The nEUROPt protocol is one of two new protocols developed within the European project nEUROPt to characterize the performances of time-domain systems for optical imaging of the brain. It was applied in joint measurement campaigns to compare the various instruments and to assess the impact of technical improvements. This protocol addresses the characteristic of optical brain imaging to detect, localize, and quantify absorption changes in the brain. It was implemented with two types of inhomogeneous liquid phantoms based on Intralipid and India ink with well-defined optical properties. First, small black inclusions were used to mimic localized changes of the absorption coefficient. The position of the inclusions was varied in depth and lateral direction to investigate contrast and spatial resolution. Second, two-layered liquid phantoms with variable absorption coefficients were employed to study the quantification of layer-wide changes and, in particular, to determine depth selectivity, i.e., the ratio of sensitivities for deep and superficial absorption changes. We introduce the tests of the nEUROPt protocol and present examples of results obtained with different instruments and methods of data analysis. This protocol could be a useful step toward performance tests for future standards in diffuse optical imaging.
Performance assessment of instruments devised for clinical applications is of key importance for validation and quality assurance. Two new protocols were developed and applied to facilitate the design and optimization of instruments for time-domain optical brain imaging within the European project nEUROPt. Here, we present the “Basic Instrumental Performance” protocol for direct measurement of relevant characteristics. Two tests are discussed in detail. First, the responsivity of the detection system is a measure of the overall efficiency to detect light emerging from tissue. For the related test, dedicated solid slab phantoms were developed and quantitatively spectrally characterized to provide sources of known radiance with nearly Lambertian angular characteristics. The responsivity of four time-domain optical brain imagers was found to be of the order of 0.1 m2 sr. The relevance of the responsivity measure is demonstrated by simulations of diffuse reflectance as a function of source-detector separation and optical properties. Second, the temporal instrument response function (IRF) is a critically important factor in determining the performance of time-domain systems. Measurements of the IRF for various instruments were combined with simulations to illustrate the impact of the width and shape of the IRF on contrast for a deep absorption change mimicking brain activation.
Multi-source operation in time-domain optical brain imaging often relies on the use of piezomechanical fiber switches which limit the speed when recording dynamic processes. The concept presented in this work overcomes this limitation by multiplexing on the nanosecond and microsecond time scales. In particular, the source positions were encoded by different delays on the nanosecond time scale. Multiplexing of wavelengths on the microsecond time scale (e.g. within 100 μs) was achieved by burst-mode operation of picosecond diode lasers in combination with addressing of different memory blocks in time-correlated single photon counting by means of routing inputs. This concept was implemented for 4 detectors and 5 source optodes yielding 12 measurement channels per hemisphere. In order to largely equalize the count rates for all source-detector pairs with minimal overall losses, a setup was developed that enabled the freely adjustable distribution of laser power to the various source optodes. It was based on polarization splitters and motorized broadband polarization rotators. The method was successfully demonstrated in an in vivo experiment employing two different types of motor activation of the brain.
KEYWORDS: Tissues, Kidney, Monte Carlo methods, Tissue optics, Oxygen, Optical properties, In vivo imaging, Absorption, Scattering, Diffuse reflectance spectroscopy
We have developed a method to quantify hemoglobin concentration and oxygen saturation within the renal cortex by near-infrared spectroscopy. A fiber optic probe was used to transmit the radiation of three semiconductor lasers at 690 nm, 800 nm and 830 nm to the tissue, and to collect diffusely remitted light at source-detector separations from 1 mm to 4 mm. To derive tissue hemoglobin concentration and oxygen saturation of hemoglobin the spatial dependence of the measured cw intensities was fitted by a Monte Carlo model. In this model the tissue was assumed to be homogeneous. The scaling factors between measured intensities and simulated photon flux were obtained by applying the same setup to a homogeneous semi-infinite phantom with known optical properties and by performing Monte Carlo simulations for this phantom. To accelerate the fit of the tissue optical properties a look-up table of the simulated reflected intensities was generated for the needed range of absorption and scattering coefficients. The intensities at the three wavelengths were fitted simultaneously using hemoglobin concentration, oxygen saturation, the reduced scattering coefficient at 800 nm and the scatter power coefficient as fit parameters. The method was employed to study the temporal changes of renal hemoglobin concentration and blood oxygenation on an anesthetized rat during a short period of renal ischemia induced by aortic occlusion and during subsequent reperfusion.
Novel protocols were developed and applied in the European project “nEUROPt” to assess and compare the performance
of instruments for time-domain optical brain imaging and of related methods of data analysis. The objective of the first
protocol, “Basic Instrumental Performance”, was to record relevant basic instrumental characteristics in a direct way.
The present paper focuses on the second novel protocol (“nEUROPt” protocol) that was devoted to the assessment of
sensitivity, spatial resolution and quantification of absorption changes within inhomogeneous media. It was implemented
with liquid phantoms based on Intralipid and ink, with black inclusions and, alternatively, in two-layered geometry.
Small black cylinders of various sizes were used to mimic small localized changes of the absorption coefficient. Their
position was varied in depth and lateral direction to address contrast and spatial resolution. Two-layered liquid phantoms
were used, in particular, to determine depth selectivity, i.e. the ratio of contrasts due to a deep and a superficial
absorption change of the same magnitude. We introduce the tests of the “nEUROPt” protocol and present exemplary
results obtained with various instruments. The results are related to measurements with both types of phantoms and to
the analysis of measured time-resolved reflectance based on time windows and moments. Results are compared for the
different instruments or instrumental configurations as well as for the methods of data analysis. The nEUROPt protocol
is also applicable to cw or frequency-domain instruments and could be useful for designing performance tests in future
standards in diffuse optical imaging.
Robot-assisted motor rehabilitation proved to be an effective supplement to conventional hand-to-hand therapy in stroke
patients. In order to analyze and understand motor learning and performance during rehabilitation it is desirable to
develop a monitor to provide objective measures of the corresponding brain activity at the rehabilitation progress. We
used a portable time-domain near-infrared reflectometer to monitor the hemodynamic brain response to distal upper
extremity activities. Four healthy volunteers performed two different robot-assisted wrist/forearm movements, flexion-extension
and pronation-supination in comparison with an unassisted squeeze ball exercise. A special headgear with four
optical measurement positions to include parts of the pre- and postcentral gyrus provided a good overlap with the
expected activation areas. Data analysis based on variance of
time-of-flight distributions of photons through tissue was
chosen to provide a suitable representation of intracerebral signals. In all subjects several of the four detection channels
showed a response. In some cases indications were found of differences in localization of the activated areas for the
various tasks.
To facilitate the design and optimization of instruments for time-domain optical brain imaging within the European
project "nEUROPt", the performance of various instruments is assessed and compared. This type of instruments relies on
picosecond lasers with high repetition rates, fast detectors and time-correlated single photon counting. The first step of
the assessment included a number of basic tests that are related to parameters of the source, to the differential
nonlinearity of the timing electronics and to the temporal instrument response function (IRF). An additional test has been
devised to measure the responsivity of the detection system, i.e. the overall efficiency to collect and detect light
emerging from tissue. Dedicated solid slab phantoms have been developed and quantitatively spectrally characterized to
provide sources of known radiance with nearly Lambertian angular characteristics. The wavelength-dependent
transmittance factor of these phantoms was of the order of 1020/(W s m2sr). Measurements of the responsivity of the
detection systems of three time-domain optical brain imagers tested yielded similar values of the order of 0.1 mm2sr.
We present results of a clinical study on bedside perfusion monitoring of the human brain by optical bolus tracking. We measure the kinetics of the contrast agent indocyanine green using time-domain near-IR spectroscopy (tdNIRS) in 10 patients suffering from acute unilateral ischemic stroke. In all patients, a delay of the bolus over the affected when compared to the unaffected hemisphere is found (mean: 1.5 s, range: 0.2 s to 5.2 s). A portable time-domain near-IR reflectometer is optimized and approved for clinical studies. Data analysis based on statistical moments of time-of-flight distributions of diffusely reflected photons enables high sensitivity to intracerebral changes in bolus kinetics. Since the second centralized moment, variance, is preferentially sensitive to deep absorption changes, it provides a suitable representation of the cerebral signals relevant for perfusion monitoring in stroke. We show that variance-based bolus tracking is also less susceptible to motion artifacts, which often occur in severely affected patients. We present data that clearly manifest the applicability of the tdNIRS approach to assess cerebral perfusion in acute stroke patients at the bedside. This may be of high relevance to its introduction as a monitoring tool on stroke units.
We present a new method to reconstruct arbitrary large volumes in (fluorescence) diffuse optical tomography by
splitting the volume of reconstruction into sub-volumes. This allows to perform nonlinear reconstruction on large
grids with a larger number of measurement data and more grid nodes than conventional reconstruction schemes,
where images are reconstructed on a single grid. We investigate how the reconstructed spatial distributions of
diffusion and absorption coefficients using the new method depend on the size of the sub-volumes, compare the
convergence to the conventional nonlinear approach, and present an error estimation.
We have carried out phantom studies for optimizing the design of a fluorescence mammograph employing time-domain
and cw measurements, for improving data analysis and methods of reconstruction. By scanning pulsed (100 fs) laser
radiation across a fluorescent, rectangular breast-like phantom with a spherical inhomogeneity simulating a tumor
bearing breast slightly compressed between two parallel glass plates, distributions of times of flight of laser and
fluorescence photons were measured in transmission and reflection for various detector arrangements. Absorption
coefficients and dye concentrations were reconstructed using perturbation solutions of the diffusion equation at the laser
and fluorescence wavelengths. We additionally employed a CCD camera to measure time-integrated intensity of
fluorescence and laser radiation transmitted through the phantom. The increased number of projection angles entering the
reconstruction improved spatial resolution. Further improvements were obtained when combined cw data and time-resolved
remission data were used in the reconstruction.
We developed an eight-channel scanning time-domain fluorescence mammograph capable of imaging the distribution of
a non-specific fluorescent contrast agent in the female breast, besides imaging intrinsic absorption and scattering
properties of healthy breast tissue and tumors. The apparatus is based on the PTB multi-channel laser pulse
mammograph, originally designed for measurements of absorption and scattering coefficients at four selected
wavelengths (&lgr; = 652 nm, 684 nm, 797nm, and 830 nm). It was upgraded for time-resolved detection of fluorescence,
excited at 735 nm by a ps diode laser with 10 mW output power and detected at wavelengths &lgr; ⩾ 780 nm. Cooled PMTs
with GaAs photocathodes are used to detect laser and fluorescence photons at five positions in transmission and three
positions in reflection. Measurements are performed with the breast being slightly compressed between two parallel
glass plates. The transmitting and receiving fiber bundles are scanned synchronously over the breast in steps of typically
2.5 mm. At each scan position, distributions of times of flight of laser photons are measured by time-correlated single
photon counting at eight detector positions, followed by measurements of distributions of times of arrival of
fluorescence photons. The performance of the fluorescence mammograph was investigated by using breast-like
phantoms with a fluorescent inhomogeneity with dye enrichment varying between 2:1 and 10:1 over background values.
We report on the reconstruction of absorption and fluorescence from measured time-domain diffuse reflectance
and transmittance of laser and fluorescence radiation. Measurements were taken on slab-like, diffusely scattering
and fluorescent phantoms containing fluorescent inhomogeneities, using fs laser pulses (&lgr; = 730 nm) and time
correlated single photon counting. The source was scanned across the entrance face of the phantom, and at
each source position data were collected in transmission and reflection at various detector positions. These
measurements simulate in vivo data that will be obtained employing a scanning, time-domain fluorescence
mammograph, where the breast is gently compressed between two parallel glass plates, and source and detector
optical fibers scan synchronously at various source-detector offsets, allowing to record laser and fluorescence
mammograms.
The diffusion equations for the propagation of the laser and fluorescence radiation were solved in frequency
domain by the finite element method. Measured time-resolved phantom data were Fourier-transformed to frequency
domain prior to image reconstruction. Signal-to-noise ratios were high enough to use several data sets
simultaneously in the reconstruction process belonging to various modulation frequencies up to several hundred
MHz. To obtain the spatial distribution of the fluorescent contrast agent the Born approximation of the
fluorescence diffusion equation was used.
The nonlinear optical response of carbon nanotubes (CNTs) to the interaction with intense ultrashort laser pulses was studied theoretically and experimentally. A full quantum-mechanical theory for harmonics generation from a single-walled CNT has been developed, using the quantum kinetic equations for π-electrons with both intraband and interband transitions taken into account. In the regime of strong driving fields, a non-perturbative approach with the numerical solution of the quantum kinetic equations in the time domain was used to calculate the density of the axial electric current in CNTs. The results of this theory are compared to experiments performed on samples of multi-walled CNTs, using pulses of 160 fs generated by a Cr:Forsterite laser, at a wavelength of 1250 nm. The experimental results show indeed an unusual nonperturbative behavior of the third-harmonic yield, for relatively low input laser fields of ~ 1010 W/cm2, in very good agreement with the theoretical predictions. The interaction of CNTs with strong laser fields results not only in the generation of harmonics, but also in the generation of a broad spectral background. Generation of a continuous background in the vicinity of the third-harmonic of the laser field was also obtained from the quantum-mechanical calculations, however, with lower intensities than observed experimentally. Possible explanations for this discrepancy will be discussed.
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