Imaging Cerebral Blood Vessels Using Near-Infrared Optical Tomography: A Simulation Study.

Cerebral veins have received increasing attention due to their importance in preoperational planning and the brain oxygenation measurement. There are different modalities to image those vessels, such as magnetic resonance angiography (MRA) and recently, contrast-enhanced (CE) 3D gradient-echo sequences. However, the current techniques have certain disadvantages, i.e., the long examination time, the requirement of contrast agents or inability to measure oxygenation. Near-infrared optical tomography (NIROT) is emerging as a viable new biomedical imaging modality that employs near infrared light (650-950 nm) to image biological tissue. It was proven to easily penetrate the skull and therefore enables the brain vessels to be assessed. NIROT utilizes safe non-ionizing radiation and can be applied in e.g., early detection of neonatal brain injury and ischemic strokes. The aim is to develop non-invasive label-free dynamic time domain (TD) NIROT to image the brain vessels. A simulation study was performed with the software (NIRFAST) which models light propagation in tissue with the finite element method (FEM). Both a simple shape mesh and a real head mesh including all the segmented vessels from MRI images were simulated using both FEM and a hybrid FEM-U-Net network, we were able to visualize the superficial vessels with NIROT with a Root Mean Square Error (RMSE) lower than 0.079.

Effects of Different Optical Properties of Head Tissues on Near-Infrared Spectroscopy Using Monte Carlo Simulations.

In near-infrared spectroscopy (NIRS), it is crucial to have an accurate and realistic model of photon transport in the adult head for obtaining accurate brain oxygenation values. There are several studies on the influence of thickness, the morphology of extracerebral layers, and source-detector distance on the sensitivity of NIRS to the brain. However, the optical properties of the different layers vary between different publications. How is the performance of NIRS affected when the real optical properties differ from the assumed ones?We aim to investigate the influence of variation in scattering and absorption in a five-layered head model (scalp, skull, CSF, grey and white matter). We performed Monte Carlo simulations focusing on a five-layered slab mesh. The range of optical properties is based on a review of the published literature. We assessed the effect on light propagation by measuring the difference in the mean partial path lengths, attenuation, and the number of the detected photons between the different optical properties performing Monte Carlo simulations. For changes in the reduced scattering, we found that the upper layers tend to have a negative impact. In contrast, changes in lower layers tend to impact the brain's influence metrics positively. Furthermore, for small source-detector distances, the relative percentage difference between lower and higher values is greater than larger distances. Conclusions: We conclude that the assumption of different optical properties has a substantial effect on the sensitivity to the brain. This means that it is important to determine the correct optical properties for NIRS measurements in vitro and in vivo.

Development and Validation of Robust and Cost-Effective Liquid Heterogeneous Phantom for Time Domain Near-Infrared Optical Tomography.

Diffused light imaging techniques, such as near-infrared optical tomography (NIROT), require a stable platform for testing and validation that imitates tissue optical properties. The aim of this work was to build a robust, but flexible liquid phantom for BORL time-domain NIROT system Pioneer. The phantom was designed to assess penetration depth and resolution of the system, and to provide a heterogeneous inner structure that can be changed in controllable manner with adjustable optical properties. We used only in-house produced 3D-printed elements and mechanics of a budget 3D-printer to build the phantom, and managed to keep the overall costs below $500. We achieved stable and repeatable movement of an arbitrary structure in 3+1 degree of freedom inside the phantom and demonstrated its performance in a series of tests. Thus, we presented a universal and cost-effective solution for testing NIROT, that can be easily customised to various systems or testing paradigms.

In Phantom Validation of Time-Domain Near-Infrared Optical Tomography Pioneer for Imaging Brain Hypoxia and Hemorrhage.

The neonatal brain is a vulnerable organ, and lesions due to hemorrhage and/or ischemia occur frequently in preterm neonates. Even though neuroprotective therapies exist, there is no tool available to detect the ischemic lesions. To address this problem, we have recently designed and built the new time-domain near-infrared optical tomography (TD NIROT) system - Pioneer. Here we present the results of a phantom study of the system performance. We used silicone phantoms to mimic risky situations for brain lesions: hemorrhage and hypoxia. Employing Pioneer, we were able to reconstruct accurately both position and optical properties of these inhomogeneities.

Probe Design Optimization for Time-Domain NIROT "Pioneer" System for Imaging the Oxygenation of the Preterm Brain.

In preterm infants, there is a risk of life-lasting impairments due to hemorrhagic/ischemic lesions. Our time-domain (TD) near-infrared optical tomography (NIROT) system "Pioneer" aims at detecting both disorders with high spatial resolution. Successfully tested on phantoms, "Pioneer" entered the phase of improvements and enhancements. The current probe (A-probe) was adapted for an optoacoustics instrument. A new probe (B-probe) optimized for TD measurements is required. Our aim is to determine the optimal arrangement of light sources in the B-probe to increase the sensitivity and the resolution of Pioneer and to improve the ability of the system to detect both ischemia and hemorrhage. To do this, we simulated TD-NIROT signals in NIRFAST, a MATLAB-based package used to model near-infrared light propagation through tissue. We used 16 × 16 detector array, with ~2.2 mm distance between the detectors. Light sources were arranged around the field of view (FoV). We performed forward simulations of light propagation through a "homogeneous case" (HC) tissue (µ's = 5.6 cm-1, µa = 0.07 cm-1). Next, we simulated light propagation through "inhomogeneous case" -tissue' (IC) tissue by adding ischemia (µa = µa · 2.5 cm-1) or hemorrhage (µa = µa · 50 cm-1) to HT as a spherical inclusion of 5 mm radius at different depths in the FoV center and identified the source location that provides the higher contrast on the FoV: maxi ∈ I (FoVContrastSOURCE). It was found that sources located closer to the FoV center generate greater contrast for late photons. This study suggests the light sources in B-probe should be closer to the FoV center. The higher sensitivity is expected to lead to a higher image quality.

Time-Resolved NIROT 'Pioneer' System for Imaging Oxygenation of the Preterm Brain: Preliminary Results.

In preterm infants, there is a risk of long-term cognitive, motor and behavioral impairments due to hemorrhagic and/or ischemic lesions. If detected early, lesions can be prevented. A bedside imaging modality, capable of early detection of both disorders, is necessary. We present the state of development of a tomographic imager (named Pioneer), that will be capable of determining the oxygenation of the preterm-infant brain with high spatial resolution. Pioneer is a time-resolved near-infrared optical tomography (TR NIROT) instrument. It employs multiple wavelength laser light in short pulses on 11 distinct locations and measures the re-emerging light in a contactless fashion by means of a time-correlated single-photon counting (TCSPC) camera (named Piccolo) covering ~4.9 cm2 with 300 detectors. Timing response of the entire system is 116 ps. An in-house designed biocompatible source ring ensures fixed relative positions of sources and detectors and provides a secure interface between the patient and the probe. At the present state, the NIROT Pioneer system successfully detected a 6x6x50 mm3 inclusion 3 cm deep inside a phantom. These results confirm that the Pioneer imager is working as expected and is on a solid path towards full 3D tissue oxygenation imaging.

Multispectral Near-Infrared Optical Tomography for Cancer Hypoxia Study in Mice.

Oxygenation of a tumor is one of the most important predictive factors: hypoxia is associated with aggressive tumors and substantially lower survival rate. Despite this high relevance of tumor oxygenation, there is currently no bedside technique available to measure it in clinical routine care. The aim of this work is to determine the oxygenation of tissue in mice by a continuous wave multispectral near-infrared optical tomograph (mNIROT). Tomographic reconstructions were processed by a massively modified NIRFAST software. We quantitatively measured the tissue oxygen saturation of the tumors in 4 BALB/c nude, female mice with human colon carcinoma cancer cells DLD-1 KRASwt injected subcutaneously. The study revealed changes of oxygenation in tumors on the long-term.

Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response.

We have hypothesized that the adaptive response to low doses of ionizing radiation (IR) is mediated by oxidized cell-free DNA (cfDNA) fragments. Here, we summarize our experimental evidence for this model. Studies involving measurements of ROS, expression of the NOX (superoxide radical production), induction of apoptosis and DNA double-strand breaks, antiapoptotic gene expression and cell cycle inhibition confirm this hypothesis. We have demonstrated that treatment of mesenchymal stem cells (MSCs) with low doses of IR (10 cGy) leads to cell death of part of cell population and release of oxidized cfDNA. cfDNA has the ability to penetrate into the cytoplasm of other cells. Oxidized cfDNA, like low doses of IR, induces oxidative stress, ROS production, ROS-induced oxidative modifications of nuclear DNA, DNA breaks, arrest of the cell cycle, activation of DNA reparation and antioxidant response, and inhibition of apoptosis. The MSCs pretreated with low dose of irradiation or oxidized cfDNA were equally effective in induction of adaptive response to challenge further dose of radiation. Our studies suggest that oxidized cfDNA is a signaling molecule in the stress signaling that mediates radiation-induced bystander effects and that it is an important component of the development of radioadaptive responses to low doses of IR.