Flexible Neural Probes Research Articles

Chronic implantable flexible serpentine probe reveals impaired spatial coding of place cells in epilepsy

Abstract Developing minimally invasive and reliable electrode probes for neural signal recording is crucial for advancing neuroscience and treating major brain disorders. Flexible neural probes offer superior long-term recording capabilities over traditional rigid probes. This study introduces a parylene-based serpentine electrode probe for stable, long-term neural monitoring. Inspired by the flexibility and morphology of snakes, the probe's serpentine design ensures stable anchorage within the brain tissue during subject movement. The probe features a hydrophilic surface and is combined with a biodegradable silk fibroin-PEG coating, significantly enhancing biocompatibility and mitigating inflammatory responses. In vivo experiments demonstrate that these probes maintain stable, high-quality neural recordings for over eight months. The probes are also used to investigate the neural bases of epilepsy-induced cognitive deficits. By analyzing place cell dynamics in mice pre- and post-epileptic events, we identified the correlation between impaired spatial encoding and the observed cognitive deficits in epileptic mice. This study highlights the potential of our flexible probes in neurological research and medical applications.

A stealthy neural recorder for the study of behaviour in primates.

By monitoring brain neural signals, neural recorders allow for the study of neurological mechanisms underlying specific behavioural and cognitive states. However, the large brain volumes of non-human primates and their extensive range of uncontrolled movements and inherent wildness make it difficult to carry out covert and long-term recording and analysis of deep-brain neural signals. Here we report the development and performance of a stealthy neural recorder for the study of naturalistic behaviours in non-human primates. The neural recorder includes a fully implantable wireless and battery-free module for the recording of local field potentials and accelerometry data in real time, a flexible 32-electrode neural probe with a resorbable insertion shuttle, and a repeater coil-based wireless-power-transfer system operating at the body scale. We used the device to record neurobehavioural data for over 1 month in a freely moving monkey and leveraged the recorded data to train an artificial intelligence model for the classification of the animals' eating behaviours.

Enhancing Flexible Neural Probe Performance via Platinum Deposition: Impedance Stability under Various Conditions and In Vivo Neural Signal Monitoring.

Monitoring neural activity in the central nervous system often utilizes silicon-based microelectromechanical system (MEMS) probes. Despite their effectiveness in monitoring, these probes have a fragility issue, limiting their application across various fields. This study introduces flexible printed circuit board (FPCB) neural probes characterized by robust mechanical and electrical properties. The probes demonstrate low impedance after platinum coating, making them suitable for multiunit recordings in awake animals. This capability allows for the simultaneous monitoring of a large population of neurons in the brain, including cluster data. Additionally, these probes exhibit no fractures, mechanical failures, or electrical issues during repeated-bending tests, both during handling and monitoring. Despite the possibility of using this neural probe for signal measurement in awake animals, simply applying a platinum coating may encounter difficulties in chronic tests and other applications. Furthermore, this suggests that FPCB probes can be advanced by any method and serve as an appropriate type of tailorable neural probes for monitoring neural systems in awake animals.

Flexible Acetylcholine Neural Probe with a Hydrophobic Laser-Induced Graphene Electrode and a Fluorous-Phase Sensing Membrane.

This work develops the first laser-induced graphene (LIG)-based electrochemical sensor with a superhydrophobic fluorous membrane for a flexible acetylcholine (ACh) sensor. ACh regulates several physiological functions, including synaptic transmission and glandular secretion. The ACh sensing membrane is doped with a fluorophilic cation-exchanger that can selectively measure ACh based on the inherent selectivity of the fluorous phase for hydrophobic ions, such as ACh. The fluorous-phase sensor improves the selectivity for ACh over Na+ and K+ by 2 orders of magnitude (compared to traditional lipophilic membranes), thus lowering the detection limit in artificial cerebrospinal fluid (aCSF) from 331 to 0.38 μ M, thereby allowing measurement in physiologically relevant ranges of ACh. Engraving LIG under argon creates a hydrophobic surface with a 133.7° contact angle, which minimizes the formation of a water layer. The flexible solid-contact LIG fluorous sensor exhibited a slope of 59.3 mV/decade in aCSF and retained function after 20 bending cycles, thereby paving the way for studying ACh's role in memory and neurodegenerative diseases.

3D-printed flexible neural probes for recordings at single-neuron level

3D-printed flexible neural probes for recordings at single-neuron level

Fully flexible implantable neural probes for electrophysiology recording and controlled neurochemical modulation

Targeted delivery of neurochemicals and biomolecules for neuromodulation of brain activity is a powerful technique that, in addition to electrical recording and stimulation, enables a more thorough investigation of neural circuit dynamics. We have designed a novel, flexible, implantable neural probe capable of controlled, localized chemical stimulation and electrophysiology recording. The neural probe was implemented using planar micromachining processes on Parylene C, a mechanically flexible, biocompatible substrate. The probe shank features two large microelectrodes (chemical sites) for drug loading and sixteen small microelectrodes for electrophysiology recording to monitor neuronal response to drug release. To reduce the impedance while keeping the size of the microelectrodes small, poly(3,4-ethylenedioxythiophene) (PEDOT) was electrochemically coated on recording microelectrodes. In addition, PEDOT doped with mesoporous sulfonated silica nanoparticles (SNPs) was used on chemical sites to achieve controlled, electrically-actuated drug loading and releasing. Different neurotransmitters, including glutamate (Glu) and gamma-aminobutyric acid (GABA), were incorporated into the SNPs and electrically triggered to release repeatedly. An in vitro experiment was conducted to quantify the stimulated release profile by applying a sinusoidal voltage (0.5 V, 2 Hz). The flexible neural probe was implanted in the barrel cortex of the wild-type Sprague Dawley rats. As expected, due to their excitatory and inhibitory effects, Glu and GABA release caused a significant increase and decrease in neural activity, respectively, which was recorded by the recording microelectrodes. This novel flexible neural probe technology, combining on-demand chemical release and high-resolution electrophysiology recording, is an important addition to the neuroscience toolset used to dissect neural circuitry and investigate neural network connectivity.

Multifunctional and Flexible Neural Probe with Thermally Drawn Fibers for Bidirectional Synaptic Probing in the Brain.

Synapses in the brain utilize two distinct communication mechanisms: chemical and electrical. For a comprehensive investigation of neural circuitry, neural interfaces should be capable of both monitoring and stimulating these types of physiological interactions. However, previously developed interfaces for neurotransmitter monitoring have been limited in interaction modality due to constraints in device size, fabrication techniques, and the usage of flexible materials. To address this obstacle, we propose a multifunctional and flexible fiber probe fabricated through the microwire codrawing thermal drawing process, which enables the high-density integration of functional components with various materials such as polymers, metals, and carbon fibers. The fiber enables real-time monitoring of transient dopamine release in vivo, real-time stimulation of cell-specific neuronal populations via optogenetic stimulation, single-unit electrophysiology of individual neurons localized to the tip of the neural probe, and chemical stimulation via drug delivery. This fiber will improve the accessibility and functionality of bidirectional interrogation of neurochemical mechanisms in implantable neural probes.

Flexible multi-electrode neural probe using active-matrix design of transistor array

To realize a brain-machine interface, a neural probe is one of key hardware. For the neural probe, a high spatial resolution of an electrode array, high electrical sensitivity, and mechanical flexibility remain challenging and essential issues. In regard to these, implantable multi-electrode neural probe employing active-matrix design with field effect transistors (FETs) can attract attention due to their advantages of a suitable integration density and good signal-amplifying abilities. Therefore, we developed a flexible multi-electrode neural probe employing an active-matrix design based on a two-transistor (2T) scheme for application to a flexible neural signal recording probe. As a proof of concept, 4 × 8 electrode array (32 channels) with TFTs was demonstrated. For the flexible active-matrix design, back-gate indium-gallium-zinc-oxide (IGZO) thin film transistors (TFTs) were fabricated on a polyimide (PI). The TFTs used here can amplify signals and achieve a switching function to drive the active matrix. The probe structure was encapsulated by the same PI material again to achieve flexibility with good reliability, as the sandwich-like structure can induce a neutral plane on the TFT and electrodes. To ensure a high signal-to-noise ratio, the structural and process parameters of the TFT were studied. Among different annealing times and temperatures of the IGZO TFT, the optimized annealing condition of the TFT was found to be 250 °C a 1 hour on a flexible substrate. The width over length of the transistors was optimized to 50 μm/10 μm, and the field-effect mobility was 8.33 cm2/V·s. The on current was 2.28 × 10−6 A at a low driving voltage of 5 V. The transconductance was 2.16 μS and the threshold voltage (Vth) was 1.6 V. By applying 5 V, the switching TFT was turned on, and a doubly amplified signal (> 2.4 times) could be measured on the drain line. The electrode array probe with the active-matrix design can use for accurate neural recording and herald a new generation of flexible neural probes with high spatial resolutions.

Impact of Impedance Levels on Recording Quality in Flexible Neural Probes.

Flexible neural probes are attractive emerging technologies for brain recording because they can effectively record signals with minimal risk of brain damage. Reducing the electrode impedance of the probe before recording is a common practice of many researchers. However, studies investigating the impact of low impedance levels on high-quality recordings using flexible neural probes are lacking. In this study, we electrodeposited Pt onto a commercial flexible polyimide neural probe and investigated the relationship between the impedance level and the recording quality. The probe was inserted into the brains of anesthetized mice. The electrical signals of neurons in the brain, specifically the ventral posteromedial nucleus of the thalamus, were recorded at impedance levels of 50, 250, 500 and 1000 kΩ at 1 kHz. The study results demonstrated that as the impedance decreased, the quality of the signal recordings did not consistently improve. This suggests that extreme lowering of the impedance may not always be advantageous in the context of flexible neural probes.

Self‐Stretchable Christmas‐Tree‐Shaped Ultraflexible Neural Probes†

This paper devised a novel Christmas‐tree structure for flexible neural probes, which features recording sites on side‐branches that can be folded along the shank of the probe by temporary encapsulation before implantation. This design reduces the size of the implant and minimizes the surgical footprint. Upon implantation, the temporary encapsulation dissolves in vivo, leading to self‐stretching of the branches, and an expansion of the lateral detecting range of the probe. We conducted in vitro experiment with our probe in 0.6% agar that mimics the brain tissue environment. The results demonstrate that the neural probe we have developed exhibits self‐stretching ability and provides an increased lateral recording range without causing additional damage to the brain tissue. © 2024 Institute of Electrical Engineer of Japan and Wiley Periodicals LLC.

A Brain‐to‐Brain Interface with a Flexible Neural Probe for Mouse Turning Control by Human Mind

We proposed a brain‐to‐brain interface (B2BI) that enabled effective control of mouse turning behavior by human mind using an implantable, ultra‐flexible neural probe. The neural probe was capable of writing in neural signals to the mouse brain, with effective electrical stimulation observed at a low current of 5 μA. Additionally, a wireless electroencephalogram (EEG) device was developed for the remote transmission of human brain signals, which were decoded by the canonical correlation analysis (CCA) method with an accuracy rate of up to 98.6%. These results demonstrate the potential of B2BI technology to enable communication and control between humans and animals. © 2024 Institute of Electrical Engineer of Japan and Wiley Periodicals LLC.

Multimodal integrated flexible neural probe for in situ monitoring of EEG and lactic acid.

In physiological activities, the brain's electroencephalogram (EEG) signal and chemical concentration change are crucial for diagnosing and treating neurological disorders. Despite the advantages of flexible neural probes, such as their flexibility and biocompatibility, it remains a challenge to achieve in situ monitoring of electrophysiological and chemical signals on a small scale simultaneously. This study developed a new method to construct an efficient dual-sided multimodal integrated flexible neural probe, which combines a density electrode array for EEG recordings and an electrochemical sensor for detecting lactic acid. The EEG electrode array includes a 6-channel recording electrode array with each electrode 30 × 50 μm in size, and the lactic acid sensor with overall contact is approximately 100 μm wide. The EEG electrodes have an average impedance of 2.57 kΩ at 1 kHz and remained stable after immersing in NS (normal saline) for 3 months. The lactic acid sensor showed a sensitivity of 52.8 nA mM-1. The in vivo experiments demonstrated that the probe can reliably monitor electrophysiological signals. The probe is able to be implanted into the desired site with the help of a guide port. This flexible neural probe can provide more comprehensive insights into brain activity in the field of neuroscience and clinical practices.

Free-Standing Carbon Nanotube Embroidered Graphene Film Electrode Array for Stable Neural Interfacing.

Implantable neural probes that are mechanically flexible yet robust are attractive candidates for achieving stable neural interfacing in the brain. Current flexible neural probes consist mainly of metal thin-film electrodes integrated on micrometer-thick polymer substrates, making it challenging to achieve electrode-tissue interfacing on the cellular scale. Here, we describe implantable neural probes that consist of robust carbon nanotube network embroidered graphene (CeG) films as free-standing recording microelectrodes. Our CeG film microelectrode arrays (CeG_MEAs) are ultraflexible yet mechanically robust, thus enabling cellular-scale electrode-tissue interfacing. Chronically implanted CeG_MEAs can stably track the activities of the same population of neurons over two months. Our results highlight the potential of ultraflexible and free-standing carbon nanofilms for stable neural interfacing in the brain.

High‐Resolution Recording of Neural Activity in Epilepsy Using Flexible Neural Probes (Adv. Mater. Technol. 24/2023)

High‐Resolution Recording of Neural Activity in Epilepsy Using Flexible Neural Probes (Adv. Mater. Technol. 24/2023)

High‐Resolution Recording of Neural Activity in Epilepsy Using Flexible Neural Probes

AbstractEpilepsy, a prevalent neurological disorder, necessitates precise and reliable electrophysiological recording for accurate study and diagnosis. Although traditional stereo‐electroencephalography and micro‐wire probes are widely used in epilepsy research, they are limited by recording site numbers and mechanical properties. This study explores the use of high‐density, ultra‐flexible neural probes in epilepsy monitoring, highlighting their advantages in terms of recording performance, scalability, and tissue compatibility. This work validates the effectiveness of the probes in detecting characteristic epileptic signals across various stages, including resting, preictal, and ictal stages, in two different mouse models of epilepsy. Additionally, the high spatial resolution of the probes allows to capture fine spatial propagation of epilepsy‐associated high‐frequency oscillations. Furthermore, the flexible probes exhibit superior biocompatibility, reducing inflammation and neuronal apoptosis compared to rigid electrodes. The results underscore the promising potential of ultra‐flexible neural probes for advancing epilepsy research, providing a powerful technological platform for future studies in the field.

Fabrication of a photo-crosslinkable fluoropolymer-passivated flexible neural probe and acute recording and stimulation performances in vivo

Herein, we fabricated fluorine-containing, polymer-based, flexible neural probes with fluorinated ethylene propylene (FEP) films as the substrates and photo-crosslinkable fluoropolymers as the passivation material. For fabrication, metal-free Au layer formation on the FEP film, the simultaneous photo-adhesion and photo-patterning technique, and the pulsed-laser scanning probe shaping technique were combined, followed by Au electrode surface modification. The resultant probes achieved a charge injection limit equal to 5.18 mC cm−2 by implementing iridium oxide-modified nanoporous Au (IrOx/NPG) structures. We performed simultaneous in vivo micro-stimulations of the Schaffer collateral fibres and recorded the evoked field excitatory postsynaptic potentials (fEPSPs) in the stratum radiatum layer of the hippocampal Cornu Ammonis 1 region using a single probe. Inducing the fEPSP at very low charge per pulse settings (3.2–3.6 nC/pulse) indicates the efficient charge injection capability of the IrOx/NPG electrode, thereby enabling safe, prolonged, and thrifty micro-stimulations. Furthermore, the single probe-induced and recorded long-term potentiation persisted for periods longer than 60 min following theta-burst stimulation. The materials used in this study are all biocompatible and chemically robust. The fabricated neural probes can be applied in chronic clinical trials in vivo.

A fully-flexible and thermally adjustable implantable neural probe with a U-turn polyester microchannel.

This work presents a fully flexible implantable neural probe fabricated with Polydimethylsiloxane (PDMS) and including a thermally-tunable stiffness microchannel filled with Polyester. The probe includes an optimized microfluidics mixer for drug delivery. Polyester, which is solid at room temperature and has a low melting point close to body temperature, is used to decrease the stiffness of the probe after insertion, after getting in contact with tissues. We designed a U-turn microchannel inside the PDMS neural probe and filled it up with melted polyester. The microchannel has a cross-section of 30 μm × 5 μm and a length of 14.7 mm. The following probe dimensions were chosen after extensive simulation: thickness = 20 μm, width = 300 μm, and length = 7 mm. These values yield a buckling force above 1 mN, which is sufficient for proper insertion into the brain tissues. Simulation results show that the microfluidics mixer with a cross-section of 90 μm × 5 μm and a length of 7 mm has optimum performance for the desired flow rate and quantity of drug to deliver. The pressure drop inside the microfluidic channel is less than 0.43 kPa, which is appropriate for PDMS-PDMS bonding, whereas the Reynolds number is near 1.91k in the laminar regime. No leakage or bubble occurred during the experimental validation, which suggests an appropriate pressure and a laminar flow in the channel.

Ultraflexible endovascular probes for brain recording through micrometer-scale vasculature.

Implantable neuroelectronic interfaces have enabled advances in both fundamental research and treatment of neurological diseases but traditional intracranial depth electrodes require invasive surgery to place and can disrupt neural networks during implantation. We developed an ultrasmall and flexible endovascular neural probe that can be implanted into sub-100-micrometer-scale blood vessels in the brains of rodents without damaging the brain or vasculature. In vivo electrophysiology recording of local field potentials and single-unit spikes have been selectively achieved in the cortex and olfactory bulb. Histology analysis of the tissue interface showed minimal immune response and long-term stability. This platform technology can be readily extended as both research tools and medical devices for the detection and intervention of neurological diseases.

Tunable organic active neural probe enabling near-sensor signal processing.

Neural recording systems have significantly progressed to provide an advanced understanding and treatment for neurological diseases. Flexible transistor-based active neural probes exhibit great potential in electrophysiology applications due to their intrinsic amplification capability and tissue-compliant nature. However, most current active neural probes exhibit bulky back-end connectivity since the output is current, and the development of an integrated circuit for voltage output is crucial for near-sensor signal processing at the abiotic/biotic interface. Here, wepresent inkjet-printed organic voltage amplifiers by monolithically integrating organic electrochemical transistors and thin-film polymer resistors on a single, highly flexible substrate for in vivo brain activity recording. Additive inkjet printing enables the seamless integration of multiple active and passive components on the somatosensory cortex, leading to significant noise reduction over the externally connected typical configuration. It also facilitates fine-tuning of the voltage amplification and frequency properties. Wevalidate the organic voltage amplifiers as electrocorticography devices in a rat in vivo model, showing their ability to record local field potentials in an experimental model of spontaneous and epileptiform activity. Ourresults bring organic active neural probes to the forefront in applications where efficient sensory data processing is performed at sensor endpoints. This article is protected by copyright. All rights reserved.

A mosquito mouthpart-like bionic neural probe

Advancements in microscale electrode technology have revolutionized the field of neuroscience and clinical applications by offering high temporal and spatial resolution of recording and stimulation. Flexible neural probes, with their mechanical compliance to brain tissue, have been shown to be superior to rigid devices in terms of stability and longevity in chronic recordings. Shuttle devices are commonly used to assist flexible probe implantation; however, the protective membrane of the brain still makes penetration difficult. Hidden damage to brain vessels during implantation is a significant risk. Inspired by the anatomy of the mosquito mouthparts, we present a biomimetic neuroprobe system that integrates high-sensitivity sensors with a high-fidelity multichannel flexible electrode array. This customizable system achieves distributed and minimally invasive implantation across brain regions. Most importantly, the system’s nonvisual monitoring capability provides an early warning detection for intracranial soft tissues, such as vessels, reducing the potential for injury during implantation. The neural probe system demonstrates exceptional sensitivity and adaptability to environmental stimuli, as well as outstanding performance in postoperative and chronic recordings. These findings suggest that our biomimetic neural-probe device offers promising potential for future applications in neuroscience and brain-machine interfaces.A mosquito mouthpart-like bionic neural probe consisting of a highly sensitive tactile sensor module, a flexible microelectrode array, and implanted modules that mimic the structure of mosquito mouthparts. The system enables distributed implantation of electrode arrays across multiple brain regions while making the implantation minimally invasive and avoiding additional dural removal. The tactile sensor array can monitor the implantation process to achieve early warning of vascular damage. The excellent postoperative short-term recording performance and long-term neural activity tracking ability demonstrate that the system is a promising tool in the field of brain-computer interfaces.