A Fibreless Multiwavelength NIRS System for Imaging Localised Changes in Cerebral Oxidised Cytochrome C Oxidase.

Measurement of the oxidation state of cytochrome c oxidase (oxCCO) can inform directly on neuronal metabolism. Conventionally this has been measured in vivo using benchtop broadband near infrared spectroscopy (NIRS) systems. Spatially resolved measures of oxCCO have recently been made possible using a multichannel fibre-based broadband NIRS system. We describe the use of a fibreless multiwavelength NIRS system using light emitting diodes (LED) designed specifically to image localised changes in oxCCO and hence neuronal metabolism. A fibreless system consisting of four modules, each containing two LED sources and four photodiode detectors, was developed. Each LED source contained eight LED dies (780, 811, 818, 842, 850, 882, 891 and 901 nm) assembled in an area of 1.5 × 1.5 mm. A well-established hyperoxia protocol was used to evaluate the oxCCO spatially resolved measurement capabilities of the system and, subsequently, its imaging capabilities were tested using a functional activation paradigm. A multi-spectral image reconstruction approach was used to provide images of Δ[HbO2], Δ[HHb] and Δ[oxCCO] from the multi-distance, multi-channel optical datasets. This novel fibreless multiwavelength NIRS system allows imaging of localised changes in oxCCO in the human brain, and has potential for development as an inexpensive, wearable, continuous monitor of cerebral energetics in a range of experimental and clinical scenarios.

Neurovascular Interactions in the Neurologically Compromised Neonatal Brain.

Neurological brain injuries such as hypoxic ischaemic encephalopathy (HIE) and associated conditions such as seizures have been associated with poor developmental outcome in neonates. Our limited knowledge of the neurological and cerebrovascular processes underlying seizures limits their diagnosis and timely treatment. Diffuse optical tomography (DOT) provides haemodynamic information in the form of changes in concentration of de/oxygenated haemoglobin, which can improve our understanding of seizures and the relationship between neural and vascular processes. Using simultaneous EEG-DOT, we observed distinct haemodynamic changes which are temporally correlated with electrographic seizures. Here, we present DOT-EEG data from two neonates clinically diagnosed as HIE. Our results highlight the wealth of mutually-informative data that can be obtained using DOT-EEG techniques to understand neurovascular coupling in HIE neonates.

Evaluation of microbubble contrast agents for dynamic imaging with x-ray phase contrast.

X-rays are commonly used as a means to image the inside of objects opaque to visible light, as their short wavelength allows penetration through matter and the formation of high spatial resolution images. This physical effect has found particular importance in medicine where x-ray based imaging is routinely used as a diagnostic tool. Increasingly, however, imaging modalities that provide functional as well as morphological information are required. In this study the potential to use x-ray phase based imaging as a functional modality through the use of microbubbles that can be targeted to specific biological processes is explored. We show that the concentration of a microbubble suspension can be monitored quantitatively whilst in flow using x-ray phase contrast imaging. This could provide the basis for a dynamic imaging technique that combines the tissue penetration, spatial resolution, and high contrast of x-ray phase based imaging with the functional information offered by targeted imaging modalities.

Functional near infrared spectroscopy (fNIRS) to assess cognitive function in infants in rural Africa.

Cortical mapping of cognitive function during infancy is poorly understood in low-income countries due to the lack of transportable neuroimaging methods. We have successfully piloted functional near infrared spectroscopy (fNIRS) as a neuroimaging tool in rural Gambia. Four-to-eight month old infants watched videos of Gambian adults perform social movements, while haemodynamic responses were recorded using fNIRS. We found distinct regions of the posterior superior temporal and inferior frontal cortex that evidenced either visual-social activation or vocally selective activation (vocal > non-vocal). The patterns of selective cortical activation in Gambian infants replicated those observed within similar aged infants in the UK. These are the first reported data on the measurement of localized functional brain activity in young infants in Africa and demonstrate the potential that fNIRS offers for field-based neuroimaging research of cognitive function in resource-poor rural communities.

Optical imaging of brain activation in Gambian infants.

We used optical topography (OT) to investigate cognitive function in infants in rural Gambia. Images of changes in oxyhaemoglobin and deoxyhaemoglobin concentrations were reconstructed using a multispectral algorithm which uses the finite element method (FEM) to model the propagation of light through scattering tissue using the diffusion equation. High quality OT data enabled us to reconstruct images with robust representation of haemodynamic changes. OT is a feasible neuroimage technology for this resource-poor setting.

A portable wireless near-infrared spatially resolved spectroscopy system for use on brain and muscle.

We have designed, built and successfully tested a prototype portable and wireless near-infrared spectroscopy system. It takes forward the well-established series of NIRO spectroscopy instruments made by Hamamatsu Photonics (Hamamatsu City, Japan). It uses an identical optical probe, and has a data acquisition rate of 10 Hz. It illuminates the tissue with laser diode sources at 3 wavelengths of 775, 810 and 850 nm, and detects the reflected light with 2 silicon photodiode detectors at 2 different separations, enabling spatially resolved spectroscopy to be performed. We have tested it with both in vitro and in vivo experiments to establish its basic functionality for use in studies of both brain and muscle.

Transient haemodynamic events in neurologically compromised infants: a simultaneous EEG and diffuse optical imaging study.

We describe a series of novel simultaneous EEG and diffuse optical imaging studies of newborn infants. These experiments provide evidence of large, transient haemodynamic events which occur repeatedly and consistently within and across several infants with neurological damage, all of whom were diagnosed with seizures. A simple but independent process of rejecting artifacts and identifying events within diffuse optical imaging data is described, and this process is applied to data from 4 neurologically damaged neonates and from 19 healthy, age-matched controls. This method results in the consistent identification of events in three out of four of the neurologically damaged infant group which are dominated by a slow (>30s) and significant increase in oxyhaemoglobin concentration, followed by a rapid and significant decrease before a slow return to baseline. No comparable events are found in any of our control data sets. The importance and physiological implications of our findings are discussed, as is the suitability of a combined EEG and diffuse optical imaging approach to the study and monitoring of neonatal brain injury.

Multispectral imaging of the ocular fundus using light emitting diode illumination.

We present an imaging system based on light emitting diode (LED) illumination that produces multispectral optical images of the human ocular fundus. It uses a conventional fundus camera equipped with a high power LED light source and a highly sensitive electron-multiplying charge coupled device camera. It is able to take pictures at a series of wavelengths in rapid succession at short exposure times, thereby eliminating the image shift introduced by natural eye movements (saccades). In contrast with snapshot systems the images retain full spatial resolution. The system is not suitable for applications where the full spectral resolution is required as it uses discrete wavebands for illumination. This is not a problem in retinal imaging where the use of selected wavelengths is common. The modular nature of the light source allows new wavelengths to be introduced easily and at low cost. The use of wavelength-specific LEDs as a source is preferable to white light illumination and subsequent filtering of the remitted light as it minimizes the total light exposure of the subject. The system is controlled via a graphical user interface that enables flexible control of intensity, duration, and sequencing of sources in synchrony with the camera. Our initial experiments indicate that the system can acquire multispectral image sequences of the human retina at exposure times of 0.05 s in the range of 500-620 nm with mean signal to noise ratio of 17 dB (min 11, std 4.5), making it suitable for quantitative analysis with application to the diagnosis and screening of eye diseases such as diabetic retinopathy and age-related macular degeneration.

A quantitative assessment of the depth sensitivity of an optical topography system using a solid dynamic tissue-phantom.

A solid dynamic phantom with tissue-like optical properties is presented, which contains seven discrete targets impregnated with thermochromic pigment located at different depths from the surface. Changes in absorption are obtained in response to localized heating of the targets, simulating haemodynamic changes occurring in the brain and other tissues. The depth sensitivity of a continuous wave optical topography system was assessed successfully using the phantom. Images of the targets have been reconstructed using a spatially variant regularization, and the determined spatial localization in the depth direction is shown to be accurate within an uncertainty of about 3 mm down to a depth of about 30 mm.

A tissue-like optically turbid and electrically conducting phantom for simultaneous EEG and near-infrared imaging.

We describe a phantom for simultaneous electroencephalography (EEG) and near-infrared imaging which consists of a solid, optically turbid and electrically conducting interface enclosing a tissue-mimicking aqueous scattering solution. The interface provides an electrical contact impedance comparable to that of the human scalp while the phantom as a whole has optical properties and electrical conductivity equivalent to that of head tissue. The construction is described and our design is evaluated experimentally using an optically absorbing target which also provides an EEG-equivalent electric field source. The results of this simultaneous EEG and near-infrared imaging experiment are presented.

Design and evaluation of a probe for simultaneous EEG and near-infrared imaging of cortical activation.

We present a novel probe design which enables simultaneous electroencephalography (EEG) and near-infrared (NIR) optical imaging to be performed in a manner which is easy to apply, allows for optimum co-registration of the two forms of data and maximizes the number of sensors which can be applied to a given area. Our probe design is evaluated using a dual-modality, tissue-mimicking phantom and by performing a simple functional activation study of the human motor cortex. We successfully acquired NIR optical and EEG data simultaneously for both our phantom and our human motor cortex experiments, clearly demonstrating the effectiveness and suitability of our 'opto-electrode'.

A dynamic optical imaging phantom based on an array of semiconductor diodes.

An electrically-activated phantom for evaluating diffuse optical imaging systems has been designed based on an array of semiconductor diodes which are used to heat a thermochromic dye embedded in a solidified polyester resin with tissue-like optical properties. The array allows individual diodes to be addressed sequentially, thus simulating the movement of a small volume of contrasting optical absorption. Two designs of diode-array phantom are described and results of imaging experiments are presented.

An electrically-activated dynamic tissue-equivalent phantom for assessment of diffuse optical imaging systems.

A novel design of solid dynamic phantom with tissue-like optical properties is presented, which contains variable regions of contrast which are activated electrically. Reversible changes in absorption are produced by localized heating of targets impregnated with thermochromic pigment. A portable, battery-operated prototype has been constructed, and its optical and temporal characteristics have been investigated. The phantom has been developed as a means of assessing the performance of diffuse optical imaging systems, such as those used to monitor haemodynamic changes in the brain and other tissues. Images of the phantom have been reconstructed using data acquired with a continuous wave optical topography system.

Investigation of depth dependent changes in cerebral haemodynamics during face perception in infants.

Near-infrared spectroscopy has been used to record oxygenation changes in the visual cortex of 4 month old infants. Our in-house topography system, with 30 channels and 3 different source-detector separations, recorded changes in the concentration of oxy-, deoxy- and total haemoglobin (HbO2, HHb and HbT) in response to visual stimuli (face, scrambled visual noise and cartoons as rest). The aim of this work was to demonstrate the capability of the system to spatially localize functional activation and study the possibility of depth discrimination in the haemodynamic response. The group data show both face stimulation and visual noise stimulation induced significant increases in HbO2 from rest, but the increase in HbO2 with face stimulation was not significantly different from that seen with visual noise stimulation. The face stimuli induced increases in HbO2 were spread across a greater area across all depths than visual noise induced changes. In results from a single subject there was a significant increase of HbO2 in the inferior area of the visual cortex in response to both types of stimuli, and a larger number of channels (source-detector pairs) showed HbO2 increase to face stimuli, especially at the greatest depth. Activation maps were obtained using 3D reconstruction methods on multi source-detector separation optical topography data.

A haemodialysis system for the treatment of acute renal failure and metabolic disorders in neonates.

A prototype dialysis system for the treatment of premature babies has been designed, built and successfully tested. It can be used to treat babies who are suffering from renal failure or metabolic disorders. These patients are difficult or impossible to treat conventionally, due to their very small total blood volume (typically 40ml) and their intolerance to donated blood. There was a strong case for developing a dialysis system specifically designed for the treatment of such patients. The system is based on a manually operated device that had been previously developed. The method differs from conventional dialysis in several ways. Blood access to the patient is via a single venous catheter. Only a very small amount of blood is needed to prime the extracorporeal circuit--this can be as little as 6.8ml in the smallest patients. This compares very favourably with the volumes needed in conventional circuits, which are in the range of 15-40ml. This small priming volume means that donated blood is not needed to prime the circuit, which reduces the risks and complexity of the treatment. The clearance and ultrafiltration rates that can be achieved are independent of the rate that blood can be accessed from the patient, since the same blood passes back and forth through the dialyser several times. In vitro testing covered several areas of operation. The accuracy of the ultrafiltration process was established. The clearance rates that could be achieved were determined. The clearances that have been obtained experimentally with the new system are consistently above 40% of the mean blood flow rate through the system. The largest mean blood flow rate available is 5ml/min, so the maximum clearance is approximately 2ml/min. The maximum ultrafiltration rate that can be obtained is 50ml/h. The amount of damage caused to the blood by the system was found to be well within acceptable clinical limits. In vivo testing established the feasibility of using a computer algorithm to control the withdrawal of blood from the patient. The system has been used successfully to treat seven patients at the time of publication.

Three-dimensional whole-head optical tomography of passive motor evoked responses in the neonate.

Optical tomography has been used to reconstruct three-dimensional images of the entire neonatal head during motor evoked responses. Data were successfully acquired during passive movement of each arm on four out of six infants examined, from which eight sets of bilateral images of hemodynamic parameters were reconstructed. Six out of the eight images showed the largest change in total hemoglobin in the region of the contralateral motor cortex. The mean distance between the peak response in the image and the estimated position of the contralateral motor cortex was 10.8 mm. These results suggest that optical tomography may provide an appropriate technique for non-invasive cot-side imaging of brain function.