A Fully Implantable Miniaturized Liquid Crystal Polymer (LCP)-Based Spinal Cord Stimulator for Pain Control.

Spinal cord stimulation is a therapy to treat the severe neuropathic pain by suppressing the pain signal via electrical stimulation of the spinal cord. The conventional metal packaged and battery-operated implantable pulse generator (IPG) produces electrical pulses to stimulate the spinal cord. Despite its stable operation after implantation, the implantation site is limited due to its bulky size and heavy weight. Wireless communications including wireless power charging is also restricted, which is mainly attributed to the electromagnetic shielding of the metal package. To overcome these limitations, here, we developed a fully implantable miniaturized spinal cord stimulator based on a biocompatible liquid crystal polymer (LCP). The fabrication of electrode arrays in the LCP substrate and monolithically encapsulating the circuitries using LCP packaging reduces the weight (0.4 g) and the size (the width, length, and thickness are 25.3, 9.3, and 1.9 mm, respectively). An inductive link was utilized to wirelessly transfer the power and the data to implanted circuitries to generate the stimulus pulse. Prior to implantation of the device, operation of the pulse generator was evaluated, and characteristics of stimulation electrode such as an electrochemical impedance spectroscopy (EIS) were measured. The LCP-based spinal cord stimulator was implanted into the spared nerve injury rat model. The degree of pain suppression upon spinal cord stimulation was assessed via the Von Frey test where the mechanical stimulation threshold was evaluated by monitoring the paw withdrawal responses. With no spinal cord stimulation, the mechanical stimulation threshold was observed as 1.47 ± 0.623 g, whereas the stimulation threshold was increased to 12.7 ± 4.00 g after spinal cord stimulation, confirming the efficacy of pain suppression via electrical stimulation of the spinal cord. This LCP-based spinal cord stimulator opens new avenues for the development of a miniaturized but still effective spinal cord stimulator.

One-Pot Four-Component Coupling Approach to Polyheterocycles: 6H-Furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine.

A novel polyheterocyclic chemical space, 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine, was generated by a one-pot four-component coupling reaction where multiple bonds (three C-C, one C-O, and one C-N) were formed through a domino sequence. Two heterocyclic rings (furan and diazepine) were sequentially constructed from the monocyclic pyrrole derivative under environment-friendly reaction conditions to furnish the tricyclic fused scaffold.

A preliminary implementation of an active intraocular prosthesis as a new image acquisition device for a cortical visual prosthesis.

An active intraocular prosthesis is herein proposed as a new image acquisition device for a cortical visual prosthesis. A conventional intraocular prosthesis is a passive device that helps blind patients underwent eye enucleation to maintain the shape of an eyeball. In contrast, an active intraocular prosthesis, which works as an implantable wireless camera, can capture real-time images and transmit them to a cortical visual prosthesis to restore partial vision of the patients. This active device has distinct advantages in that it can garner a variety of image information while focusing on objects in accordance with natural eye movements, compared with a glasses-mounted camera and implanted micro-photodiodes in typical artificial vision systems. Coated with an epoxy and sealed by an elastomer for biocompatibility as well as durability, the active intraocular prosthesis was fabricated in a spherical form miniaturized enough to be inserted into the eye. Its operation was evaluated by wireless image acquisition displaying a processed gray-scale image. Furthermore, signal-to-noise ratio measurements were conducted to find a reliable communication range of the fabricated prosthesis, while it was covered by an 8-mm-thick biological medium that mimicked in vivo environments. In conclusion, the feasibility of the active intraocular prosthesis to cooperate with a cortical visual prosthesis is discussed.

Investigation of stereotactic surgery for avian brain stimulation by a fully implanted wireless system.

OBJECTIVE: The authors' goal was to study avian motor brain mapping via wireless stimulation to induce certain behaviors. In this paper, the authors propose an electrode design that is suitable for avian brain stimulation as well as a stereotactic implant procedure for the proposed electrode. METHODS: An appropriate breed for avian brain study was chosen. A fully implantable remote-controlled electrical stimulation system was inserted to minimize discomfort. A suitable electrode design and stereotactic surgery method based on the electrode design were investigated. RESULTS: Using a wireless stimulation system, flapping and rotation behaviors were induced by stimulating the ventral part of the nucleus intercollicularis and formatio reticularis medialis mesencephali both on the ground and during flight. CONCLUSIONS: The authors were able to implant the entire brain stimulation system inside the avian body without any surgical complications. Postoperative observations suggested that the bird did not find the implant uncomfortable.

CNT bundle-based thin intracochlear electrode array.

OBJECTIVE: It is known that the insertion of the intracochlear electrode is critical procedure because the damage around cochlear structures can deteriorate hearing restoration. To reduce the trauma during the electrode insertion surgery, we developed a thin and flexible intracochlear electrode array constructed with carbon nanotube (CNT) bundles. METHODS: Each CNT bundle was used for an individual electrode channel after coated with parylene C for insulation. By encapsulating eight CNT bundles with silicone elastomer, an 8-channel intracochlear electrode array was fabricated. The mechanical and electrochemical characteristics were assessed to evaluate the flexibility and feasibility of the electrode as a stimulation electrode. The functionality of the electrode was confirmed by electrically evoked auditory brainstem responses (eABR) recorded from a rat. RESULTS: The proposed electrode has a thickness of 135 µm at the apex and 395 µm at the base. It was demonstrated that the CNT bundle-based electrodes require 6-fold the lower insertion force than metal wire-based electrodes. The electrode impedance and the cathodic charge storage capacitance (CSCc) were 2.70 kΩ âˆ -20.4° at 1 kHz and - 708 mC/cm2, respectively. The eABR waves III and V were observed when stimulation current is greater than 50 µA. CONCLUSION: A thin and flexible CNT bundle-based intracochlear electrode array was successfully developed. The feasibility of the proposed electrode was shown in terms of mechanical and electrochemical characteristics. A proposed CNT bundle-based intracochlear electrode may reduce the risk of trauma during electrode insertion surgery.

Recent Progress on Non-Conventional Microfabricated Probes for the Chronic Recording of Cortical Neural Activity.

Microfabrication technology for cortical interfaces has advanced rapidly over the past few decades for electrophysiological studies and neuroprosthetic devices offering the precise recording and stimulation of neural activity in the cortex. While various cortical microelectrode arrays have been extensively and successfully demonstrated in animal and clinical studies, there remains room for further improvement of the probe structure, materials, and fabrication technology, particularly for high-fidelity recording in chronic implantation. A variety of non-conventional probes featuring unique characteristics in their designs, materials and fabrication methods have been proposed to address the limitations of the conventional standard shank-type ("Utah-" or "Michigan-" type) devices. Such non-conventional probes include multi-sided arrays to avoid shielding and increase recording volumes, mesh- or thread-like arrays for minimized glial scarring and immune response, tube-type or cylindrical probes for three-dimensional (3D) recording and multi-modality, folded arrays for high conformability and 3D recording, self-softening or self-deployable probes for minimized tissue damage and extensions of the recording sites beyond gliosis, nanostructured probes to reduce the immune response, and cone-shaped electrodes for promoting tissue ingrowth and long-term recording stability. Herein, the recent progress with reference to the many different types of non-conventional arrays is reviewed while highlighting the challenges to be addressed and the microfabrication techniques necessary to implement such features.

Theoretical Study on Gold-Nanorod-Enhanced Near-Infrared Neural Stimulation.

Over the past decade, optical methods have emerged for modulating brain functions as an alternative to electrical stimulation. Among various optical techniques, infrared neural stimulation has been effective via a thermal mechanism enabling focused and noninvasive stimulation without any genetic manipulation, but it results in bulk heating of neural tissue. Recently, it has been shown that neural cells can be activated more efficiently by pulsed near-infrared (NIR) light delivered to gold nanorods (GNRs) near the neural cells. Despite its potential, however, the biophysical mechanism underlying this GNR-enhanced NIR stimulation has not been clearly explained yet. Here, we propose an integrative and quantitative model to elucidate the mechanism by modeling heat generated from interaction between NIR light and GNRs, the temperature-dependent ion channels (transient receptor potential vanilloid 1; TRPV1) in the neuronal membrane, and a heat-induced capacitive current through the membrane. Our results show that NIR pulses induce abrupt temperature elevation near the neuronal membrane and lead to both the TRPV1-channel and capacitive currents. Both current sources synergistically increase the membrane potential and elicit an action potential, and which mechanism is dominant depends on conditions such as the laser pulse duration and TRPV1 channel density. Although the TRPV1 mechanism dominates in most cases we tested, the capacitive current makes a larger contribution when a very short laser pulse is illuminated on neural cells with relatively low TRPV1 channel densities.

Selectivity of Neuromodulatory Projections from the Basal Forebrain and Locus Ceruleus to Primary Sensory Cortices.

UNLABELLED: Acetylcholine and noradrenaline are major neuromodulators that affect sensory processing in the cortex. Modality-specific sensory information is processed in defined areas of the cortex, but it is unclear whether cholinergic neurons in the basal forebrain (BF) and noradrenergic neurons in the locus ceruleus (LC) project to and modulate these areas in a sensory modality-selective manner. Here, we mapped BF and LC projections to different sensory cortices of the mouse using dual retrograde tracing. We found that while the innervation of cholinergic neurons into sensory cortices is predominantly modality specific, the projections of noradrenergic neurons diverge onto multiple sensory cortices. Consistent with this anatomy, optogenetic activation of cholinergic neurons in BF subnuclei induces modality-selective desynchronization in specific sensory cortices, whereas activation of noradrenergic LC neurons induces broad desynchronization throughout multiple sensory cortices. Thus, we demonstrate a clear distinction in the organization and function of cholinergic BF and noradrenergic LC projections into primary sensory cortices: cholinergic BF neurons are highly selective in their projections and modulation of specific sensory cortices, whereas noradrenergic LC neurons broadly innervate and modulate multiple sensory cortices. SIGNIFICANCE STATEMENT: Neuromodulatory inputs from the basal forebrain (BF) and locus ceruleus (LC) are widespread in the mammalian cerebral cortex and are known to play important roles in attention and arousal, but little is known about the selectivity of their cortical projections. Using a dual retrobead tracing technique along with optogenetic stimulation, we have identified anatomic and functional differences in the way cholinergic BF neurons and noradrenergic LC neurons project into primary sensory cortices. While BF projections are highly selective to individual sensory cortices, LC projections diverge into multiple sensory cortices. To our knowledge, this is the first definitive proof that BF and LC projections to primary sensory cortices show both anatomic and functional differences in selectivity for modulating cortical activity.

Ultrafast Flame Annealing of TiO2 Paste for Fabricating Dye-Sensitized and Perovskite Solar Cells with Enhanced Efficiency.

Mesoporous TiO2 nanoparticle (NP) films are broadly used as electrodes in photoelectrochemical cells, dye-sensitized solar cells (DSSCs), and perovskite solar cells (PSCs). State-of-the-art mesoporous TiO2 NP films for these solar cells are fabricated by annealing TiO2 paste-coated fluorine-doped tin oxide glass in a box furnace at 500 °C for ≈30 min. Here, the use of a nontraditional reactor, i.e., flame, is reported for the high throughput and ultrafast annealing of TiO2 paste (≈1 min). This flame-annealing method, compared to conventional furnace annealing, exhibits three distinct benefits. First, flame removes polymeric binders in the initial TiO2 paste more completely because of its high temperature (≈1000 °C). Second, flame induces strong interconnections between TiO2 nanoparticles without affecting the underlying transparent conducting oxide substrate. Third, the flame-induced carbothermic reduction on the TiO2 surface facilitates charge injection from the dye/perovskite to TiO2 . Consequently, when the flame-annealed mesoporous TiO2 film is used to fabricate DSSCs and PSCs, both exhibit enhanced charge transport and higher power conversion efficiencies than those fabricated using furnace-annealed TiO2 films. Finally, when the ultrafast flame-annealing method is combined with a fast dye-coating method to fabricate DSSC devices, its total fabrication time is reduced from over 3 h to ≈10 min.

Rostral Agranular Insular Cortex Lesion with Motor Cortex Stimulation Enhances Pain Modulation Effect on Neuropathic Pain Model.

It is well known that the insular cortex is involved in the processing of painful input. The aim of this study was to evaluate the pain modulation role of the insular cortex during motor cortex stimulation (MCS). After inducing neuropathic pain (NP) rat models by the spared nerve injury method, we made a lesion on the rostral agranular insular cortex (RAIC) unilaterally and compared behaviorally determined pain threshold and latency in 2 groups: Group A (NP + MCS; n = 7) and Group B (NP + RAIC lesion + MCS; n = 7). Also, we simultaneously recorded neuronal activity (NP; n = 9) in the thalamus of the ventral posterolateral nucleus and RAIC to evaluate electrophysiological changes from MCS. The pain threshold and tolerance latency increased in Group A with "MCS on" and in Group B with or without "MCS on." Moreover, its increase in Group B with "MCS on" was more than that of Group B without MCS or of Group A, suggesting that MCS and RAIC lesioning are involved in pain modulation. Compared with the "MCS off" condition, the "MCS on" induced significant threshold changes in an electrophysiological study. Our data suggest that the RAIC has its own pain modulation effect, which is influenced by MCS.

Highly Efficient Solar Water Splitting from Transferred TiO2 Nanotube Arrays.

We report a synergistic effect of flame and chemical reduction methods to maximize the efficiency of solar water splitting in transferred TiO2 nanotube (TNT) arrays on a transparent conducting oxide (TCO) substrate. The flame reduction method (>1000 °C) leads to few oxygen vacancies in the anatase TNT arrays, but it exhibits unique advantages for excellent interfacial characteristics between transferred TNT arrays and TCO substrates, which subsequently induce a cathodic on-set potential shift and sharp photocurrent evolution. By contrast, the employed chemical reduction method for TNT arrays/TCO gives rise to an abrupt increase in photocurrent density, which results from the efficient formation of oxygen vacancies in the anatase TiO2 phase, but a decrease in charge transport efficiency with increasing chemical reduction time. We show that flame reduction followed by chemical reduction could significantly improve the saturation photocurrent density and interfacial property of TNT arrays/TCO photoanodes simultaneously without mechanical fracture via the synergistic effects of coreducing methods.

Fabrication and evaluation of an improved polymer-based cochlear electrode array for atraumatic insertion.

An atraumatic cochlear electrode array has become indispensable to high-performance cochlear implants such as electric acoustic stimulation (EAS), wherein the preservation of residual hearing is significant. For an atraumatic implantation, we propose and demonstrate a new improved design of a cochlear electrode array based on liquid crystal polymer (LCP), which can be fabricated by precise batch processes and a thermal lamination process, in contrast to conventional wire-based cochlear electrode arrays. Using a thin-film process of LCP-film-mounted silicon wafer and thermal press lamination, we devise a multi-layered structure with variable layers of LCP films to achieve a sufficient degree of basal rigidity and a flexible tip. A peripheral blind via and self-aligned silicone elastomer molding process can reduce the width of the array. Measuring the insertion and extraction forces in a human scala tympani model, we investigate five human temporal bone insertion trials and record electrically evoked auditory brainstem responses (EABR) acutely in a guinea pig model. The diameters of the finalized electrode arrays are 0.3 mm (tip) and 0.75 mm (base). The insertion force with a displacement of 8 mm from a round window and the maximum extraction force are 2.4 mN and 34.0 mN, respectively. The electrode arrays can be inserted from 360° to 630° without trauma at the basal turn. The EABR data confirm the efficacy of the array. A new design of LCP-based cochlear electrode array for atraumatic implantation is fabricated. Verification indicates that foretells the development of an atraumatic cochlear electrode array and clinical implant.

Synthesis of nanoparticle CT contrast agents: in vitro and in vivo studies.

Water-soluble and biocompatible D-glucuronic acid coated Na2WO4 and BaCO3 nanoparticles were synthesized for the first time to be used as x-ray computed tomography (CT) contrast agents. Their average particle diameters were 3.2 ± 0.1 and 2.8 ± 0.1 nm for D-glucuronic acid coated Na2WO4 and BaCO3 nanoparticles, respectively. All the nanoparticles exhibited a strong x-ray attenuation. In vivo CT images were obtained after intravenous injection of an aqueous sample suspension of D-glucuronic acid coated Na2WO4 nanoparticles, and positive contrast enhancements in the kidney were clearly shown. These findings indicate that the nanoparticles reported in this study may be promising CT contrast agents.

Enhanced infrared neural stimulation using localized surface plasmon resonance of gold nanorods.

An advanced optical activation of neural tissues is demonstrated using pulsed infrared light and plasmonic gold nanorods. Photothermal effect localized in plasma membrane triggers action potentials of in vivo neural tissues. Compared with conventional infrared stimulation, the suggested method can increase a neural responsivity and lower a threshold stimulation level significantly, thereby reducing a requisite radiant exposure and the concern of tissue damage.

Multi-color fluorescence imaging based on plasmonic wavelength selection and double illumination by white light.

We demonstrate the proof-of-concept for developing a multi-color fluorescence imaging system based on plasmonic wavelength selection and double illumination by white light source. This technique is associated with fluorescence excitation by transmitted light via a diffraction of propagating surface plasmons. Since double illumination through both sides of isosceles triangle prism in the Kretschmann configuration enables multiple transmission beams of different wavelengths to interact with the specimen, our approach can be an alternative to conventional fluorescence detection owing to alignment stability and functional expandability. After fabricating a plasmonic wavelength splitter and integrating it with microscopic imaging system, we successfully confirm the performance by visualizing in vitro neuron cells labeled with green and red fluorescence dyes. The suggested method has a potential that it could be combined with plasmonic biosensor scheme to realize a multi-functional platform which allows imaging and sensing of biological samples at the same time.

A liquid crystal polymer-based neuromodulation system: an application on animal model of neuropathic pain.

OBJECTIVE: We developed a custom-made miniaturized neural stimulation system with a liquid crystal polymer (LCP)-based electrode array for animal experiments. In order to verify the feasibility of the system, motor cortex stimulation (MCS) was applied on the rat pain model induced by sciatic nerve injury. MATERIALS AND METHODS: LCP is mechanically stable and chemically inert and has a much lower water absorption rate than other biocompatible polymers such as polyimide or parylene. In the present study, a film-type LCP substrate is used to microfabricate the cortical stimulation electrode array. A miniaturized electrical neuromodulation system is implemented using an application-specific integrated chip for generation of electrical stimulation current. In vivo experiment was performed using a rat neuropathic pain model induced by sciatic nerve injury. The electrodes were attached to the contralateral primary motor cortex, which processes the hind limb movement. Mechanical allodynia was measured before, during, and after electrical stimulation to determine the effects on pain threshold. RESULTS: Electrical stimulation into the brain structure processing pain perception was effective in alleviating neuropathic pain. The pain threshold of the rats increased more than fivefold during the electrical stimulation. CONCLUSION: We developed a miniaturized electrical stimulation system with a novel flexible LCP electrode array for MCS in rats. This system is expected to be used in studying various neurological diseases and examining in vivo brain function.

Ventral posterolateral deep brain stimulation treatment for neuropathic pain shortens pain response after cold stimuli.

Neuropathic pain is often severe. Deep brain stimulation (DBS) is a treatment method for neuropathic pain, but its mechanism of action remains unclear. Patients with neuropathic pain are affected by various stimulations, such as mechanical and cold stimuli, but studies of cold allodynia showed the associated pain to be less than that caused by mechanical stimuli. This study focused on the effects of DBS on cold allodynia in rats. To observe the effects of DBS, we established three groups: a normal group (normal), a neuropathic pain group (pain), and a DBS with neuropathic pain group (DBS). The stimulation target was the ventral posterolateral nucleus (VPL). We observed differences in the degree of cold allodynia elicited between a conventional method that measured the number of pain responses and our altered novel method that measured the duration of pain responses. Cold allodynia after DBS did not differ when conventional analysis was applied, but the pain response duration was decreased. We suggest that VPL DBS was partially effective in cold allodynia, implicating complex pathways of pain signaling.

The effect of topic familiarity and volatility of auditory scene on selective auditory attention.

Selective auditory attention has been shown to modulate the cortical representation of speech. This effect has been well documented in acoustically more challenging environments. However, the influence of top-down factors, in particular topic familiarity, on this process remains unclear, despite evidence that semantic information can promote speech-in-noise perception. Apart from individual features forming a static listening condition, dynamic and irregular changes of auditory scenes-volatile listening environments-have been less studied. To address these gaps, we explored the influence of topic familiarity and volatile listening on the selective auditory attention process during dichotic listening using electroencephalography. When stories with unfamiliar topics were presented, participants' comprehension was severely degraded. However, their cortical activity selectively tracked the speech of the target story well. This implies that topic familiarity hardly influences the speech tracking neural index, possibly when the bottom-up information is sufficient. However, when the listening environment was volatile and the listeners had to re-engage in new speech whenever auditory scenes altered, the neural correlates of the attended speech were degraded. In particular, the cortical response to the attended speech and the spatial asymmetry of the response to the left and right attention were significantly attenuated around 100-200 ms after the speech onset. These findings suggest that volatile listening environments could adversely affect the modulation effect of selective attention, possibly by hampering proper attention due to increased perceptual load.

Computational analysis of multichannel magnetothermal neural stimulation using magnetic resonator array.

Heating nanoparticles with a magnetic field could facilitate selective remote control of neural activity in deep tissue. However, current magnetothermal stimulation approaches are limited to single-channel stimulation. Here, we investigated various designs for multichannel magnetothermal stimulation based on an array of resonant coils that are driven by a single loop coil. Using a tuning capacitor that allows resonant coils to resonate at the operating frequency, each coil's ON and OFF resonance can be controlled, enabling us to select stimulation channels. We found that smaller inner diameters of resonant coils produce more localized magnetic fields while larger coils produce magnetic fields over a longer distance. The constructed multichannel resonant coil arrays can provide a high enough magnetic field intensity to raise the temperature of nanoparticles by 8 °C when we apply 35.2 W into the loop coil that is spaced 1 mm from the target neurons. This multichannel stimulation using a simple resonant circuit approach would be useful for clinical applications of magnetothermal neural stimulation.