Solving analytically the simplified spherical harmonics equations in cylindrical turbid media.

A methodology is presented for analytically solving simplified spherical harmonics equations (SPN) in a finite homogeneous absorbing and scattering cylindrical medium. The SPN equations are a reliable approximation to the radiative transfer equation for describing light propagation inside turbid media. The equations consist of a set of coupled partial differential equations (PDEs). The analytical solution developed here is for a steady-state isotropic point source located at an arbitrary point inside a cylindrical turbid medium. Partial-reflection boundary conditions are considered, as they realistically model the refractive index mismatch between a turbid medium and its surroundings (air), as occurs in practice in biomedical optics. The eigen method is used to decouple the set of SPN PDEs. The methodology is applied to the SP3, which has proved to be sufficiently accurate in practice, but it is readily generalizable to higher orders. The solution is compared with the analytical solution of the diffusion equation as well as to gold standard Monte Carlo simulations for validation, against which it shows good agreement. This work is important, as it provides an additional tool for validating numerical solutions of SPN equations for curved geometries, namely, cylindrical shapes, which are often used in practice.

Stimulation of triple negative breast cancer cell migration and metastases formation is prevented by chloroquine in a pre-irradiated mouse model.

BACKGROUND: Some triple negative breast cancer (TNBC) patients are at higher risk of recurrence in the first three years after treatment. This rapid relapse has been suggested to be associated with inflammatory mediators induced by radiation in healthy tissues that stimulate cancer cell migration and metastasis formation. In this study, the ability of chloroquine (CQ) to inhibit radiation-stimulated development of metastasis was assessed. METHODS: The capacity of CQ to prevent radiation-enhancement of cancer cell invasion was assessed in vitro with the TNBC cell lines D2A1, 4T1 and MDA-MB-231 and the non-TNBC cell lines MC7-L1, and MCF-7. In Balb/c mice, a single mammary gland was irradiated with four daily doses of 6 Gy. After the last irradiation, irradiated and control mammary glands were implanted with D2A1 cells. Mice were treated with CQ (vehicle, 40 or 60 mg/kg) 3 h before each irradiation and then every 72 h for 3 weeks. Migration of D2A1 cells in the mammary gland, the number of circulating tumor cells and lung metastasis were quantified, and also the expression of some inflammatory mediators. RESULTS: Irradiated fibroblasts have increased the invasiveness of the TNBC cell lines only, a stimulation that was prevented by CQ. On the other hand, invasiveness of the non-TNBC cell lines, which was not enhanced by irradiated fibroblasts, was also not significantly modified by CQ. In Balb/c mice, treatment with CQ prevented the stimulation of D2A1 TNBC cell migration in the pre-irradiated mammary gland, and reduced the number of circulating tumor cells and lung metastases. This protective effect of CQ was associated with a reduced expression of the inflammatory mediators interleukin-1ß, interleukin-6, and cyclooxygenase-2, while the levels of matrix metalloproteinases-2 and -9 were not modified. CQ also promoted a blocking of autophagy. CONCLUSION: CQ prevented radiation-enhancement of TNBC cell invasion and reduced the number of lung metastases in a mouse model.

Increasing the collection efficiency of time-correlated single-photon counting with single-photon avalanche diodes using immersion lenses.

Single-photon avalanche diodes (SPADs) achieving high timing resolution (≈20-50 ps) developed for time-correlated single-photon counting (TCSPC) generally have very small photosensitive areas (25-100 µm in diameter). This limits the achievable photon counting rate and signal-to-noise ratio and may lead to long counting times. This is detrimental in applications requiring several measurements, such as fluorescence lifetime imaging (FLIM) microscopy, which requires scanning, and time-domain diffuse optical tomography (TD-DOT). We show in this work that the use of an immersion lens directly affixed onto the photosensitive area of the SPAD helps alleviate this problem by allowing more light to be concentrated onto the detector. Following careful optical design and simulations, our experimental results show that it is actually possible to achieve the predicted theoretical increase in the photon counting rate (we achieve a factor of ≈4 here). This work is of high relevance in high timing resolution TCSPC with small photosensitive area detectors and should find widespread interest in FLIM and TD-DOT with SPADs.

Diffuse photon density wavefront speed as a contrast for tomographic imaging of heterogeneous diffusive media.

An imaging algorithm is implemented for tomographically reconstructing contrast maps of the space variant speed of diffuse photon density wavefronts (DPDWFs) propagating in biological tissue-like diffusing media. This speed serves as a novel contrast not previously exploited in the literature. The algorithm employs early photon arrival times (EPATs) extracted from a set of time domain measurements. A relationship between EPATs and the speed of DPDWFs is exploited as the forward model. The forward model and its use in an inverse problem are supported by experimental results. These are carried out for 3D media with tissue-like optical properties. The resulting inverse problem is formulated as a set of algebraic equations and solved within a constrained linear least squares framework. The results indicate that the algorithm provides tomographic information on heterogeneities locations and distributions.

Scatter estimation and correction using time-of-flight and deconvolution in x-ray medical imaging.

Objective Time-of-flight (TOF) scatter rejection requires a total timing jitter, including the detector timing jitter and the X-ray source's pulses width, of 50 ps or less to mitigate most of the effects of scattered photons in radiography and CT imaging. However, since the total contribution of the source and detector to the timing jitter can be retrieved during an acquisition with nothing between the source and detector, it can be demonstrated that this contribution may be partially removed to improve the image quality. Approach A scatter correction method using iterative deconvolution of the measured time point-spread function estimates the number of scattered photons detected in each pixel. To evaluate the quality of the estimation, GATE was used to simulate the radiography of a water cylinder with bone inserts, and a head and torso in a system with total timing jitters from 100 ps up to 500 ps full-width-at-half-maximum. Main results With a total timing jitter of 200 ps, 89% of the contrast degradation caused by scattered photons was recovered in a head and torso radiography, compared to 28% with a simple time threshold method. Corrected images using the estimation have a percent root-mean square error between 2 and 14% in both phantoms with timing jitters from 100 to 500 ps which is lower than the error achieved with scatter rejection alone at 100 ps. Significance TOF X-ray imaging has the potential to mitigate the effects of the scattering contribution and offers an alternative to anti-scatter grids that avoids loss of primary photons. Compare to simple TOF scatter rejection using only a threshold, the deconvolution estimation approach has lower requirements on both the source and detector. These requirements are now within reach of state-of-the-art systems.

(68)Ga/DOTA- and (64)Cu/NOTA-phthalocyanine conjugates as fluorescent/PET bimodal imaging probes.

In this paper, we describe the synthesis and characterization of a series of new bimodal probes combining water-soluble sulfonated zinc phthalocyanine (ZnPc) as a fluorescence imaging unit and either (68)Ga/1,4,7,10-tetraazocyclododecane-N,N'N″,N'″-tetraacetic acid (DOTA) or (64)Cu/1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for PET imaging. The two moieties were linked through aliphatic chains of different lengths to modulate amphiphilicity. Labeling of DOTA- or NOTA-ZnPc conjugates with (68)Ga (t1/2 = 68 min) and (64)Cu (t1/2 = 12.7 h) was performed at 100 °C for 15 min with >90% efficiency for all conjugates. In vitro plasma stability assays demonstrated high stability of the (64)Cu/NOTA-ZnPc conjugate, which remained intact over a 24 h time period, and reasonably high stability of the (68)Ga/DOTA-ZnPc conjugate, which released up to 7% of free (68)Ga over a 3 h period. Based on in vitro plasma stability results, we performed biodistribution studies on two (64)Cu-labeled derivatives, which allowed us to select a single candidate for preliminary in vivo experiments. Fluorescence and PET imaging confirmed the potential of these novel conjugates to act as bimodal probes.

Time-domain geometrical localization of point-like fluorescence inclusions in turbid media with early photon arrival times.

We introduce a novel approach for localizing a plurality of discrete point-like fluorescent inclusions embedded in a thick turbid medium using time-domain measurements. The approach uses early photon information contained in measured time-of-flight distributions originating from fluorescence emission. Fluorescence time point-spread functions (FTPSFs) are acquired with ultrafast time-correlated single photon counting after short pulse laser excitation. Early photon arrival times are extracted from the FTPSFs obtained from several source-detector positions. Each source-detector measurement allows defining a geometrical locus where an inclusion is to be found. These loci take the form of ovals in 2D or ovoids in 3D. From these loci a map can be built, with the maxima thereof corresponding to positions of inclusions. This geometrical approach is supported by Monte Carlo simulations performed for biological tissue-like media with embedded fluorescent inclusions. To validate the approach, several experiments are conducted with a homogeneous phantom mimicking tissue optical properties. In the experiments, inclusions filled with indocyanine green are embedded in the phantom and the fluorescence response to a short pulse of excitation laser is recorded. With our approach, several inclusions can be localized with low millimeter positional error. Our results support the approach as an accurate, efficient, and fast method for localizing fluorescent inclusions embedded in highly turbid media mimicking biological tissues. Further Monte Carlo simulations on a realistic mouse model show the feasibility of the technique for small animal imaging.

Fat emulsions as diffusive reference standards for tissue simulating phantoms?

Intralipid 20% was recently suggested as a diffusive reference standard for tissue simulating phantoms. In this work, we extend previously obtained results to other fat emulsions, specifically Intralipid 10%, Intralipid 30%, Lipovenoes 10%, Lipovenoes 10% PhosphoLipid Reduced, Lipovenoes 20%, Lipofundin S 10%, and Lipofundin S 20%. Of particular importance for practical applications, our measurements carried out at a wavelength of 751 nm show the following features. First, these products show high stability and small batch-to-batch variations in their diffusive optical properties, similar to Intralipid 20%. Second, the absorption coefficient of Intralipid, Lipovenoes, and Lipofundin S are very similar and their measured values are within the experimental errors; moreover the reduced scattering coefficient of Intralipid 20%, Lipovenoes 20%, and Lipofundin S 20% are similar and their measured values are within 5%. Third, the reduced scattering coefficient of Intralipid 10% and Intralipid 30% can be scaled from that of Intralipid 20% with an error of 9% and 2%, respectively. A similar scaling property is valid for Lipovenoes and Lipofundin S. We have verified that this scaling property depends on the composition of the fat emulsions: If the ingredients exactly scale with the concentration then the reduced scattering coefficient almost exactly scale as well.

High-Intensity Laser Therapy (HILT) as an Emerging Treatment for Vulvodynia and Chronic Musculoskeletal Pain Disorders: A Systematic Review of Treatment Efficacy.

High-intensity laser therapy (HILT) has been gaining popularity in the treatment of chronic musculoskeletal pain, including vulvodynia. The objective of this study was to critically appraise and synthesize the available evidence on the efficacy of HILT for reducing pain and improving function in vulvodynia and other chronic primary musculoskeletal pain conditions. Electronic databases and the grey literature were searched. Effects on pain intensity, function, and adverse events were assessed. One study investigating HILT in the treatment of vulvodynia and 13 studies on the treatment of chronic musculoskeletal pain were selected. The study assessing vulvodynia showed favorable results for reducing pain. Regarding chronic musculoskeletal pain, 12 out of the 13 studies selected consistently showed that HILT was more effective than the placebo/active comparator for reducing pain and improving function. The available effect sizes for pain showed large to huge effects. Similar effects were observed for function except for two studies showing moderate effects. The GRADE score was moderate. Conclusions: There are insufficient data to support the use of HILT in vulvodynia, but the promising results encourage further research. HILT appears to be effective in musculoskeletal pain conditions. More high-quality studies are needed to identify effective laser protocols.

Efficient numerical modelling of time-domain light propagation in curved 3D absorbing and scattering media with finite differences.

An efficient approach is introduced for modelling light propagation in the time domain in 3D heterogeneous absorbing and scattering media (e.g. biological tissues) with curved boundaries. It relies on the finite difference method (FDM) in conjuction with the Crank-Nicolson method for accurately solving the optical diffusion equation (DE). The strength of the FDM lies in its simplicity and efficiency, since the equations are easy to set up, and accessing neighboring grid points only requires simple memory operations, leading to efficient code execution. Owing to its use of Cartesian grids, the FDM is generally thought cumbersome compared to the finite element method (FEM) for dealing with media with curved boundaries. However, to apply the FDM to such media, the blocking-off method can be resorted to. To account for the change of the refractive index at the boundary, Robin-type boundary conditions are considered. This requires the computation of surface normals. We resort here for the first time to the Sobel operator borrowed from image processing to perform this task. The Sobel operator is easy to implement, fast, and allows obtaining a smooth field of normal vectors along the boundary. The main contribution of this work is to arrive at a complete numerical FDM-based model of light propagation in the time domain in 3D absorbing and scattering media with curved geometries, taking into account realistic refractive index mismatch boundary conditions. The fluence rate obtained with this numerical model is shown to reproduce well that obtained with independent gold-standard Monte Carlo simulations.

Diffuse light propagation in biological media by a time-domain parabolic simplified spherical harmonics approximation with ray-divergence effects.

We present a simplified spherical harmonics approximation for the time-domain radiative transfer equation including the source-divergence effect. This leads to a set of coupled partial differential equations (PDEs) of the parabolic type that model diffuse light propagation in biological-tissue-like media. We introduce a finite element approach for solving these PDEs, thereby obtaining the time-dependent spatial profile of the fluence. We compare the results with the diffusion equation and Monte Carlo simulations. The fluence obtained via our model is shown to reproduce well the Monte Carlo results in all cases and improves on the solution of the diffusion equation in homogeneous diffusive-defying media. Our solution also shows more sensitivity than the diffusion equation to changes in the absorption coefficient of small inclusions.

Structural impacts on the timing and amplitude of the negative BOLD response.

The positive (PBR) and negative BOLD responses (NBR) arising in task-fMRI display varying magnitudes and dynamics across voxels. While the effects of structure, particularly of veins, on the PBR have been studied, little is known of NBR-structure relationships. Like the PBR, the NBR is often used as a surrogate marker of neuronal activation in both basic and clinical research and assessing its relationship with cortical structure may help interpret group differences. We therefore investigated how local structure affects BOLD amplitude and timing in PBR and NBR areas using multi-band fMRI during visual stimulation to obtain high temporal resolution (TR=0.45s) data combined with T1 imaging and susceptibility-weighted imaging (SWI) to quantify the local densities of gray/white matter and veins, respectively. In both PBRs and NBRs, larger venous density was consistently associated with larger BOLD amplitude and delay, up to 1-2s larger relative to areas devoid of large veins. Both binary and sinusoidal visual stimulus modulation yielded similar activation maps and results, suggesting that underlying vasculature affects PBR and NBR temporal dynamics in the same manner. Accounting for structural impacts on PBR and NBR magnitude and timing could help enhance activation map accuracy, better assess functional connectivity, and better characterize neurovascular coupling.

Cortical Thinning in Healthy Aging Correlates with Larger Motor-Evoked EEG Desynchronization.

Although electroencephalography (EEG) is a valuable tool to investigate neural activity in patients and controls, exactly how local anatomy impacts the measured signal remains unclear. Better characterizing this relationship is important to improve the understanding of how inter-subject differences in the EEG signal are related to neural activity. We hypothesized that cortical structure might affect event-related desynchronization (ERD) in EEG. Since aging is a well-documented cause of cortical thinning, we investigated the effects of cortical thickness (CT) and cortical depth (CD - the skull-to-cortex distance) on ERD using anatomical MRI and motor-evoked EEG in 17 healthy young adults and 20 healthy older persons. Results showed a significant negative correlation between ERD and CT, but no consistent relationship between ERD and CD. A thinner cortex was associated with a larger ERD in the α/ß band and correcting for CT removed most of the inter-group difference in ERD. This indicates that differences in neural activity might not be the primary cause for the observed aging-related differences in ERD, at least in the motor cortex. Further, it emphasizes the importance of considering conditions affecting the EEG signal, such as cortical anatomical changes due to aging, when interpreting differences between healthy controls and/or patients.

Diffuse optical tomographic imaging of biological media by time-dependent parabolic SP(N) equations: a two-dimensional study.

We investigate the problem of retrieving the optical properties (absorption and scattering) of biological tissue from a set of optical measurements. A diffuse optical tomography (DOT) algorithm that incorporates constrained optimization methods is implemented. To improve image quality, the DOT algorithm exploits full time-domain data. The time-dependent parabolic simplified spherical harmonics equations (TD-pSPN) are used as the forward model. Time-dependent adjoint variables are resorted to in the calculation of the gradient of the objective function. Several numerical experiments for small geometric media with embedded inclusions that mimic small animal imaging are performed. In the experiments, optical coefficient values are varied in the range of realistic values for the near-infrared spectrum, including high absorption values. Single and multiparameter reconstructions are performed with the diffusion equation and higher orders of the TD-pSPN equations. The results suggest the DOT algorithm based on the TD-pSPN model outperforms the DE, and accurately reconstructs optical parameter distributions of biological media both spatially and quantitatively.

A multi-view time-domain non-contact diffuse optical tomography scanner with dual wavelength detection for intrinsic and fluorescence small animal imaging.

We present a non-contact diffuse optical tomography (DOT) scanner with multi-view detection (over 360°) for localizing fluorescent markers in scattering and absorbing media, in particular small animals. It relies on time-domain detection after short pulse laser excitation. Ultrafast time-correlated single photon counting and photomultiplier tubes are used for time-domain measurements. For light collection, seven free-space optics non-contact dual wavelength detection channels comprising 14 detectors overall are placed around the subject, allowing the measurement of time point-spread functions at both excitation and fluorescence wavelengths. The scanner is endowed with a stereo camera pair for measuring the outer shape of the subject in 3D. Surface and DOT measurements are acquired simultaneously with the same laser beam. The hardware and software architecture of the scanner are discussed. Phantoms are used to validate the instrument. Results on the localization of fluorescent point-like inclusions immersed in a scattering and absorbing object are presented. The localization algorithm relies on distance ranging based on the measurement of early photons arrival times at different positions around the subject. This requires exquisite timing accuracy from the scanner. Further exploiting this capability, we show results on the effect of a scattering hetereogenity on the arrival time of early photons. These results demonstrate that our scanner provides all that is necessary for reconstructing images of small animals using full tomographic reconstruction algorithms, which will be the next step. Through its free-space optics design and the short pulse laser used, our scanner shows unprecedented timing resolution compared to other multi-view time-domain scanners.

Light propagation from fluorescent probes in biological tissues by coupled time-dependent parabolic simplified spherical harmonics equations.

We introduce a system of coupled time-dependent parabolic simplified spherical harmonic equations to model the propagation of both excitation and fluorescence light in biological tissues. We resort to a finite element approach to obtain the time-dependent profile of the excitation and the fluorescence light fields in the medium. We present results for cases involving two geometries in three-dimensions: a homogeneous cylinder with an embedded fluorescent inclusion and a realistically-shaped rodent with an embedded inclusion alike an organ filled with a fluorescent probe. For the cylindrical geometry, we show the differences in the time-dependent fluorescence response for a point-like, a spherical, and a spherically Gaussian distributed fluorescent inclusion. From our results, we conclude that the model is able to describe the time-dependent excitation and fluorescent light transfer in small geometries with high absorption coefficients and in nondiffusive domains, as may be found in small animal diffuse optical tomography (DOT) and fluorescence DOT imaging.