Altered diffusivity of the subarachnoid cisterns in the rat brain following neurological disorders.

BACKGROUND: Although changes in diffusion characteristics of the brain parenchyma in neurological disorders are widely studied and used in clinical practice, the change in diffusivity in the cerebrospinal fluid (CSF) system is rarely reported. In this study, free water diffusion in the subarachnoid cisterns and ventricles of the rat brain was examined using diffusion magnetic resonance imaging (MRI), and the effects of neurological disorders on diffusivity in CSF system were investigated. METHODS: Diffusion MRI and T2-weighted images were obtained in the intact rats, 24 h after ischemic stroke, and 50 days after mild traumatic brain injury (mTBI). We conducted the assessment of diffusivity in the rat brain in the subarachnoid cisterns around the midbrain, as well as the lateral ventricles. One-way ANOVA and Kruskal-Wallis test were used to evaluate the change in mean diffusivity (MD) and MD histogram, respectively, in CSF system following different neurological disease. RESULTS: A significant decrease in the mean MD value of the subarachnoid cisterns was observed in the stroke rats compared with the intact and mTBI rats (p < 0.005). In addition, the skewness (p < 0.002), maximum MD (p < 0.002), and MD percentiles (p < 0.002) in the stroke rats differed significantly from those in the intact and mTBI rats. By contrast, no difference was observed in the mean MD value of the lateral ventricles among three groups of rats. We proposed that the assessment of the subarachnoid cisterns, rather than the lateral ventricles, in the rat brain would be useful in providing diffusion information in the CSF system. CONCLUSIONS: Alterations in MD parameters of the subarachnoid cisterns after stroke provide evidence that brain injury may alter the characteristics of free water diffusion not only in the brain parenchyma but also in the CSF system.

Vascular responses of penetrating vessels during cortical spreading depolarization with ultrasound dynamic ultrafast Doppler imaging.

The dynamic vascular responses during cortical spreading depolarization (CSD) are causally related to pathophysiological consequences in numerous neurovascular conditions, including ischemia, traumatic brain injury, cerebral hemorrhage, and migraine. Monitoring of the hemodynamic responses of cerebral penetrating vessels during CSD is motivated to understand the mechanism of CSD and related neurological disorders. Six SD rats were used, and craniotomy surgery was performed before imaging. CSDs were induced by topical KCl application. Ultrasound dynamic ultrafast Doppler was used to access hemodynamic changes, including cerebral blood volume (CBV) and flow velocity during CSD, and further analyzed those in a single penetrating arteriole or venule. The CSD-induced hemodynamic changes with typical duration and propagation speed were detected by ultrafast Doppler in the cerebral cortex ipsilateral to the induction site. The hemodynamics typically showed triphasic changes, including initial hypoperfusion and prominent hyperperfusion peak, followed by a long-period depression in CBV. Moreover, different hemodynamics between individual penetrating arterioles and venules were proposed by quantification of CBV and flow velocity. The negative correlation between the basal CBV and CSD-induced change was also reported in penetrating vessels. These results indicate specific vascular dynamics of cerebral penetrating vessels and possibly different contributions of penetrating arterioles and venules to the CSD-related pathological vascular consequences. We proposed using ultrasound dynamic ultrafast Doppler imaging to investigate CSD-induced cerebral vascular responses. With this imaging platform, it has the potential to monitor the hemodynamics of cortical penetrating vessels during brain injuries to understand the mechanism of CSD in advance.

Ultrasound Sample Entropy Imaging: A New Approach for Evaluating Hepatic Steatosis and Fibrosis.

Objective: Hepatic steatosis causes nonalcoholic fatty liver disease and may progress to fibrosis. Ultrasound is the first-line approach to examining hepatic steatosis. Fatty droplets in the liver parenchyma alter ultrasound radiofrequency (RF) signal statistical properties. This study proposes using sample entropy, a measure of irregularity in time-series data determined by the dimension [Formula: see text] and tolerance [Formula: see text], for ultrasound parametric imaging of hepatic steatosis and fibrosis. Methods: Liver donors and patients were enrolled, and their hepatic fat fraction (HFF) ([Formula: see text]), steatosis grade ([Formula: see text]), and fibrosis score ([Formula: see text]) were measured to verify the results of sample entropy imaging using sliding-window processing of ultrasound RF data. Results: The sample entropy calculated using [Formula: see text] 4 and [Formula: see text] was highly correlated with the HFF when a small window with a side length of one pulse was used. The areas under the receiver operating characteristic curve for detecting hepatic steatosis that was [Formula: see text]mild, [Formula: see text]moderate, and [Formula: see text]severe were 0.86, 0.90, and 0.88, respectively, and the area was 0.87 for detecting liver fibrosis in individuals with significant steatosis. Discussion/Conclusions: Ultrasound sample entropy imaging enables the identification of time-series patterns in RF signals received from the liver. The algorithmic scheme proposed in this study is compatible with general ultrasound pulse-echo systems, allowing clinical fibrosis risk evaluations of individuals with developing hepatic steatosis.

Early neuroimaging and ultrastructural correlates of injury outcome after neonatal hypoxic-ischaemia.

Hypoxic ischaemia encephalopathy is the major cause of brain injury in new-borns. However, to date, useful biomarkers which may be used to early predict neurodevelopmental impairment for proper commencement of hypothermia therapy is still lacking. This study aimed to determine whether the early neuroimaging characteristics and ultrastructural correlates were associated with different injury progressions and brain damage severity outcomes after neonatal hypoxic ischaemia. Longitudinal 7 T MRI was performed within 6 h, 24 h and 7 days after hypoxic ischaemia in rat pups. The brain damage outcome at 7 days post-hypoxic ischaemia assessed using histopathology and MRI were classified as mild, moderate and severe. We found there was a spectrum of different brain damage severity outcomes after the same duration of hypoxic ischaemia. The severity of brain damage determined using MRI correlated well with that assessed by histopathology. Quantitative MRI characteristics denoting water diffusivity in the tissue showed significant differences in the apparent diffusion coefficient deficit volume and deficit ratios within 6 h, at 24 h and 7 days after hypoxic ischaemia among the 3 different outcome groups. The susceptible brain areas to hypoxic ischaemia were revealed by the temporal changes in regional apparent diffusion coefficient values among three outcome groups. Within 6 h post-hypoxic ischaemia, a larger apparent diffusion coefficient deficit volume and deficit ratios and lower apparent diffusion coefficient values were highly associated with adverse brain damage outcome. In the apparent diffusion coefficient deficit areas detected early after hypoxic ischaemia which were highly associated with severe damage outcome, transmission electron microscopy revealed fragmented nuclei; swollen rough endoplasmic reticulum and degenerating mitochondria in the cortex and prominent myelin loss and axon detraction in the white matter. Taken together, different apparent diffusion coefficient patterns obtained early after hypoxic ischaemia are highly associated with different injury progression leading to different brain damage severity outcomes, suggesting the apparent diffusion coefficient characteristics may be applicable to early identify the high-risk neonates for hypothermia therapy.

Technical Note: Radiotherapy dose characterization of gel dosimetry using shear wave elasticity imaging.

PURPOSE: Radiotherapy is an effective treatment for many types of cancer in clinical settings. Gel dosimetry has the potential to record three-dimensional (3D) dose distribution compared to a conventional ion chamber. As the elasticity of the gel is altered after irradiation due to gel polymerization, we aim to measure the dose recorded in gel dosimetry with ultrasonic shear wave elasticity imaging (SWEI), a nondestructive and quantitative elasticity imaging tool. METHODS: In this study, a cylindrical N-isopropylacrylamide (NIPAM) polymer gel with a diameter of 10 cm and a height of 10 cm and with cellulose as an ultrasonic scatterer was irradiated by a linear accelerator with the irradiation parameters of 6 MV x-ray, dose rate of 100 cGy/min and field size of 10  ×  20 mm2 . The six gel phantoms were irradiated with the dose of 0, 1, 3, 5, 8, or 10 Gy. The gel phantoms were measured with SWEI at 24, 36, and 48 h after x-ray irradiation. The two-dimensional (2D) shear wave velocity and Young's modulus maps corresponding to x-ray dose distribution were reconstructed following a time-of-flight reconstruction from a set of time-series displacement maps. The spatial resolution of the reconstructed SWEI image is ~1 mm. RESULTS: Our results show that the elastic modulus increases linearly as irradiation dose increases (R2  = 0.94 at 24 h, R2  = 0.98 at 36 h, R2  = 0.98 at 48 h), suggesting that the gel elasticity is highly associated with x-ray irradiation dose at 36 h post irradiation, and the dose resolution was 0.66 kPa/Gy. From the 3D elastic modulus maps, the dose distribution along the depth and lateral direction can be reflected in the NIPAM gel dosimetry using SWEI as well. CONCLUSIONS: In this study, the irradiated NIPAM gel phantom was quantitatively measured with SWEI for the first time to read the dose distribution recorded in the gel dosimetry. The results suggest that the gel elasticity is highly associated with x-ray irradiation dose. In the future, 2D/or 3D dose distribution from intensity modulated radiotherapy (IMRT) or other potential particle radiotherapy will be measured and reconstructed with SWEI and compared with the dose map from a treatment planning system (TPS) in the clinic.

Moving-source elastic wave reconstruction for high-resolution optical coherence elastography.

Optical coherence tomography (OCT)-based elasticity imaging can map soft tissue elasticity based on speckle-tracking of elastic wave propagation using highly sensitive phase measurements of OCT signals. Using a fixed elastic wave source and moving detection, current imaging sequences have difficulty in reconstructing tissue elasticity within speckle-free regions, for example, within the crystalline lens of the eye. We present a moving acoustic radiation force imaging sequence to reconstruct elastic properties within a speckle-free region by tracking elastic wave propagation from multiple laterally moving sources across the field of view. We demonstrate the proposed strategy using heterogeneous and partial speckle-free tissue-mimicking phantoms. Harder inclusions within the speckle-free region can be detected, and the contrast-to-noise ratio slightly enhanced compared to current OCE imaging sequences. The results suggest that a moving source approach may be appropriate for OCE studies within the large speckle-free regions of the crystalline lens.

Strategies to improve phase-stability of ultrafast swept source optical coherence tomography for single shot imaging of transient mechanical waves at 16 kHz frame rate.

We present single-shot phase-sensitive imaging of propagating mechanical waves within tissue, enabled by an ultrafast optical coherence tomography (OCT) system powered by a 1.628 MHz Fourier domain mode-locked (FDML) swept laser source. We propose a practical strategy for phase-sensitive measurement by comparing the phases between adjacent OCT B-scans, where the B-scan contains a number of A-scans equaling an integer number of FDML buffers. With this approach, we show that micro-strain fields can be mapped with ∼3.0 nm sensitivity at ∼16 000 fps. The system's capabilities are demonstrated on porcine cornea by imaging mechanical wave propagation launched by a pulsed UV laser beam, promising non-contact, real-time, and high-resolution optical coherence elastography.

Stably Doped Conducting Polymer Nanoshells by Surface Initiated Polymerization.

Despite broad applications ranging from electronics to biomedical sensing and imaging, a long-standing problem of conducting polymers is the poor resistance to dedoping, which directly affects their signature electrical and optical properties. This problem is particularly significant for biomedical uses because of fast leaching of dopant ions in physiological environments. Here, we describe a new approach to engineer multimodal core-shell nanoparticles with a stably doped conductive polymer shell in biological environments. It was achieved by making a densely packed polymer brush rather than changing its molecular structure. Polyaniline (PANI) was used as a model compound due to its concentrated near-infrared (NIR) absorption. It was grafted onto a magnetic nanoparticle via a polydopamine intermediate layer. Remarkably, at pH 7 its conductivity is ca. 2000× higher than conventional PANI nanoshells. Similarly, its NIR absorption is enhanced by 2 orders of magnitude, ideal for photothermal imaging and therapy. Another surprising finding is its nonfouling property, even outperforming polyethylene glycol. This platform technology is also expected to open exciting opportunities in engineering stable conductive materials for electronics, imaging, and sensing.

Concurrent photoacoustic-ultrasound imaging using single-laser pulses.

Conventional ultrasound (US) and photoacoustic (PA) multimodality imaging require the use of a US pulse for US data acquisition and a laser pulse for PA data acquisition. We propose a method for concurrent US and PA data acquisition with a single-laser pulse. A light-absorbing multilayer film that can generate a US pulse based on the thermoelastic effect is used. The selection of appropriate layer thickness, interlayer spacing, and absorption coefficient allows the spectral characteristics of the generated US signal to be adjusted so that it does not overlap with the spectrum of the PA signal generated by the light transmitting through the layer. Thus, the US signal and the PA signal can be generated, received, and separated by using a single-laser pulse combined with spectral filtering. This method is demonstrated using a multilayer film that generates US signals with a center frequency of 24.2 MHz and fractional bandwidth of 26.8%. The synthetic-aperture focusing technique is applied to improve the lateral resolution and the signal-to-noise ratio. A cyst-like phantom and a film phantom were used to demonstrate the feasibility of this method of concurrent PA-US imaging using single-laser pulses.

Optimization of the laser irradiation pattern in a high frame rate integrated photoacoustic / ultrasound (PAUS) imaging system.

To integrate real-time photoacoustics (PA) into ultrasound (US) scanners and accelerate clinical translation of combined PAUS imaging, we previously developed a system using a portable, low-cost, low pulse energy, high-repetition rate laser (~1kHz) with a 1D galvo-mirror for rapid laser beam scanning over the imaging area. However, the frame rate and pulse energy are limited because of regulations on the radiance (1 W/cm2). Therefore, a laser scan scheme needs to be optimized to provide high frame rate within this safety limit. In addition, the laser light should be evenly distributed to minimize any artifacts caused by the scanning approach. In this paper, we calculated the laser light distribution using 3D Monte Carlo simulation and further developed the system to scan the laser beam in elevation as well as laterally using a 2-dimensional galvo-mirror scanner to achieve higher frame rates within the radiance safety limit. Insertion of a needle into chicken breast tissue was used to demonstrate our optimized scan scheme.

All-optical scanhead for ultrasound and photoacoustic imaging-Imaging mode switching by dichroic filtering.

Ultrasound (US) and photoacoustic (PA) multimodality imaging has the advantage of combining good acoustic resolution with high optical contrast. The use of an all-optical scanhead for both imaging modalities can simplify integration of the two systems and miniaturize the imaging scanhead. Herein we propose and demonstrate an all-optical US/PA scanhead using a thin plate for optoacoustic generation in US imaging, a polymer microring resonator for acoustic detection, and a dichroic filter to switch between the two imaging modes by changing the laser wavelength. A synthetic-aperture focusing technique is used to improve the resolution and contrast. Phantom images demonstrate the feasibility of this design, and show that axial and lateral resolutions of 125 µm and 2.52°, respectively, are possible.

All-optical scanhead for ultrasound and photoacoustic dual-modality imaging.

We propose a new scanhead design for combined ultrasound (US)/photoacoustic (PA) imaging that can be applied to dual-modality microscopy and biomedical imaging. Both imaging modalities employ the optical generation and detection of acoustic waves. The scanhead consists of an optical fiber with an axicon tip for excitation, and a microring for acoustic detection. No conventional piezoelectric device is needed, and the cost of the design makes it suitable for one-time, disposable use. Furthermore, a single laser pulse is employed to generate both US and PA signals. A subband imaging method can be applied to the receiver to enhance the contrast between the US and PA signals. Phantom data demonstrate the feasibility of this approach.

Image reconstruction in intravascular photoacoustic imaging.

Intravascular photoacoustic (IVPA) imaging is a technique for visualizing atherosclerotic plaques with differential composition. Unlike conventional photoacoustic tomography scanning, where the scanning device rotates around the subject, the scanning aperture in IVPA imaging is enclosed within the imaged object. The display of the intravascular structure is typically obtained by converting detected photoacoustic waves into Cartesian coordinates, which can produce images with severe artifacts. Because the acquired data are highly limited, there does not exist a stable reconstruction algorithm for such imaging geometry. The purpose of this work was to apply image reconstruction concepts to explore the feasibility and efficacy of image reconstruction algorithms in IVPA imaging using traditional analytical formulas, such as a filtered back-projection (FBP) and the lambda-tomography method. Although the closed-form formulas are not exact for the IVPA system, a general picture of and interface information about objects are provided. To improve the quality of the reconstructed image, the iterative expectation maximization and penalized least-squares methods were adopted to minimize the difference between the measured signals and those generated by a reconstructed image. In this work, we considered both the ideal point detector and the acoustic transducers with finite- size aperture. The transducer effects including the spatial response of aperture and acoustoelectrical impulse responses were incorporated in the system matrix to reduce the aroused distortion in the IVPA reconstruction. Computer simulations and experiments were carried out to validate the methods. The applicability and the limitation of the reconstruction method were also discussed.

Integrated intravascular ultrasound and photoacoustic imaging scan head.

The combination of intravascular ultrasound and intravascular photoacoustic imaging has been proposed for improving the diagnosis of arterial diseases. We describe a novel scan-head design for implementing such multimodality imaging. The proposed device has the potential to achieve a sufficiently small size for clinical intravascular applications. The design aims for efficient image data acquisition for facilitating real-time three-dimensional imaging and reducing the required laser pulse repetition frequency. The integrated scan head consists of a single-element, ring-shaped transducer for sideward ultrasound transmission, a multimode fiber with a cone-shaped mirror for optical illumination, and a single polymer microring with mechanical scanning. The phantom imaging and some experimental results are presented. A microring array can be realized in the future to achieve high-frame-rate intravascular multimodality imaging.

Quantitative measurement of binding kinetics in sandwich assay using a fluorescence detection fiber-optic biosensor.

Fiber-optic biosensors have been studied intensively because they are very useful and important tools for monitoring biomolecular interactions. Here we describe a fluorescence detection fiber-optic biosensor (FD-FOB) using a sandwich assay to detect antibody-antigen interaction. In addition, the quantitative measurement of binding kinetics, including the association and dissociation rate constants for immunoglobulin G (IgG)/anti-mouse IgG, is achieved, indicating 0.38 x 10(6) M(-1) s(-1) for k(a) and 3.15 x 10(-3) s(-1) for k(d). These constants are calculated from the fluorescence signals detected on fiber surface only where the excited evanescent wave can be generated. Thus, a confined fluorescence-detecting region is achieved to specifically determine the binding kinetics at the vicinity of the interface between sensing materials and uncladded fiber surface. With this FD-FOB, the mathematical deduction and experimental verification of the binding kinetics in a sandwich immunoassay provide a theoretical basis for measuring rate constants and equilibrium dissociation constants. A further measurement to study the interaction between human heart-type fatty acid-binding protein and its antibody gave the calculated kinetic constants k(a), k(d), and K(D) as 8.48 x 10(5) M(-1) s(-1), 1.7 x 10(-3) s(-1), and 2.0 nM, respectively. Our study is the first attempt to establish a theoretical basis for the florescence-sensitive immunoassay using a sandwich format. Moreover, we demonstrate that the FD-FOB as a high-throughput biosensor can provide an alternative to the chip-based biosensors to study real-time biomolecular interaction.

Localized surface plasmon coupled fluorescence fiber-optic biosensor with gold nanoparticles.

A novel fiber-optic biosensor based on a localized surface plasmon coupled fluorescence (LSPCF) system is proposed and developed. This biosensor consists of a biomolecular complex in a sandwich format of . It is immobilized on the surface of an optical fiber where a complex forms the fluorescence probe and is produced by mixing Cy5-labeled antibody and protein A conjugated gold nanoparticles (Au-PA). The LSPCF is excited by localized surface plasmon on the GNP surface where the evanescent field is applied near the core surface of the optical fiber. At the same time, the fluorescence signal is detected by a photomultiplier tube located beside the unclad optical fiber with high collection efficiency. Experimentally, this novel LSPCF biosensor is able to detect mouse immunoglobulin G (IgG) at a minimum concentration of 1 pg/mL (7 fM) during the biomolecular interaction of the IgG with anti-mouse IgG. The analysis is expanded by a discussion of the amplification of the LSPCF intensity by GNP coupling, and overall, this LSPCF biosensor is confirmed experimentally as a biosensor with very high sensitivity.