64×64 pixel smart sensor array for laser Doppler blood flow imaging.

What is believed to be the first fully integrated two-dimensional complementary metal oxide semiconductor (CMOS) imaging array for laser Doppler blood flow imaging is demonstrated. The sensor has 64×64 pixels and includes both analog and digital on-chip processing electronics. This offers several potential advantages over commercial sensors as the processing is tailored to the signals of interest and the data bottleneck that exists between the sensor and processing electronics is overcome. To obtain a space efficient design over 64×64 pixels means that standard processing electronics used off-chip cannot be implemented. Images of both simulated blood flow responses and a blood flow occlusion test demonstrate the capability.

The effect of citalopram treatment on amyloid-ß precursor protein processing and oxidative stress in human hNSC-derived neurons.

Selective Serotonin Reuptake Inhibitors (SSRIs) may hold therapeutic benefits for people with Alzheimer's disease (AD). SSRIs may perturb AD progression, or the conversion from MCI to AD, via increased neurogenesis, reduced oxidative stress and/or favourable Amyloid-ß Precursor Protein (AßPP) processing. This study used iPSC derived cortical neuronal cells carrying 3 different PSEN1 mutations, to investigate the effect of treatment with the SSRI, Citalopram on AßPP processing and oxidative stress. Control and PSEN1 mutation (L286V, A246E, M146L) iPSC-derived neurons were treated with Citalopram for 45 days. ADAM10 activity, AßPP processing and Aß generation was measured in addition to cellular redox status. Citalopram treatment reduced the Aß1-42:40 ratio in control but not in fAD PSEN1 cells. ADAM10 activity was increased with Citalopram treatments in fAD PSEN1 cell lines, which was also seen for sAßPPα secretion. Lower superoxide generation in fAD PSEN1 cells following Citalopram treatment was identified, although there was no effect on end markers of oxidative stress. Treatment with Citalopram appears to have little effect on Aß generation in fADPSEN1 cells, but our findings suggest that treatment can significantly increase non-amyloidogenic AßPP processing and reduce oxidative stress. These changes may explain why SSRIs appear most effective in the prodromal period of the disease progression, as opposed to reducing established AD pathology. Further investigation of specific pathways conferring the beneficial effects of SSRIs treatment are warranted.

Development of two-photon polymerised scaffolds for optical interrogation and neurite guidance of human iPSC-derived cortical neuronal networks.

Recent progress in the field of human induced pluripotent stem cells (iPSCs) has led to the efficient production of human neuronal cell models for in vitro study. This has the potential to enable the understanding of live human cellular and network function which is otherwise not possible. However, a major challenge is the generation of reproducible neural networks together with the ability to interrogate and record at the single cell level. A promising aid is the use of biomaterial scaffolds that would enable the development and guidance of neuronal networks in physiologically relevant architectures and dimensionality. The optimal scaffold material would need to be precisely fabricated with submicron resolution, be optically transparent, and biocompatible. Two-photon polymerisation (2PP) enables precise microfabrication of three-dimensional structures. In this study, we report the identification of two biomaterials that support the growth and differentiation of human iPSC-derived neural progenitors into functional neuronal networks. Furthermore, these materials can be patterned to induce alignment of neuronal processes and enable the optical interrogation of individual cells. 2PP scaffolds with tailored topographies therefore provide an effective method of producing defined in vitro human neural networks for application in influencing neurite guidance and complex network activity.

In situ monitoring of 3D in vitro cell aggregation using an optical imaging system.

Bioreactor systems that maintain cells and tissues in suspension are increasingly popular for culturing 3D constructs to avoid the loss of in vivo cell function associated with traditional 2D culture methods. There is a need for the online monitoring of such systems to provide better understanding and control of the processes involved and to prevent the disruption of these processes caused by offline sampling and endpoint analysis. We describe a system for the imaging and analysis of cell aggregation, over long periods, within a high aspect rotating vessel (HARV). The system exploits side illumination, using an adjustable beam pattern, to restrict the detected light to that scattered by the cell aggregates, thus eliminating the need for the fluorescent labeling of the cells. The in situ aggregation of mammalian cells (MCF-7 breast carcinoma cells) was monitored over an 8 h period and image sequences showing the growth and motion of the aggregates within the bioreactor were obtained. Detailed size and population data have been derived characterizing the development of the aggregates during this time. We show how the number of resolvable aggregates increases to reach a peak and then declines as these aggregates merge. Once formed, remaining aggregates are found to consolidate to form more tightly packed bodies, typically reducing in cross-sectional area by one third. These results provide the basis for the development of an automated feedback system to control the growth of 3D cell cultures for repeatable, reliable, and quality controlled experimentation.

Detection of previously unrecognized daytime desaturation in children with chronic lung disease.

PRIMARY OBJECTIVE: The prime rationale of this research is to investigate the possible occurrence of previously unrecognized episodes of desaturation apparent in preterm infants with chronic lung disease as they freely move around a non-artificial environment. RESEARCH DESIGN: The study comprises 58 hours of telemetric recordings of SpO2, heart rate, body movement and temperature, along with full ECG and photoplethysmographic waveforms for eight preterm subjects in their home environment. MAIN OUTCOME/RESULTS: The data is analysed for remarkable events, more particularly periods of spontaneous desaturation. Statistical results for all case studies are collated into a table along with examples of graphical analysis. CONCLUSIONS: This study has shown that some patients are prone to episodes of hypoxemia during the course of normal daily activity or daytime sleep that would usually go unrecognized and that more effective management of supplemental oxygen treatment may be possible with continual unobtrusive monitoring.

Comparison of methods for reducing the effects of scattering in spectrophotometry.

Light scattering provides a problem in optical spectroscopy as the relationship between attenuation and absorption in the presence of scattering is nonlinear. Three simple methods of reducing the effects of scattering and hence returning to an approximately linear relationship are considered in this paper, namely, extracting light that has maintained its original polarization state through subtraction of orthogonal polarization states, use of an added absorber, and spatial filtering. These can all be applied relatively easily to conventional spectrophotometers. However, there is an inevitable trade-off between the accuracy of the measurement and the signal-to-noise ratio as scattered light is rejected from the detector. It is demonstrated that polarization subtraction is the most efficient technique at selecting weakly scattered photons from a scattered light background as it enables the relationship between attenuation and absorption coefficient to become more linear while maintaining a higher number of detected photons. In practical use, the drawback of polarization subtraction over added absorber and spatial filtering methods is that a large dc background light level is maintained, which contributes to a higher shot noise. This means that when the scattering coefficient is high (micros > or = 7 mm(-1)) the added absorber method offers better performance for shot noise limited detection.

Motion limitations of non-contact photoplethysmography due to the optical and topological properties of skin.

Non-contact photoplethysmography (PPG) provides multiple benefits over in-contact methods, but is not as tolerant to motion due to the lack of mechanical coupling between the subject and sensor. One limitation of non-contact photoplethysmography is discussed here, specifically looking at the topology and optical variations of the skin and how this impacts upon the ability to extract a photoplethysmogram when a subject moves horizontally across the field of view of the detector (a panning motion). When this occurs it is shown that whilst the general relationships between the speed of traversal, detection area and resultant signal quality can be found, the quality of signal in each individual case is determined by the properties of the area of skin chosen.

An automated quasi-continuous capillary refill timing device.

Capillary refill time (CRT) is a simple means of cardiovascular assessment which is widely used in clinical care. Currently, CRT is measured through manual assessment of the time taken for skin tone to return to normal colour following blanching of the skin surface. There is evidence to suggest that manually assessed CRT is subject to bias from ambient light conditions, a lack of standardisation of both blanching time and manually applied pressure, subjectiveness of return to normal colour, and variability in the manual assessment of time. We present a novel automated system for CRT measurement, incorporating three components: a non-invasive adhesive sensor incorporating a pneumatic actuator, a diffuse multi-wavelength reflectance measurement device, and a temperature sensor; a battery operated datalogger unit containing a self contained pneumatic supply; and PC based data analysis software for the extraction of refill time, patient skin surface temperature, and sensor signal quality. Through standardisation of the test, it is hoped that some of the shortcomings of manual CRT can be overcome. In addition, an automated system will facilitate easier integration of CRT into electronic record keeping and clinical monitoring or scoring systems, as well as reducing demands on clinicians. Summary analysis of volunteer (n = 30) automated CRT datasets are presented, from 15 healthy adults and 15 healthy children (aged from 5 to 15 years), as their arms were cooled from ambient temperature to 5°C. A more detailed analysis of two typical datasets is also presented, demonstrating that the response of automated CRT to cooling matches that of previously published studies.

The feasibility of long-term fetal heart rate monitoring in the home environment using maternal abdominal electrodes.

It is well established that fetal and maternal electrocardiograms (ECGs) can be obtained from the maternal abdomen using standard surface electrodes, although this cannot be guaranteed. The unobtrusive and non-invasive nature of such monitoring lends itself naturally to the long-term ambulatory collection of this data on cardiac activity. By employing suitable algorithms it would then be possible to extract records of both fetal and maternal heart rate. This article presents results of the collection of raw electrophysiological signals, containing both fetal and maternal ECGs from a single volunteer from the 20th week of gestation until term. The significance of the data is that they were recorded by the mother herself in her own environment. Previously written software was then used to extract fetal and maternal heart rate data. These results demonstrate the feasibility of using this method for the long-term recording of fetal and maternal heart rate in the mother's normal surroundings.

A method for foetal heart rate monitoring during magnetic resonance imaging using Doppler ultrasound.

A means of monitoring foetal heart rate (FHR) during magnetic resonance imaging (MRI) is presented. Foetal heart rate was measured using a modified standard Doppler ultrasound based monitor. The transducer and lead from the monitor required alteration to reduce interference and distortion in the MR images to acceptable levels. These changes enabled high quality images to be produced with insignificant additional noise and distortion when the foetal heart rate was recorded simultaneously.

Sequential recording of the abdominal fetal electrocardiogram and magnetocardiogram.

The aim of this study was to demonstrate the acquisition of both the fetal magnetocardiogram (FMCG) and fetal electrocardiogram (FECG) from the abdomen of the same subject. This contrasts with previous reported studies which have generally recorded one or other of these signals but not the two together. Both signals were successfully recorded and averaged to produce a typical complex, thus allowing their direct comparison.

Detrended fluctuation analysis: a suitable method for studying fetal heart rate variability?

We evaluate the suitability of an enhanced detrended fluctuation analysis for studying fetal heart rate series involving imperfect quality of information. Our results indicate that to explore persistent long-range correlations, or fractality, the collection requirements of the data can be relaxed by allowing the possibility of using averaged fetal heart rate series. In addition, it also appears feasible to employ, without producing major alterations in the long-range scaling behaviour, fragmented fetal heart rate series involving up to 50% of random missing values, or up to 50 min of consecutive missing samples in recordings of approximately equal to 8 h length. These are crucial advantages to overcome the often variable quality of fetal data. Consequently, these findings may open the possibility of obtaining information concerning the development of neural processes from fetal heart rate series, despite their non-stationary and fragmented nature.

Detection of fetal electrocardiogram signals using matched filters with adaptive normalisation.

The authors discuss the application of matched litters to the detection of R-waves in fetal electrocardiogram (FECG) data, recorded during labour using a scalp electrode. When using the basic matched filter, one correlates a template representing the clean signal with the noisy signal. This method is optimal when the underlying noise is white in nature. However, it is known that false detection of R-waves can occur in the presence of extraneous peaks which have a similar shape to the fetal R-wave. It is proposed to switch between two different normalisations of the impulse response of the matched filter to alleviate this problem. When the signal-to-noise ratio is lower than a predetermined threshold, then normalisation to the geometric mean of the template and noisy data energies is carried out, otherwise only normalisation to the template energy is made. In the former case, the background noise and spikes that are larger than the underlying FECG are attenuated, hence increasing the probability of detection of the R-waves. In the latter case, noise, which has a lower amplitude than the underlying R-wave, is reduced. The effectiveness of this method is demonstrated by application to scalp electrode data.

Application of empirical mode decomposition to heart rate variability analysis.

The analysis of heart rate variability, involving changes in the autonomic modulation conditions, demands specific capabilities not provided by either parametric or non-parametric spectral estimation methods. Moreover, these methods produce time-averaged power estimates over the entire length of the record. Recently, empirical mode decomposition and the associated Hilbert spectra have been proposed for non-linear and non-stationary time series. The application of these techniques to real and simulated short-term heart rate variability data under stationary and non-stationary conditions is presented. The results demonstrate the ability of empirical mode decomposition to isolate the two main components of one chirp series and three signals simulated by the integral pulse frequency modulation model, and consistently to isolate at least four main components localised in the autonomic bands of 14 real signals under controlled breathing manoeuvres. In addition, within the short time-frequency range that is recognised for heart rate variability phenomena, the Hilbert amplitude component ratio and the instantaneous frequency representation are assessed for their suitability and accuracy in time-tracking changes in amplitude and frequency in the presence of non-stationary and non-linear conditions. The frequency tracking error is found to be less than 0.22% for two simulated signals and one chirp series.

The information content of Doppler ultrasound signals from the fetal heart.

Knowledge of the content of Doppler ultrasound signals from the fetal heart is essential if the performance of fetal heart rate (FHR) monitors based upon this technology is to be improved. For this reason instrumentation was constructed to enable the simultaneous collection of Doppler audio signals and the transabdominal fetal ECG (for signal registration), with a total of 22 recordings being made with an average length of around 20 minutes. These data demonstrate the transient nature of the Doppler audio data with wide variations in the signal content observable on a beat-to-beat basis. Short-time Fourier analysis enabled the content of the Doppler signals to be linked to six cardiac events, four valve and two wall motions, with higher frequency components being associated with the latter. This differing frequency content together with information regarding the direction of movement that can be discerned from Doppler signals provided a potential means of discriminating between these six events (which are unlikely to all contribute to the Doppler signal within the same cardiac cycle). Analysis of 100 records showed that wall contractions generate the most prominent signals, with atrial contraction recognisable in all records and ventricular wall contraction in 95% (although its amplitude is only around 30% of that of the atrial signal). Valve motion, with amplitudes between 15 and 25% that of the atrial wall signal, were visible in 75% of records. These results suggest means by which the six events that contribute to the Doppler signal may be distinguished, providing information that should enable an improvement in the current performance of Doppler ultrasound-based FHR monitors.

Compact long-term recorder for the transabdominal foetal and maternal electrocardiogram.

Foetal heart rate (FHR) monitoring is a proven means of assessing foetal health during the antenatal period. Currently, the only widely available instrumentation for producing these data is based on Doppler ultrasound, a technology that is unsuitable for long-term use. For nearly a century, it has been known that the foetal electrocardiogram (FECG) can be detected using electrodes placed on the maternal abdomen. Although these signals suggest an alternative means of FHR derivation, their use has been limited owing to problems of poor signal-to-noise ratio. However, the eminent suitability of the transabdominal FECG for long-term FHR monitoring has suggested that perseverance with the technique would be worthwhile. The paper describes the design, construction and use of a compact, long-term recorder of three channels of 24 h antenatal transabdominal data. Preliminary use of the recorder in around 400 short recording sessions demonstrates that FHR records of equivalent quality to those from Doppler ultrasound-based instruments can be extracted from such data. The success of FHR derivation is, on average, around 65% of the recording period from around 20 weeks gestation (although this figure is reduced from around 28-32 weeks, and the success rates exhibit a wide range when individual subjects are considered). These results demonstrate that the technique offers, not only a means of acquiring long-term FHR data that are problematic to obtain by other means, but also a more patient-friendly alternative to the Doppler ultrasound technique.

Iterative method to derive an approximate matched filter template for fetal electrocardiogram signals.

Fetal electrocardiogram (FECG) signals that are extracted from the maternal abdomen have a signal-to-noise ratio that is so low that the determination of the times of location of the R-waves can be difficult. A matched filter could, in principle, be used, but in theory this requires prior knowledge of the shape of the QRS complex of the FECG. In the work that is described in this paper, a digital low-pass filter, with an impulse response that is triangular in shape, is applied to the first M complexes of a simulated FECG signal. An average based on the detected R-wave locations is determined and this is used as an approximation to the matched filter template for the next block of M complexes. It is shown that this method can be iterated to obtain an effectiveness in detecting R-wave locations that is competitive with the corresponding performance that is obtained with the pure matched filter. The resilience of this technique to increasing noise levels is investigated.

Towards multi-patient leadless and wireless cardiotocography via RF telemetry.

During labour the condition of the fetus is monitored by a cardiotocograph which displays fetal heart rate and a measure of uterine contractions. Ultrasound and tocodynamometer transducers are placed on the mother's abdomen and connected to a bedside monitor and display unit via a cable. This paper describes a prototype wireless system aimed at demonstrating the potential elimination of the cable which is undesirable in a number of respects. The radio link utilised operates at a frequency of 418 MHz with data compression and time division multiplexing (TDM) employed to allow up to 10 units to operate simultaneously on the same frequency in the same area. Data compression is achieved by extracting the Doppler ultrasound signal envelope and representing the frequency content of the signal using a zero crossing counting technique. Two Medium Access Control (MAC) protocols were considered, with a synchronised time division multiplexing system shown to offer greater throughput and resistance to interference than Carrier Sense Multiple Access (CSMA). This wireless RF telemetry system could be readily adapted for other multi-patient monitoring applications.

Data compression of fetal Doppler ultrasound audio signals using zero-crossings analysis.

This paper outlines a method of reducing the data rate for transmitting fetal Doppler ultrasound audio signals. A specific application is cited where compression of the fetal Doppler signal is required to transmit information to cardiotocographs (CTGs) using radio telemetry. The method involves splitting the signal into amplitude and frequency components. The amplitude is represented by samples of the signal envelope whilst the frequency information is represented by the number of zero-crossings within fixed intervals (windows). With a careful choice of window size, it is shown that this method can be used to reproduce the signal with no audible difference when compared with the original waveform. A reduction in data rate of 15:1 is achieved.

Selection of pulse oximetry equipment for ambulatory monitoring.

PRIMARY OBJECTIVE: This communication describes the initial stage of a research project concerning the monitoring of SpO2 in infants prone to periods of spontaneous oxygen desaturation whilst freely moving around their home environment. The primary aim was to determine an appropriate probe type and site together with an assessment of the suitability of two commercially available oximeter units. RESEARCH DESIGN: The study comprised 19 comparative tests, totalling 162 hours of recordings at resolution one sample every four seconds. Comparisons are drawn between probes, probe sites and pulse oximeters. MAIN OUTCOMES/RESULTS: The bias and precision is presented with respect to the probe and measurement site. Also, correlation between the trial and reference recordings is considered. CONCLUSIONS: It is concluded that ambulatory recording of SpO2 in infants utilizing equipment suitable for home monitoring can produce diagnostic data equivalent to that of the Ohmeda 3700 biox, but that an indication of movement artefact may be required for confirmation of accuracy. It became apparent that 'wrap around' probes, used on the index finger or big toe are the most suitable.