Simulation of ambulatory electrodermal activity and the handling of low-quality segments.

BACKGROUND AND OBJECTIVES: Monitoring electrodermal activity (EDA) in daily life requires effective handling of low-quality segments, which are common in ambulatory EDA data. Although several low-quality handling methods have been implemented, systematic comparison of these methods, which requires a large annotated dataset, is lacking. METHODS: Therefore, we proposed the simulation of realistic ambulatory EDA data starting from high-quality EDA signals, which were subsequently contaminated with varying concentrations of artifacts. Subsequently, three approaches for handling low-quality data were evaluated regarding the preservation of several EDA-derived features: removing all artifacts, interpolating over removed artifacts, and retaining all artifacts. Specifically, multiple EDA features were assessed, derived from response detection (evaluated using F1, precision, recall) as well as EDA, phasic, and tonic features (assessed using absolute error), by comparing the simulated EDA data with and without the inserted artifacts, using the latter as ground truth. RESULTS: For response detection, retaining artifacts resulted in the highest F1-scores, while interpolating over removed artifacts achieved the highest F1-scores for the phasic signal. The approaches did significantly differ in the mean error for the phasic but not for the tonic component and raw EDA. CONCLUSION: This work generated ambulatory EDA datasets of 200 h, containing 0.125 to 3 artifacts per minute, and showed that interpolation over removed artifacts was an effective approach to reconstruct phasic-derived features up to 2 artifacts per minute. The proposed simulation and evaluation methodology, which are easily customizable, offer opportunities for future research to develop and systematically compare signal quality indicators, decomposition methods, and response detectors for processing ambulatory EDA.

Learning based Quality Indicator Aiding Heart Rate Estimation in Wrist-Worn PPG.

Technological advancements and miniaturization of wearable sensors have enabled long-term pervasive physiological monitoring. Wrist-worn photoplethysmography (PPG) sensors, although quite popular owing to their form factor, suffer from poor signal quality in ambulatory settings due to motion artifacts. This affects the reliable estimation of vital cardiac parameters, especially during motion/activities of daily living. Hence, in this paper, we have developed a learningbased quality indicator engine (QIE), evaluating on 23 PPG records of the TROIKA database. The engine comprises the fundamental steps of frequency-domain feature extraction, feature selection and classification by an ensemble of decision trees, achieving an accuracy of 83% in the testing set. To the best of our knowledge, the proposed quality engine is the first to be evaluated on wrist-PPG data acquired during various physical activities and with respect to improvement in heart rate (HR) estimation. The QIE demonstrated an average improvement of 43% in HR estimation, when used in conjunction with state-ofthe-art WFPV algorithm.Clinical Relevance- The proposed quality indicator engine helps to increase the efficacy of vital parameter estimation (e.g. heart rate) from pervasive, wrist-worn PPG sensors on the backdrop of motion artifacts when used in ambulatory settings (e.g. activities of daily living).

A novel method for monolithic fabrication of polymer microneedles on a platform for transdermal drug delivery.

This paper reports on the creation of a novel method for monolithic fabrication of out-of-plane polymer (SU-8) microneedles incorporating sharpness of needle-tips, hollowness of needle lumen as well as a platform on which the microneedles stand orthogonally with the hollow of the needle lumen continuous through the platform. In essence, both the microneedle as well as the platform on which it stands, are made of the same polymer material, rendering the process monolithic. The microneedle tips produced were quite sharp with tip diameters ranging between 5 to 10 µm, needle heights greater than 1 mm and resulting aspect ratio of 40. Further, mechanical tests performed on the fabricated microneedles demonstrate a critical compressive failure load of about 173 mN on average per microneedle, which translates into a safety factor greater than one for skin penetration.

Comb-shaped polymer-based Dry electrodes for EEG/ECG measurements with high user comfort.

Soft, comfortable polymer-based dry electrodes are fabricated. Impedance and biopotential measurements are carried out to compare the performance of conventional gel electrodes with our dry electrodes. The impedance of our dry electrodes is reduced by adding more conductive additives to the polymer material. To further lower the impedance, two skin pretreatment techniques are evaluated regarding their influence on skin impedance. However, these techniques are found to have only temporary beneficial effects. Finally biopotential measurements (both ECG and EEG) are performed using our soft polymer electrodes. The ECG signal acquired with both gel and our polymer electrodes demonstrates high degree of similarity. Therefore, heart beat detection is straightforward. To enable monitoring of EEG signals with smaller amplitudes, our dry electrodes need to be combined with pre-amplifiers. Initial EEG tests show that the alpha waves are clearly identifiable with the dry electrodes when subjects close their eyes. Based on the results, combining with sophisticated signal acquisition electronics, the dry electrodes provide a high user comfort solution for high quality biopotential measurements, even on very hairy skin.

Two-dimensional multi-channel neural probes with electronic depth control.

This paper presents multi-electrode arrays for in vivo neural recording applications incorporating the principle of electronic depth control (EDC), i.e., the electronic selection of recording sites along slender probe shafts independently for multiple channels. Two-dimensional (2D) arrays were realized using a commercial 0.5- µm complementary-metal-oxide-semiconductor (CMOS) process for the EDC circuits combined with post-CMOS micromachining to pattern the comb-like probes and the corresponding electrode metallization. A dedicated CMOS integrated front-end circuit was developed for pre-amplification and multiplexing of the neural signals recorded using these probes.

A 160 µW 8-Channel Active Electrode System for EEG Monitoring.

This paper presents an active electrode system for gel-free biopotential EEG signal acquisition. The system consists of front-end chopper amplifiers and a back-end common-mode feedback (CMFB) circuit. The front-end AC-coupled chopper amplifier employs input impedance boosting and digitally-assisted offset trimming. The former increases the input impedance of the active electrode to 2 GΩ at 1 Hz and the latter limits the chopping induced output ripple and residual offset to 2 mV and 20 mV, respectively. Thanks to chopper stabilization, the active electrode achieves 0.8 µVrms (0.5-100 Hz) input referred noise. The use of a back-end CMFB circuit further improves the CMRR of the active electrode readout to 82 dB at 50 Hz. Both front-end and back-end circuits are implemented in a 0.18 µm CMOS process and the total current consumption of an 8-channel readout system is 88 µA from 1.8 V supply. EEG measurements using the proposed active electrode system demonstrate its benefits compared to passive electrode systems, namely reduced sensitivity to cable motion artifacts and mains interference.

2-Scale topography dry electrode for biopotential measurements.

The design and fabrication of a novel 2-scale topography dry electrode using macro and micro needles is presented. The macro needles enable biopotential measurements on hairy skin, the function of the micro needles is to decrease the electrode impedance even further by penetrating the outer skin layer. Also, a fast and reliable impedance characterization protocol is described. Based on this impedance measurement protocol, a comparison study is made between our dry electrode, 3 other commercial dry electrodes and a standard wet gel electrode. Promising results are already obtained with our electrodes which do not have skin piercing micro needles. For the proposed electrodes, three different conductive coatings (Ag/AgCl/Au) are compared. AgCl is found to be slightly better than Ag as coating material, while our Au coated electrodes have the highest impedance.

Hydrogel optimization towards fibroblast-friendly biomimetic coatings for implantable devices.

In this paper we present our investigations related to the optimization of hydrogels for the coating/packaging of biomedical devices. In order for hydrogels to be a viable interface/packaging material, a number of conditions must be met. We outline the tailoring of the mechanical properties of a HEMA based hydrogel by exploiting the influence of individual hydrogel components to achieve these requirements. The water sorption, the elasticity and the porosity of various hydrogel materials were tested and the effects of the different hydrogel components was determined. These components include gelatin (used as a pore generator or porogen), alginate (to influence mechanical properties) and collagen (to improve cell adhesion). We also report the results of in vitro fibroblast testing on various hydrogel types.

Out-of-plane, high strength, polymer microneedles for transdermal drug delivery.

This paper reports on the high strength of high-aspect ratio (> 50) hollow, polymer microneedles fabricated out-of-plane using a fairly repeatable fabrication process. Further, these microneedle tips were sharpened by a molding principle, with a simple anisotropic etch of silicon wafer. Also, an enhanced elegant process was explored to incorporate the mounting of the microneedle onto a platform without using any additional material, such that the bore of the microneedle is continuous with the bore of the platform in order to facilitate microfluidic delivery through the hollow needles. The high aspect ratio microneedles undergo failure at the critical load of around 4 N, while the insertion force for such a needle into agar gel, which is a fairly good equivalent of the human skin due to its inherent visco-elastic properties, is 7 mN, which translates into a safety factor (ratio of critical loading force to the maximum applied force) of greater than 500 thus, making it adequately strong for skin penetration.

Integrated fluidic system for bio-molecule separation.

An integrated fluidic system has been fabricated, capable of separating a mixture of different bio-molecules into its components. It is composed of a filter and an actuator; the pressure generated by the actuator sustains the flow of the mixture through the filter. The actuator is made by stacking several layers of conductive polymer. Actuator strain in excess of 10% has been obtained, which corresponds to a fluid flow of 3 microL/min in the fabricated system. The filter consists of an ordered array of Si micro-pillars. A mixture composed of DNA fragments of different length (300 and 400 base-pair) has been effectively separated by using the fabricated filter and chromatographic techniques.

Power optimization in body sensor networks: the case of an autonomous wireless EMG sensor powered by PV-cells.

Recent advances in ultra-low-power circuits and energy harvesters are making self-powered body sensor nodes a reality. Power optimization at the system and application level is crucial in achieving ultra-low-power consumption for the entire system. This paper reviews system-level power optimization techniques, and illustrates their impact on the case of autonomous wireless EMG monitoring. The resulting prototype, an Autonomous wireless EMG sensor power by PV-cells, is presented.

Wireless EEG systems: increasing functionality, decreasing power.

Recent advances in low-power wireless technologies for health are instrumental in bringing EEG monitoring from the hospital to the home environment. This talk provides an overview of imec's research on low-power wireless EEG monitoring. Enabling technologies, integrated systems and remaining challenges are discussed.

Tuning electrode impedance for the electrical recording of biopotentials.

Tuning the electrode impedance through the DC biasing of iridium oxide is presented. Impedance reduction of up to two orders of magnitude was reproducibly observed in 20 microm diameter microelectrodes at a biasing of 1V.

Ultra-low-power wearable biopotential sensor nodes.

This paper discusses ultra-low-power wireless sensor nodes intended for wearable biopotential monitoring. Specific attention is given to mixed-signal design approaches and their impact on the overall system power dissipation. Examples of trade-offs in power dissipation between analog front-ends and digital signal processing are also given. It is shown how signal filtering can further reduce the internal power consumption of a node. Such power saving approaches are indispensable as real-life tests of custom wireless ECG patches reveal the need for artifact detection and correction. The power consumption of such additional features has to come from power savings elsewhere in the system as the overall power budget cannot increase.

Self-assembly from milli- to nanoscales: methods and applications.

The design and fabrication techniques for microelectromechanical systems (MEMS) and nanodevices are progressing rapidly. However, due to material and process flow incompatibilities in the fabrication of sensors, actuators and electronic circuitry, a final packaging step is often necessary to integrate all components of a heterogeneous microsystem on a common substrate. Robotic pick-and-place, although accurate and reliable at larger scales, is a serial process that downscales unfavorably due to stiction problems, fragility and sheer number of components. Self-assembly, on the other hand, is parallel and can be used for device sizes ranging from millimeters to nanometers. In this review, the state-of-the-art in methods and applications for self-assembly is reviewed. Methods for assembling three-dimensional (3D) MEMS structures out of two-dimensional (2D) ones are described. The use of capillary forces for folding 2D plates into 3D structures, as well as assembling parts onto a common substrate or aggregating parts to each other into 2D or 3D structures, is discussed. Shape matching and guided assembly by magnetic forces and electric fields are also reviewed. Finally, colloidal self-assembly and DNA-based self-assembly, mainly used at the nanoscale, are surveyed, and aspects of theoretical modeling of stochastic assembly processes are discussed.

A 3D slim-base probe array for in vivo recorded neuron activity.

This paper introduces the first experimental results of a new implantable slim-base three-dimensional (3D) probe array for cerebral applications. The probes are assembled perpendicularly into the slim-base readout platform where electrical and mechanical connections are achieved simultaneously. A new type of micromachined interconnect has been developed to establish electrical connection using extreme planarization techniques. Due to the modular approach of the platform, probe arrays of different dimensions and functionality can be assembled. The platform is only several hundred microns thick which is highly relevant for chronic experiments in which the probe array should be able to float on top of the brain. Preliminary tests were carried out with the implantation of a probe array into the auditory cortex of a rat.

Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A.

Axin, a negative regulator of the Wnt signaling pathway, forms a complex with glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, adenomatous polyposis coli (APC) gene product, and Dvl, and it regulates GSK-3beta-dependent phosphorylation in the complex and the stability of beta-catenin. Using yeast two-hybrid screening, we found that regulatory subunits of protein phosphatase 2A, PR61beta and -gamma, interact with Axin. PR61beta or -gamma formed a complex with Axin in intact cells, and their interaction was direct. The binding site of PR61beta on Axin was different from those of GSK-3beta, beta-catenin, APC, and Dvl. Although PR61beta did not affect the stability of beta-catenin, it inhibited Dvl- and beta-catenin-dependent T cell factor activation in mammalian cells. Moreover, it suppressed beta-catenin-induced axis formation and expression of siamois, a Wnt target gene, in Xenopus embryos, suggesting that PR61beta acts either at the level of beta-catenin or downstream of it. Taken together with the previous observations that PR61 interacts with APC and functions upstream of beta-catenin, these results demonstrate that PR61 regulates the Wnt signaling pathway at various steps.

The Saccharomyces cerevisiae phosphotyrosyl phosphatase activator proteins are required for a subset of the functions disrupted by protein phosphatase 2A mutations.

In Saccharomyces cerevisiae, PTPA is encoded by two genes, YPA1 and YPA2. In order to examine the biological role of PTPA as potential regulator of protein phosphatase 2A (PP2A), we compared the phenotypes of the ypaDelta mutants with these of PP2A-deficient strains. While deletion of both YPA genes is lethal, deletion of YPA1 alone results in a phenotype resembling that of PP2A-deficient strains in specific aspects such as aberrant bud morphology, abnormal actin distribution, and similar growth defects under various growth conditions. These phenotypes were even more pronounced when YPA1 was deleted in a pph21Delta genetic background. Moreover, ypaDelta mutants are hypersensitive to nocodazole and show inappropriate mitotic spindle formation as previously described for mutants in the catalytic subunit of PP2A, suggesting that Ypa, like PP2A, has a function in mitotic spindle formation. These results are consistent with an in vivo role of Ypa as a regulator of PP2A. However, unlike a PP2A-deficient strain, ypaDelta mutants do not show a G2 arrest. Therefore, Ypa does not seem to play a role in the regulation of PP2A at this stage of the cell cycle. These results imply that Ypa regulates a specific subset of PP2A functions, possibly by controlling the subunit composition of PP2A.

The Saccharomyces cerevisiae homologue YPA1 of the mammalian phosphotyrosyl phosphatase activator of protein phosphatase 2A controls progression through the G1 phase of the yeast cell cycle.

The Saccharomyces cerevisiae gene YPA1 encodes a protein homologous to the phosphotyrosyl phosphatase activator, PTPA, of the mammalian protein phosphatase type 2A (PP2A). In order to examine the biological role of PTPA, we disrupted YPA1 and characterised the phenotype of the ypa1Delta mutant. Comparison of the growth rate of the wild-type strain and the ypa1Delta mutant on glucose-rich medium after nutrient depletion showed that the ypa1Delta mutant traversed the lag period more rapidly. This accelerated progression through "Start" was also observed after release from alpha-factor-induced G1 arrest as evidenced by a higher number of budding cells, a faster increase in CLN2 mRNA expression and a more rapid reactivation of Cdc28 kinase activity. This phenotype was specific for deletion of YPA1 since it was not observed when YPA2, the second PTPA gene in budding yeast was deleted. Reintroduction of YPA1 or the human PTPA cDNA in the ypa1Delta mutant suppressed this phenotype as opposed to overexpression of YPA2. Disruption of both YPA genes is lethal, since sporulation of heterozygous diploids resulted in at most three viable spores, none of them with a ypa1Delta ypa2Delta genotype. This observation indicates that YPA1 and YPA2 share some essential functions. We compared the ypa1Delta mutant phenotype with a PP2A double deletion mutant and a PP2A temperature-sensitive mutant. The PP2A-deficient yeast strain also showed accelerated progression through the G1 phase. In addition, both PP2A and ypa1Delta mutants show similar aberrant bud morphology. This would support the notion that YPA1 may act as a positive regulator of PP2A in vivo.

Identification and characterization of alternative splice products encoded by the human phosphotyrosyl phosphatase activator gene.

The phosphotyrosyl phosphatase activator (PTPA), a protein phosphatase 2A (PP2A) regulatory protein, specifically stimulates the phosphotyrosyl phosphatase activity of PP2A in vitro. Human PTPA is encoded by a single gene, the structure and chromosomal localization of which have been determined in our previous work. In this paper, we report the identification and characterization of six additional splice variants, termed PTPAbeta to PTPAeta, in addition to the originally identified PTPAalpha form. Interestingly, PTPAbeta and PTPAgamma contain a novel exon that had been overlooked in the formerly identified gene structure. As revealed by nested PCR, all these PTPA transcripts are expressed in various human cDNA libraries and cell lines. However, a quantitative approach, using a single PCR reaction followed by detection of the reaction products with a radioactively labeled probe, revealed only PTPAalpha, beta and delta, suggesting that the other transcripts are expressed very poorly. In vitro transcription-translation revealed that only PTPAalpha, beta, delta and epsilon are translated into functional proteins, whereas translation of PTPAgamma, zeta and eta is stopped prematurely due to a frameshift resulting from skipping exon 2, suggesting that the latter isoforms may result from splicing errors. By western analysis of HepG2 and Saos-2 cell extracts, only PTPAalpha and beta were detected. PTPAalpha and beta were expressed as GST fusion proteins in bacteria, and were found to contain the same specific phosphotyrosyl phosphatase stimulatory activity towards PP2A. The identification of this family of PTPA variants adds another level of complexity to the in vivo function(s) of PTPA, opening up the possibility that different isoforms may perform different functions.