the impairment of interlaminar connectivity near the microelectrode was unidirectional, showing decreased connectivity from Layers 2/3 to Layers 5/6 but not the reverse direction. In the hippocampus, CA1 neurons gradually became unable to properly entrain to the surrounding LFP oscillations. Significance. This study provides a detailed characterization of network connectivity dysfunction over long-term microelectrode implantation periods. This new knowledge could contribute to the development of targeted therapeutic strategies aimed at improving the health of the tissue surrounding brain implants and potentially inform engineering of adaptive decoders as the FBR progresses. Our study’s understanding of the dynamic changes in the functional network over time opens the door to developing interventions for improving the long-term stability and performance of intracortical microelectrodes.

A PEDOT: PSS/GO fiber microelectrode fabricated by microfluidic spinning for dopamine detection in human serum and PC12 cells.

Rapid and accurate in situ determinationof dopamine is of great significance in the study of neurological diseases. In this work, poly (3,4-ethylenedioxythiophene): poly (styrenesulfonic acid) (PEDOT: PSS)/graphene oxide (GO) fibers were fabricated by an effective method based on microfluidic wet spinning technology. The composite microfibers with stratified and dense arrangement were continuously prepared by injecting PEDOT: PSS and GO dispersion solutions into a microfluidic chip. PEDOT: PSS/GO fiber microelectrodes with high electrochemical activity and enhanced electrochemical oxidation activity of dopamine were constructed by controlling the structure composition of the microfibers with varying flow rate. The fabricated fiber microelectrode had a low detection limit (4.56 nM) and wide detection range (0.01-8.0 µM) for dopamine detection with excellent stability, repeatability, and reproducibility. In addition, the PEDOT: PSS/GO fiber microelectrode prepared was successfully used for the detection of dopamine in human serum and PC12 cells. The strategy for the fabrication of multi-component fiber microelectrodes isa new and effective approach for monitoring the intercellular neurotransmitter dopamine and has highpotential as an implantable neural microelectrode.

High-Performance Bidirectional Microelectrode Array for Assessing Sevoflurane Anesthesia Effects and In Situ Electrical Stimulation in Deep Brain Regions.

Precise assessment of wakefulness states during sevoflurane anesthesia and timely arousal are of paramount importance to refine the control of anesthesia. To tackle this issue, a bidirectional implantable microelectrode array (MEA) is designed with the capability to detect electrophysiological signal and perform in situ deep brain stimulation (DBS) within the dorsomedial hypothalamus (DMH) of mice. The MEA, modified with platinum nanoparticles/IrOx nanocomposites, exhibits exceptional characteristics, featuring low impedance, minimal phase delay, substantial charge storage capacity, high double-layer capacitance, and longer in vivo lifetime, thereby enhancing the sensitivity of spike firing detection and electrical stimulation (ES) effectiveness. Using this MEA, sevoflurane-inhibited neurons and sevoflurane-excited neurons, together with changes in the oscillation characteristics of the local field potential within the DMH, are revealed as indicative markers of arousal states. During the arousal period, varying-frequency ESs are applied to the DMH, eliciting distinct arousal effects. Through in situ detection and stimulation, the disparity between these outcomes can be attributed to the influence of DBS on different neurons. These advancements may further our understanding of neural circuits and their potential applications in clinical contexts.

Development of a Neuropeptide Y-Sensitive Implantable Microelectrode for Continuous Measurements.

In this work, we present the development of the first implantable aptamer-based platinum microelectrode for continuous measurement of a nonelectroactive molecule, neuropeptide Y (NPY). The aptamer immobilization was performed via conjugation chemistry and characterized using cyclic voltammetry before and after the surface modification. The redox label, methylene blue (MB), was attached at the end of the aptamer sequence and characterized using square wave voltammetry (SWV). NPY standard solutions in a three-electrode cell were used to test three aptamers in steady-state measurement using SWV for optimization. The aptamer with the best performance in the steady-state measurements was chosen, and continuous measurements were performed in a flow cell system using intermittent pulse amperometry. Dynamic measurements were compared against confounding and similar peptides such as pancreatic polypeptide and peptide YY, as well as somatostatin to determine the selectivity in the same modified microelectrode. Our Pt-microelectrode aptamer-based NPY biosensor provides signals 10 times higher for NPY compared to the confounding molecules. This proof-of-concept shows the first potential implantable microelectrode that is selectively sensitive to NPY concentration changes.

Implantable Neural Microelectrodes: How to Reduce Immune Response.

Implantable neural microelectrodes exhibit the great ability to accurately capture the electrophysiological signals from individual neurons with exceptional submillisecond precision, holding tremendous potential for advancing brain science research, as well as offering promising avenues for neurological disease therapy. Although significant advancements have been made in the channel and density of implantable neural microelectrodes, challenges persist in extending the stable recording duration of these microelectrodes. The enduring stability of implanted electrode signals is primarily influenced by the chronic immune response triggered by the slight movement of the electrode within the neural tissue. The intensity of this immune response increases with a higher bending stiffness of the electrode. This Review thoroughly analyzes the sequential reactions evoked by implanted electrodes in the brain and highlights strategies aimed at mitigating chronic immune responses. Minimizing immune response mainly includes designing the microelectrode structure, selecting flexible materials, surface modification, and controlling drug release. The purpose of this paper is to provide valuable references and ideas for reducing the immune response of implantable neural microelectrodes and stimulate their further exploration in the field of brain science.

Measurement of neuropeptide Y in aptamer-modified planar electrodes

Electrochemical impedance spectroscopy (EIS) is a powerful technique for studying the interaction at electrode/solution interfaces. The adoption of EIS for obtaining analytical signals in biosensors based on aptamers is gaining popularity because of its advantageous characteristics for molecular recognition. Neuropeptide Y (NPY), the most abundant neuropeptide in the body, plays a crucial role with its stress-relieving properties. Quantitative measurement of NPY is imperative for understanding its role in these and other biological processes. Although aptamer-modified electrodes for NPY detection using EIS present a promising alternative, the correlation between the data obtained and the adsorption process on the electrodes is not fully understood. Various studies utilize the change in charge transfer resistance when employing an active redox label. In contrast, label-free measurement relies on changes in capacitance. To address these challenges, we focused on the interaction between aptamer-modified planar electrodes and their target, NPY. We proposed utilizing −ω*Zimag as the analytical signal, which facilitated the analysis of the adsorption process using an analogous Langmuir isotherm equation. This approach differs from implantable microelectrodes, which adhere to the Freundlich adsorption isotherm. Notably, our method obviates the need for a redox label and enables the detection of NPY at concentrations as low as 20 pg/mL. This methodology demonstrated exceptional selectivity, exhibiting a signal difference of over 20-to-1 against potential interfering molecules.

Robot-assisted implantation of a microelectrode array in the occipital lobe as a visual prosthesis: technical note.

The prospect of direct interaction between the brain and computers has been investigated in recent decades, revealing several potential applications. One of these is sight restoration in profoundly blind people, which is based on the ability to elicit visual perceptions while directly stimulating the occipital cortex. Technological innovation has led to the development of microelectrodes implantable on the brain surface. The feasibility of implanting a microelectrode on the visual cortex has already been shown in animals, with promising results. Current research has focused on the implantation of microelectrodes into the occipital brain of blind volunteers. The technique raises several technical challenges. In this technical note, the authors suggest a safe and effective approach for robot-assisted implantation of microelectrodes in the occipital lobe for sight restoration.

Depletion of complement factor 3 delays the neuroinflammatory response to intracortical microelectrodes

The neuroinflammatory response to intracortical microelectrodes (IMEs) used with brain-machine interfacing (BMI) applications is regarded as the primary contributor to poor chronic performance. Recent developments in high-plex gene expression technologies have allowed for an evolution in the investigation of individual proteins or genes to be able to identify specific pathways of upregulated genes that may contribute to the neuroinflammatory response. Several key pathways that are upregulated following IME implantation are involved with the complement system. The complement system is part of the innate immune system involved in recognizing and eliminating pathogens – a significant contributor to the foreign body response against biomaterials. Specifically, we have identified Complement 3 (C3) as a gene of interest because it is the intersection of several key complement pathways. In this study, we investigated the role of C3 in the IME inflammatory response by comparing the neuroinflammatory gene expression at the microelectrode implant site between C3 knockout (C3–/-) and wild-type (WT) mice. We have found that, like in WT mice, implantation of intracortical microelectrodes in C3–/- mice yields a dramatic increase in the neuroinflammatory gene expression at all post-surgery time points investigated. However, compared to WT mice, C3 depletion showed reduced expression of many neuroinflammatory genes pre-surgery and 4 weeks post-surgery. Conversely, depletion of C3 increased the expression of many neuroinflammatory genes at 8 weeks and 16 weeks post-surgery, compared to WT mice. Our results suggest that C3 depletion may be a promising therapeutic target for acute, but not chronic, relief of the neuroinflammatory response to IME implantation. Additional compensatory targets may also be required for comprehensive long-term reduction of the neuroinflammatory response for improved intracortical microelectrode performance.

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.