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.

Epidural catheter with integrated light guides for spectroscopic tissue characterization.

Epidural catheters are used to deliver anesthetics and opioids for managing pain in many clinical scenarios. Currently, epidural catheter insertion is performed without information about the tissues that are directly ahead of the catheter. As a result, the catheter can be incorrectly positioned within a blood vessel, which can cause toxicity. Recent studies have shown that optical reflectance spectroscopy could be beneficial for guiding needles that are used to insert catheters. In this study, we investigate the whether this technique could benefit the placement of catheters within the epidural space. We present a novel optical epidural catheter with integrated polymer light guides that allows for optical spectra to be acquired from tissues at the distal tip. To obtain an initial indication of the information that could be obtained, reflectance values and photon penetration depth were estimated using Monte Carlo simulations, and optical reflectance spectra were acquired during a laminectomy of a swine ex vivo. Large differences between the spectra acquired from epidural adipose tissue and from venous blood were observed. The optical catheter has the potential to provide real-time detection of intravascular catheter placement that could reduce the risk of complications.

The reproducibility of optical mammography in healthy volunteers.

This study was designed to determine the reproducibility of optical mammography. Eight healthy pre-menopausal volunteers were scanned at different time intervals (minutes, weeks and months apart) to investigate the effects of within-subject variation, between-subject variation and systematic variations on both the raw data and images. The study shows that the greatest source of variation in optical mammography raw data and images is between different subjects, and scans of the same subject are very reproducible. The averaged total haemoglobin concentration from the eight volunteers was (24 ± 10) µM, and the average tissue oxygen saturation was (70 ± 10)%, which is comparable with other data in the literature. The average absorption coefficient at 780 nm was (0.0048 ± 0.0017) mm(-1) and the average reduced scatter coefficient at 780 nm was (0.80 ± 0.12) mm(-1). Again, this is comparable with published values. When our data are combined with the published values, the weighted average total haemoglobin concentration and tissue oxygen saturation for pre-menopausal breasts are (29 ± 8) µM and (73 ± 3)%, respectively. The results of our study show that we can be reassured that any changes within the tumour region seen during neoadjuvant therapy are likely to be due to a real physiological response to treatment, as the physiological properties of the breast remain relatively constant. However, in this study, we cannot distinguish between a tumour response to treatment and systemic changes in the healthy breast.

Monitoring the response to primary medical therapy for breast cancer using three- dimensional time-resolved optical mammography.

Primary medical therapy is used to reduce tumour size prior to surgery in women with locally advanced breast cancer. Optical tomography is a functional imaging technique using near- infrared light to produce three-dimensional breast images of tissue oxygen saturation and haemoglobin concentration. Its advantages include the ability to display quantitative physiological information, and to allow repeated scans without the hazards associated with exposure to ionising radiation. There is a need for a non-invasive functional imaging tool to evaluate response to treatment, so that non-responders can be given the opportunity to change their treatment regimen. Here, we evaluate the use of optical tomography for this purpose. Four women with newly diagnosed breast cancer who were about to undergo primary medical therapy gave informed and voluntary consent to take part in the study. Changes in physiological and optical properties within the tumour were evaluated during the course of neoadjuvant chemotherapy. Optical imaging was performed prior to treatment, after the first cycle of chemotherapy, halfway through, and on completion of chemotherapy. Images of light absorption and scatter at two wavelengths were produced, from which images of total haemoglobin concentration and oxygen saturation were derived. All patients that showed a good or complete response to treatment on MRI showed a corresponding recovery in the haemoglobin concentration images. Changes in mean tumour total haemoglobin concentration could be seen four weeks into treatment. The tumour oxygen saturation was low compared to background in three out of four patients, and also showed a return to baseline over treatment. Optical imaging of the breast is feasible during primary medical therapy and can be used to assess response to treatment over six months.

Assessing the validity of modulation transfer function evaluation techniques with application to small area and scanned digital detectors.

A novel prototype step and shoot x-ray system, the intelligent imaging system (I-Imas), has been developed in the UCL Radiation Physics laboratories. The system uses collimators to split the beam into two: the first, "scout" beam, strongly attenuated, identifies regions of interest in the image. This information is then fed back to the system so that the intensity of the second beam is modulated to optimize the dose distribution--i.e., "interesting" regions of the sample receive a higher dose, whereas other regions receive a lower one. Such systems may be capable of improved diagnostic capability at the same overall patient dose levels as typical when using large area digital plates. This acquisition mode means that large overall images are obtained by aligning many smaller images. This paper investigates the effects that this acquisition modality has on the overall spatial resolution of the system. We review different modulation transfer function (MTF) evaluation techniques and those shown to be optimal are used in the investigation of two considerations key to such a system: (i) whether there is a minimum size sensor whose MTF can accurately be determined using these techniques and (ii) whether the MTF of the large overall image differs significantly from those of the many constituent images. As the use of step and shoot systems is becoming more and more widespread, both are important considerations. We found that, for a fixed pixel pitch, the MTF is determined marginally less accurately the smaller the sensor area, with the perceived resolution varying by up to 0.1 lp/mm. It was also found that use of such a step and shoot technique does cause a very small overall degradation in resolution. The resolution of overall images was calculated to be 0.1 lp/mm lower than that of the individual images acquired.

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.

Three dimensional optical imaging of blood volume and oxygenation in the neonatal brain.

Optical methods provide a means of monitoring cerebral oxygenation in newborn infants at risk of brain injury. A 32-channel optical imaging system has been developed with the aim of reconstructing three-dimensional images of regional blood volume and oxygenation. Full image data sets were acquired from 14 out of 24 infants studied; successful images have been reconstructed in 8 of these infants. Regional variations in cerebral blood volume and tissue oxygen saturation are present in healthy preterm infants. In an infant with a large unilateral intraventricular haemorrhage, a corresponding region of low oxygen saturation was detected. These results suggest that optical tomography may provide an appropriate technique for investigating regional cerebral haemodynamics and oxygenation at the cotside.

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.

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.

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.

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.

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.

Three-dimensional time-resolved optical tomography of a conical breast phantom.

A 32-channel time-resolved imaging device for medical optical tomography has been employed to evaluate a scheme for imaging the human female breast. The fully automated instrument and the reconstruction procedure have been tested on a conical phantom with tissue-equivalent optical properties. The imaging protocol has been designed to obviate compression of the breast and the need for coupling fluids. Images are generated from experimental data with an iterative reconstruction algorithm that employs a three-dimensional (3D) finite-element diffusion-based forward model. Embedded regions with twice the background optical properties are revealed in separate 3D absorption and scattering images of the phantom. The implications for 3D time-resolved optical tomography of the breast are discussed.

Multiple-slice imaging of a tissue-equivalent phantom by use of time-resolved optical tomography.

Following several years of development the construction of a multichannel time-resolved imaging device for medical optical tomography has been completed. Images are reconstructed from time-resolved measurements by use of a scheme that employs a finite-element diffusion-based forward model and an iterative reconstruction solver. Prior to testing on clinical subjects the fully automated instrument and the reconstruction software are evaluated with tissue-equivalent phantoms. We describe our first attempt to generate multiple-slice images of a phantom without uniform properties along the axial direction, while still using a computationally fast two-dimensional reconstruction algorithm. The image quality is improved by the employment of an approximate correction method that uses scaling factors derived from the ratios of finite-element forward simulations in two and three spatial dimensions. The 32-channel system was employed to generate maps of the internal scattering and the absorption properties at 14 different transverse planes across the phantom. The images clearly reveal the locations of small inhomogeneous regions embedded within the phantom. These results were obtained by use of purely temporal data and without resource to reference measurements.

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.

Simultaneous reconstruction of absorption and scattering images by multichannel measurement of purely temporal data.

We present what is believed to be the first simultaneous reconstruction of the internal scattering and absorbing properties of a highly scattering medium by use of purely temporal data. These results are also the first acquired with the multichannel time-resolved imaging system developed at University College London.

Time-dependent contrast functions for quantitative imaging in time-resolved transillumination experiments.

We have developed a methodology that can be used in reconstruction algorithms to quantify the optical coefficients and the geometrical cross section of a weakly abnormal optical target embedded in an otherwise homogeneous medium. This novel procedure uses differenttime-dependent point-spread functions to analyze the diffusive and absorptive contrasts obtained from time-of-flight measurements. Data obtained from time-resolved transillumination of a tissuelike phantom are used to test the accuracy of this new deconvolution methodology.

Evaluation of the temporally extrapolated absorbance method for dual-wavelength imaging through tissuelike scattering media.

An independent assessment is described of a dual-wavelength imaging technique, known as the temporally extrapolated absorbance method (TEAM), proposed by Yamada et al. [Opt. Eng. 32, 634-641 (1993)]. The technique involves recording the temporal distribution of light transmitted across a scattering medium at two carefully chosen wavelengths at which the scattering properties of the medium are assumed to be identical. The objective is to image internal structure that absorbs more strongly at one wavelength than it does at the other. A simple theoretical treatment of TEAM is presented that employs a perturbation model of photon transport. This indicates that despite the lack of a secure theoretical basis, the technique may provide a potentially effective ad hoc method of generating images of highly scattering media. The method was also evaluated experimentally by using, for the first time to our knowledge, a single object and two wavelengths. A single-projection, two-dimensional image was obtained of a solid phantom with optical properties representative of breast tissue. The results exhibited good agreement with the theoretical model, and a small embedded feature that absorbs 3.5 times as strongly as the surrounding medium at one wavelength was revealed successfully.

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.