Mark Cope

Estimation of optical pathlength through tissue from direct time of flight measurement.

Quantitation of near infrared spectroscopic data in a scattering medium such as tissue requires knowledge of the optical pathlength in the medium. This can now be estimated directly from the time of flight of picosecond length light pulses. Monte Carlo modelling of light pulses in tissue has shown that the mean value of the time dispersed light pulse correlates with the pathlength used in quantitative spectroscopic calculations. This result has been verified in a phantom material. Time of flight measurements of pathlength across the rat head give a pathlength of 5.3 +/- 0.3 times the head diameter.

Characterization of the near infrared absorption spectra of cytochrome aa3 and haemoglobin for the non-invasive monitoring of cerebral oxygenation

Near infrared (IR) spectroscopy can give continuous, direct information about cerebral oxygenation in vivo by providing signals from oxygenated and deoxygenated haemoglobin and cytochrome aa3. Due to a lack of precise spectral information and uncertainties about optical path length it has previously been impossible to quantify the data. We have therefore obtained the cytochrome aa3 spectrum in vivo from the brains of rats after replacing the blood with a fluorocarbon substitute. Near infrared haemoglobin spectra were also obtained, at various oxygenation levels, from cuvette studies of lysed human red blood cells. Estimates of optical path length have been obtained. The data were used to construct an algorithm for calculating the changes in oxygenated and deoxygenated haemoglobin and oxygenated cytochrome aa3 in tissue from changes in near IR absorption.

OPTICAL PATHLENGTH MEASUREMENTS ON ADULT HEAD, CALF AND FOREARM AND THE HEAD OF THE NEWBORN-INFANT USING PHASE-RESOLVED OPTICAL SPECTROSCOPY

We have used an intensity modulated optical spectrometer, which measures the phase shift across tissue experienced by intensity modulated near-infrared light, to determine the absolute optical pathlength through tissue. The instrument is portable and takes only 5 s to record pathlength at four wavelengths (690 nm, 744 nm, 807 nm and 832 nm). The absolute pathlength divided by the known spacing between the light source and detector on the skin is the differential pathlength factor (DPF) which previous studies have shown is approximately constant for spacings greater than 2.5 cm. DPF results are presented for measurements on 100 adults and 35 newborn infants to determine the statistical variation on the DPF. All measurements were made at a frequency of 200 MHz with source-detector spacings of > 4 cm. Results at 807 nm show a DPF of 4.16(+/- 18.8%) for adult arm, 5.51(+/- 18%) for adult leg, 6.26(+/- 14.1%) for adult head and 4.99(+/- 9%) for the head of a newborn infant. A wavelength dependence was obtained for DPF on all tissues and a difference in DPF between male and female was observed for both the adult arm and leg. The results can be used to improve the quantitation of chromophore concentration changes in adults and newborn infants.

THE THEORETICAL BASIS FOR THE DETERMINATION OF OPTICAL PATHLENGTHS IN TISSUE - TEMPORAL AND FREQUENCY-ANALYSIS

A concise theoretical treatment is developed for the calculation of mean time, differential pathlength, phase shift, modulation depth and integrated intensity of measurements of light intensity as a function of time on the surface of tissue, resulting from either the input of picosecond light pulses, or radio frequency-modulated light. The treatment uses the Greens function of the diffusion approximation to the radiative transfer equation, and develops this and its Fourier transform in a variety of geometries. Detailed comparisons are made of several of these parameters in several geometries, and their relation to experimentally measured clinical data. The limitations of the use of phase measurements is discussed.

Experimentally Measured Optical Pathlengths for the Adult Head, Calf and Forearm and the Head of the Newborn Infant as a Function of Inter Optode Spacing

The Differential Pathlength Factor (DPF) has been measured for several different tissues. The results showed that the DPF varied with the type of tissue studied, and in the case of the adult calf with sex. However, the DPF for all tissues studied was constant once the inter optode spacing exceeded 2.5 cm. Thus, measurements can be made by NIR spectroscopy at a range of inter optode spacings, and a single DPF used in the calculation of chromophore concentration. The results also showed that the major source of error in the DPF lay in the measurement of the inter optode spacing. To improve accuracy, two options are possible. Firstly, some means of continuous measurement of inter optode spacing could be incorporated in the NIR instrumentation. The better alternative would be an instrument incorporating a method of directly measuring the optical pathlength at each wavelength. This could be done either by time of flight measurement, or if it can be validated, by phase shift measurement.

Theoretical and experimental investigation of near-infrared light propagation in a model of the adult head

Near-infrared light propagation in various models of the adult head is analyzed by both time-of-flight measurements and mathematical prediction. The models consist of three- or four-layered slabs, the latter incorporating a clear cerebrospinal fluid (CSF) layer. The most sophisticated model also incorporates slots that imitate sulci on the brain surface. For each model, the experimentally measured mean optical path length as a function of source-detector spacing agrees well with predictions from either a Monte Carlo model or a finite-element method based on diffusion theory or a hybrid radiosity-diffusion theory. Light propagation in the adult head is shown to be highly affected by the presence of the clear CSF layer, and both the optical path length and the spatial sensitivity profile of the models with a CSF layer are quite different from those without the CSF layer. However, the geometry of the sulci and the boundary between the gray and the white matter have little effect on the detected light distribution.

Methods of Quantitating Cerebral Near Infrared Spectroscopy Data

Non invasive infrared spectroscopy is a well established technique for monitoring changes in the oxygenation status of tissues (1). The technique has in particular been successfully employed to monitor changes in cerebral blood and tissue oxygenation by observing the absorption of haemoglobin and cytochrome aa3 respectively. Because of the highly light scattering nature of the tissues studied, it has normally not been possible to quantitate the observed changes.

Measurement of cranial optical path length as a function of age using phase resolved near infrared spectroscopy

Near infrared spectroscopy (NIRS) has been used to measure concentration changes of cerebral hemoglobin and cytochrome in neonates, children, and adults, to study cerebral oxygenation and hemodynamics. To derive quantitative concentration changes from measurements of light attenuation, the optical path length must be known. This is obtained by multiplying the source/detector separation by a laboratory measured differential path length factor (DPF) which accounts for the increased distance traveled by light due to scattering. DPF has been measured by time of flight techniques on small populations of adults and postmortem infants. The values for adults are greater than those for newborns, and it is not clear how to interpolate the present data for studies on children. Recent developments in instrumentation using phase resolved spectroscopy techniques have produced a bedside unit which can measure optical path length on any subject. We have developed an intensity modulated optical spectrometer which measures path length at four wavelengths. Two hundred and eighty three subjects from 1 d of age to 50 y were studied. Measurements were made at a fixed frequency of 200 MHz and a source detector separation of 4.5 cm. Results suggest a slowly varying age dependence of DPF, following the relation DPF690 = 5.38 + 0.049A0.877, DPF744 = 5.11 + 0.106A0.723, DPF807 = 4.99 + 0.067A0.814, and DPF832 = 4.67 + 0.062A0.819, where DPF690 is the DPF measured at 690 nm and A is age is expressed in years from full term. There was a wide scatter of values, however, implying that ideally DPF should be measured at the time of each study.

A Monte Carlo investigation of optical pathlength in inhomogeneous tissue and its application to near-infrared spectroscopy

In order to quantify near-infrared spectroscopic (NIRS) data on an inhomogeneous medium, knowledge of the contribution of the various parts of the medium to the total NIRS signal is required. This is particularly true in the monitoring of cerebral oxygenation by NIRS, where the contribution of the overlying tissues must be known. The concept of the time point spread function (TPSF), which is used extensively in NIRS to determine the effective optical pathlength, is expanded to the more general inhomogeneous case. This is achieved through the introduction of the partial differential pathlength, which is the effective optical pathlength in the inhomogeneous medium, and an analytical proof of the applicability of the modified Beer-Lambert law in an inhomogeneous medium is shown. To demonstrate the use of partial differential pathlength, a Monte Carlo simulation of a two-concentric-sphere medium representing a simplified structure of the head is presented, and the possible contribution of the overlying medium to the total NIRS signal is discussed.

Absolute quantification methods in tissue near-infrared spectroscopy

Recent work aimed at providing an absolute measurement of tissue haemoglobin saturation and a new instrument development, the spatially resolved spectrometer (SRS), are discussed. The theoretical basis of operation of this device and its hardware implementation are described and the results of validation studies on tissue simulating phantoms are presented as are preliminary measurements on human volunteers and observations on patients undergoing neurosurgery. In its present form the instrument appears to produce absolute haemoglobin saturation values for resting human skeletal muscle and the normally perfused human head which are rather low based on physiological expectations. However, we obtained a tight correlation between the saturation values measured by the SRS instrument and those obtained from blood-gas analysis of samples drawn from a jugular bulb catheter in one neurosurgery subject during clamping of the right carotid arteries.