Characterization of a commercial bioluminescence tomography-guided system for pre-clinical radiation research.

BACKGROUND: Widely used Cone-beam computed tomography (CBCT)-guided irradiators have limitations in localizing soft tissue targets growing in a low-contrast environment. This hinders small animal irradiators achieving precise focal irradiation. PURPOSE: To advance image-guidance for soft tissue targeting, we developed a commercial-grade bioluminescence tomography-guided system (BLT, MuriGlo) for pre-clinical radiation research. We characterized the system performance and demonstrated its capability in target localization. We expect this study can provide a comprehensive guideline for the community in utilizing the BLT system for radiation studies. METHODS: MuriGlo consists of four mirrors, filters, lens, and charge-coupled device (CCD) camera, enabling a compact imaging platform and multi-projection and multi-spectral BLT. A newly developed mouse bed allows animals imaged in MuriGlo and transferred to a small animal radiation research platform (SARRP) for CBCT imaging and BLT-guided irradiation. Methods and tools were developed to evaluate the CCD response linearity, minimal detectable signal, focusing, spatial resolution, distortion, and uniformity. A transparent polycarbonate plate covering the middle of the mouse bed was used to support and image animals from underneath the bed. We investigated its effect on 2D Bioluminescence images and 3D BLT reconstruction accuracy, and studied its dosimetric impact along with the rest of mouse bed. A method based on pinhole camera model was developed to map multi-projection bioluminescence images to the object surface generated from CBCT image. The mapped bioluminescence images were used as the input data for the optical reconstruction. To account for free space light propagation from object surface to optical detector, a spectral derivative (SD) method was implemented for BLT reconstruction. We assessed the use of the SD data (ratio imaging of adjacent wavelength) in mitigating out of focusing and non-uniformity seen in the images. A mouse phantom was used to validate the data mapping. The phantom and an in vivo glioblastoma model were utilized to demonstrate the accuracy of the BLT target localization. RESULTS: The CCD response shows good linearity with < 0.6% residual from a linear fit. The minimal detectable level is 972 counts for 10 × 10 binning. The focal plane position is within the range of 13-18 mm above the mouse bed. The spatial resolution of 2D optical imaging is < 0.3 mm at Rayleigh criterion. Within the region of interest, the image uniformity is within 5% variation, and image shift due to distortion is within 0.3 mm. The transparent plate caused < 6% light attenuation. The use of the SD imaging data can effectively mitigate out of focusing, image non-uniformity, and the plate attenuation, to support accurate multi-spectral BLT reconstruction. There is < 0.5% attenuation on dose delivery caused by the bed. The accuracy of data mapping from the 2D bioluminescence images to CBCT image is within 0.7 mm. Our phantom test shows the BLT system can localize a bioluminescent target within 1 mm with an optimal threshold and only 0.2 mm deviation was observed for the case with and without a transparent plate. The same localization accuracy can be maintained for the in vivo GBM model. CONCLUSIONS: This work is the first systematic study in characterizing the commercial BLT-guided system. The information and methods developed will be useful for the community to utilize the imaging system for image-guided radiation research.

Mobile bioluminescence tomography-guided system for pre-clinical radiotherapy research.

Due to low imaging contrast, a widely-used cone-beam computed tomography-guided small animal irradiator is less adept at localizing in vivo soft tissue targets. Bioluminescence tomography (BLT), which combines a model of light propagation through tissue with an optimization algorithm, can recover a spatially resolved tomographic volume for an internal bioluminescent source. We built a novel mobile BLT system for a small animal irradiator to localize soft tissue targets for radiation guidance. In this study, we elaborate its configuration and features that are indispensable for accurate image guidance. Phantom and in vivo validations show the BLT system can localize targets with accuracy within 1 mm. With the optimal choice of threshold and margin for target volume, BLT can provide a distinctive opportunity for investigators to perform conformal biology-guided irradiation to malignancy.

Quantitative molecular bioluminescence tomography.

SIGNIFICANCE: Bioluminescence imaging and tomography (BLT) are used to study biologically relevant activity, typically within a mouse model. A major limitation is that the underlying optical properties of the volume are unknown, leading to the use of a "best" estimate approach often compromising quantitative accuracy. AIM: An optimization algorithm is presented that localizes the spatial distribution of bioluminescence by simultaneously recovering the optical properties and location of bioluminescence source from the same set of surface measurements. APPROACH: Measured data, using implanted self-illuminating sources as well as an orthotopic glioblastoma mouse model, are employed to recover three-dimensional spatial distribution of the bioluminescence source using a multi-parameter optimization algorithm. RESULTS: The proposed algorithm is able to recover the size and location of the bioluminescence source while accounting for tissue attenuation. Localization accuracies of <1 mm are obtained in all cases, which is similar if not better than current "gold standard" methods that predict optical properties using a different imaging modality. CONCLUSIONS: Application of this approach, using in-vivo experimental data has shown that quantitative BLT is possible without the need for any prior knowledge about optical parameters, paving the way toward quantitative molecular imaging of exogenous and indigenous biological tumor functionality.

Bioluminescence tomography system for in vivo irradiation guidance.

We constructed a bioluminescence tomography(BLT) to localize soft tissue targets for preclinical radiotherapy study. With the threshold and margin designed for target volume, BLT can provide opportunity to perform conformal irradiation to malignancy.

Quantitative Bioluminescence Tomography for In Vivo Volumetric-Guided Radiotherapy.

Several groups, including ours, have initiated efforts to develop small-animal irradiators that mimic radiation therapy (RT) for human treatment. The major image modality used to guide irradiation is cone-beam computed tomography (CBCT). While CBCT provides excellent guidance capability, it is less adept at localizing soft tissue targets growing in a low image contrast environment. In contrast, bioluminescence imaging (BLI) provides strong image contrast and thus is an attractive solution for soft tissue targeting. However, commonly used 2D BLI on an animal surface is inadequate to guide irradiation, because optical transport from an internal bioluminescent tumor is highly susceptible to the effects of optical path length and tissue absorption and scattering. Recognition of these limitations led us to integrate 3D bioluminescence tomography (BLT) with the small animal radiation research platform (SARRP). In this chapter, we introduce quantitative BLT (QBLT) with the advanced capabilities of quantifying tumor volume for irradiation guidance. The detail of system components, calibration protocol, and step-by-step procedure to conduct the QBLT-guided irradiation are described.

Quantitative Bioluminescence Tomography-Guided Conformal Irradiation for Preclinical Radiation Research.

PURPOSE: Widely used cone beam computed tomography (CBCT)-guided irradiators in preclinical radiation research are limited to localize soft tissue target because of low imaging contrast. Knowledge of target volume is a fundamental need for radiation therapy (RT). Without such information to guide radiation, normal tissue can be overirradiated, introducing experimental uncertainties. This led us to develop high-contrast quantitative bioluminescence tomography (QBLT) for guidance. The use of a 3-dimensional bioluminescence signal, related to cell viability, for preclinical radiation research is one step toward biology-guided RT. METHODS AND MATERIALS: Our QBLT system enables multiprojection and multispectral bioluminescence imaging to maximize input data for the tomographic reconstruction. Accurate quantification of spectrum and dynamic change of in vivo signal were also accounted for the QBLT. A spectral-derivative method was implemented to eliminate the modeling of the light propagation from animal surface to detector. We demonstrated the QBLT capability of guiding conformal RT using a bioluminescent glioblastoma (GBM) model in vivo. A threshold was determined to delineate QBLT reconstructed gross target volume (GTVQBLT), which provides the best overlap between the GTVQBLT and CBCT contrast labeled GBM (GTV), used as the ground truth for GBM volume. To account for the uncertainty of GTVQBLT in target positioning and volume delineation, a margin was determined and added to the GTVQBLT to form a QBLT planning target volume (PTVQBLT) for guidance. RESULTS: The QBLT can reconstruct in vivo GBM with localization accuracy within 1 mm. A 0.5-mm margin was determined and added to GTVQBLT to form PTVQBLT, largely improving tumor coverage from 75.0% (0 mm margin) to 97.9% in average, while minimizing normal tissue toxicity. With the goal of prescribed dose 5 Gy covering 95% of PTVQBLT, QBLT-guided 7-field conformal RT can effectively irradiate 99.4 ± 1.0% of GTV. CONCLUSIONS: The QBLT provides a unique opportunity for investigators to use biologic information for target delineation, guiding conformal irradiation, and reducing normal tissue involvement, which is expected to increase reproducibility of scientific discovery.

In vivo bioluminescence tomography-guided radiation research platform for pancreatic cancer: an initial study using subcutaneous and orthotopic pancreatic tumor models.

Genetically engineered mouse model(GEMM) that develops pancreatic ductal adenocarcinoma(PDAC) offers an experimental system to advance our understanding of radiotherapy(RT) for pancreatic cancer. Cone beam CT(CBCT)-guided small animal radiation research platform(SARRP) has been developed to mimic the RT used for human. However, we recognized that CBCT is inadequate to localize the PDAC growing in low image contrast environment. We innovated bioluminescence tomography(BLT) to guide SARRP irradiation for in vivo PDAC. Before working on the complex PDAC-GEMM, we first validated our BLT target localization using subcutaneous and orthotopic pancreatic tumor models. Our BLT process involves the animal transport between the BLT system and SARRP. We inserted a titanium wire into the orthotopic tumor as the fiducial marker to track the tumor location and to validate the BLT reconstruction accuracy. Our data shows that with careful animal handling, minimum disturbance for target position was introduced during our BLT imaging procedure(<0.5mm). However, from longitudinal 2D bioluminescence image(BLI) study, the day-to-day location variation for an abdominal tumor can be significant. We also showed that the 2D BLI in single projection setting cannot accurately capture the abdominal tumor location. It renders that 3D BLT with multiple-projection is needed to quantify the tumor volume and location for precise radiation research. Our initial results show the BLT can retrieve the location at 2mm accuracy for both tumor models, and the tumor volume can be delineated within 25% accuracy. The study for the subcutaneous and orthotopic models will provide us valuable knowledge for BLT-guided PDAC-GEMM radiation research.

Development of a Mobile Fluorescence Tomography-guided System for Pre-clinical Radiotherapy Research.

We proposed to build a mobile fluorescence tomography (mFT) system as an image-guided platform for pre-clinical radiotherapy research. The mFT system is expected to localize functional target/tumor, guide irradiation, and provide longitudinal treatment assessment.

In Vivo Bioluminescence Tomography Center of Mass-Guided Conformal Irradiation.

PURPOSE: The cone-beam computed tomography (CBCT)-guided small animal radiation research platform (SARRP) has provided unique opportunities to test radiobiologic hypotheses. However, CBCT is less adept to localize soft tissue targets growing in a low imaging contrast environment. Three-dimensional bioluminescence tomography (BLT) provides strong image contrast and thus offers an attractive solution. We introduced a novel and efficient BLT-guided conformal radiation therapy and demonstrated it in an orthotopic glioblastoma (GBM) model. METHODS AND MATERIALS: A multispectral BLT system was integrated with SARRP for radiation therapy (RT) guidance. GBM growth curve was first established by contrast CBCT/magnetic resonance imaging (MRI) to derive equivalent sphere as approximated gross target volume (aGTV). For BLT, mice were subject to multispectral bioluminescence imaging, followed by SARRP CBCT imaging and optical reconstruction. The CBCT image was acquired to generate anatomic mesh for the reconstruction and RT planning. To ensure high accuracy of the BLT-reconstructed center of mass (CoM) for target localization, we optimized the optical absorption coefficients µa by minimizing the distance between the CoMs of BLT reconstruction and contrast CBCT/MRI-delineated GBM volume. The aGTV combined with the uncertainties of BLT CoM localization and target volume determination was used to generate estimated target volume (ETV). For conformal irradiation procedure, the GBM was first localized by the predetermined ETV centered at BLT-reconstructed CoM, followed by SARRP radiation. The irradiation accuracy was qualitatively confirmed by pathologic staining. RESULTS: Deviation between CoMs of BLT reconstruction and contrast CBCT/MRI-imaged GBM is approximately 1 mm. Our derived ETV centered at BLT-reconstructed CoM covers >95% of the tumor volume. Using the second-week GBM as an example, the ETV-based BLT-guided irradiation can cover 95.4% ± 4.7% tumor volume at prescribed dose. The pathologic staining demonstrated the BLT-guided irradiated area overlapped well with the GBM location. CONCLUSIONS: The BLT-guided RT enables 3-dimensional conformal radiation for important orthotopic tumor models, which provides investigators a new preclinical research capability.

Breaking the quantum adiabatic speed limit by jumping along geodesics.

Quantum adiabatic evolutions find a broad range of applications in quantum physics and quantum technologies. The traditional form of the quantum adiabatic theorem limits the speed of adiabatic evolution by the minimum energy gaps of the system Hamiltonian. Here, we experimentally show using a nitrogen-vacancy center in diamond that, even in the presence of vanishing energy gaps, quantum adiabatic evolution is possible. This verifies a recently derived necessary and sufficient quantum adiabatic theorem and offers paths to overcome the conventionally assumed constraints on adiabatic methods. By fast modulation of dynamic phases, we demonstrate near-unit-fidelity quantum adiabatic processes in finite times. These results challenge traditional views and provide deeper understanding on quantum adiabatic processes, as well as promising strategies for the control of quantum systems.

Quantitative bioluminescence tomography using spectral derivative data.

Bioluminescence imaging (BLI) is a non-contact, optical imaging technique based on measurement of emitted light due to an internal source, which is then often directly related to cellular activity. It is widely used in pre-clinical small animal imaging studies to assess the progression of diseases such as cancer, aiding in the development of new treatments and therapies. For many applications, the quantitative assessment of accurate cellular activity and spatial distribution is desirable as it would enable direct monitoring for prognostic evaluation. This requires quantitative spatially-resolved measurements of bioluminescence source strength inside the animal to be obtained from BLI images. This is the goal of bioluminescence tomography (BLT) in which a model of light propagation through tissue is combined with an optimization algorithm to reconstruct a map of the underlying source distribution. As most models consider only the propagation of light from internal sources to the animal skin surface, an additional challenge is accounting for the light propagation from the skin to the optical detector (e.g. camera). Existing approaches typically use a model of the imaging system optics (e.g. ray-tracing, analytical optical models) or approximate corrections derived from calibration measurements. However, these approaches are typically computationally intensive or of limited accuracy. In this work, a new approach is presented in which, rather than directly using BLI images acquired at several wavelengths, the spectral derivative of that data (difference of BLI images at adjacent wavelengths) is used in BLT. As light at similar wavelengths encounters a near-identical system response (path through the optics etc.) this eliminates the need for additional corrections or system models. This approach is applied to BLT with simulated and experimental phantom data and shown that the error in reconstructed source intensity is reduced from 49% to 4%. Qualitatively, the accuracy of source localization is improved in both simulated and experimental data, as compared to reconstruction using the standard approach. The outlined algorithm can widely be adapted to all commercial systems without any further technological modifications.

Experimental Adiabatic Quantum Factorization under Ambient Conditions Based on a Solid-State Single Spin System.

The adiabatic quantum computation is a universal and robust method of quantum computing. In this architecture, the problem can be solved by adiabatically evolving the quantum processor from the ground state of a simple initial Hamiltonian to that of a final one, which encodes the solution of the problem. Adiabatic quantum computation has been proved to be a compatible candidate for scalable quantum computation. In this Letter, we report on the experimental realization of an adiabatic quantum algorithm on a single solid spin system under ambient conditions. All elements of adiabatic quantum computation, including initial state preparation, adiabatic evolution (simulated by optimal control), and final state read-out, are realized experimentally. As an example, we found the ground state of the problem Hamiltonian S_{z}I_{z} on our adiabatic quantum processor, which can be mapped to the factorization of 35 into its prime factors 5 and 7.

High-resolution vector microwave magnetometry based on solid-state spins in diamond.

The measurement of the microwave field is crucial for many developments in microwave technology and related applications. However, measuring microwave fields with high sensitivity and spatial resolution under ambient conditions remains elusive. In this work, we propose and experimentally demonstrate a scheme to measure both the strength and orientation of the microwave magnetic field by utilizing the quantum coherent dynamics of nitrogen vacancy centres in diamond. An angular resolution of 5.7 mrad and a sensitivity of 1.0 µT Hz(-1/2) are achieved at a microwave frequency of 2.6000 GHz, and the microwave magnetic field vectors generated by a copper wire are precisely reconstructed. The solid-state microwave magnetometry with high resolution and wide frequency range that can work under ambient conditions proposed here enables unique potential applications over other state-of-art microwave magnetometry.

Observation of time-domain Rabi oscillations in the Landau-Zener regime with a single electronic spin.

It is theoretically known that the quantum interference of a long sequence of Landau-Zener transitions can result in Rabi oscillations. Because of its stringent requirements, however, this phenomenon has never been experimentally observed in the time domain. Using a nitrogen-vacancy (NV) center spin in isotopically purified diamond, we observed the Rabi oscillations resulting from more than 100 Landau-Zener processes. Our results demonstrate favorable quantum controllability of NV centers, which could find applications in quantum metrology and quantum information processing.

Coherence-protected quantum gate by continuous dynamical decoupling in diamond.

In order to achieve reliable quantum-information processing results, we need to protect quantum gates along with the qubits from decoherence. Here we demonstrate experimentally on a nitrogen-vacancy system that by using a continuous-wave dynamical decoupling method, we might not only prolong the coherence time by about 20 times but also protect the quantum gates for the duration of the controlling time. This protocol shares the merits of retaining the superiority of prolonging the coherence time and at the same time easily combining with quantum logic tasks. This method can be useful in tasks where the duration of quantum controlling exceeds far beyond the dephasing time.