Construction and validation of a database of head models for functional imaging of the neonatal brain.

The neonatal brain undergoes dramatic structural and functional changes over the last trimester of gestation. The accuracy of source localisation of brain activity recorded from the scalp therefore relies on accurate age-specific head models. Although an age-appropriate population-level atlas could be used, detail is lost in the construction of such atlases, in particular with regard to the smoothing of the cortical surface, and so such a model is not representative of anatomy at an individual level. In this work, we describe the construction of a database of individual structural priors of the neonatal head using 215 individual-level datasets at ages 29-44 weeks postmenstrual age from the Developing Human Connectome Project. We have validated a method to segment the extra-cerebral tissue against manual segmentation. We have also conducted a leave-one-out analysis to quantify the expected spatial error incurred with regard to localising functional activation when using a best-matching individual from the database in place of a subject-specific model; the median error was calculated to be 8.3 mm (median absolute deviation 3.8 mm). The database can be applied for any functional neuroimaging modality which requires structural data whereby the physical parameters associated with that modality vary with tissue type and is freely available at www.ucl.ac.uk/dot-hub.

Diffuse optical tomography for the detection of perinatal stroke at the cot side: a pilot study.

BACKGROUND: Perinatal stroke is a potentially debilitating injury, often under-diagnosed in the neonatal period. We conducted a pilot study investigating the role of the portable, non-invasive brain monitoring technique, diffuse optical tomography (DOT), as an early detection tool for infants with perinatal stroke. METHODS: Four stroke-affected infants were scanned with a DOT system within the first 3 days of life and compared to four healthy control subjects. Spectral power, correlation, and phase lag between interhemispheric low frequency (0.0055-0.3 Hz) hemoglobin signals were assessed. Optical data analyses were conducted with and without magnetic resonance imaging (MRI)-guided stroke localization to assess the efficacy of DOT when used without stroke anatomical information. RESULTS: Interhemispheric correlations of both oxyhemoglobin and deoxyhemoglobin concentration were significantly reduced in the stroke-affected group within the very low (0.0055-0.0095 Hz) and resting state (0.01-0.08 Hz) frequencies (p < 0.003). There were no interhemispheric differences for spectral power. These results were observed even without MRI stroke localization. CONCLUSION: This suggests that DOT and correlation-based analyses in the low-frequency range can potentially aid the early detection of perinatal stroke, prior to MRI acquisition. Additional methodological advances are required to increase the sensitivity and specificity of this technique.

Using spectral derivatives to remove the influence of hair on optical images of the static absorbing properties of tissue-like turbid media.

Significance: Although measurements of near-infrared light diffusely reflected from the head and other biological tissues are commonly used to generate images revealing changes in the concentrations of oxy- and deoxy-hemoglobin, static imaging of absolute concentrations has been inhibited by the unknown and variable coupling between the optical probe and the skin, to which hair is often a significant contributor. Measurements of spectral derivatives provide a means of overcoming this shortcoming. Aim: The aim is to demonstrate experimentally that measurements of the derivative of the attenuation of the detected signal with respect to wavelength can be used to achieve images that are immune to the spatial variation of hair on the surface. The objective is to generate topographic images representative of static absorbing properties rather than retrieving absolute optical coefficients, which requires a tomographic approach. Approach: The surface of a tissue-equivalent phantom, containing targets with different concentrations of absorbing dye, was coated with a layer of dark hair. The phantom was then imaged using a broadband source and spectrometer, and prior knowledge of the absorbing characteristics of the dye and of melanin was used to acquire separate images of each. Results: The targets within the phantom are revealed with remarkable clarity, although a nonlinear relationship between the target contrast and absorption was observed. This nonlinear behavior was confirmed and explained using a Monte Carlo model of light propagation in a slab of similar absorbing properties. Conclusions: A spectral derivative approach could be an effective tool for in vivo topographic imaging of the static optical properties of the brain and other tissues, avoiding the deleterious effects of hair.

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.

Exploring the feasibility of wavelength modulated near-infrared spectroscopy.

SIGNIFICANCE: The application of near-infrared spectroscopy (NIRS) to determine the concentrations of tissue chromophores has typically relied on three alternative technological approaches: continuous-wave, frequency-domain, and time-domain. It is often the case that uncertain and variable coupling of light into and out of the skin surface renders absolute measurements unreliable, and NIRS methods are mostly used to measure changes of chromophore concentrations and of physiological parameters such as blood volume and oxygenation. AIM: The aim has been to investigate whether an approach based on a wavelength-modulated source may enable measurements to be acquired, which are independent of surface coupling and may facilitate derivation of absolute values of tissue parameters. APPROACH: An analysis is performed using the modified Beer-Lambert law. RESULTS: It is shown that the relative modulation in detected intensity resulting from a wavelength-modulated source could be used to estimate absolute concentrations of chromophores if unknown surface coupling losses and geometrical factors are insensitive to small changes in wavelength. CONCLUSIONS: Wavelength modulated NIRS could be an effective tool for quantitative in vivo analysis of tissues, although it may be technically challenging.

Dual wavelength spread-spectrum time-resolved diffuse optical instrument for the measurement of human brain functional responses.

Near-infrared spectroscopy has proven to be a valuable method to monitor tissue oxygenation and haemodynamics non-invasively and in real-time. Quantification of such parameters requires measurements of the time-of-flight of light through tissue, typically achieved using picosecond pulsed lasers, with their associated cost, complexity, and size. In this work, we present an alternative approach that employs spread-spectrum excitation to enable the development of a small, low-cost, dual-wavelength system using vertical-cavity surface-emitting lasers. Since the optimal wavelengths and drive parameters for optical spectroscopy are not served by commercially available modules as used in our previous single-wavelength demonstration platform, we detail the design of a custom instrument and demonstrate its performance in resolving haemodynamic changes in human subjects during apnoea and cognitive task experiments.

Sleep State Modulates Resting-State Functional Connectivity in Neonates.

The spontaneous cerebral activity that gives rise to resting-state networks (RSNs) has been extensively studied in infants in recent years. However, the influence of sleep state on the presence of observable RSNs has yet to be formally investigated in the infant population, despite evidence that sleep modulates resting-state functional connectivity in adults. This effect could be extremely important, as most infant neuroimaging studies rely on the neonate to remain asleep throughout data acquisition. In this study, we combine functional near-infrared spectroscopy with electroencephalography to simultaneously monitor sleep state and investigate RSNs in a cohort of healthy term born neonates. During active sleep (AS) and quiet sleep (QS) our newborn neonates show functional connectivity patterns spatially consistent with previously reported RSN structures. Our three independent functional connectivity analyses revealed stronger interhemispheric connectivity during AS than during QS. In turn, within hemisphere short-range functional connectivity seems to be enhanced during QS. These findings underline the importance of sleep state monitoring in the investigation of RSNs.

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.

A spread spectrum approach to time-domain near-infrared diffuse optical imaging using inexpensive optical transceiver modules.

We introduce a compact time-domain system for near-infrared spectroscopy using a spread spectrum technique. The proof-of-concept single channel instrument utilises a low-cost commercially available optical transceiver module as a light source, controlled by a Kintex 7 field programmable gate array (FPGA). The FPGA modulates the optical transceiver with maximum-length sequences at line rates up to 10Gb/s, allowing us to achieve an instrument response function with full width at half maximum under 600ps. The instrument is characterised through a set of detailed phantom measurements as well as proof-of-concept in vivo measurements, demonstrating performance comparable with conventional pulsed time-domain near-infrared spectroscopy systems.

Gel wax-based tissue-mimicking phantoms for multispectral photoacoustic imaging.

Tissue-mimicking phantoms are widely used for the calibration, evaluation and standardisation of medical imaging systems, and for clinical training. For photoacoustic imaging, tissue-mimicking materials (TMMs) that have tuneable optical and acoustic properties, high stability, and mechanical robustness are highly desired. In this study, gel wax is introduced as a TMM that satisfies these criteria for developing photoacoustic imaging phantoms. The reduced scattering and optical absorption coefficients were independently tuned with the addition of TiO2 and oil-based inks. The frequency-dependent acoustic attenuation obeyed a power law; for native gel wax, it varied from 0.71 dB/cm at 3 MHz to 9.93 dB/cm at 12 MHz. The chosen oil-based inks, which have different optical absorption spectra in the range of 400 to 900 nm, were found to have good photostability under pulsed illumination with photoacoustic excitation light. Optically heterogeneous phantoms that comprised of inclusions with different concentrations of carbon black and coloured inks were fabricated, and multispectral photoacoustic imaging was performed with an optical parametric oscillator and a planar Fabry-Pérot sensor. We conclude that gel wax is well suited as a TMM for multispectral photoacoustic imaging.

Mid-infrared optical coherence tomography.

A time domain optical coherence tomography (OCT) system is described that uses mid-infrared light (6-8 microm). To the best of our knowledge, this is the first OCT system that operates in the mid-infrared spectral region. It has been designed to characterize bioengineered tissues in terms of their structure and biochemical composition. The system is based upon a free-space Michelson interferometer with a germanium beam splitter and a liquid nitrogen cooled HgCdTe detector. A key component of this work has been the development of a broadband quantum cascade laser source (InGaAs/AlInAs containing 11 different active regions of the three well vertical transition type) that emits continuously over the 6-8 microm wavelength range. This wavelength range corresponds to the so called "mid-infrared fingerprint region" which exhibits well-defined absorption bands that are specifically attributable to the absorbing molecules. Therefore, this technology provides an opportunity for optical coherence molecular imaging without the need for molecular contrast agents. Preliminary measurements are presented.

Probe for evaluating the absorbing and transport scattering properties of turbid fluids using low-cost time-of-flight technology.

A probe is described that when immersed into a highly scattering fluid provides a measurement of its scattering and absorbing properties at a single optical wavelength. It uses recently available low-cost proximity sensor modules to estimate the mean flight times of photons diffusely transmitted between near-infrared sources and detectors at two different separations. The probe has been designed with a specific application for enabling the rapid and efficient production of fluids, which mimic the optical properties of biological tissues. The potential of the device is demonstrated using precalibrated solutions of intralipid, an intravenous nutrient, and absorbing dye. It is shown that a combination of time-of-flight measurements at two source­detector separations can uniquely specify the absorption coefficient and the transport scattering coefficient.

Geometrically complex 3D-printed phantoms for diffuse optical imaging.

Tissue-equivalent phantoms that mimic the optical properties of human and animal tissues are commonly used in diffuse optical imaging research to characterize instrumentation or evaluate an image reconstruction method. Although many recipes have been produced for generating solid phantoms with specified absorption and transport scattering coefficients at visible and near-infrared wavelengths, the construction methods are generally time-consuming and are unable to create complex geometries. We present a method of generating phantoms using a standard 3D printer. A simple recipe was devised which enables printed phantoms to be produced with precisely known optical properties. To illustrate the capability of the method, we describe the creation of an anatomically accurate, tissue-equivalent premature infant head optical phantom with a hollow brain space based on MRI atlas data. A diffuse optical image of the phantom is acquired when a high contrast target is inserted into the hollow space filled with an aqueous scattering solution.

Comparison between a time-domain and a frequency-domain system for optical tomography.

The quality of phase and amplitude data from two medical optical tomography systems were compared. The two systems are a 32-channel time-domain system developed at University College London (UCL) and a 16-channel frequency-domain system developed at Helsinki University of Technology (HUT). Difference data measured from an inhomogeneous and a homogeneous phantom were compared with a finite-element method (diffusion equation) and images of scattering and absorption were reconstructed based on it. The measurements were performed at measurement times between 1 and 30 s per source. The mean rms errors in the data measured by the HUT system were 3.4% for amplitude and 0.51 deg for phase, while the corresponding values for the UCL data were 6.0% and 0.46 deg, respectively. The reproducibility of the data measured with the two systems was tested with a measurement time of 5 s per source. It was 0.4% in amplitude for the HUT system and 4% for the UCL system, and 0.08 deg in phase for both systems. The image quality of the reconstructions from the data measured with the two systems were compared with several quantitative criteria. In general a higher contrast was observed in the images calculated from the HUT data.

A soft deformable tissue-equivalent phantom for diffuse optical tomography.

A recipe is presented for the manufacture of highly compressible phantoms for diffuse optical tomography. The recipe is based on polyvinyl alcohol (PVA) slime, a viscoelastic fluid which readily deforms under moderate pressure. Scattering particles and absorbing compounds can be added to provide a uniform material with stable and reproducible optical properties. A linear relationship between the concentration of scattering particles (either titanium dioxide or microspheres) and the transport scatter coefficient is demonstrated. Phantoms of an arbitrary size and shape may be produced by containing the slime within a thin latex shell, and a stability over a period of at least 3 months has been established. The deformable phantoms may be used to test and calibrate optical tomography systems designed for use on patients with irregular or variable geometries.

Functional imaging of the human brain using a modular, fibre-less, high-density diffuse optical tomography system.

We present the first three-dimensional, functional images of the human brain to be obtained using a fibre-less, high-density diffuse optical tomography system. Our technology consists of independent, miniaturized, silicone-encapsulated DOT modules that can be placed directly on the scalp. Four of these modules were arranged to provide up to 128, dual-wavelength measurement channels over a scalp area of approximately 60 × 65 mm2. Using a series of motor-cortex stimulation experiments, we demonstrate that this system can obtain high-quality, continuous-wave measurements at source-detector separations ranging from 14 to 55 mm in adults, in the presence of hair. We identify robust haemodynamic response functions in 5 out of 5 subjects, and present diffuse optical tomography images that depict functional haemodynamic responses that are well-localized in all three dimensions at both the individual and group levels. This prototype modular system paves the way for a new generation of wearable, wireless, high-density optical neuroimaging technologies.

Towards a wearable near infrared spectroscopic probe for monitoring concentrations of multiple chromophores in biological tissue in vivo.

The first wearable multi-wavelength technology for functional near-infrared spectroscopy has been developed, based on a custom-built 8-wavelength light emitting diode (LED) source. A lightweight fibreless probe is designed to monitor changes in the concentrations of multiple absorbers (chromophores) in biological tissue, the most dominant of which at near-infrared wavelengths are oxyhemoglobin and deoxyhemoglobin. The use of multiple wavelengths enables signals due to the less dominant chromophores to be more easily distinguished from those due to hemoglobin and thus provides more complete and accurate information about tissue oxygenation, hemodynamics, and metabolism. The spectroscopic probe employs four photodiode detectors coupled to a four-channel charge-to-digital converter which includes a charge integration amplifier and an analogue-to-digital converter (ADC). Use of two parallel charge integrators per detector enables one to accumulate charge while the other is being read out by the ADC, thus facilitating continuous operation without dead time. The detector system has a dynamic range of about 80 dB. The customized source consists of eight LED dies attached to a 2 mm × 2 mm substrate and encapsulated in UV-cured epoxy resin. Switching between dies is performed every 20 ms, synchronized to the detector integration period to within 100 ns. The spectroscopic probe has been designed to be fully compatible with simultaneous electroencephalography measurements. Results are presented from measurements on a phantom and a functional brain activation study on an adult volunteer, and the performance of the spectroscopic probe is shown to be very similar to that of a benchtop broadband spectroscopy system. The multi-wavelength capabilities and portability of this spectroscopic probe will create significant opportunities for in vivo studies in a range of clinical and life science applications.