A High CMRR Differential Difference Amplifier Employing Combined Input Pairs for Neural Signal Recordings.

This article introduces a Combined .symmetrical and complementary Input Pairs (CIP) of a Differential Difference Amplifier (DDA), to boost the total Common-Mode Rejection Ratio (CMRR) for multi-channel neural signal recording. The proposed CIP-DDA employs three input pairs (transconductors). The dc-coupled input neural signal connection, via the gate terminal of the first transconductor, yields a high input impedance. The high-pass corner frequency and dc quiescent operation point are stabilized by the second transconductor. The calibration path of differential-mode gain and Common-Mode Feedback (CMFB) is provided by the proposed third transconductor. The parallel connection has no need for extra voltage headroom of input and output. The proposed CIP-DDA is targeted at integrated circuit realization and designed in a 0.18-µm CMOS technology. The proposed CIP-DDAs with system CMFB achieve an average CMRR of 103 dB, and each channel consumes circa 3.6 µW power consumption.

Suppression of cortical electrostimulation artifacts using pre-whitening and null projection.

Objective.Invasive brain-computer interfaces (BCIs) have shown promise in restoring motor function to those paralyzed by neurological injuries. These systems also have the ability to restore sensation via cortical electrostimulation. Cortical stimulation produces strong artifacts that can obscure neural signals or saturate recording amplifiers. While front-end hardware techniques can alleviate this problem, residual artifacts generally persist and must be suppressed by back-end methods.Approach.We have developed a technique based on pre-whitening and null projection (PWNP) and tested its ability to suppress stimulation artifacts in electroencephalogram (EEG), electrocorticogram (ECoG) and microelectrode array (MEA) signals from five human subjects.Main results.In EEG signals contaminated by narrow-band stimulation artifacts, the PWNP method achieved average artifact suppression between 32 and 34 dB, as measured by an increase in signal-to-interference ratio. In ECoG and MEA signals contaminated by broadband stimulation artifacts, our method suppressed artifacts by 78%-80% and 85%, respectively, as measured by a reduction in interference index. When compared to independent component analysis, which is considered the state-of-the-art technique for artifact suppression, our method achieved superior results, while being significantly easier to implement.Significance.PWNP can potentially act as an efficient method of artifact suppression to enable simultaneous stimulation and recording in bi-directional BCIs to biomimetically restore motor function.

A CMOS Multi-Electrode Array for Four-Electrode Bioimpedance Measurements.

This work demonstrates how a multi-electrode array (MEA) dedicated to four-electrode bioimpedance measurements can be implemented on a complementary metal-oxide-semiconductor (CMOS) chip. As a proof of concept, an 8 × 8 pixel array along with dedicated amplifiers was designed and fabricated in the TSMC 180 nm process. Each pixel in the array contains a circular current carrying (CC) electrode that can act as a current source or sink. In order to measure a differential voltage between the pixels, each CC electrode is surrounded by a ring shaped pick up (PU) electrode. The differential voltages can be measured by an on-board instrumentation amplifier, while the currents can be measured with an on-bard transimpedance amplifier. Openings in the passivation layer exposed the aluminum top metal layer, and a metal stack of zinc, nickel and gold was deposited in an electroless plating process. The chips were then wire bonded to a ceramic package and prepared for wet experiments by encapsulating the bonding wires and pads in the photoresist SU-8. Measurements in liquids with different conductivities were performed to demonstrate the functionality of the chip.

Pig Ulnar Nerve Recording with Sinusoidal and Temporal Interference Stimulation.

Temporal interference stimulation has been suggested as a method to reach deep targets during transcutaneous electrical stimulation. Despite its growing use in transcutaneous stimulation therapies, the mechanism of its operation is not fully understood. Recent efforts to fill that gap have focused on computational modelling, in vitro and in vivo experiments relying on physical observations - e.g., sensation or movement. This paper expands the current range of experimental methods by demonstrating in vivo extraneural recordings from the ulnar nerve of a pig while applying temporal interference stimulation at a location targeting a distal part of the nerve. The main aim of the experiment was to compare neural activation using sinusoidal stimulation (100 Hz, 2 kHz, 4 kHz) and temporal interference stimulation (2 kHz and 4 kHz). The recordings showed a significant increase in the magnitude of stimulation artefacts at higher frequencies. While those artefacts could be removed and provided an indication of the depth of modulation, they resulted in the saturation of the amplifiers, limiting the stimulation currents and amplifier gains used. The results of the 100 Hz sine wave stimulation showed clear neural activity correlated to the stimulation waveform. However, this was not observed with temporal interference stimulation. The results suggest that, despite its greater penetration, higher currents might be required to observe a neural response with temporal interference stimulation, and more complex artefact rejection techniques may be required to validate the method.

Multiscale real time and high sensitivity ion detection with complementary organic electrochemical transistors amplifier.

Ions are ubiquitous biological regulators playing a key role for vital processes in animals and plants. The combined detection of ion concentration and real-time monitoring of small variations with respect to the resting conditions is a multiscale functionality providing important information on health states. This multiscale functionality is still an open challenge for current ion sensing approaches. Here we show multiscale real-time and high-sensitivity ion detection with complementary organic electrochemical transistors amplifiers. The ion-sensing amplifier integrates in the same device both selective ion-to-electron transduction and local signal amplification demonstrating a sensitivity larger than 2300 mV V-1 dec-1, which overcomes the fundamental limit. It provides both ion detection over a range of five orders of magnitude and real-time monitoring of variations two orders of magnitude lower than the detected concentration, viz. multiscale ion detection. The approach is generally applicable to several transistor technologies and opens opportunities for multifunctional enhanced bioelectronics.

An Area-Efficient and Highly Linear Reconfigurable Continuous-Time Filter for Biomedical Sensor Applications.

This paper proposes a compact, high-linearity, and reconfigurable continuous-time filter with a wide frequency-tuning capability for biopotential conditioning. It uses an active filter topology and a new operational-transconductance-amplifier (OTA)-based current-steering (CS) integrator. Consequently, a large time constant τ , good linearity, and linear bandwidth tuning could be achieved in the presented filter with a small silicon area. The proposed filter has a reconfigurable structure that can be operated as a low-pass filter (LPF) or a notch filter (NF) for different purposes. Based on the novel topology, the filter can be readily implemented monolithically and a prototype circuit was fabricated in the 0.18 µm standard complementary-metal-oxide-semiconductor (CMOS) process. It occupied a small area of 0.068 mm2 and consumed 25 µW from a 1.8 V supply. Measurement results show that the cutoff frequency of the LPF could be linearly tuned from 0.05 Hz to 300 Hz and the total-harmonic-distortion (THD) was less than -76 dB for a 2 Hz, 200 mVpp sine input. The input-referred noises were 5.5 µVrms and 6.4 µVrms for the LPF and NF, respectively. A comparison with conventional designs reveals that the proposed design achieved the lowest harmonic distortion and smallest on-chip capacitor. Moreover, its ultra-low cutoff frequency and relatively linear frequency tuning capability make it an attractive solution as an analog front-end for biopotential acquisitions.

Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart.

The sympathetic nervous system modulates cardiac function by controlling key parameters such as chronotropy and inotropy. Sympathetic control of ventricular function occurs through extrinsic innervation arising from the stellate ganglia and thoracic sympathetic chain. In the healthy heart, sympathetic release of norepinephrine (NE) results in positive modulation of chronotropy, inotropy, and dromotropy, significantly increasing cardiac output. However, in the setting of myocardial infarction or injury, sympathetic activation persists, contributing to heart failure and increasing the risk of arrhythmias, including sudden cardiac death. Methodologies for detection of norepinephrine in cardiac tissue are limited. Present techniques rely on microdialysis for analysis by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ED), radioimmunoassay, or other immunoassays, such as enzyme-linked immunosorbent assay (ELISA). Although significant information about the release and action of norepinephrine has been obtained with these methodologies, they are limited in temporal resolution, require large sample volumes, and provide results with a significant delay after sample collection (hours to weeks). In this study, we report a novel approach for measurement of interstitial cardiac norepinephrine, using minimally invasive, electrode-based, fast-scanning cyclic voltammetry (FSCV) applied in a beating porcine heart. The first multispatial and high temporal resolution, multichannel measurements of NE release in vivo are provided. Our data demonstrate rapid changes in interstitial NE profiles with regional differences in response to coronary ischemia, sympathetic nerve stimulation, and alterations in preload/afterload.NEW & NOTEWORTHY Pharmacological, electrical, or surgical regulation of sympathetic neuronal control can be used to modulate cardiac function and treat arrhythmias. However, present methods for monitoring sympathetic release of norepinephrine in the heart are limited in spatial and temporal resolution. Here, we provide for the first time a methodology and demonstration of practice and rapid measures of individualized regional autonomic neurotransmitter levels in a beating heart. We show dynamic, spatially resolved release profiles under normal and pathological conditions.

Instrumentation for electrodiagnostic studies.

The instrument and accessories are an important part of the electrodiagnostic (EDX) testing. Their functional understanding is useful to recognize and reduce various artifacts and noise/interference in the signal. In this review, we will describe the technical specifications of various components of the instrument, and their effect on signals and noise. This will be illustrated using example of electromyography and nerve conduction studies. However the same principles also apply to other modalities of testing. We will also provide general strategies to reduce noise and artifacts, followed by some modality specific examples.

Acoustic Stimulation by Shunt-Diode Pre-Linearizer using Very High Frequency Piezoelectric Transducer for Cancer Therapeutics.

In this paper, we proposed cancer cell acoustic stimulation by shunt-diode pre-linearizer scheme using a very high frequency (≥100 MHz) piezoelectric transducer. To verify the concept of our proposed scheme, we performed pulse-echo detection, and accessed therapeutic effects of human cervical cancer cells exposed to acoustic stimulation experiments using 100 MHz focused piezoelectric transducer triggered by PA with and without the proposed shunt-diode pre-linearizer scheme. In the pulse-echo detection responses, the peak-to-peak voltage of the echo signal when using the PA with shunt-diode pre-linearizer (49.79 mV) was higher than that when using the PA alone (29.87 mV). In the experimental results, the cell densities of cancer cells on Day 4 when using no acoustic stimulation (control group), the very high-frequency piezoelectric transducer triggered by PA only and PA combined with proposed pre-linearizer schemes (1 V and 5 V DC bias voltages) showed 100%, 92.8 ± 4.2%, 84.2 ± 4.6%, and 78 ± 2.9%, respectively. Therefore, we confirmed that the shunt-diode pre-linearizer could improve the performances of the pulse signals of the PA, thus, enabling better therapeutic stimulation performances for cancer cell suppression.

Validation and Benchmarking of a Wearable EEG Acquisition Platform for Real-World Applications.

This paper presents the experimental validation of a readout circuit for the acquisition, amplification, and transmission of extremely weak biopotentials with a focus on electroencephalography (EEG) signals. The device, dubbed CochlEEG, benefits from a low-power design for long-term power autonomy and provides configurable gain and sampling rates to suit the needs of various EEG applications. CochlEEG features high sampling rates, up to 4 kHz, low-noise signal acquisitions, support for active electrodes, and a potential for Wi-Fi data transmission. Moreover, it is lightweight, pocket size, and affordable, which makes CochlEEG suitable for wearable and real-world applications. The efficiency of CochlEEG in EEG data acquisition is also investigated in this paper. Auditory steady-state responses acquisition results validate CochlEEG's capability in recording EEG with a signal quality comparable to commercial mobile or research EEG acquisition devices. Moreover, the results of an oddball paradigm experiment prove the capability of CochlEEG in recording event-related potentials and demonstrate its potential for brain-computer interface applications and electrophysiological research applications requiring higher temporal resolution.

A systematic review and meta-analysis assessing the effectiveness of alternative listening devices to conventional hearing aids in adults with hearing loss.

Recent technological advances have led to a rapid increase in alternative listening devices to conventional hearing aids. The aim was to systematically review the existing evidence to assess the effectiveness of alternative listening devices in adults with mild and moderate hearing loss. A systematic search strategy of the scientific literature was employed, reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) checklist. Eleven studies met eligibility for inclusion: two studies evaluated personal sound amplification products, and nine studies assessed remote microphone systems (frequency modulation, Bluetooth, wireless). The evidence in this review suggests that alternative listening devices improve behavioural measures of speech intelligibility relative to unaided and/or aided conditions. Evidence for whether alternative listening devices improve self-reported outcomes is inconsistent. The evidence was judged to be of poor to good quality and subject to bias due to limitations in study design. Our overall recommendation is that high-quality evidence (i.e. randomised controlled trials) is required to demonstrate the effectiveness of alternative listening devices. Such evidence is not currently available and is necessary to guide healthcare commissioners and policymakers when considering new service delivery models for adults with hearing loss. Review registration: Prospective Register of Systematic Reviews (PROSPERO), CRD42015029582.

A Bidirectional Neural Interface IC With Chopper Stabilized BioADC Array and Charge Balanced Stimulator.

We present a bidirectional neural interface with a 4-channel biopotential analog-to-digital converter (bioADC) and a 4-channel current-mode stimulator in 180 nm CMOS. The bioADC directly transduces microvolt biopotentials into a digital representation without a voltage-amplification stage. Each bioADC channel comprises a continuous-time first-order ∆Σ modulator with a chopper-stabilized OTA input and current feedback, followed by a second-order comb-filter decimator with programmable oversampling ratio. Each stimulator channel contains two independent digital-to-analog converters for anodic and cathodic current generation. A shared calibration circuit matches the amplitude of the anodic and cathodic currents for charge balancing. Powered from a 1.5 V supply, the analog and digital circuits in each recording channel draw on average [Formula: see text] and [Formula: see text] of supply current, respectively. The bioADCs achieve an SNR of [Formula: see text] and a SFDR of [Formula: see text] , for better than 9-b ENOB. Intracranial EEG recordings from an anesthetized rat are shown and compared to simultaneous recordings from a commercial reference system to validate performance in-vivo . Additionally, we demonstrate bidirectional operation by recording cardiac modulation induced through vagus nerve stimulation, and closed-loop control of cardiac rhythm. The micropower operation, direct digital readout, and integration of electrical stimulation circuits make this interface ideally suited for closed-loop neuromodulation applications.

Long-Term Stability and Clinical Utility of Amplified Atrial Electrograms in a Single-Lead ICD System with Floating Atrial Electrodes.

BACKGROUND: Available atrial electrograms in implantable cardioverter defibrillators (ICDs) improve arrhythmia diagnosis, allow monitoring for atrial fibrillation, and may reduce the risk of inappropriate therapies. A recently introduced ICD system using a single-lead with floating atrial electrodes provides diagnostic capability of a dual-chamber system without placing an additional lead. Data on long-term clinical performance of this system are limited. METHODS: We retrospectively analyzed data from 35 consecutive patients implanted with Biotronik VR-T DX devices and LinoxSmart DX leads. (Biotronik, SE & Co., Berlin, Germany) RESULTS: Of 35 patients (77% male, age 52 ± 11.28 years), 32 were followed for a mean of 432 ± 197 days (range 56-765). During implantation, average preamplified and amplified sinus P-wave amplitudes were 2.61 ± 1.39 mV (range 0.9-6.8 mV) and 8.7 ± 4.51 mV (range 1.4-18 mV), respectively. Despite statistically significant variations, the amplified P-wave amplitude measurements (calculated mean values over 3 months) remained within a clinically acceptable range during follow-up (5.4-8.7 mV). R-wave amplitude and ventricular pacing threshold measurements were stable over time. A total of 13 stored arrhythmia events (three ventricular tachycardia, eight supraventricular tachycardia, two atrial fibrillation) were reviewed. All of them showed readily interpretable atrial electrograms. Eight out of 10 (80%) supraventricular events were correctly classified by the device. Three patients received inappropriate ICD therapies. CONCLUSION: The single-lead ICD system using a floating atrial dipole provides reliable recording of atrial signals during sinus rhythm and arrhythmias. Our data suggest that the system may offer diagnostic advantages of a dual-chamber device without potential risks of an additional atrial lead.

Modeling human echolocation of near-range targets with an audible sonar.

Blind humans echolocate nearby targets by emitting palatal clicks and perceiving echoes that the auditory system is not able to resolve temporally. The mechanism for perceiving near-range echoes is not known. This paper models the direct mouth-to-ear signal (MES) and the echo to show that the echo enhances the high-frequency components in the composite MES/echo signal with features that allow echolocation. The mouth emission beam narrows with increasing frequency and exhibits frequency-dependent transmission notches in the backward direction toward the ears as predicted by the piston-in-sphere model. The ears positioned behind the mouth detect a MES that contains predominantly the low frequencies contained in the emission. Hence the high-frequency components in the emission that are perceived by the ears are enhanced by the echoes. A pulse/echo audible sonar verifies this model by echolocating targets from 5 cm range, where the MES and echo overlap significantly, to 55 cm. The model predicts that unambiguous ranging occurs over a limited range and that there is an optimal range that produces the highest range resolution.

Comparison of mouse minimum audible angle determined in prepulse inhibition and operant conditioning procedures.

Both reward based operant conditioning (OC) and reflex-based prepulse inhibition (PPI) procedures are used in sound localisation studies in mice. Since the results of both procedures are compared in the literature, it is important to assess whether they provide similar results if the same stimulus paradigm is applied. Here, we compare the sensitivity of C57BL/6 mice in OC and PPI procedures for detecting a switch in speaker location using broadband and narrowband noise stimuli and determined their minimum audible angle (MAA). In the OC procedure, we calculated d' values from the hit and false alarm rates. In the PPI procedure, we calculated the area under ROC curves from the startle response amplitudes and derived da values to obtain a sensitivity measure that corresponds to d'. For both procedures, the mean sensitivity to the speaker switch increased with an increase in angular separation. For broadband noise stimuli, a d' of up to 3.3 (OC) and a da of up to 1.1 (PPI) were observed at large speaker separations. Narrowband noise stimuli resulted in lower sensitivities in both procedures, resulting in a maximum d' of 2.0 (OC) and a maximum da of 0.3 (PPI). Using a sensitivity of 1.0 as the threshold criterion, broadband noise MAAs in the range from 32° to 46° were observed in the OC procedure whereas a broadband noise MAAs of 108° or higher were observed in the PPI procedure. In the OC procedure, narrowband noise MAAs in the range from 37° to 62° were observed. In the PPI procedure, no narrowband noise MAA could be determined since none of the subjects reached the threshold. Thus, OC procedures result in a better performance of the subjects in the sound localization task than PPI procedures, challenging the view that both procedures can be used interchangeably.

[Design and Implementation of the Multi-Channel Meridian Impedance Detector Based on Current Driving].

A multi-channel meridian impedance detector used to the 3D meridian visualization positioning is presented. The detector is designed with the four-electrode method based on current driving according to low impedance of the meridian. The detector consists of power-supply module, sinusoidal signal generator, voltage-controlled current source, isolation amplifiers, filter circuit, amplitude detectors and so on.

Ventriloquism effect with sound stimuli varying in both azimuth and elevation.

When presented with a spatially discordant auditory-visual stimulus, subjects sometimes perceive the sound and the visual stimuli as coming from the same location. Such a phenomenon is often referred to as perceptual fusion or ventriloquism, as it evokes the illusion created by a ventriloquist when his voice seems to emanate from his puppet rather than from his mouth. While this effect has been extensively examined in the horizontal plane and to a lesser extent in distance, few psychoacoustic studies have focused on elevation. In the present experiment, sequences of a man talking were presented to subjects. His voice could be reproduced on different loudspeakers, which created disparities in both azimuth and elevation between the sound and the visual stimuli. For each presentation, subjects had to indicate whether the voice seemed to emanate from the mouth of the actor or not. Results showed that ventriloquism could be observed with larger audiovisual disparities in elevation than in azimuth.

Reduction in time-to-sleep through EEG based brain state detection and audio stimulation.

We developed an EEG- and audio-based sleep sensing and enhancing system, called iSleep (interactive Sleep enhancement apparatus). The system adopts a closed-loop approach which optimizes the audio recording selection based on user's sleep status detected through our online EEG computing algorithm. The iSleep prototype comprises two major parts: 1) a sleeping mask integrated with a single channel EEG electrode and amplifier, a pair of stereo earphones and a microcontroller with wireless circuit for control and data streaming; 2) a mobile app to receive EEG signals for online sleep monitoring and audio playback control. In this study we attempt to validate our hypothesis that appropriate audio stimulation in relation to brain state can induce faster onset of sleep and improve the quality of a nap. We conduct experiments on 28 healthy subjects, each undergoing two nap sessions - one with a quiet background and one with our audio-stimulation. We compare the time-to-sleep in both sessions between two groups of subjects, e.g., fast and slow sleep onset groups. The p-value obtained from Wilcoxon Signed Rank Test is 1.22e-04 for slow onset group, which demonstrates that iSleep can significantly reduce the time-to-sleep for people with difficulty in falling sleep.

Design and Implementation of the Multi-Channel Meridian Impedance Detector Based on Current Driving / 中国医疗器械杂志

A multi-channel meridian impedance detector used to the 3D meridian visualization positioning is presented. The detector is designed with the four-electrode method based on current driving according to low impedance of the meridian. The detector consists of power-supply module, sinusoidal signal generator, voltage-controlled current source, isolation amplifiers, filter circuit, amplitude detectors and so on.

Optimization of noise in non-integrated instrumentation amplifier for the amplification of very low electrophysiological [corrected] signals. Case of electro cardio graphic signals (ECG).

In this paper we present an instrumentation amplifier with discrete elements and optimized noise for the amplification of very low signals. In amplifying signals of very weak amplitude, the noise can completely absorb these signals if the used amplifier does not present the optimal guarantee to minimize the noise. Based on related research and re-viewing of recent patents Journal of Medical Systems, 30:205-209, 2006, we suggest an approach of noise reduction in amplification much more thoroughly than re-viewing of recent patents and we deduce from it the general criteria necessary and essential to achieve this optimization. The comparison of these criteria with the provisions adopted in practice leads to the inadequacy of conventional amplifiers for effective noise reduction. The amplifier we propose is an instrumentation amplifier with active negative feedback and optimized noise for the amplification of signals with very low amplitude. The application of this method in the case of electro cardio graphic signals (ECG) provides simulation results fully in line with forecasts.