Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma.

Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction-mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.

Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study.

Background Low-level light therapy (LLLT) has been shown to modulate recovery in patients with traumatic brain injury (TBI). However, the impact of LLLT on the functional connectivity of the brain when at rest has not been well studied. Purpose To use functional MRI to assess the effect of LLLT on whole-brain resting-state functional connectivity (RSFC) in patients with moderate TBI at acute (within 1 week), subacute (2-3 weeks), and late-subacute (3 months) recovery phases. Materials and Methods This is a secondary analysis of a prospective single-site double-blinded sham-controlled study conducted in patients presenting to the emergency department with moderate TBI from November 2015 to July 2019. Participants were randomized for LLLT and sham treatment. The primary outcome of the study was to assess structural connectivity, and RSFC was collected as the secondary outcome. MRI was used to measure RSFC in 82 brain regions in participants during the three recovery phases. Healthy individuals who did not receive treatment were imaged at a single time point to provide control values. The Pearson correlation coefficient was estimated to assess the connectivity strength for each brain region pair, and estimates of the differences in Fisher z-transformed correlation coefficients (hereafter, z differences) were compared between recovery phases and treatment groups using a linear mixed-effects regression model. These analyses were repeated for all brain region pairs. False discovery rate (FDR)-adjusted P values were computed to account for multiple comparisons. Quantile mixed-effects models were constructed to quantify the association between the Rivermead Postconcussion Symptoms Questionnaire (RPQ) score, recovery phase, and treatment group. Results RSFC was evaluated in 17 LLLT-treated participants (median age, 50 years [IQR, 25-67 years]; nine female), 21 sham-treated participants (median age, 50 years [IQR, 43-59 years]; 11 female), and 23 healthy control participants (median age, 42 years [IQR, 32-54 years]; 13 male). Seven brain region pairs exhibited a greater change in connectivity in LLLT-treated participants than in sham-treated participants between the acute and subacute phases (range of z differences, 0.37 [95% CI: 0.20, 0.53] to 0.45 [95% CI: 0.24, 0.67]; FDR-adjusted P value range, .010-.047). Thirteen different brain region pairs showed an increase in connectivity in sham-treated participants between the subacute and late-subacute phases (range of z differences, 0.17 [95% CI: 0.09, 0.25] to 0.26 [95% CI: 0.14, 0.39]; FDR-adjusted P value range, .020-.047). There was no evidence of a difference in clinical outcomes between LLLT-treated and sham-treated participants (range of differences in medians, -3.54 [95% CI: -12.65, 5.57] to -0.59 [95% CI: -7.31, 8.49]; P value range, .44-.99), as measured according to RPQ scores. Conclusion Despite the small sample size, the change in RSFC from the acute to subacute phases of recovery was greater in LLLT-treated than sham-treated participants, suggesting that acute-phase LLLT may have an impact on resting-state neuronal circuits in the early recovery phase of moderate TBI. ClinicalTrials.gov Identifier: NCT02233413 © RSNA, 2024 Supplemental material is available for this article.

Wide-Field Three-Dimensional Depth-Invariant Cellular-Resolution Imaging of the Human Retina.

Three-dimensional (3D) cellular-resolution imaging of the living human retina over a large field of view will bring a great impact in clinical ophthalmology, potentially finding new biomarkers for early diagnosis and improving the pathophysiological understanding of ocular diseases. While hardware-based and computational adaptive optics (AO) optical coherence tomography (OCT) have been developed to achieve cellular-resolution retinal imaging, these approaches support limited 3D imaging fields, and their high cost and intrinsic hardware complexity limit their practical utility. Here, this work demonstrates 3D depth-invariant cellular-resolution imaging of the living human retina over a 3 × 3 mm field of view using the first intrinsically phase-stable multi-MHz retinal swept-source OCT and novel computational defocus and aberration correction methods. Single-acquisition imaging of photoreceptor cells, retinal nerve fiber layer, and retinal capillaries is presented across unprecedented imaging fields. By providing wide-field 3D cellular-resolution imaging in the human retina using a standard point-scan architecture routinely used in the clinic, this platform proposes a strategy for expanded utilization of high-resolution retinal imaging in both research and clinical settings.

Feature issue introduction: ultrafast optical imaging.

This feature issue of Optics Express collects 20 articles that report the most recent progress of ultrafast optical imaging. This review provides a summary of these articles that cover the spectrum of ultrafast optical imaging, from new technologies to applications.

RF properties of circular-ranging OCT signals.

Circular-ranging optical coherence tomography (CR-OCT) systems that use a time-stepped frequency comb source generate interference fringe signals that are more complex than those of a conventional swept-source OCT system. Here, we define a common terminology for describing these signals, and we develop a mathematical framework that relates the radio-frequency (RF) properties of these fringe signals to the parameters of the frequency comb source. With this framework, we highlight non-intuitive mechanisms whereby the design of the frequency comb source can affect imaging performance. We show, for example, that amplitude-pulsed time-stepped frequency comb sources have a sensitivity advantage over constant power time-stepped frequency comb sources. More broadly, this framework and associated terminology provide a foundation on which to design and optimize time-stepped frequency comb sources and systems.

Using the dynamic forward scattering signal for optical coherence tomography based blood flow quantification.

To our knowledge, all existing optical coherence tomography approaches for quantifying blood flow, whether Doppler-based or decorrelation-based, analyze light that is back-scattered by moving red blood cells (RBCs). This work investigates the potential advantages of basing these measurements on light that is forward-scattered by RBCs, i.e., by looking at the signals back-scattered from below the vessel. We show experimentally that flowmetry based on forward-scattering is insensitive to vessel orientation for vessels that are approximately orthogonal to the imaging beam. We further provide proof-of-principle demonstrations of dynamic forward-scattering (DFS) flowmetry in human retinal and choroidal vessels.

Relationship between axial resolution and signal-to-noise ratio in optical coherence tomography.

In optical coherence tomography (OCT), axial resolution and signal-to-noise ratio (SNR) are typically viewed as uncoupled parameters. We show that this is true only for mirror-like surfaces and that in diffuse scattering samples such as biological tissues there is an inherent coupling between axial resolution and measurement SNR. We explain the origin of this coupling and demonstrate that it can be used to achieve increased imaging penetration depth at the expense of resolution. Finally, we argue that this coupling should be considered during OCT system design processes that seek to balance the competing needs of resolution, sensitivity, and system/source complexity.

Local vasoregulative interventions impact drug concentrations in the skin after topical laser-assisted delivery.

INTRODUCTION: The ability of ablative fractional lasers (AFL) to enhance topical drug uptake is well established. After AFL delivery, however, drug clearance by local vasculature is poorly understood. Modifications in vascular clearance may enhance AFL-assisted drug concentrations and prolong drug dwell time in the skin. Aiming to assess the role and modifiability of vascular clearance after AFL-assisted delivery, this study examined the impact of vasoregulative interventions on AFL-assisted 5-fluorouracil (5-FU) concentrations in in vivo skin. METHODS: 5-FU uptake was assessed in intact and AFL-exposed skin in a live pig model. After fractional CO2 laser exposure (15 mJ/microbeam, 5% density), vasoregulative intervention using topical brimonidine cream, epinephrine solution, or pulsed dye laser (PDL) was performed in designated treatment areas, followed by a single 5% 5-FU cream application. At 0, 1, 4, 48, and 72 h, 5-FU concentrations were measured in 500 and 1500 µm skin layers by mass spectrometry (n = 6). A supplemental assessment of blood flow following AFL ± vasoregulation was performed using optical coherence tomography (OCT) in a human volunteer. RESULTS: Compared to intact skin, AFL facilitated a prompt peak in 5-FU delivery that remained elevated up to 4 hours (1500 µm: 1.5 vs. 31.8 ng/ml [1 hour, p = 0.002]; 5.3 vs. 14.5 ng/ml [4 hours, p = 0.039]). However, AFL's impact was transient, with 5-FU concentrations comparable to intact skin at later time points. Overall, vasoregulative intervention with brimonidine or PDL led to significantly higher peak 5-FU concentrations, prolonging the drug's dwell time in the skin versus AFL delivery alone. As such, brimonidine and PDL led to twofold higher 5-FU concentrations than AFL alone in both skin layers by 1 hour (e.g., 500 µm: 107 ng/ml [brimonidine]; 96.9 ng/ml [PDL], 46.6 ng/ml [AFL alone], p ≤ 0.024), and remained significantly elevated at 4 hours (p ≤ 0.024). A similar pattern was observed for epinephrine, although trends remained nonsignificant (p ≥ 0.09). Prolonged 5-FU delivery was provided by PDL, resulting in sustained drug deposition compared to AFL alone at both 48 and 72 hours in the superficial skin layer (p ≤ 0.024). Supporting drug delivery findings, OCT revealed that increases in local blood flow after AFL were mitigated in test areas also exposed to PDL, brimonidine, or epinephrine, with PDL providing the greatest, sustained reduction in flow over 48 hours. CONCLUSION: Vasoregulative intervention in conjunction with AFL-assisted delivery enhances and prolongs 5-FU deposition in in vivo skin.

Robust and easy-to-operate stretched-pulse mode-locked wavelength-swept laser with an all-polarization-maintaining fiber cavity for 10 MHz A-line rate optical coherence tomography.

We demonstrate robust and easy-to-operate stretched-pulse mode-locked laser (SPML) architectures using all-polarization-maintaining fiber laser cavities. Because of the polarization-maintaining construction, the laser performance is unaffected by mechanical perturbation on the cavity fibers. The lasers automatically initiate linear-in-wavenumber sweeps across 100 nm centered at 1290 nm with a 10 MHz repetition rate. OCT imaging with a sensitivity of 98 dB and a single-sided 6 dB coherence length of 2.5 mm is demonstrated. OCT angiography of a mouse brain that visualized three-dimensional cerebral microvasculature over a field of 1.5mm×1.5mm (398 A-lines × 380 B-scans) at a rate of 5.26 volumes per second is also presented. The robust all-PMF SPML lasers are a turnkey, high-performance source for ultrahigh-speed OCT imaging.

Resolving absolute depth in circular-ranging optical coherence tomography by using a degenerate frequency comb: publisher's note.

This publisher's note contains corrections to Opt. Lett.45, 371 (2020).OPLEDP0146-959210.1364/OL.379968.

Resolving absolute depth in circular-ranging optical coherence tomography by using a degenerate frequency comb.

In Fourier-domain optical coherence tomography, an interference signal is generated that spans an RF bandwidth proportional to the product of three parameters: the imaging range, the imaging speed, and the inverse of the axial resolution. Circular-ranging optical coherence tomography (CR-OCT)architectures were introduced to ease long-range imaging by decoupling the imaging range from the signal RF bandwidth. As a consequence, present CR-OCT systems resolve the relative, but not the absolute, depth location of the scatterers. We introduce here a modified implementation of CR-OCT that uses a degenerate frequency comb source that allows recovery of absolute depth information while only minimally impacting the previously described RF bandwidth compression benefits of CR. We show that this degenerate frequency comb can be created by relatively simple modifications to existing frequency comb source designs, and we present absolute ranging capabilities through imaging studies and simulations.

Lymph node effective vascular permeability and chemotherapy uptake.

OBJECTIVE: Lymph node metastases are a poor prognostic factor. Additionally, responses of lymph node metastasis to therapy can be different from the primary tumor. Investigating the physiologic lymph node blood vasculature might give insight into the ability of systemic drugs to penetrate the lymph node, and thus into the differential effect of therapy between lymph node metastasis and primary tumors. Here, we measured effective vascular permeability of lymph node blood vessels and attempted to increase chemotherapy penetration by increasing effective vascular permeability. METHODS: We developed a novel three-dimensional method to measure effective vascular permeability in murine lymph nodes in vivo. VEGF-A was systemically administered to increase effective vascular permeability. Validated high-performance liquid chromatography protocols were used to measure chemotherapeutic drug concentrations in untreated and VEGF-A-treated lymph nodes, liver, spleen, brain, and blood. RESULTS: VEGF-A-treated lymph node blood vessel effective vascular permeability (mean 3.83 × 10-7  cm/s) was significantly higher than untreated lymph nodes (mean 9.87 × 10-8  cm/s). No difference was found in lymph node drug accumulation in untreated versus VEGF-A-treated mice. CONCLUSIONS: Lymph node effective vascular permeability can be increased (~fourfold) by VEGF-A. However, no significant increase in chemotherapy uptake was measured by pretreatment with VEGF-A.

16 MHz wavelength-swept and wavelength-stepped laser architectures based on stretched-pulse active mode locking with a single continuously chirped fiber Bragg grating.

We demonstrate a novel high-speed and broadband laser architecture based on stretched pulse active mode locking that provides a wavelength-swept and wavelength-stepped output. The laser utilizes a single intracavity 8.3 meter chirped fiber Bragg grating to generate positive and negative dispersion, and can be operated with or without an intracavity fixed Fabry-Perot etalon to generate wavelength-swept and wavelength-stepped (frequency comb) outputs, respectively. Using a four-path delay line at the output, we achieved 16.3 MHz repetition rates and a 62 nm lasing bandwidth centered at 1550 nm. Single-sided double-pass coherence lengths of 1.25 mm for the wavelength-swept configuration and more than 30 mm for the wavelength-stepped configuration were obtained. Relative intensity noise was measured to be better than -140 dB/Hz. The stretched-pulse mode-locked architecture utilizing long chirped fiber Bragg gratings offers a simple and compact design for a broadband wavelength-tuned output at unprecedented speeds, and can address the need for fast sources in applications such as optical ranging, imaging, and sensing.

Compensation of spectral and RF errors in swept-source OCT for high extinction complex demodulation.

We provide a framework for compensating errors within passive optical quadrature demodulation circuits used in swept-source optical coherence tomography (OCT). Quadrature demodulation allows for detection of both the real and imaginary components of an interference fringe, and this information separates signals from positive and negative depth spaces. To achieve a high extinction (∼60 dB) between these positive and negative signals, the demodulation error must be less than 0.1% in amplitude and phase. It is difficult to construct a system that achieves this low error across the wide spectral and RF bandwidths of high-speed swept-source systems. In a prior work, post-processing methods for removing residual spectral errors were described. Here, we identify the importance of a second class of errors originating in the RF domain, and present a comprehensive framework for compensating both spectral and RF errors. Using this framework, extinctions >60 dB are demonstrated. A stability analysis shows that calibration parameters associated with RF errors are accurate for many days, while those associated with spectral errors must be updated prior to each imaging session. Empirical procedures to derive both RF and spectral calibration parameters simultaneously and to update spectral calibration parameters are presented. These algorithms provide the basis for using passive optical quadrature demodulation circuits with high speed and wide-bandwidth swept-source OCT systems.

Multi-functional angiographic OFDI using frequency-multiplexed dual-beam illumination.

Detection of blood flow inside the tissue sample can be achieved by measuring the local change of complex signal over time in angiographic optical coherence tomography (OCT). In conventional angiographic OCT, the transverse displacement of the imaging beam during the time interval between a pair of OCT signal measurements must be significantly reduced to minimize the noise due to the beam scanning-induced phase decorrelation at the expense of the imaging speed. Recent introduction of dual-beam scan method either using polarization encoding or two identical imaging systems in spectral-domain (SD) OCT scheme shows potential for high-sensitivity vasculature imaging without suffering from spurious phase noise caused by the beam scanning-induced spatial decorrelation. In this paper, we present multi-functional angiographic optical frequency domain imaging (OFDI) using frequency-multiplexed dual-beam illumination. This frequency multiplexing scheme, utilizing unique features of OFDI, provides spatially separated dual imaging beams occupying distinct electrical frequency bands that can be demultiplexed in the frequency domain processing. We demonstrate the 3D multi-functional imaging of the normal mouse skin in the dorsal skin fold chamber visualizing distinct layer structures from the intensity imaging, information about mechanical integrity from the polarization-sensitive imaging, and depth-resolved microvasculature from the angiographic imaging that are simultaneously acquired and automatically co-registered.

A rapid, dispersion-based wavelength-stepped and wavelength-swept laser for optical coherence tomography.

Optical-domain subsampling enables Fourier-domain OCT imaging at high-speeds and extended depth ranges while limiting the required acquisition bandwidth. To perform optical-domain subsampling, a wavelength-stepped rather than a wavelength-swept source is required. This preliminary study introduces a novel design for a rapid wavelength-stepped laser source that uses dispersive fibers in combination with a fast lithium-niobate modulator to achieve wavelength selection. A laser with 200 GHz wavelength-stepping and a sweep rate of 9 MHz over a 94 nm range at a center wavelength of 1550 nm is demonstrated. A reconfiguration of this source design to a continuous wavelength-swept light for conventional Fourier-domain OCT is also demonstrated.

Experimental and theoretical model of microvascular network remodeling and blood flow redistribution following minimally invasive microvessel laser ablation.

Overly dense microvascular networks are treated by selective reduction of vascular elements. Inappropriate manipulation of microvessels could result in loss of host tissue function or a worsening of the clinical problem. Here, experimental, and computational models were developed to induce blood flow changes via selective artery and vein laser ablation and study the compensatory collateral flow redistribution and vessel diameter remodeling. The microvasculature was imaged non-invasively by bright-field and multi-photon laser microscopy, and optical coherence tomography pre-ablation and up to 30 days post-ablation. A theoretical model of network remodeling was developed to compute blood flow and intravascular pressure and identify vessels most susceptible to changes in flow direction. The skin microvascular remodeling patterns were consistent among the five specimens studied. Significant remodeling occurred at various time points, beginning as early as days 1-3 and continuing beyond day 20. The remodeling patterns included collateral development, venous and arterial reopening, and both outward and inward remodeling, with variations in the time frames for each mouse. In a representative specimen, immediately post-ablation, the average artery and vein diameters increased by 14% and 23%, respectively. At day 20 post-ablation, the maximum increases in arterial and venous diameters were 2.5× and 3.3×, respectively. By day 30, the average artery diameter remained 11% increased whereas the vein diameters returned to near pre-ablation values. Some arteries regenerated across the ablation sites via endothelial cell migration, while veins either reconnected or rerouted flow around the ablation site, likely depending on local pressure driving forces. In the intact network, the theoretical model predicts that the vessels that act as collaterals after flow disruption are those most sensitive to distant changes in pressure. The model results correlate with the post-ablation microvascular remodeling patterns.

Numerical compensation of system polarization mode dispersion in polarization-sensitive optical coherence tomography.

Polarization mode dispersion (PMD), which can be induced by circulators or even moderate lengths of optical fiber, is known to be a dominant source of instrumentation noise in fiber-based PS-OCT systems. In this paper we propose a novel PMD compensation method that measures system PMD using three fixed calibration signals, numerically corrects for these instrument effects and reconstructs an improved sample image. Using a frequency multiplexed PS-OFDI setup, we validate the proposed method by comparing birefringence noise in images of intralipid, muscle, and tendon with and without PMD compensation.

Spectral binning for mitigation of polarization mode dispersion artifacts in catheter-based optical frequency domain imaging.

Polarization mode dispersion (PMD) has been recognized as a significant barrier to sensitive and reproducible birefringence measurements with fiber-based, polarization-sensitive optical coherence tomography systems. Here, we present a signal processing strategy that reconstructs the local retardation robustly in the presence of system PMD. The algorithm uses a spectral binning approach to limit the detrimental impact of system PMD and benefits from the final averaging of the PMD-corrected retardation vectors of the spectral bins. The algorithm was validated with numerical simulations and experimental measurements of a rubber phantom. When applied to the imaging of human cadaveric coronary arteries, the algorithm was found to yield a substantial improvement in the reconstructed birefringence maps.

Artifacts in polarization-sensitive optical coherence tomography caused by polarization mode dispersion.

Polarization mode dispersion (PMD) severely degrades images of biological tissue measured with polarization-sensitive optical coherence tomography. It adds a bias to the local retardation value that can be spatially confined, resulting in regions of seemingly high sample birefringence that are purely artificial. Here, we demonstrate and analyze this effect, both experimentally and with numerical simulations, and show that artifacts can be avoided by limiting the system PMD to less than the system axial resolution. Even then, spatial averaging over a dimension larger than that characteristic of speckle is required to remove a PMD-induced bias of the local retardation values.