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.

Design of Dual-Configuration Dual-Mode Stimulator in Low-Voltage CMOS Process for Neuro-Modulation.

A dual-configuration dual-mode stimulator for neuro-modulation is proposed and designed. All the electrical stimulation patterns that frequently used for neuro-modulation can be generated by the proposed stimulator chip. Dual-configuration represents the bipolar or monopolar structure, meanwhile dual-mode stands for the current or voltage output. No matter what stimulation circumstance is chosen, biphasic or monophasic waveforms can be fully supported by the proposed stimulator chip. The stimulator chip with 4 stimulation channels has been fabricated in 0.18-µm 1.8-V/3.3-V low-voltage CMOS process with common grounded p-type substrate, which is suitable for SoC integration. The design has conquered the overstress and reliability issues in the low-voltage transistors under the negative voltage power domain. Each channel in the stimulator chip only occupies the silicon area of 0.052 mm2, and the maximum output level of stimulus amplitude is up to ±3.6 mA and ±3.6 V. With the built-in discharge function, bio-safety concern of unbalanced charge in neuro-stimulation can be dealt with properly. Moreover, the proposed stimulator chip has been applied on both imitation measurement and in-vivo animal test successfully.

Verification of the beta oscillations in the subthalamic nucleus of the MPTP-induced parkinsonian minipig model.

The development of the closed-loop deep brain stimulator (DBS) for clinical trials requires verification of its safety and effectiveness in a large animal model. Due to the financial and ethical challenges of using non-human primates, it is reasonable to use an alternative large animal model. It was reported that minipigs are suitable for the establishment of the MPTP-induced parkinsonian model. However, there is currently no evidence of whether beta oscillations, the symptom-related biomarker, exist in the subthalamic nucleus (STN) of the parkinsonian minipig model. This study was to verify whether the beta oscillations could be recorded in the STN of the parkinsonian minipig model. Parkinsonism was induced by injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Through a protocol involving up to nine subcutaneous or intramuscular injections, delivering a cumulative dose of 8-10 mg/kg MPTP, the minipigs developed notable movement disturbance. By stereotactic surgery and microelectrode recording, beta oscillations were recorded in the STN of the MPTP-injected minipigs. Immunohistochemistry of the tyrosine hydroxylase (TH) was performed in the substantia nigra pars compacta (SNc) of each animal. Compared with the control animal injected with saline, the TH-positive cells in the SNc were significantly reduced in the MPTP-injected minipigs. This study showed that beta oscillations could be recorded in the STN of the MPTP-induced parkinsonian minipig model. This large animal model is suitable as an alternative pre-clinical model for developing closed-loop DBS in the future.

Monopolar Biphasic Stimulator With Discharge Function and Negative Level Shifter for Neuromodulation SoC Integration in Low-Voltage CMOS Process.

A 16-channel monopolar biphasic stimulator chip with discharge function for biomedical applications is proposed and designed. To provide monopolar biphasic stimulus currents, the positive (6V) and the negative (-6V) voltage sources are supported to generate the desired current pulses of ±3 mA. The monopolar biphasic stimulator chip was fabricated in a 0.18-µm 1.8-V/3.3-V CMOS process with the common grounded p-type substrate. The overstress and reliability issues on the low-voltage transistors in the stimulator circuits were fully overcome by circuit design. The silicon area of each single channel only occupies 0.08 mm2 and the output level of stimulus current is up to ±3 mA. By applying the discharge function, safety concern of unbalanced charge in neuro-stimulation can be dealt properly. The residual average dc current is less than 3.42 nA after discharge is activated. Moreover, this chip has also been verified with both in-vitro imitation measurement and in-vivo animal test.

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.

Design of Dual-Mode Stimulus Chip With Built-In High Voltage Generator for Biomedical Applications.

In this work, a dual-mode stimulus chip with a built-in high voltage generator was proposed to offer a broad-range current or voltage stimulus patterns for biomedical applications. With an on-chip and built-in high voltage generator, this stimulus chip could generate the required high voltage supply without additional supply voltage. With a nearly 20 V operating voltage, the overstress and reliability issues of the stimulus circuits were thoroughly considered and carefully addressed in this work. This stimulus system only requires an area of 0.22 mm2 per single channel and is fully on-chip implemented without any additional external components. The dual-mode stimulus chip was fabricated in a 0.25-µm 2.5V/5V/12V CMOS (complementary metal-oxide-semiconductor) process, which can generate the biphasic current or voltage stimulus pulses. The current level of stimulus is up to 5 mA, and the voltage level of stimulus can be up to 10 V. Moreover, this chip has been successfully applied to stimulate a guinea pig in an animal experiment. The proposed dual-mode stimulus system has been verified in electrical tests and also demonstrated its stimulation function in animal experiments.

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.

A Digitally Dynamic Power Supply Technique for 16-Channel 12 V-Tolerant Stimulator Realized in a 0.18- µm 1.8-V/3.3-V Low-Voltage CMOS Process.

A new digitally dynamic power supply technique for 16-channel 12-V-tolerant stimulator is proposed and realized in a 0.18-µm 1.8-V/3.3-V CMOS process. The proposed stimulator uses four stacked transistors as the pull-down switch and pull-up switch to withstand 4 times the nominal supply voltage (4 × V DD). With the dc input voltage of 3.3 V, the regulated three-stage charge pump, which is capable of providing 11.3-V voltage at 3-mA loading current, achieves dc conversion efficiency of up to 69% with 400-pF integrated capacitance. Power consumption is reduced by implementing the regulated charge pump to provide a dynamic dc output voltage with a 0.5-V step. The proposed digitally dynamic power supply technique, which is implemented by using a p-type metal oxide semiconductor (PMOS) inverter with pull-down current source and digital controller, greatly improves the power efficiency of a system. The silicon area of the stimulator is approximately 3.5 mm2 for a 16-channel implementation. The functionalities of the proposed stimulator have been successfully verified through animal test.

A High-Voltage-Tolerant and Precise Charge-Balanced Neuro-Stimulator in Low Voltage CMOS Process.

This paper presents a 4 × VDD neuro-stimulator in a 0.18- µm 1.8 V/3.3 V CMOS process. The self-adaption bias technique and stacked MOS configuration are used to prevent transistors from the electrical overstress and gate-oxide reliability issue. A high-voltage-tolerant level shifter with power-on protection is used to drive the neuro-stimulator The reliability measurement of up to 100 million periodic cycles with 3000- µA biphasic stimulations in 12-V power supply has verified that the proposed neuro-stimulator is robust. Precise charge balance is achieved by using a novel current memory cell with the dual calibration loops and leakage current compensation. The charge mismatch is down to 0.25% over all the stimulus current ranges (200-300 µA) The residual average dc current is less than 6.6 nA after shorting operation.

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.

Synthesis of uniform core-shell gelatin-alginate microparticles as intestine-released oral delivery drug carrier.

A core-shell gelatin-alginate composite used for intestine-released oral delivery drug carrier was synthesized through microfluidic technique. At the fixed continuous phase flow rate, the size of the core-shell gelatin-alginate microparticles increases with the dispersed phase flow rate, and monodispersity can be retained (the variation coefficient for the diameter distribution can be kept less than 10%). The fabricated microparticles could remain intact in gastric juice for at least 3 h, indicating that the gelatin core could be well protected by alginate shell in acid environment. However, the alginate shell of the microparticles would swell or collapse in alkali environment in half an hour, assuring the controlled drug release in intestinal juice. The fabricated uniform core-shell gelatin-alginate microparticles were potential as pH-responsive drug carriers.

Implantable stimulator for epileptic seizure suppression with loading impedance adaptability.

The implantable stimulator for epileptic seizure suppression with loading impedance adaptability was proposed in this work. The stimulator consisted of the high voltage generator, output driver, adaptor, and switches, can constantly provide the required 40-µA stimulus currents, as the loading impedance varied within 10 kΩ -300 kΩ. The performances of this design have been successfully verified in silicon chip fabricated by a 0.35- µm 3.3-V/24-V CMOS process. The power consumption of this work was only 1.1 mW-1.4 mW. The animal test results with the fabricated chip of proposed design have successfully verified in the Long-Evans rats with epileptic seizures.

Stimulus driver for epilepsy seizure suppression with adaptive loading impedance.

A stimulus driver circuit for a micro-stimulator used in an implantable device is presented in this paper. For epileptic seizure control, the target of the driver was to output 30 µA stimulus currents when the electrode impedance varied between 20 and 200 kΩ. The driver, which consisted of the output stage, control block and adaptor, was integrated in a single chip. The averaged power consumption of the stimulus driver was 0.24-0.56 mW at 800 Hz stimulation rate. Fabricated in a 0.35 µm 3.3 V/24 V CMOS process and applied to a closed-loop epileptic seizure monitoring and controlling system, the proposed design has been successfully verified in the experimental results of Long-Evans rats with epileptic seizures.

Fabrication of a miniature CMOS-based optical biosensor.

This work presents a novel, miniature optical biosensor by immobilizing horseradish peroxidase (HRP) or the HRP/glucose oxidase (GOx) coupled enzyme pair on a CMOS photosensing chip with a detection area of 0.5 mm x 0.5 mm. A highly transparent TEOS/PDMS Ormosil is used to encapsulate and immobilize enzymes on the surface of the photosensor. Interestingly, HRP-catalyzed luminol luminescence can be detected in real time on optical H(2)O(2) and glucose biosensors. The minimum reaction volume of the developed optical biosensors is 10 microL. Both optical H(2)O(2) and glucose biosensors have an optimal operation temperature and pH of 20-25 degrees C and pH 8.4, respectively. The linear dynamic range of optical H(2)O(2) and glucose biosensors is 0.05-20 mM H(2)O(2) and 0.5-20 mM glucose, respectively. The miniature optical glucose biosensor also exhibits good reproducibility with a relative standard deviation of 4.3%. Additionally, ascorbic acid and uric acid, two major interfering substances in the serum during electrochemical analysis, cause only slight interference with the fabricated optical glucose biosensor. In conclusion, the CMOS-photodiode-based optical biosensors proposed herein have many advantages, such as a short detection time, a small sample volume requirement, high reproducibility and wide dynamic range.