Fast noninvasive functional diffuse optical tomography for brain imaging.

Three-dimensional diffuse optical imaging of hand joints: System description and phantom studies

Convergence rate calculation of simultaneous iterative reconstruction technique algorithm for diffuse optical tomography image reconstruction: A feasibility study

Optical imaging of fluorescent probes is an essential tool for investigation of molecular events in small animals for drug developments. In order to get localization and quantification information of fluorescent labels, CEA-LETI has developed efficient approaches in classical reflectance imaging as well as in diffuse optical tomographic imaging with continuous and temporal signals. This paper presents an overview of the different approaches investigated and their performances. High quality fluorescence reflectance imaging is obtained thanks to the development of an original "multiple wavelengths" system. The uniformity of the excitation light surface area is better than 15%. Combined with the use of adapted fluorescent probes, this system enables an accurate detection of pathological tissues, such as nodules, beneath the animal's observed area. Performances for the detection of ovarian nodules on a nude mouse are shown. In order to investigate deeper inside animals and get 3D localization, diffuse optical tomography systems are being developed for both slab and cylindrical geometries. For these two geometries, our reconstruction algorithms are based on analytical expression of light diffusion. Thanks to an accurate introduction of light/matter interaction process in the algorithms, high quality reconstructions of tumors in mice have been obtained. Reconstruction of lung tumors on mice are presented. By the use of temporal diffuse optical imaging, localization and quantification performances can be improved at the price of a more sophisticated acquisition system and more elaborate information processing methods. Such a system based on a pulsed laser diode and a time correlated single photon counting system has been set up. Performances of this system for localization and quantification of fluorescent probes are presented.

A crucial parameter in Diffuse Optical Tomography (DOT) is the construction of an accurate forward model, which greatly depends on tissue boundary. Since photon propagation is a three-dimensional volumetric problem, extraction and subsequent modeling of three-dimensional boundaries is essential. Original experimental demonstration of the feasibility of DOT to reconstruct absorbers, scatterers and fluorochromes used phantoms or tissues confined appropriately to conform to easily modeled geometries such as a slab or a cylinder. In later years several methods have been developed to model photon propagation through diffuse media with complex boundaries using numerical solutions of the diffusion or transport equation (finite elements or differences) or more recently analytical methods based on the tangent-plane method . While optical examinations performed simultaneously with anatomical imaging modalities such as MRI provide well-defined boundaries, very limited progress has been done so far in extracting full-field (360 degree) boundaries for in-vivo three-dimensional DOT stand-alone imaging. In this paper, we present a desktop multi-spectrum in-vivo 3D DOT system for small animal imaging. This system is augmented with Technest's full-field 3D cameras. The built system has the capability of acquiring 3D object surface profiles in real time and registering 3D boundary with diffuse tomography. Extensive experiments are performed on phantoms and small animals by our collaborators at the Center for Molecular Imaging Research (CMIR) at Massachusetts General Hospital (MGH) and Harvard Medical School. Data has shown successful reconstructed DOT data with improved accuracy.

This article demonstrates a spectroscopic diffuse optical tomography (DOT) system for the noninvasive continuous imaging of tissue. The system was built on an embedded system architecture along with an algorithm that performs entire system control, data acquisition, noise-free lock-in detection, and wireless data transmission to a host computer, equipped with a graphics processing unit (GPU). The GPU system executes a fast 3-D DOT spectroscopic image reconstruction algorithm. The algorithm computes Jacobians and solves four different depth-sensitive inverse problems of image reconstruction. The host computer sends commands to the DOT server system and collects data, and simultaneously performs high-speed 3-D spectroscopic image reconstruction to display images in real-time. We designed a configurable optical fiber patch to collect depth-resolved diffused light exiting the imaging media by placing the patch on the surface. The simulation and experimental results from two setups showed the spectroscopic imaging capability of the system to map the concentration of oxyhemoglobin, deoxyhemoglobin, and water, and to characterize the tumor located deep inside the tissue. The proposed system uses low-cost LEDs, photodiode detectors, embedded system, and algorithms to perform high-speed 3-D functional imaging and can be further miniaturized. Our promising results pave the way for the development of a low-cost hand-held spectroscopic DOT system for the real-time onsite functional imaging of biological tissue.

Functional neuroimaging is a vital element of neuroscience and cognitive research and, increasingly, is an important clinical tool. Diffuse optical imaging is an emerging, noninvasive technique with unique portability and hemodynamic contrast capabilities for mapping brain function in young subjects and subjects in enriched or clinical environments. We have developed a high-performance, high-density diffuse optical tomography (DOT) system that overcomes previous limitations and enables superior image quality. We show herein the utility of the DOT system by presenting functional hemodynamic maps of the adult human visual cortex. The functional brain images have a high contrast-to-noise ratio, allowing visualization of individual activations and highly repeatable mapping within and across subjects. With the improved spatial resolution and localization, we were able to image functional responses of 1.7 cm in extent and shifts of <1 cm. Cortical maps of angle and eccentricity in the visual field are consistent with retinotopic studies using functional MRI and positron-emission tomography. These results demonstrate that high-density DOT is a practical and powerful tool for mapping function in the human cortex.

INTRODUCTIONDelirium is associated with mortality and new onset dementia, yet the underlying pathophysiology remains poorly understood. Development of imaging biomarkers has been difficult given the challenging nature of imaging delirious patients. Diffuse optical tomography (DOT) offers a promising approach for investigating delirium given its portability and three‐dimensional capabilities.METHODSTwenty‐five delirious and matched non‐delirious patients (n = 50) were examined using DOT, comparing cerebral oxygenation and functional connectivity in the prefrontal cortex during and after an episode of delirium.RESULTSTotal hemoglobin values were significantly decreased in the delirium group, even after delirium resolution. Functional connectivity between the dorsolateral prefrontal cortex and dorsomedial prefrontal cortex was strengthened post‐resolution compared to during an episode; however, this relationship was still significantly weaker compared to controls.DISCUSSIONThese findings highlight DOT's potential as an imaging biomarker to measure impaired cerebral oxygenation and functional dysconnectivity during and after delirium. Future studies should focus on the role of cerebral oxygenation in delirium pathogenesis and exploring the etiological link between delirium and dementias.HighlightsWe developed a portable diffuse optical tomography (DOT) system for bedside three‐dimensional functional neuroimaging to study delirium in the hospital.We implemented a novel DOT task‐focused seed‐based correlation analysis.DOT revealed decreased cerebral oxygenation and functional connectivity strength in the delirium group, even after resolution of delirium.

Optical techniques based on photon migration are rapidly emerging as a promising alternative and/or augmentation of existing medical imaging modalities. For example, real time studies of hemodynamic changes in brain tissue are possible as a step towards optical functional brain imaging. Time-resolved implementations of these techniques allow for discrimination between scattering and absorption and for depth resolution. They require sub-nanosecond pulsed light sources with high repetition rate and sufficient power for deep enough tissue penetration. Picosecond diode lasers satisfy the clinical demands of economy, compact size, and reliability almost perfectly. Today multi-channel diode laser devices are commercially available and are widely used in diffuse optical imaging and spectroscopy, in particular in optical tomography and breast cancer detection. However, the output powers of these devices are just about sufficient for moderate tissue penetration depths. An improvement that does not compromise the advantages of the diode laser sources is amplification of the diode laser output by means of solid state tapered amplifiers. We present an amplified light source for use in NIR diffuse optical spectroscopy and imaging, providing pulse widths as short as 100 ps, adjustable repetition rates up to 80 MHz, and peak power levels as high as 7 Watts, corresponding to average power levels exceeding 100 mW. In combination with time-resolved photon counting electronics matching the high throughput demands in conjunction with the new source, state-of-the-art systems for diffuse optical imaging can be built. System design features and possible application examples are presented.

In Diffuse Optical Tomography (DOT), data processing and reconstruction stages are crucial to obtain high-quality images. Thus, choosing suitable algorithms for the system is a critical choice. This study aims to determine an appropriate reconstruction algorithm for DOT imaging. There are several reconstruction algorithms used in DOT systems. Some algorithms have been improved for solving specific cases, and some still need to be improved. In this study, we used three algorithms for the reconstruction process: Singular Value Decomposition (SVD), Bi-Conjugated Gradient (Bi-CG), and Transpose Free Quasi Minimal Residual (TFQMR). In testing the algorithms, data of the simulation experiments have been used. The simulation experiments model the tumoral tissue within the breast. All three algorithms were produced correct images while the tumor close to the surface. In the case of the tumor that is not close to the breast surface, the tumor location on the images created by Bi-CG and SVD algorithms was not its actual location. However, the tumor location in the image created by the TFQMR algorithm was close to its actual location. Outcomes of the reconstruction algorithms were evaluated based on correctly defining the location of the tumors by using Mean Percentage Error (MPE), Mean Squared Error (MSE), and Mean Absolute Error (MAE) metrics. We have demonstrated the TFQMR algorithm is a more appropriate reconstruction technique for DOT systems. Thus, we have concluded that TFQMR can have the potential to be used in medical imaging systems.

We recently applied time domain near infrared diffuse optical spectroscopy (TD-NIRS) to monitor hemodynamics of the cardiac wall (oxy and desoxyhemoglobin concentration, saturation, oedema) on anesthetized swine models. Published results prove that NIRS signal can provide information on myocardial hemodynamic parameters not obtainable with conventional diagnostic clinical tools.1 Nevertheless, the high cost of equipment, acquisition length, sensitivity to ambient light are factors limiting its clinical adoption. This paper introduces a novel approach, based on the use of wavelength and code division multiplexing, applicable to TD-NIRS as well as diffuse optical imaging systems (both topography and tomography); the approach, called WS-CDM (wavelength and space code division mltiplexing), essentially consists of a double stage intensity modulation of multiwavelength CW laser sources using orthogonal codes and their parallel correlation-based decoding after propagation in the tissue; it promises better signal to noise ratio (SNR), higher acquisition speed, robustness to ambient light and lower costs compared to both the conventional systems and the more recent spread spectrum approach based on single modulation with pseudo-random bit sequences (PRBS).2 Parallel acquisition of several wavelengths and from several locations is achievable. TD-NIRS experimental results guided Matlab-based simulations aimed at correlating different coding sequences, lengths, spectrum spreading factor, with the WS-CDM performances on such tissues (achievable SNR, acquisition and reconstruction speed, robustness to channel inequalization, ...). Simulations results and preliminary experimental validation confirm the significant improvements that WS-CDM could bring to diffuse optical imaging (not limited to cardiac functional imaging).

In this paper, we present a high performance time-resolved diffuse optical tomography (DOT) system whose working principle and implementation are very different from the conventional methods and features near real-time data acquisition. Dual-wavelength near-infrared light at 784 nm and 808 nm are used as light source. A high bit rate pseudo-random bit sequence (2.488 GB/s) modulates both continuous lights when they go through the external intensity modulator. The diffuse photon density waves responding to such modulated light are detected by array of high sensitivity, high speed silicon avalanche photodetectors (APD). The temporal point spread function can be retrieved very quickly by using hardware auto-/cross-correlation. Our system implementation has achieved system impulse with rise time approaching 0.5 ns which is highly desirable for time-domain DOT application to penetrate depth in few centimeters. The temporal resolution is mainly limited by the photodetectors. System performance is stabilized with accurate temperature control over key components. Experiment results based on tissue-like phantoms verify our design is potential for breast cancer imaging.

We present a photoacoustic tomography-guided diffuse optical tomography approach using a hand-held probe for detection and characterization of deeply-seated targets embedded in a turbid medium. Diffuse optical tomography guided by coregistered ultrasound, MRI, and x ray has demonstrated a great clinical potential to overcome lesion location uncertainty and to improve light quantification accuracy. However, due to the different contrast mechanisms, some lesions may not be detectable by a nonoptical modality but yet have high optical contrast. Photoacoustic tomography utilizes a short-pulsed laser beam to diffusively penetrate into tissue. Upon absorption of the light by the target, photoacoustic waves are generated and used to reconstruct, at ultrasound resolution, the optical absorption distribution that reveals optical contrast. However, the robustness of optical property quantification of targets by photoacoustic tomography is complicated because of the wide range of ultrasound transducer sensitivity, the orientation and shape of the targets relative to the ultrasound array, and the uniformity of the laser beam. We show in this paper that the relative optical absorption map provided by photoacoustic tomography can potentially guide the diffuse optical tomography to accurately reconstruct target absorption maps.

The application of near-infrared spectroscopy (NIRS) to assess microvascular function has shown promising results. An important limitation when using a single source-detector pair, however, is the lack of depth sensitivity. Diffuse optical tomography (DOT) overcomes this limitation using an array of sources and detectors that allow the reconstruction of volumetric hemodynamic changes. This study compares the key parameters of postocclusive reactive hyperemia measured in the forearm using standard NIRS and DOT. We show that while the mean parameter values are similar for the two techniques, DOT achieves much better reproducibility, as measured by the intraclass correlation coefficient (ICC). We show that DOT achieves high reproducibility for muscle oxygen consumption (ICC: 0.99), time to maximal HbO2 (ICC: 0.94), maximal HbO2 (ICC: 0.99), and time to maximal HbT (ICC: 0.99). Absolute reproducibility as measured by the standard error of measurement is consistently smaller and close to zero (ideal value) across all parameters measured by DOT compared to NIRS. We conclude that DOT provides a more robust characterization of the reactive hyperemic response and show how the availability of volumetric hemodynamic changes allows the identification of areas of temporal consistency, which could help characterize more precisely the microvasculature.

The accuracy and clinical utility of diffuse optical imaging systems rely on continuous advancements in instrumentation, theoretical modeling, and computational methods, alongside strategies to overcome persistent barriers to clinical translation. A key challenge in diffuse optical imaging research is the development of computationally efficient numerical models that accurately describe light-tissue interactions in complex anatomical domains, along with the validation of these models and novel instrumentation using realistic tissue-mimicking phantoms. Although diffuse optical imaging remains a promising area of research for applications such as cancer detection and functional brain activity assessment, progress has been limited by the lack of anatomically complex optical phantoms and the high computational cost of Monte Carlo simulations required to model light propagation. This dissertation addresses these challenges through two key innovations. First, we designed a multi-filament-mixing 3-D printing platform which enables spatially varying absorption, scattering, and luminescent optical properties by dynamically blending multiple commercially available filaments. This platform facilitates the design and fabrication of anatomically accurate phantoms with precise control over optical absorbance and scattering parameters, while also incorporating tunable luminescence intensity through the embedding of phosphorescent materials. We printed several benchmark phantoms showcasing our method's capability of generating complex anatomical shapes with continuously varying optical properties. This method should therefore allow for the design and easy fabrication of highly complex, anatomically accurate phantoms for benchmarking, calibration, and training across a wide range of diffuse optical imaging applications. Second, we introduce a memory-efficient parametric modeling approach to address the computational challenges in capturing detected photon partial path length (PPL) distributions in Monte Carlo simulations. This method utilizes numerical stochastic estimation techniques, such as the Box-Cox transformation, skew-normal distribution modeling, and rejection sampling, to efficiently approximate the PPL distribution with a small set of statistical parameters. This approach significantly reduces the memory footprint of large-scale Monte Carlo simulations, while remaining generalizable to anatomically accurate domains. Furthermore, the ability to regenerate an arbitrary number of detected photon PPLs using the recorded parametric PPL models demonstrates significant computational savings while retaining high levels of accuracy. Together, these findings enable more accessible and accurate diffuse optical imaging modeling by substantially reducing the computational costs typically associated with simulating light transport in complex anatomical domains. In summary, this dissertation presents experimental and computational advancements that are broadly applicable to diffuse optical imaging research. Both innovations are generalizable to complex tissue-like domains, enhancing their relevance across a wide range of applications. These contributions support the continued development of diffuse optical imaging technologies and promote their clinical translation, helping to enable more accessible, cost-effective, and practical imaging systems.--Author's abstract

Local molecular and physiological processes can be imaged in vivo through perturbations in the fluorescence lifetime (FLT) of optical imaging agents. In addition to providing functional information, FLT methods can quantify specific molecular events and multiplex diagnostic and prognostic information. We have developed a fluorescence lifetime diffuse optical tomography (DOT) system for in vivo preclinical imaging. Data is captured using a time-resolved intensified charge coupled device (ICCD) system to measure fluorescence excitation and emission in the time domain. Data is then converted to the frequency domain, and we simultaneously reconstruct images of yield and lifetime using an extension to the normalized Born approach. By using differential phase measurements, we demonstrate DOT imaging of short lifetimes (from 350 ps) with high precision (+/-5 ps). Furthermore, this system retains the efficiency, speed, and flexibility of transmission geometry DOT. We demonstrate feasibility of FLT-DOT through a progressive series of experiments. Lifetime range and repeatability are first measured in phantoms. Imaging of subcutaneous implants then verifies the FLT-DOT approach in vivo in the presence of inhomogeneous optical properties. Use in a common research scenario is ultimately demonstrated by imaging accumulation of a targeted near-infrared (NIR) fluorescent-labeled peptide probe (cypate-RGD) in a mouse with a subcutaneous tumor.