Design of CMOS Analog Front-End Local-Field Potential Chopper Amplifier With Stimulation Artifact Tolerance for Real-Time Closed-Loop Deep Brain Stimulation SoC Applications.

A CMOS analog front-end (AFE) local-field potential (LFP) chopper amplifier with stimulation artifact tolerance, improved right-leg driven (RLD) circuit, and improved auxiliary path is proposed. In the proposed CMOS AFE LFP chopper amplifier, common-mode artifact voltage (CMAV) and differential-mode artifact voltage (DMAV) removal using the analog template removal method are proposed to achieve good signal linearity during stimulation. An improved auxiliary path is employed to boost the input impedance and allow the negative stimulation artifact voltage passing through. The common-mode noise is suppressed by the improved RLD circuit. The chip is implemented in 0.18- µm CMOS technology and the total chip area is 5.46-mm2. With the improved auxiliary path, the measured input impedance is larger than 133 M[Formula: see text] in the signal bandwidth and reaches 8.2 G[Formula: see text] at DC. With the improved RLD circuit, the measured CMRR is 131 - 144 dB in the signal bandwidth. Under 60-µs pulse width and 130-Hz constant current stimulation (CCS) with ±1-V CMAV and ±50-mV DMAV, the measured THD at the SC Amp output of fabricated AFE LFP chopper amplifier is 1.28%. The measurement results of In vitro agar tests have shown that with ±1.6-mA CCS pulses injecting to agar, the measured THD is 1.69%. Experimental results of both electrical and agar tests have verified that the proposed AFE LFP chopper amplifier has good stimulation artifact tolerance. The proposed CMOS AFE LFP chopper amplifier with analog template removal method is suitable for real-time closed-loop deep drain stimulation (DBS) SoC applications.

Integration of multiple prognostic predictors in a porcine spinal cord injury model: A further step closer to reality.

Introduction: Spinal cord injury (SCI) is a devastating neurological disorder with an enormous impact on individual's life and society. A reliable and reproducible animal model of SCI is crucial to have a deeper understanding of SCI. We have developed a large-animal model of spinal cord compression injury (SCI) with integration of multiple prognostic factors that would have applications in humans. Methods: Fourteen human-like sized pigs underwent compression at T8 by implantation of an inflatable balloon catheter. In addition to basic neurophysiological recording of somatosensory and motor evoked potentials, we introduced spine-to-spine evoked spinal cord potentials (SP-EPs) by direct stimulation and measured them just above and below the affected segment. A novel intraspinal pressure monitoring technique was utilized to measure the actual pressure on the cord. The gait and spinal MRI findings were assessed in each animal postoperatively to quantify the severity of injury. Results: We found a strong negative correlation between the intensity of pressure applied to the spinal cord and the functional outcome (P < 0.0001). SP-EPs showed high sensitivity for real time monitoring of intraoperative cord damage. On MRI, the ratio of the high-intensity area to the cross-sectional of the cord was a good predictor of recovery (P < 0.0001). Conclusion: Our balloon compression SCI model is reliable, predictable, and easy to implement. By integrating SP-EPs, cord pressure, and findings on MRI, we can build a real-time warning and prediction system for early detection of impending or iatrogenic SCI and improve outcomes.

An electroactive hybrid biointerface for enhancing neuronal differentiation and axonal outgrowth on bio-subretinal chip.

Retinal prostheses offer viable vision restoration therapy for patients with blindness. However, a critical requirement for maintaining the stable performance of electrical stimulation and signal transmission is the biocompatibility of the electrode interface. Here, we demonstrated a functionalized electrode-neuron biointerface composed of an annealed graphene oxide-collagen (aGO-COL) composite and neuronal cells. The aGO-COL exhibited an electroactive 3D crumpled surface structure and enhanced the differentiation efficiency of PC-12 â€‹cells. It is integrated into a photovoltaic self-powered retinal chip to develop a biohybrid retinal implant that facilitates biocompatibility and tissue regeneration. Moreover, aGO-COL micropatterns fabricated via 3D bioprinting can be used to create neuronal cell microarrays, which supports the possibility of retaining the high spatial resolution achieved through electrical stimulation of the retinal chip. This study paves the way for the next generation of biohybrid retinal implants based on biointerfaces.

Design and Ex Vivo Experimental Validations of the CMOS 256-Pixel Photovoltaic-Powered Subretinal Prosthetic Chip With Auto-Adaptive Pixels for a Wide Image Illuminance Range.

OBJECTIVE: To design and verify a CMOS 256-pixel photovoltaic-powered subretinal prosthetic chip with key advances over the state-of-the-art. The three key advances are: 1) automatic adaptation to changing background illuminance levels; 2) increase of injection charges with reduced crosstalk leakage charges, enhanced charge balance, and low process variations; 3) stable stimulation voltage to keep the safety of water window. METHODS: The novel auto-adaptive pixel circuit is designed to realize the Michealis - Menten equation (MME) so that the automatic adaptation to changing background illuminance can be achieved. Both improved biphasic constant current stimulator (CCS) via bi-directional shared electrodes (BDSEs) with optimized stimulation pattern and improved constant current generator/ring oscillator are designed to achieve the above second advance on injection charges. The closed-loop charge pump is designed to achieve the third advance. RESULTS: The measured dynamic range of image illuminance is increased to 54.7 dB. The maximum stimulation charge is 8.89nC. The measured stimulation current mismatch is 1.7% and the measured residual charge is 0.150 nC. The measured variations of stimulation frequencies are from 26 Hz to 29.7 Hz. The results of ex vivo tests have shown that the proposed subretinal chip can evoke spiking responses of RGCs. The function of adaptation process to background illuminance has also been verified. CONCLUSION AND SIGNIFICANCE: Through both electrical measurement and ex vivo tests, the functions of designed subretinal chip have been validated successfully. It is shown that the proposed subretinal chip is a promising solution for subretinal prostheses.

Miniaturized Intracerebral Potential Recorder for Long-Term Local Field Potential of Deep Brain Signals.

A miniaturized intracerebral potential recorder for long-term local field potential (LFP) of deep brain signals is proposed. LFP can be recorded by deep brain electrodes. The abnormal beta-band oscillation of LFP in subthalamic nucleus and internal globus pallidus in patients with Parkinson's disease (PD) are associated with the severity of the symptoms. The LFP signal from patients who have been implanted with deep brain electrode can be monitored by our system for at least 24 hours in real time. Graphical user interface has also been developed for use by medical personnel. Imitation experiments and in vivo experiments were performed to successfully verify that our system can measure LFP signals. With 24-hour intracerebral signals, researchers can analyze what is happened in the brain in daily life. In the future, more effective PD treatment can be developed, such as intelligent closed-loop deep brain stimulation.

Graphene Oxide-Based Nanomaterials: An Insight into Retinal Prosthesis.

Retinal prosthesis has recently emerged as a treatment strategy for retinopathies, providing excellent assistance in the treatment of age-related macular degeneration (AMD) and retinitis pigmentosa. The potential application of graphene oxide (GO), a highly biocompatible nanomaterial with superior physicochemical properties, in the fabrication of electrodes for retinal prosthesis, is reviewed in this article. This review integrates insights from biological medicine and nanotechnology, with electronic and electrical engineering technological breakthroughs, and aims to highlight innovative objectives in developing biomedical applications of retinal prosthesis.

Spatiotemporal integration of visual stimuli and its relevance to the use of a divisional power supply scheme for retinal prosthesis.

A wireless photovoltaic retinal prosthesis is currently being studied with the aim of providing prosthetic vision to patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The major challenge of a photovoltaic device is its limited power efficiency. Our retinal prosthetic design implements a unique divisional power supply scheme (DPSS) system that provides the electrical power generated by all of the solar cells to only a subset of electrodes at any moment in time. The aim of the present study was to systematically characterize the spatiotemporal integration performance of the system under various DPSS conditions using human subjects and a psychophysical approach. A 16x16 pixels LED array controlled by Arduino was used to simulate the output signal of the DPSS design, and human performance under different visual stimulations at various update frequencies was then used to assess the spatiotemporal capability of retinal prostheses. The results showed that the contrast polarity of the image, image brightness, and division number influenced the lower limit of the update frequency of the DPSS system, while, on the other hand, visual angle, ambient light level, and stimulation order did not affect performance significantly. Pattern recognition by visual persistence with spatiotemporal integration of multiple frames of sparse dots is a feasible approach in retinal prosthesis design. These findings provide an insight into how to optimize a photovoltaic retinal prosthesis using a DPSS design with an appropriate update frequency for reliable pattern recognition. This will help the development of a wireless device able to restore vision to RP and AMD patients in the future.

Improved Charge Pump Design and Ex Vivo Experimental Validation of CMOS 256-Pixel Photovoltaic-Powered Subretinal Prosthetic Chip.

An improved design of CMOS 256-pixel photovoltaic-powered implantable chip for subretinal prostheses is presented. In the proposed subretinal chip, a high-efficiency fully-integrated 4× charge pump is designed and integrated with on-chip photovoltaic (PV) cells and a 256-pixel array with active pixel sensors (APS) for image light sensing, biphasic constant current stimulators, and electrodes. Thus the PV voltage generated by infrared (IR) light can be boosted to above 1V so that the charge injection is increased. The proposed chip adopts the 32-phase divisional power supply scheme (DPSS) to reduce the required supply current and thus the required area of the PV cells. The proposed chip is designed and fabricated in 180-nm CMOS image sensor (CIS) technology and post-processed with biocompatible IrOx electrodes and silicone packaging. From the electrical measurement results, the measured stimulation frequency is 28.3 Hz under the equivalent electrode impedance load. The measured maximum output stimulation current is 7.1 µA and the amount of injected charges per pixel is 7.36 nC under image light intensity of 3200 lux and IR light intensity of 100 mW/cm2. The function of the proposed chip has been further validated successfully with the ex vivo experimental results by recording the electrophysiological responses of retinal ganglion cells (RGCs) of retinas from retinal degeneration (rd1) mice with a multi-electrode array (MEA). The measured average threshold injected charge is about 3.97 nC which is consistent with that obtained from the patch clamp recording on retinas from wild type (C57BL/6) mice with a single electrode pair.

Design and In Vivo Verification of a CMOS Bone-Guided Cochlear Implant Microsystem.

OBJECTIVE: To develop and verify a CMOS bone-guided cochlear implant (BGCI) microsystem with electrodes placed on the bone surface of the cochlea and the outside of round window for treating high-frequency hearing loss. METHODS: The BGCI microsystem consists of an external unit and an implanted unit. The external system-on-chip is designed to process acoustic signals through an acquisition circuit and an acoustic DSP processor to generate stimulation patterns and commands that are transmitted to the implanted unit through a 13.56 MHz wireless power and bidirectional data telemetry. In the wireless power telemetry, a voltage doubler/tripler (2X/3X) active rectifier is used to enhance the power conversion efficiency and generate 2 and 3 V output voltages. In the wireless data telemetry, phase-locked loop based binary phase-shift keying and load-shift keying modulators/demodulators are adopted for the downlink and uplink data through high-Q coils, respectively. The implanted chip with four-channel high-voltage-tolerant stimulator generates biphasic stimulation currents up to 800 µA. RESULTS: Electrical tests on the fabricated BGCI microsystem have been performed to verify the chip functions. The in vivo animal tests in guinea pigs have shown the evoked third wave of electrically evoked auditory brainstem response waveforms. It is verified that auditory nerves can be successfully stimulated and acoustic hearing can be partially preserved. CONCLUSION AND SIGNIFICANCE: Different from traditional cochlear implants, the proposed BGCI microsystem is less invasive, preserves partially acoustic hearing, and provides an effective alternative for treating high-frequency hearing loss.

Printable Graphene Oxide Micropatterns for a Bio-Subretinal Chip.

Recently, implantable artificial subretinal chips using electronic components have replaced photoreceptors to serve as the most feasible treatment for retinal diseases. As such a chip that is meant to be implanted and used for very long periods, growing retinal cells on it to improve the electrical stimulation efficiency and attraction of neuronal elements remains a challenge. Here, an inkjet printing technology is employed to create graphene oxide (GO) micropatterns onto microelectrodes of a photovoltaic-powered implantable retinal chip. These GO micropatterns allow human retinal pigment epithelium (RPE) cells to specially attach and grow in each microelectrode. In addition, the cell proliferation, viability, and tight junction of RPE cells are improved during culturing. The development of a simple surface-coating technology would pave the way for the development of the first fully integrated and encapsulated retinal prostheses with biocompatible on-chip microelectrodes for long-term implantation, which could be effectively applied in retina tissue engineering and therapy.

A 16-Channel CMOS Chopper-Stabilized Analog Front-End ECoG Acquisition Circuit for a Closed-Loop Epileptic Seizure Control System.

In this paper, a 16-channel analog front-end (AFE) electrocorticography signal acquisition circuit for a closed-loop seizure control system is presented. It is composed of 16 input protection circuits, 16 auto-reset chopper-stabilized capacitive-coupled instrumentation amplifiers (AR-CSCCIA) with bandpass filters, 16 programmable transconductance gain amplifiers, a multiplexer, a transimpedance amplifier, and a 128-kS/s 10-bit delta-modulated successive-approximation-register analog-to-digital converter (SAR ADC). In closed-loop seizure control system applications, the stimulator shares the same electrode with the AFE amplifier for effective suppression of epileptic seizures. To prevent from overstress in MOS devices caused by high stimulation voltage, an input protection circuit with a high-voltage-tolerant switch is proposed for the AFE amplifier. Moreover, low input-referred noise is achieved by using the chopper modulation technique in the AR-CSCCIA. To reduce the undesired effects of chopper modulation, an improved offset reduction loop is proposed to reduce the output offset generated by input chopper mismatches. The digital ripple reduction loop is also used to reduce the chopper ripple. The fabricated AFE amplifier has 49.1-/59.4-/67.9-dB programmable gain and 2.02-µVrms input referred noise in a bandwidth of 0.59-117 Hz. The measured power consumption of the AFE amplifier is 3.26 µW per channel, and the noise efficiency factor is 3.36. The in vivo animal test has been successfully performed to verify the functions. It is shown that the proposed AFE acquisition circuit is suitable for implantable closed-loop seizure control systems.

Novel active comb-shaped dry electrode for EEG measurement in hairy site.

Electroencephalography (EEG) is an important biopotential, and has been widely applied in clinical applications. The conventional EEG electrode with conductive gels is usually used for measuring EEG. However, the use of conductive gel also encounters with the issue of drying and hardening. Recently, many dry EEG electrodes based on different conductive materials and techniques were proposed to solve the previous issue. However, measuring EEG in the hairy site is still a difficult challenge. In this study, a novel active comb-shaped dry electrode was proposed to measure EEG in hairy site. Different form other comb-shaped or spike-shaped dry electrodes, it can provide more excellent performance of avoiding the signal attenuation, phase distortion, and the reduction of common mode rejection ratio. Even under walking motion, it can effectively acquire EEG in hairy site. Finally, the experiments for alpha rhythm and steady-state visually evoked potential were also tested to validate the proposed electrode.

The coagulation characteristics of humic acid by using acid-soluble chitosan, water-soluble chitosan, and chitosan coagulant mixtures.

Chitosan is a potential substitute for traditional aluminium salts in water treatment systems. This study compared the characteristics of humic acid (HA) removal by using acid-soluble chitosan, water-soluble chitosan, and coagulant mixtures of chitosan with aluminium sulphate (alum) or polyaluminium chloride (PACl). In addition, we evaluated their respective coagulation efficiencies at various coagulant concentrations, pH values, turbidities, and hardness levels. Furthermore, we determined the size and settling velocity of flocs formed by these coagulants to identify the major factors affecting HA coagulation. The coagulation efficiency of acid- and water-soluble chitosan for 15 mg/l of HA was 74.4% and 87.5%, respectively. The optimal coagulation range of water-soluble chitosan (9-20 mg/l) was broader than that of acid-soluble chitosan (4-8 mg/l). Notably, acid-soluble chitosan/PACl and water-soluble chitosan/alum coagulant mixtures exhibited a higher coagulation efficiency for HA than for PACl or alum alone. Furthermore, these coagulant mixtures yielded an acceptable floc settling velocity and savings in both installation and operational expenses. Based on these results, we confidently assert that coagulant mixtures with a 1:1 mass ratio of acid-soluble chitosan/PACl and water-soluble chitosan/alum provide a substantially more cost-effective alternative to using chitosan alone for removing HA from water.

Evaluation of subcortical grey matter abnormalities in patients with MRI-negative cortical epilepsy determined through structural and tensor magnetic resonance imaging.

BACKGROUND: Although many studies have found abnormalities in subcortical grey matter (GM) in patients with temporal lobe epilepsy or generalised epilepsies, few studies have examined subcortical GM in focal neocortical seizures. Using structural and tensor magnetic resonance imaging (MRI), we evaluated subcortical GM from patients with extratemporal lobe epilepsy without visible lesion on MRI. Our aims were to determine whether there are structural abnormalities in these patients and to correlate the extent of any observed structural changes with clinical characteristics of disease in these patients. METHODS: Twenty-four people with epilepsy and 29 age-matched normal subjects were imaged with high-resolution structural and diffusion tensor MR scans. The patients were characterised clinically by normal brain MRI scans and seizures that originated in the neocortex and evolved to secondarily generalised convulsions. We first used whole brain voxel-based morphometry (VBM) to detect density changes in subcortical GM. Volumetric data, values of mean diffusivity (MD) and fractional anisotropy (FA) for seven subcortical GM structures (hippocampus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, thalamus and amygdala) were obtained using a model-based segmentation and registration tool. Differences in the volumes and diffusion parameters between patients and controls and correlations with the early onset and progression of epilepsy were estimated. RESULTS: Reduced volumes and altered diffusion parameters of subcortical GM were universally observed in patients in the subcortical regions studied. In the patient-control group comparison of VBM, the right putamen, bilateral nucleus accumbens and right caudate nucleus of epileptic patients exhibited a significantly decreased density Segregated volumetry and diffusion assessment of subcortical GM showed apparent atrophy of the left caudate nucleus, left amygdala and right putamen; reduced FA values for the bilateral nucleus accumbens; and elevated MD values for the left thalamus, right hippocampus and right globus pallidus A decreased volume of the nucleus accumbens consistently related to an early onset of disease. The duration of disease contributed to the shrinkage of the left thalamus. CONCLUSIONS: Patients with neocortical seizures and secondary generalisation had smaller volumes and microstructural anomalies in subcortical GM regions. Subcortical GM atrophy is relevant to the early onset and progression of epilepsy.

Through diffusion tensor magnetic resonance imaging to evaluate the original properties of neural pathways of patients with partial seizures and secondary generalization by individual anatomic reference atlas.

To investigate white matter (WM) abnormalities in neocortical epilepsy, we extract supratentorial WM parameters from raw tensor magnetic resonance images (MRI) with automated region-of-interest (ROI) registrations. Sixteen patients having neocortical seizures with secondarily generalised convulsions and 16 age-matched normal subjects were imaged with high-resolution and diffusion tensor MRIs. Automated demarcation of supratentorial fibers was accomplished with personalized fiber-labeled atlases. From the individual atlases, we observed significant elevation of mean diffusivity (MD) in fornix (cres)/stria terminalis (FX/ST) and sagittal stratum (SS) and a significant difference in fractional anisotropy (FA) among FX/ST, SS, posterior limb of the internal capsule (PLIC), and posterior thalamic radiation (PTR). For patients with early-onset epilepsy, the diffusivities of the SS and the retrolenticular part of the internal capsule were significantly elevated, and the anisotropies of the FX/ST and SS were significantly decreased. In the drug-resistant subgroup, the MDs of SS and PTR and the FAs of SS and PLIC were significantly different. Onset age was positively correlated with increases in FAs of the genu of the corpus callosum. Patients with neocortical seizures and secondary generalisation had microstructural anomalies in WM. The changes in WM are relevant to early onset, progression, and severity of epilepsy.

Demonstration of a broad band spectral head-mounted display with freeform mirrors.

It has been demonstrated that electrical stimulation of the retina can produce visual perception for blind patients suffering from macular degeneration and retinitis pigmentosa. In order to let the retinal chip generate enough electrical stimulation, the near infrared ray source is added to enhance the stimulation current. However, it is a challenge to design a head-mounted display (HMD) that covers both visible and infrared rays. Since the HMD system covers such a broad spectral band, large color aberrations will be induced. In order to eliminate these large aberrations, a mirror system is adopted that will create a no color aberration system. We also use two freeform mirrors (FFMs) to reduce residual aberrations such as spherical aberrations and coma. The FFMs serve as the near-eye viewing optics that magnifies the image which is displayed through a microdisplay. Based on a 0.61 in. microdisplay, the HMD system demonstrates a diagonal field of view (FOV) of 30 degree and an f/# of 3.75, with an exit pupil diameter of 8 mm and eye clearance of 15mm.

A 65nm CMOS low-power MedRadio-band integer-N cascaded phase-locked loop for implantable medical systems.

This paper presents a low-power MedRadio-band integer-N phase-locked Loop (PLL) system which is composed of two charge-pump PLLs cascade connected. The PLL provides the operation clock and local carrier signals for an implantable medical electronic system. In addition, to avoid the off-chip crystal oscillator, the 13.56 MHz Industrial, Scientific and Medical (ISM) band signal from the wireless power transmission system is adopted as the input reference signal for the PLL. Ring-based voltage controlled oscillators (VCOs) with current control units are adopted to reduce chip area and power dissipation. The proposed cascaded PLL system is designed and implemented in TSMC 65-nm CMOS technology. The measured jitter for 216.96 MHz signal is 12.23 ps and the phase noise is -65.9 dBc/Hz at 100 kHz frequency offset under 402.926 MHz carrier frequency. The measured power dissipations are 66 µW in the first PLL and 195 µW in the whole system under 1-V supply voltage. The chip area is 0.1088 mm(2) and no off-chip component is required which is suitable for the integration of the implantable medical electronic system.

A MedRadio-band low-energy-per-bit 4-Mbps CMOS OOK receiver for implantable medical devices.

A 4-Mbps 400-MHz On-Off Keying (OOK) receiver implemented in 0.18-um CMOS technology for implantable epilepsy sense-and-stimulation devices is presented. The proposed receiver is composed of a new current-mode full-wave envelope detector and differential cascaded gain amplifiers which is operated at MedRadio band. The fabricated receiver has power consumption of 0.27 mW and energy consumption of 0.07 nJ per bit at 4-Mbps. The sensitivity of receiver is -45.67 dBm.

A CMOS power-efficient low-noise current-mode front-end amplifier for neural signal recording.

In this paper, a new current-mode front-end amplifier (CMFEA) for neural signal recording systems is proposed. In the proposed CMFEA, a current-mode preamplifier with an active feedback loop operated at very low frequency is designed as the first gain stage to bypass any dc offset current generated by the electrode-tissue interface and to achieve a low high-pass cutoff frequency below 0.5 Hz. No reset signal or ultra-large pseudo resistor is required. The current-mode preamplifier has low dc operation current to enhance low-noise performance and decrease power consumption. A programmable current gain stage is adopted to provide adjustable gain for adaptive signal scaling. A following current-mode filter is designed to adjust the low-pass cutoff frequency for different neural signals. The proposed CMFEA is designed and fabricated in 0.18-µm CMOS technology and the area of the core circuit is 0.076 mm(2). The measured high-pass cutoff frequency is as low as 0.3 Hz and the low-pass cutoff frequency is adjustable from 1 kHz to 10 kHz. The measured maximum current gain is 55.9 dB. The measured input-referred current noise density is 153 fA /√Hz , and the power consumption is 13 µW at 1-V power supply. The fabricated CMFEA has been successfully applied to the animal test for recording the seizure ECoG of Long-Evan rats.

Multi-function all optical packet switch by periodic wavelength arrangement in an arrayed waveguide grating and wideband optical filters.

By utilizing the cyclic filtering function of an NxN arrayed waveguide grating (AWG), we propose and experimentally demonstrate a novel multi-function all optical packet switching (OPS) architecture by applying a periodical wavelength arrangement between the AWG in the optical routing/buffering unit and a set of wideband optical filters in the switched output ports to achieve the desired routing and buffering functions. The proposed OPS employs only one tunable wavelength converter at the input port to convert the input wavelength to a designated wavelength which reduces the number of active optical components and thus the complexity of the traffic control is simplified in the OPS. With the proposed OPS architecture, multiple optical packet switching functions, including arbitrary packet switching and buffering, first-in-first-out (FIFO) packet multiplexing, packet demultiplexing and packet add/drop multiplexing, have been successfully demonstrated.