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.

Time domain optical imaging device based on a commercial time-to-digital converter.

Time-domain diffuse optical imaging is a noninvasive technique that uses pulsed near-infrared light as the interrogation source to produce quantitative images displaying the variation in blood volume and oxygenation in the human brain. Measuring the times of flights of photons provides information on the photon pathlengths in tissue, which enables absolute concentrations of the oxygenated and deoxygenated forms of hemoglobin to be estimated. Recent advances in silicon electronics have enabled the development of time-domain systems, which are lightweight and low cost, potentially enabling the imaging technique to be applied to a far greater cohort of subjects in a variety of environments. While such technology usually depends on customized circuits, in this article, we present a system assembled from commercially available components, including a low-cost time-to-digital converter and a silicon photomultiplier detector. The system is able to generate histograms of photon flight times at a rate of 81-90 kS/s and with a sampled bin width of 54 ps. The linearity and performance of the system are presented, and its potential as the basis for a modular multi-detector imaging system is explored.

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.

Anisotropic photon migration in human skeletal muscle.

It is demonstrated in the short head of the human biceps brachii of 16 healthy subjects (12 males and 4 females) that near infrared photon migration is anisotropic. The probability for a photon to travel along the direction of the muscle fibres is higher (approximately 0.4) than that of travelling along a perpendicular axis (approximately 0.3) while in the adipose tissue the probability is the same (approximately 0.33) in all directions. Considering that the muscle fibre orientation is different depending on the type of muscle considered, and that inside a given skeletal muscle the orientation may change, the present findings in part might explain the intrasubject variability observed in the physiological parameters measured by near infrared spectroscopy techniques. In other words, the observed regional differences might not only be physiological differences but also optical artefacts.

Tissue phantom for optical diagnostics based on a suspension of microspheres with a fractal size distribution.

We demonstrate experimentally the possibility of reproducing the phase function, absorption, and scattering coefficients of a real biological tissue (adult brain white matter and liver) using a suspension of polystyrene microspheres with a fractal size distribution. The design of a light scattering goniometer with a cylindrical cell in air is discussed, and phase function measurements using the device are described. The scattering coefficient is measured using transmission spectrophotometry and the absorption and reduced scattering coefficients are measured using a time-resolved method. A good match between real tissue and phantom parameters is demonstrated.

Recent advances in diffuse optical imaging.

We review the current state-of-the-art of diffuse optical imaging, which is an emerging technique for functional imaging of biological tissue. It involves generating images using measurements of visible or near-infrared light scattered across large (greater than several centimetres) thicknesses of tissue. We discuss recent advances in experimental methods and instrumentation, and examine new theoretical techniques applied to modelling and image reconstruction. We review recent work on in vivo applications including imaging the breast and brain, and examine future challenges.

Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis.

BACKGROUND: Active distal ulcerative colitis is often resistant to topically acting oral formulations. We speculated that the left side of the colon is underexposed to orally-dosed topical agents in patients with active distal colitis. METHODS: Twenty-two healthy volunteers (12 males, aged 22-47 years), and 10 patients (6 males, aged 33-73 years) with active left-sided ulcerative colitis ingested a Eudragit-coated gelatine capsule containing 111In-labelled amberlite resin on four successive days. Regional colonic distribution, transit times and percentage of daily dose resident were calculated from the average of four serial gamma camera images on the 4th day. RESULTS: (mean [95% CI]). When compared to controls, patients with colitis had significantly faster total colon transit (24.3 h [9.5-39.1] vs. 51.7 h [41.1-62.3]) as well as faster proximal colon transit (18.7 h [9.1-28.3] vs. 36.7 [28.5-44.9]), and distal colon transit (3.1 h [-0.5 to 6.8] vs. 15.0 h [10.5-19.5]), respectively (all P < 0.01). Material was asymmetrically distributed in health (proximal colon 69% [63-76] vs. distal colon 31% [24-37]). This asymmetry was more extreme in colitis, with corresponding values of 91% [85-96] vs. 9% [4-15]. As a result colitics had less material in the left-sided colon (9% [4-15] vs. 31% [24-37]), P < 0. 001. Colitics had a significantly lower percentage of the daily dose resident within the left side of the colon compared to controls (13% [-2 to 28] vs. 63% [44-81]), P < 0.01. CONCLUSIONS: Delayed release oral formulation is asymmetrically distributed within the colon in health. This asymmetry is exaggerated in active left-sided ulcerative colitis and, together with faster colonic transit, results in reduced exposure of the distal colon to orally-dosed topical agents.

An episodic outbreak of genetically related Burkholderia cepacia among non-cystic fibrosis patients at a university hospital.

OBJECTIVE: To investigate an outbreak of Burkholderia cepacia. DESIGN: Observational study and chart review. PATIENTS: Adult non-cystic fibrosis (CF) patients. SETTING: Intensive care units (ICUs) at a university-affiliated teaching hospital. METHODS: As part of the epidemiological investigation, we conducted a chart review and collected environmental samples. A review of work schedules of healthcare workers also was performed. We used B. cepacia selective agar for preliminary screening for all isolates, which subsequently were confirmed as members of the B. cepacia complex by polyphasic analysis employing conventional biochemical reactions and genus- and species-specific polymerase chain reaction assays. Pulsed-field gel electrophoresis, randomly amplified polymorphic DNA typing, and automated ribotyping were used to genotype the isolates. As part of the intervention, contact isolation precautions were initiated for all patients identified as having had a culture positive for B. cepacia. RESULTS: Between September 1997 and September 1999, B. cepacia was isolated from 31 adult patients without CF in ICUs at a university-affiliated teaching hospital. Based on geographic clustering and genotypic analysis, three distinct clusters were observed involving 20 patients. Isolates from 17 of these patients were available for testing and were found to be of the same strain (outbreak strain). Further taxonomic analysis indicated that the outbreak strain was B. cepacia complex genomovar III. Twelve (71%) of the 17 patients were judged to be infected, and 5 (29%) were colonized with this strain. Six of 200 environmental cultures from multiple sources in the hospital's ICUs yielded B. cepacia. Two of these isolates, both recovered from rooms of colonized patients, were the same genotype as the outbreak strain recovered from patients. CONCLUSION: Despite an extensive investigation, the source of the B. cepacia clone involved in this outbreak remains unknown. The spatial and temporal pattern of cases suggests that cross-transmission of a genetically related strain contributed to clustering among patients. The initiation of contact isolation may have limited the extent of this transmission. Additional studies are needed to elucidate better the epidemiology of nosocomial B. cepacia infection among non-CF adult patients.

Evaluating the spatial resolution performance of a time-resolved optical imaging system.

An imaging system is being developed as a possible means of screening for breast cancer using harmless doses of visible or near-infrared radiation. This system produces transmission images of highly scattering objects by recording and discriminating between the times-of-flight of transmitted photons. Experiments have been performed to evaluate the likely spatial resolution performance of such a system. This involved measuring the edge profile produced by an opaque mask embedded in a highly scattering medium, and evaluating the spatial resolution as a function of the period of time over which transmitted light was integrated. The results suggest that a resolution of a few millimeters is achievable with a system with a temporal resolution of about 10 ps.

Transillumination imaging performance: spatial resolution simulation studies.

Monte Carlo calculations were used to simulate the propagation of visible and near-infrared light through homogenous tissue in order to quantitate the potential spatial resolution performance for transillumination imaging. Specifically, the relative effectiveness of coaxial collimation and time of flight (TOF) detection for improving spatial resolution was investigated. The results demonstrate that significant improvements in spatial resolution can be achieved through these techniques, with TOF methods offering superior performance for a given level of detected signal intensity.

Transillumination imaging performance: a time-of-flight imaging system.

A series of Monte Carlo simulations have been performed in order to investigate the feasibility of constructing a time-of-flight transillumination imaging system that could be used as an effective tool for screening for breast disease. The conceptual design of such a system is described, and simulated images are presented that demonstrate its likely performance. It is found that, whereas the spatial resolution achievable with such a system is only dependent upon its temporal resolution, the scattering characteristics of the tissue being imaged will strongly affect the ultimate imaging performance of such a system.

The spatial resolution performance of a time-resolved optical imaging system using temporal extrapolation.

Optical imaging methods are being explored as a potential means of screening for breast cancer. Previous investigations of time-resolved imaging techniques have suggested that due to the lack of photons with sufficiently small pathlengths, the spatial resolution achievable through a human breast would be unlikely to be better than a centimeter. Experimental results presented here indicate, however, that higher resolution may be achieved by extrapolating the measured temporal distribution of transmitted photons. This is performed using a least-squares fit between data and an analytic model of photon transport. The spatial resolution of a time-resolved imaging system was evaluated by measuring the edge response produced by an opaque mask embedded in the center of a 51-mm-thick, very highly scattering medium. The limiting spatial resolution was improved from about 13 mm to about 5 mm.

Evaluation of spatial resolution as a function of thickness for time-resolved optical imaging of highly scattering media.

Previous experimental and theoretical investigations of the utility of time-resolved methods as a means of optical imaging through the human breast have indicated that a spatial resolution of approximately 1 cm is achievable by isolating the shortest path length photons which propagate through the tissue. Studies have also shown that resolution may be improved further by extrapolating the measured distribution using an appropriate model of photon transport. The experiments described here were performed in order to observe the relationship between achievable spatial resolution and the thickness of the medium. For a given time gate, an improvement in the spatial resolution was observed as the object thickness was reduced. Overall, the results indicate that a breast compression of about 1 cm may improve the limiting spatial resolution by as much as 7 mm. Less encouraging is the implication that temporal extrapolation over several orders of magnitude in intensity is required to achieve a comparable improvement in spatial resolution.

Effect of lateral boundaries on contrast functions in time-resolved transillumination measurements.

The method of images is employed to insert the effects of the presence of a single lateral boundary on contrast functions previously derived for an infinite slab using a random walk model of photon transport. The predictions of the model for zero and extrapolated boundary conditions are compared with Monte Carlo (MC) simulations and with experimental results obtained using a homogenous phantom with tissue-like optical properties. As expected, the extrapolated boundary condition yields better agreement between the theoretical predictions and results obtained from MC and experiments. This indicates that the random walk model has potential as a forward model in iterative imaging schemes developed for optical tomography.

Night-time quiescence and morning activation in the human colon: effect on transit of dispersed and large single unit formulations.

OBJECTIVES: Controlling the delivery of drugs to different regions of the colon remains an elusive goal. The aim of this study was to define the diurnal variation in colonic transit and show how this influences the colonic distribution and residence time of different formulations given either in the morning or evening. METHODS: Colonic transit of small particulates and a large capsule was measured during nocturnal sleep and daytime wakefulness. Eighteen healthy volunteers participated in a randomised crossover study. 111In-labelled resin (150-300 microm) and a large 99mTc-labelled non-disintegrating capsule (22 x 8 mm) were swallowed at either 0800h or 1700h. MAIN OUTCOME MEASURES: The geometric centre of isotope (range 1-9) was calculated from serial scintiscans allowing comparison of overnight and daytime transit. RESULTS: Transit of resin was delayed in the overnight compared to daytime 8 h periods (change in geometric centres (GCs), mean +/- SEM, 0.59 +/- 0.14 vs 1.46 +/- 0.39 respectively, P < 0.02). Maximal resin movement occurred immediately after awakening, prior to breakfast, in 9/18 studies (P < 0.05). The capsule was more distal than the resin at the end of the study 15 h after dosing (P < 0.001). There was marked inter-individual variability in distribution of both resin and capsule at 15 h, the range of GCs being 2.8-9 and 2.2-9, respectively. CONCLUSION: Sleep delays colonic transit and large capsules travel faster than dispersed small particles. However, substantial inter-individual variability in transit makes targeting specific regions of the human colon unreliable with either dispersed or single unit formulations.

Optical imaging in medicine: II. Modelling and reconstruction.

The desire for a diagnostic optical imaging modality has motivated the development of image reconstruction procedures involving solution of the inverse problem. This approach is based on the assumption that, given a set of measurements of transmitted light between pairs of points on the surface of an object, there exists a unique three-dimensional distribution of internal scatterers and absorbers which would yield that set. Thus imaging becomes a task of solving an inverse problem using an appropriate model of photon transport. In this paper we examine the models that have been developed for this task, and review current approaches to image reconstruction. Specifically, we consider models based on radiative transfer theory and its derivatives, which are either stochastic in nature (random walk, Monte Carlo, and Markov processes) or deterministic (partial differential equation models and their solutions). Image reconstruction algorithms are discussed which are based on either direct backprojection, perturbation methods, nonlinear optimization, or Jacobian calculation. Finally we discuss some of the fundamental problems that must be addressed before optical tomography can be considered to be an understood problem, and before its full potential can be realized.

Optical imaging in medicine: I. Experimental techniques.

The overwhelming scatter which occurs when optical radiation propagates through tissue severely limits the ability to image internal structure using measurements of transmitted intensity. A broad range of methods has been proposed during the past decade or so in order to improve imaging performance. Direct methods involve isolating an unscattered or least-scattered component of transmitted scattered light. Indirect methods generally involve measuring some characteristic of the temporal distribution of transmitted light, or an equivalent in the frequency domain, and obtaining a computational solution to the inverse problem. In this paper, we review the experimental techniques which have been proposed in order to explore both direct and indirect imaging. The relative merits and limitations of the various experimental methods are discussed, and we consider the future directions and likelihood of success of optical imaging in medicine.

A method for generating patient-specific finite element meshes for head modelling.

Finite element modelling of fields within the body, whether electrical or optical, requires knowledge of the geometry of the object being examined. It can be clinically impractical to obtain accurate surface information for individual patients, although a limited set of measurements such as the locations of sensors attached to the body, can be acquired more readily. In this paper, we describe how a generic surface taken from an adult head is warped to fit points measured on a neonatal head surface to provide a new, individual surface from which a finite element mesh was generated. Simulations show that data generated from this mesh and from the original neonatal head surface are similar to within experimental errors. However, data generated from a mesh of the best fit sphere were significantly different from data generated from the original neonatal head surface.

Time resolved optical tomography of the human forearm.

A 32-channel time-resolved optical imaging instrument has been developed principally to study functional parameters of the new-born infant brain. As a prelude to studies on infants, the device and image reconstruction methodology have been evaluated on the adult human forearm. Cross-sectional images were generated using time-resolved measurements of transmitted light at two wavelengths. All data were acquired using a fully automated computer-controlled protocol. Images representing the internal scattering and absorbing properties of the arm are presented, as well as images that reveal physiological changes during a simple finger flexion exercise. The results presented in this paper represent the first simultaneous tomographic reconstruction of the internal scattering and absorbing properties of a clinical subject using purely temporal data, with additional co-registered difference images showing repeatable absorption changes at two wavelengths in response to exercise.