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The emergence of the global coronavirus pandemic in 2019 (COVID-19 disease) created a need for remote methods to detect and continuously monitor patients with infectious respiratory diseases. Many different devices, including thermometers, pulse oximeters, smartwatches, and rings, were proposed to monitor the symptoms of infected individuals at home. However, these consumer-grade devices are typically not capable of automated monitoring during both day and night. This study aims to develop a method to classify and monitor breathing patterns in real-time using tissue hemodynamic responses and a deep convolutional neural network (CNN)-based classification algorithm. Tissue hemodynamic responses at the sternal manubrium were collected in 21 healthy volunteers using a wearable near-infrared spectroscopy (NIRS) device during three different breathing conditions. We developed a deep CNN-based classification algorithm to classify and monitor breathing patterns in real time. The classification method was designed by improving and modifying the pre-activation residual network (Pre-ResNet) previously developed to classify two-dimensional (2D) images. Three different one-dimensional CNN (1D-CNN) classification models based on Pre-ResNet were developed. By using these models, we were able to obtain an average classification accuracy of 88.79% (without Stage 1 (data size reducing convolutional layer)), 90.58% (with 1 × 3 Stage 1), and 91.77% (with 1 × 5 Stage 1).

Little is known empirically about connectivity and communication between the two hemispheres of the brain in the first year of life, and what theoretical opinion exists appears to be at variance with the meager extant anatomical evidence. To shed initial light on the question of interhemispheric connectivity and communication, this study investigated brain correlates of interhemispheric transmission of information in young human infants. We analyzed EEG data from 12 4-month-olds undergoing a face-related oddball ERP protocol. The activity in the contralateral hemisphere differed between odd-same and odd-difference trials, with the odd-different response being weaker than the response during odd-same trials. The infants' contralateral hemisphere "recognized" the odd familiar stimulus and "discriminated" the odd-different one. These findings demonstrate connectivity and communication between the two hemispheres of the brain in the first year of life and lead to a better understanding of the functional integrity of the developing human infant brain.

The worldwide outbreak of the novel Coronavirus (COVID-19) has highlighted the need for a screening and monitoring system for infectious respiratory diseases in the acute and chronic phase. The purpose of this study was to examine the feasibility of using a wearable near-infrared spectroscopy (NIRS) sensor to collect respiratory signals and distinguish between normal and simulated pathological breathing. Twenty-one healthy adults participated in an experiment that examined five separate breathing conditions. Respiratory signals were collected with a continuous-wave NIRS sensor (PortaLite, Artinis Medical Systems) affixed over the sternal manubrium. Following a three-minute baseline, participants began five minutes of imposed difficult breathing using a respiratory trainer. After a five minute recovery period, participants began five minutes of imposed rapid and shallow breathing. The study concluded with five additional minutes of regular breathing. NIRS signals were analyzed using a machine learning model to distinguish between normal and simulated pathological breathing. Three features: breathing interval, breathing depth, and O 2 Hb signal amplitude were extracted from the NIRS data and, when used together, resulted in a weighted average accuracy of 0.87. This study demonstrated that a wearable NIRS sensor can monitor respiratory patterns continuously and non-invasively and we identified three respiratory features that can distinguish between normal and simulated pathological breathing.

The action observation network (AON) is a network of brain regions involved in the execution and observation of a given action. The AON has been investigated in humans using mostly electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI), but shared neural correlates of action observation and action execution are still unclear due to lack of ecologically valid neuroimaging measures. In this study, we used concurrent EEG and functional Near Infrared Spectroscopy (fNIRS) to examine the AON during a live-action observation and execution paradigm. We developed structured sparse multiset canonical correlation analysis (ssmCCA) to perform EEG-fNIRS data fusion. MCCA is a generalization of CCA to more than two sets of variables and is commonly used in medical multimodal data fusion. However, mCCA suffers from multi-collinearity, high dimensionality, unimodal feature selection, and loss of spatial information in interpreting the results. A limited number of participants (small sample size) is another problem in mCCA, which leads to overfitted models. Here, we adopted graph-guided (structured) fused least absolute shrinkage and selection operator (LASSO) penalty to mCCA to conduct feature selection, incorporating structural information amongst the variables (i.e., brain regions). Benefitting from concurrent recordings of brain hemodynamic and electrophysiological responses, the proposed ssmCCA finds linear transforms of each modality such that the correlation between their projections is maximized. Our analysis of 21 right-handed participants indicated that the left inferior parietal region was active during both action execution and action observation. Our findings provide new insights into the neural correlates of AON which are more fine-tuned than the results from each individual EEG or fNIRS analysis and validate the use of ssmCCA to fuse EEG and fNIRS datasets., (© 2022. The Author(s).)

Brain activity in the action observation network (AON) is lateralized during action execution, with greater activation in the contralateral hemisphere to the side of the body used to perform the task. However, it is unknown whether the AON is also lateralized when watching another person perform an action. In this study, we use fNIRS to measure brain activity over the left and right cortex while participants completed actions with their left and right hands and watched an actor complete action with their left and right hands. We show that while activation is lateralized when the participants themselves are moving, brain lateralization is not affected by the side of the body when the participant is observing another person's action. In addition, we demonstrate that individual differences in hand preference and dexterity between the right and left hands are related to brain lateralization patterns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Khaksari, Smith, Miguel, Zeytinoglu, Fox and Gandjbakhche.)

The purpose of this study was to determine which thermometry technique is the most accurate for regular measurement of body temperature. We compared seven different commercially available thermometers with a gold standard medical-grade thermometer (Welch-Allyn): four digital infrared thermometers (Wellworks, Braun, Withings, MOBI), one digital sublingual thermometer (Braun), one zero heat flux thermometer (3M), and one infrared thermal imaging camera (FLIR One). Thirty young healthy adults participated in an experiment that altered core body temperature. After baseline measurements, participants placed their feet in a cold-water bath while consuming cold water for 30 min. Subsequently, feet were removed and covered with a blanket for 30 min. Throughout the session, temperature was recorded every 10 min with all devices. The Braun tympanic thermometer (left ear) had the best agreement with the gold standard (mean error: 0.044 °C). The FLIR One thermal imaging camera was the least accurate device (mean error: -0.522 °C) . A sign test demonstrated that all thermometry devices were significantly different than the gold standard except for the Braun tympanic thermometer (left ear). Our study showed that not all temperature monitoring techniques are equal, and suggested that tympanic thermometers are the most accurate commercially available system for the regular measurement of body temperature.

This study aimed to assess transabdominal placental oxygenation levels non-invasively. A wearable device was designed and tested in 12 pregnant women with an anterior placenta, 5 of whom had maternal pregnancy complications. Preliminary results revealed that the placental oxygenation level is closely related to pregnancy complications and placental pathology. Women with maternal pregnancy complications were found to have a lower placental oxygenation level (69.4% ± 6.7%) than those with uncomplicated pregnancy (75.0% ± 5.8%). This device is a step in the development of a point-of-care method designed to continuously monitor placental oxygenation and to assess maternal and fetal health., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Purpose: The recent coronavirus disease 2019 (COVID-19) pandemic, which spread across the globe in a very short period of time, revealed that the transmission control of disease is a crucial step to prevent an outbreak and effective screening for viral infectious diseases is necessary. Since the severe acute respiratory syndrome (SARS) outbreak in 2003, infrared thermography (IRT) has been considered a gold standard method for screening febrile individuals at the time of pandemics. The objective of this review is to evaluate the efficacy of IRT for screening infectious diseases with specific applications to COVID-19. Approach: A literature review was performed in Google Scholar, PubMed, and ScienceDirect to search for studies evaluating IRT screening from 2002 to present using relevant keywords. Additional literature searches were done to evaluate IRT in comparison to traditional core body temperature measurements and assess the benefits of measuring additional vital signs for infectious disease screening. Results: Studies have reported on the unreliability of IRT due to poor sensitivity and specificity in detecting true core body temperature and its inability to identify asymptomatic carriers. Airport mass screening using IRT was conducted during occurrences of SARS, Dengue, Swine Flu, and Ebola with reported sensitivities as low as zero. Other studies reported that screening other vital signs such as heart and respiratory rates can lead to more robust methods for early infection detection. Conclusions: Studies evaluating IRT showed varied results in its efficacy for screening infectious diseases. This suggests the need to assess additional physiological parameters to increase the sensitivity and specificity of non-invasive biosensors., (© 2021 The Authors.)

Significance: Placenta is an essential organ for fetal development and successful reproduction. Placental insufficiency can lead to fetal hypoxia and, in extreme cases anoxia, leading to fetal death. Of the 145 million deliveries per year worldwide, ∼15 million neonates are small for gestational age and, therefore, at risk for antepartum and intrapartum hypoxia. Clinical methods to assess placental function largely rely on the assessment of fetal heart rate changes but do not assess placental oxygenation. Near-infrared spectroscopy (NIRS) allows non-invasive, real-time assessment of tissue oxygenation in intact organs, which can be used to assess placental oxygenation. However, tissue optical properties can affect the accuracy of methods to measure tissue oxygenation., Aim: This study was performed to estimate the scattering coefficient of the human placenta. We have computed the scattering coefficients of the human placenta for the range of 659 to 840 nm using two methods of diffuse reflectance spectroscopy (DRS)., Approach: Measurements were performed using an in-house DRS device and a well-established frequency-domain diffuse optical spectroscopic system (DOSI). Measurements were performed in eight placentas obtained after cesarean deliveries. Placentas were perfused with normal saline to minimize the effects of absorption due to blood. Three sites per placenta were measured. Absorption and scattering coefficients were then calculated from the measured reflectance using the random walk theory for DRS and frequency-domain algorithm for DOSI., Results: Average reduced scattering coefficient (μs  '  ) was 0.943  ±  0.015  mm  -  1 at 760 nm and 0.831  ±  0.009  mm  -  1 at 840 nm, and a power function μs  '    =  1.6619 (λ/500  nm)  -  1.426 was derived for the human placental scattering coefficient., Conclusion: We report for the first time the scattering coefficient of the human placenta. This information can be used to assess baseline scattering and improve measurements of placental oxygen saturation with NIRS.

Ornithine transcarbamylase deficiency (OTCD) is the most common form of urea cycle disorder characterized by the presence of hyperammonemia (HA). In patients with OTCD, HA is known to cause impairments in domains of executive function and working memory. Monitoring OTCD progression and investigating neurocognitive biomarkers can, therefore, become critical in understanding the underlying brain function in a population with OTCD. We used functional near infrared spectroscopy (fNIRS) to examine the hemodynamics of prefrontal cortex (PFC) in a fraternal twin with and without OTCD. fNIRS is a non-invasive and wearable optical technology that can be used to assess cortical hemodynamics in a realistic clinical setting. We quantified the hemodynamic variations in total-hemoglobin as assessed by fNIRS while subjects performed the N -back working memory (WM) task. Our preliminary results showed that the sibling with OTCD had higher variation in a very low frequency band (<0.03 Hz, related to mechanism of cerebral autoregulation) compared to the control sibling. The difference between these variations was not as prominent in the higher frequency band, indicating the possible role of impaired autoregulation and cognitive function due to presence of HA. We further examined the functional connectivity in PFC, where the OTCD sibling showed lower interhemispheric functional connectivity as the task load increased. Our pilot results are the first to show the utility of fNIRS in monitoring OTCD cortical hemodynamics, indicating the possibility of inefficient neurocognitive function. This study provides a novel insight into the monitoring of OTCD focusing on the contribution of physiological process and neurocognitive function in this population., (Copyright © 2020 Anderson, Gropman, Le Mons, Stratakis and Gandjbakhche.)

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3-6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p<0.001). All patients that were followed up for up to 12 months showed the same decrease from preoperative values and they remained in remission from CD. We conclude that MSI can be used for the evaluation of remission from CD, at least in the immediate post-operative period and up to one year after surgery. The use of this technology can supplement biochemical and other testing for the evaluation of the various treatment modalities available for patients with CD., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This paper presents a novel method for early detection of hematomas using highly sensitive optical fNIR imaging methods based on broadband photon migration. The NIR experimental measurements of inhomogeneous multi-layer phantoms representing human head are compared to 3D numerical modeling over broadband frequencies of 30-1000 MHz. A finite element method (FEM) simulation of the head phantom are compared to measurements of insertion loss and phase using custom-designed broadband free space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 670 nm, 795 nm, 850 nm, though results of 670 nm are discussed here. Standard error is used to compute error between 3D FEM modeling and experimental measurements by fitting experimental data to the [Formula: see text]. Error results are shown at narrowband and broadband frequency modulation in order to have confidence in 3D numerical modeling. A novel method is established here to identify presence of hematoma based on first and second derivatives of changes in insertion loss and phase (∆IL and ∆IP), where frequency modulated photons sensitive to different sizes of hematoma is identified for wavelength of 670 nm. The high accuracy of this comparison provides confidence in optical bio-imaging and its eventual application to TBI detection.

Existing literature outlines the quality and location of activation in the prefrontal cortex (PFC) during working memory (WM) tasks. However, the effects of individual differences on the underlying neural process of WM tasks are still unclear. In this functional near infrared spectroscopy study, we administered a visual and auditory n-back task to examine activation in the PFC while considering the influences of task performance, and preferred learning strategy (VARK score). While controlling for age, results indicated that high performance (HP) subjects (accuracy > 90%) showed task dependent lower activation compared to normal performance subjects in PFC region Specifically HP groups showed lower activation in left dorsolateral PFC (DLPFC) region during performance of auditory task whereas during visual task they showed lower activation in the right DLPFC. After accounting for learning style, we found a correlation between visual and aural VARK score and level of activation in the PFC. Subjects with higher visual VARK scores displayed lower activation during auditory task in left DLPFC, while those with higher visual scores exhibited higher activation during visual task in bilateral DLPFC. During performance of auditory task, HP subjects had higher visual VARK scores compared to NP subjects indicating an effect of learning style on the task performance and activation. The results of this study show that learning style and task performance can influence PFC activation, with applications toward neurological implications of learning style and populations with deficits in auditory or visual processing., Competing Interests: The authors have declared that no competing interests exist.

Background: Assessment of the status of tumor biomarkers in individual patients would facilitate personalizing treatment strategy, and continuous monitoring of those biomarkers and their binding process to the therapeutic drugs would provide a means for early evaluation of the efficacy of therapeutic intervention. Fluorescent probes can accumulate inside the tumor region due to the leakiness of its vascularization and this can make it difficult to distinguish if the measured fluorescence intensity is from probes bound to target receptors or just accumulated unbound probes inside the tumor. In this paper, we have studied the fluorescence lifetime as a means to distinguish bound HER2 specific affibody probes to HER2 receptors. Our imaging system is a time-resolved fluorescence system using a Ti-Sapphire femtosecond pulse laser as source and Time correlated Single photon Counting (TCSPC) system as detector for calculating the lifetime of the contrast agent. HER2-specific Affibody (His6-ZHER2:GS-Cys) (Affibody, Stockholm, Sweden) conjugated with a Dylight750 fluorescent probe (Thermo-Fisher-Scientific, Waltham, Massachusetts) was used as contrast agent and six human cancer cell lines, BT-474, SKOV-3, NCI-N87, MDA-MB-361, MCF-7, and MDA-MB-468, known to express different levels of HER2/neu, are used in athymic mice xenografts., Results: By comparing the lifetime of unbound contrast agent (at the contralateral site) to the fluorescence lifetime at the tumor site, our results show that the fluorescence lifetime decreases as HER2 specific Affibody probes bind to the tumor receptors. A decrease of ~15% (100ps) in tumor fluorescence lifetime was observed in tumors with mid to high HER2 expression. Smaller decreases were observed in tumors with low-level of HER2 receptors and no change was observed in the non-HER2-expressing tumors., Conclusions: Using HER2-specific Affibody conjugated with the Dylight750 fluorescent probe as contrast agent, we demonstrated in live animals that change in fluorescence lifetime of the bound contrast agent can be used to assess the high to mid-level expression of HER2 expressing tumors in-vivo in only one measurement. The rationale is that the fluorescence lifetime of our specific probe is sensitive to affinity to, and specific interaction with, other molecules.

Functional near infrared spectroscopy (fNIRS) is a non-invasive functional neuroimaging modality. Although, it is amenable to use in infants and young children, there is a lack of fNIRS research within the toddler age range. In this study, we used fNIRS to measure cerebral hemodynamics in the prefrontal cortex (PFC) in 18-36 months old toddlers ( n = 29) as part of a longitudinal study that enrolled typically-developing toddlers as well as those "at risk" for language and other delays based on presence of early language delays. In these toddlers, we explored two hemodynamic response indices during periods of rest during which time audiovisual children's programming was presented. First, we investigate Lateralization Index, based on differences in oxy-hemoglobin saturation from left and right prefrontal cortex. Then, we measure oxygenation variability (OV) index, based on variability in oxygen saturation at frequencies attributed to cerebral autoregulation. Preliminary findings show that lower cognitive (including language) abilities are associated with fNIRS measures of both lower OV index and more extreme Lateralization index values. These preliminary findings show the feasibility of using fNIRS in toddlers, including those at risk for developmental delay, and lay the groundwork for future studies.

Background: We have explored the potential prefrontal hemodynamic biomarkers to characterize subjects with Traumatic Brain Injury (TBI) by employing the multivariate machine learning approach and introducing a novel task-related hemodynamic response detection followed by a heuristic search for optimum set of hemodynamic features. To achieve this goal, the hemodynamic response from a group of 31 healthy controls and 30 chronic TBI subjects were recorded as they performed a complexity task., Methods: To determine the optimum hemodynamic features, we considered 11 features and their combinations in characterizing TBI subjects. We investigated the significance of the features by utilizing a machine learning classification algorithm to score all the possible combinations of features according to their predictive power., Results and Conclusions: The identified optimum feature elements resulted in classification accuracy, sensitivity, and specificity of 85%, 85%, and 84%, respectively. Classification improvement was achieved for TBI subject classification through feature combination. It signified the major advantage of the multivariate analysis over the commonly used univariate analysis suggesting that the features that are individually irrelevant in characterizing the data may become relevant when used in combination. We also conducted a spatio-temporal classification to identify regions within the prefrontal cortex (PFC) that contribute in distinguishing between TBI and healthy subjects. As expected, Brodmann areas (BA) 10 within the PFC were isolated as the region that healthy subjects (unlike subjects with TBI), showed major hemodynamic activity in response to the High Complexity task. Overall, our results indicate that identified temporal and spatio-temporal features from PFC's hemodynamic activity are promising biomarkers in classifying subjects with TBI.

Cerebral hemodynamics reflect cognitive processes and underlying physiological processes, both of which are captured by functional near infrared spectroscopy (fNIRS). Here, we introduce a novel parameter of Oxygenation Variability directly obtained from fNIRS data -the OV Index-and we demonstrate its use in children. fNIRS data were collected from 17 children (ages 4-8 years), while they performed a standard Go/No-Go task. Data were analyzed using two frequency bands-the first attributed to cerebral autoregulation (CA) (<0.1 Hz) and the second to respiration (0.2-0.3 Hz). Results indicate differences in variability of oscillations of oxygen saturation (SO2) between the two different bands. These pilot data reveal a dynamic relationship between chronological age and OV index in CA associated frequency of <0.1 Hz. Specifically, OV index increased with age between 4 and 6 years. In addition, there was much higher variability in frequencies associated with CA than for respiration across subjects. These findings provide preliminary evidence for the utility of the OV index and are the first to describe the relationship between cerebral autoregulation and age in children using fNIRS methodology.

HER2 overexpression and amplification of the HER2/neu gene have been found in approximately 25% of invasive breast carcinomas. They are associated with a poor prognosis and resistance to therapy in breast cancer patients. Up to now, clinical evaluation of human epidermal growth factor receptor 2 (HER2) expression is based on ex vivo methods (immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) staining of biopsied tissue). Our goal is to realize "image and treat" paradigm using targeted fluorescent probes to evaluate expression levels of cell biomarkers responsible for cancer progression and to monitor the efficacy of corresponding monoclonal antibody treatments. We used fluorescent Affibody-based probes for in vivo analysis of HER2 receptors using near-infrared optical imaging that do not interfere with binding of the therapeutic agents to these receptors. We have analyzed two types of breast carcinoma xenografts with significant differences in HER2 expression (31 and 21 according to classification) in the mouse model. Using our kinetic model to analyze the temporal variations of the fluorescence intensity in the tumor area after two subsequent injections allowed us to assess quantitatively the difference in HER2 expression levels for two tumor types (BT-474 and MD-MBA-361). This result was substantiated by ELISA ex vivo assays of HER2 expression in the same tumors.

Real-time monitoring of the thermal penetration depth (TPD) is essential in various clinical procedures, such as Laser Interstitial Thermal Therapy (LITT). MRI is commonly used to this end, though bulky and expensive. In this paper, we present an alternative novel method for an optical feedback system based on changes in the diffused reflection from the tissue during treatment. Monte-Carlo simulation was used to deduce the relations between the backscattered pattern and the TPD. Several methods of image analysis are developed for TPD estimation. Each yields a set of parameters which are linearly dependent on the TPD. In order to test these experimentally, tissue samples were monitored in-vitro during treatment at multiple wavelengths. The SNR and coefficient of determination were used to compare the various methods and wavelengths and to determine the preferred method. Such system and algorithms may be used for real-time in-vivo control during laser thermotherapy and other clinical procedures., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We describe a compact, non-contact design for a total emission detection (c-TED) system for intra-vital multiphoton imaging. To conform to a standard upright two-photon microscope design, this system uses a parabolic mirror surrounding a standard microscope objective in concert with an optical path that does not interfere with normal microscope operation. The non-contact design of this device allows for maximal light collection without disrupting the physiology of the specimen being examined. Tests were conducted on exposed tissues in live animals to examine the emission collection enhancement of the c-TED device compared to heavily optimized objective-based emission collection. The best light collection enhancement was seen from murine fat (5×-2× gains as a function of depth), whereas murine skeletal muscle and rat kidney showed gains of over two and just under twofold near the surface, respectively. Gains decreased with imaging depth (particularly in the kidney). Zebrafish imaging on a reflective substrate showed close to a twofold gain throughout the entire volume of an intact embryo (approximately 150 μm deep). Direct measurement of bleaching rates confirmed that the lower laser powers, enabled by greater light collection efficiency, yielded reduced photobleaching in vivo. The potential benefits of increased light collection in terms of speed of imaging and reduced photo-damage, as well as the applicability of this device to other multiphoton imaging methods is discussed., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Diffuse multi-spectral imaging has been evaluated as a potential non-invasive marker of tumor response. Multi-spectral images of Kaposi sarcoma skin lesions were taken over the course of treatment, and blood volume and oxygenation concentration maps were obtained through principal component analysis (PCA) of the data. These images were compared with clinical and pathological responses determined by conventional means. We demonstrate that cutaneous lesions have increased blood volume concentration and that changes in this parameter are a reliable indicator of treatment efficacy, differentiating responders and non-responders. Blood volume decreased by at least 20% in all lesions that responded by clinical criteria and increased in the two lesions that did not respond clinically. Responses as assessed by multi-spectral imaging also generally correlated with overall patient clinical response assessment, were often detectable earlier in the course of therapy, and are less subject to observer variability than conventional clinical assessment. Tissue oxygenation was more variable, with lesions often showing decreased oxygenation in the center surrounded by a zone of increased oxygenation. This technique could potentially be a clinically useful supplement to existing response assessment in KS, providing an early, quantitative, and non-invasive marker of treatment effect.

Modeling behavior of broadband (30 to 1000 MHz) frequency modulated near-infrared (NIR) photons through a phantom is the basis for accurate extraction of optical absorption and scattering parameters of biological turbid media. Photon dynamics in a phantom are predicted using both analytical and numerical simulation and are related to the measured insertion loss (IL) and insertion phase (IP) for a given geometry based on phantom optical parameters. Accuracy of the extracted optical parameters using finite element method (FEM) simulation is compared to baseline analytical calculations from the diffusion equation (DE) for homogenous brain phantoms. NIR spectroscopy is performed using custom-designed, broadband, free-space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 680, 780, and 820 nm. Differential detection between two optical Rx locations separated by 0.3 cm is employed to eliminate systemic artifacts associated with interfaces of the optical Tx and Rx with the phantoms. Optical parameter extraction is achieved for four solid phantom samples using the least-square-error method in MATLAB (for DE) and COMSOL (for FEM) simulation by fitting data to measured results over broadband and narrowband frequency modulation. Confidence in numerical modeling of the photonic behavior using FEM has been established here by comparing the transmission mode's experimental results with the predictions made by DE and FEM for known commercial solid brain phantoms.

In vivo optical imaging is being conducted in a variety of medical applications, including optical breast cancer imaging, functional brain imaging, endoscopy, exercise medicine, and monitoring the photodynamic therapy and progress of neoadjuvant chemotherapy. In the past three decades, in vivo diffuse optical breast cancer imaging has shown promising results in cancer detection, and monitoring the progress of neoadjuvant chemotherapy. The use of near infrared spectroscopy for functional brain imaging has been growing rapidly. In fluorescence imaging, the difference between autofluorescence of cancer lesions compared to normal tissues were used in endoscopy to distinguish malignant lesions from normal tissue or inflammation and in determining the boarders of cancer lesions in surgery. Recent advances in drugs targeting specific tumor receptors, such as monoclonal antibodies (mAb), has created a new demand for developing non-invasive in vivo imaging techniques for detection of cancer biomarkers, and for monitoring their down regulations during therapy. Targeted treatments, combined with new imaging techniques, are expected to potentially result in new imaging and treatment paradigms in cancer therapy. Similar approaches can potentially be applied for the characterization of other disease-related biomarkers. In this chapter, we provide a review of diffuse optical and fluorescence imaging techniques with their application in functional brain imaging and cancer diagnosis.

The ability to assess frontal lobe function in a rapid, objective, and standardized way, without the need for expertise in cognitive test administration might be particularly helpful in mild traumatic brain injury (TBI), where objective measures are needed. Functional near infrared spectroscopy (fNIRS) is a reliable technique to noninvasively measure local hemodynamic changes in brain areas near the head surface. In this paper, we are combining fNIRS and frameless stereotaxy which allowed us to co-register the functional images with previously acquired anatomical MRI volumes. In our experiment, the subjects were asked to perform a task, evaluating the complexity of daily life activities, previously shown with fMRI to activate areas of the anterior frontal cortex. We reconstructed averaged oxyhemoglobin and deoxyhemoglobin data from 20 healthy subjects in a spherical coordinate. The spherical coordinate is a natural representation of surface brain activation projection. Our results show surface activation projected from the medial frontopolar cortex which is consistent with previous fMRI results. With this original technique, we will construct a normative database for a simple cognitive test which can be useful in evaluating cognitive disability such as mild traumatic brain injury., (Published by Elsevier Inc.)

In vivo optical imaging is being conducted in a variety of medical applications, including optical breast cancer imaging, functional brain imaging, endoscopy, exercise medicine, and monitoring the photodynamic therapy and progress of neoadjuvant chemotherapy. In the past three decades, in vivo diffuse optical breast cancer imaging has shown promising results in cancer detection, and monitoring the progress of neoadjuvant chemotherapy. The use of near infrared spectroscopy for functional brain imaging has been growing rapidly. In fluorescence imaging, the difference between autofluorescence of cancer lesions compared to normal tissues were used in endoscopy to distinguish malignant lesions from normal tissue or inflammation and in determining the boarders of cancer lesions in surgery. Recent advances in drugs targeting specific tumor receptors, such as AntiBodies (MAB), has created a new demand for developing non-invasive in vivo imaging techniques for detection of cancer biomarkers, and for monitoring their down regulations during therapy. Targeted treatments, combined with new imaging techniques, are expected to potentially result in new imaging and treatment paradigms in cancer therapy. Similar approaches can potentially be applied for the characterization of other disease-related biomarkers. In this chapter, we provide a review of diffuse optical and fluorescence imaging techniques with their application in functional brain imaging and cancer diagnosis.

In this paper we discuss results based on using instrumental motion as a signal rather than treating it as noise in Near Infra-Red (NIR) imaging. As a practical application to demonstrate this approach we show the design of a novel NIR hematoma detection device. The proposed device is based on a simplified single source configuration with a dual separation detector array and uses motion as a signal for detecting changes in blood volume in the dural regions of the head. The rapid triage of hematomas in the emergency room will lead to improved use of more sophisticated/expensive imaging facilities such as CT/MRI units. We present simulation results demonstrating the viability of such a device and initial phantom results from a proof of principle device. The results demonstrate excellent localization of inclusions as well as good quantitative comparisons., (2011 Optical Society of America)

We describe a novel reconstruction algorithm based on Principal Component Analysis (PCA) applied to multi-spectral imaging data. Using numerical phantoms, based on a two layered skin model developed previously, we found analytical expressions, which convert qualitative PCA results into quantitative blood volume and oxygenation values, assuming the epidermal thickness to be known. We also evaluate the limits of accuracy of this method when the value of the epidermal thickness is not known. We show that blood volume can reliably be extracted (less than 6% error) even if the assumed thickness deviates 0.04mm from the actual value, whereas the error in blood oxygenation can be as large as 25% for the same deviation in thickness. This PCA based reconstruction was found to extract blood volume and blood oxygenation with less than 8% error, if the underlying structure is known. We then apply the method to in vivo multi-spectral images from a healthy volunteer's lower forearm, complemented by images of the same area using Optical Coherence Tomography (OCT) for measuring the epidermal thickness. Reconstruction of the imaging results using a two layered analytical skin model was compared to PCA based reconstruction results. A point wise correlation was found, showing the proof of principle of using PCA based reconstruction for blood volume and oxygenation extraction.

We develop an analytic model of time-resolved fluorescent imaging of photons migrating through a semi-infinite turbid medium bounded by an infinite plane in the presence of a single stationary point fluorophore embedded in the medium. In contrast to earlier models of fluorescent imaging in which photon motion is assumed to be some form of continuous diffusion process, the present analysis is based on a continuous-time random walk (CTRW) on a simple cubic lattice, the object being to estimate the position and lifetime of the fluorophore. Such information can provide information related to local variations in pH and temperature with potential medical significance. Aspects of the theory were tested using time-resolved measurements of the fluorescence from small inclusions inside tissue-like phantoms. The experimental results were found to be in good agreement with theoretical predictions provided that the fluorophore was not located too close to the planar boundary, a common problem in many diffusive systems.

Near-infrared spectroscopy is a novel imaging technique potentially sensitive to both brain hemodynamics (slow signal) and neuronal activity (fast optical signal, FOS). The big challenge of measuring FOS noninvasively lies in the presumably low signal-to-noise ratio. Thus, detectability of the FOS has been controversially discussed. We present reliable detection of FOS from 11 individuals concurrently with electroencephalogram (EEG) during a Go-NoGo task. Probes were placed bilaterally over prefrontal cortex. Independent component analysis (ICA) was used for artifact removal. Correlation coefficient in the best correlated FOS-EEG ICA pairs was highly significant (p < 10(-8)), and event-related optical signal (EROS) was found in all subjects. Several EROS components were similar to the event-related potential (ERP) components. The most robust "optical N200" at t = 225 ms coincided with the N200 ERP; both signals showed significant difference between targets and nontargets, and their timing correlated with subject's reaction time. Correlation between FOS and EEG even in single trials provides further evidence that at least some FOS components "reflect" electrical brain processes directly. The data provide evidence for the early involvement of prefrontal cortex in rapid object recognition. EROS is highly localized and can provide cost-effective imaging tools for cortical mapping of cognitive processes.

Noncontact optical imaging of curved objects can result in strong artifacts due to the object's shape, leading to curvature biased intensity distributions. This artifact can mask variations due to the object's optical properties, and makes reconstruction of optical/physiological properties difficult. In this work we demonstrate a curvature correction method that removes this artifact and recovers the underlying data, without the necessity of measuring the object's shape. This method is applicable to many optical imaging modalities that suffer from shape-based intensity biases. By separating the spatially varying data (e.g., physiological changes) from the background signal (dc component), we show that the curvature can be extracted by either averaging or fitting the rows and columns of the images. Numerical simulations show that our method is equivalent to directly removing the curvature, when the object's shape is known, and accurately recovers the underlying data. Experiments on phantoms validate the numerical results and show that for a given image with 16.5% error due to curvature, the method reduces that error to 1.2%. Finally, diffuse multispectral images are acquired on forearms in vivo. We demonstrate the enhancement in image quality on intensity images, and consequently on reconstruction results of blood volume and oxygenation distributions.

Multispectral images of skin contain information on the spatial distribution of biological chromophores, such as blood and melanin. From this, parameters such as blood volume and blood oxygenation can be retrieved using reconstruction algorithms. Most such approaches use some form of pixelwise or volumetric reconstruction code. We explore the use of principal component analysis (PCA) of multispectral images to access blood volume and blood oxygenation in near real time. We present data from healthy volunteers under arterial occlusion of the forearm, experiencing ischemia and reactive hyperemia. Using a two-layered analytical skin model, we show reconstruction results of blood volume and oxygenation and compare it to the results obtained from our new spectral analysis based on PCA. We demonstrate that PCA applied to multispectral images gives near equivalent results for skin chromophore mapping and quantification with the advantage of being three orders of magnitude faster than the reconstruction algorithm.

Biomedical applications of near infrared radiation (NIR) techniques (i.e., based on light wavelengths roughly between 400 and 1100 nm) require that a preliminary estimate of the tissue volume being investigated be found. One possible estimate is the depth to which a photon penetrates a tissue before it eventually emerges at a separating plane at a given time. A simple model for this problem can be based on a lattice random walk and was initially analyzed when the associated optical coefficients are isotropic with respect to the geometry. Here we include the effects of anisotropy in the optical coefficients, finding that at long times the statistical properties of the depth of penetration can be accounted for by very simple scaling factors while at short times the anisotropy factors can be quite significant.

In vivo optical imaging using fluorescently labeled self-quenched monoclonal antibodies, activated through binding and internalization within target cells, results in excellent target-to-background ratios. We hypothesized that these molecular probes could be utilized to accurately report on cellular internalization with fluorescence lifetime imaging (FLI). Two imaging probes were synthesized, consisting of the antibody trastuzumab (targeting HER2/neu) conjugated to Alexa Fluor750 in ratios of either 1:8 or 1:1. Fluorescence intensity and lifetime of each conjugate were initially determined at endosomal pHs. Since the 1:8 conjugate is self-quenched, the fluorescence lifetime of each probe was also determined after exposure to the known dequencher SDS. In vitro imaging experiments were performed using 3T3/HER2(+) and BALB/3T3 (HER2(-)) cell lines. Changes in fluorescence lifetime correlated with temperature- and time-dependent cellular internalization. In vivo imaging studies in mice with dual flank tumors [3T3/HER2(+) and BALB/3T3 (HER2(-))] detected a minimal difference in FLI. In conclusion, fluorescence lifetime imaging monitors the internalization of target-specific activatable antibody-fluorophore conjugates in vitro. Challenges remain in adapting this methodology to in vivo imaging., ((c) 2010 John Wiley & Sons, Ltd.)

The present work shows that the optical/biological information contained in a typical spectral image mainly reflects the properties of a small (conic like) volume of tissue situated vertically under each individual pixel. The objects appearing on a spectral image reasonably reproduce the correct geometrical shape and size (like a non-deformed shadow) of underlying inclusions of pathological tissue. The information contained in a spectral image comes from a depth that does not exceed approximately 2-3 mm. The number of photons that visit a given tissue voxel situated at a depth larger than approximately 2 mm represents less than the 1% of the total number of photons reaching the corresponding detection pixel (forming the image). A pathological inclusion (e.g. a pool of blood or vascular tumor) situated at a depth of approximately 0.5 mm with a thickness of 0.5 mm produces an image intensity contrast of approximately 5% (for images taken at wavelengths in the 600-1000 nm range) when compared to the normal skin background. The same inclusion at a depth of 20 microm provides a contrast decreasing from 55 to 20% with respect to an increase in wavelength. The dermis/hypodermis interface behaves as a partial barrier for the photons, limiting their access to deeper skin regions. The image contrast depends on the depth and the type of chromophore contained in the inclusion. An increase in the concentration of a given molecule may produce different contrast, independently of the depth, depending on the characteristics of the skin layer where this change occurs.

Monte Carlo (MC) based simulations of photon transport in living tissues have become the "gold standard" technique in biomedical optics. Three-dimensional (3D) voxel-based images are the natural way to represent human (and animal) tissues. It is generally believed that the combination of 3D images and MC based algorithms allows one to produce the most realistic models of photon propagation. In the present work, it is shown that this approach may lead to large errors in the MC data due to the "roughness" of the geometrical boundaries generated by the presence of the voxels. In particular, the computed intensity of the light detected on the tissue surface of a simple cubic tissue phantom may display errors from -80% to 120%. It is also shown that these errors depend in a complex manner on optical and geometrical parameters such as the interoptode distance, scattering coefficient, refractive index, etc. and on the degree of voxelization ("roughness") of the boundaries. It is concluded that if one wants to perform reliable 3D Monte Carlo simulations on complex geometries, such as human brain, skin or trabecular bone, it is necessary to introduce boundary meshing techniques or other equivalent procedures in the MC code to eliminate the deleterious effect of voxelization.

We have constructed a device that maximizes the probability of collecting all of the scattered and ballistic light isotropically generated at the focal spot of multiphoton excited emissions (MPE) to optimize the signal-to-noise ratio (SNR) for micro-imaging. This was accomplished by optically coupling a parabolic reflector (that surrounds the sample and top of the objective) to a pair of collimating lenses (above the sample) that redirects emitted light to a separate detector. These additional optics, combined with the objective, allow the total emission detection (TED) condition to be approached. Numerical simulations suggest an approximately 10-fold improvement in SNR with TED. Comparisons between the objective detection and TED reveal an enhancement of 8.9 in SNR (77% of predicted) for GFP-labelled brain slices and similar results for fluorescent beads. This increase in SNR can be used to improve time resolution, reduce laser power requirements/photodynamic damage, and, in certain cases, detection depth, for MPE imaging techniques.

This research describes a noninvasive, noncontact method used to quantitatively analyze the functional characteristics of tissue. Multispectral images collected at several near-infrared wavelengths are input into a mathematical optical skin model that considers the contributions from different analytes in the epidermis and dermis skin layers. Through a reconstruction algorithm, we can quantify the percent of blood in a given area of tissue and the fraction of that blood that is oxygenated. Imaging normal tissue confirms previously reported values for the percent of blood in tissue and the percent of blood that is oxygenated in tissue and surrounding vasculature, for the normal state and when ischemia is induced. This methodology has been applied to assess vascular Kaposi's sarcoma lesions and the surrounding tissue before and during experimental therapies. The multispectral imaging technique has been combined with laser Doppler imaging to gain additional information. Results indicate that these techniques are able to provide quantitative and functional information about tissue changes during experimental drug therapy and investigate progression of disease before changes are visibly apparent, suggesting a potential for them to be used as complementary imaging techniques to clinical assessment.

In this article, a fluorescence lifetime imaging system for small animals is presented. Data were collected by scanning a region of interest with a measurement head, a linear fiber array with fixed separations between a single source fiber and several detection fibers. The goal was to localize tumors and monitor their progression using specific fluorescent markers. We chose a near-infrared contrast agent, Alexa Fluor 750 (Invitrogen Corp., Carlsbad, CA). Preliminary results show that the fluorescence lifetime for this dye was sensitive to the immediate environment of the fluorophore (in particular, pH), making it a promising candidate for reporting physiologic changes around a fluorophore. To quantify the intrinsic lifetime of deeply embedded fluorophores, we performed phantom experiments to investigate the contribution of photon migration effects on observed lifetime by calculating the fluorescence intensity decay time. A previously proposed theoretical model of migration, based on random walk theory, is also substantiated by new experimental data. The developed experimental system has been used for in vivo mouse imaging with Alexa Fluor 750 contrast agent conjugated to tumor-specific antibodies (trastuzumab [Herceptin]). Three-dimensional mapping of the fluorescence lifetime indicates lower lifetime values in superficial breast cancer tumors in mice.

Monte Carlo (MC) simulations are often at the heart of the testing procedure in biomedical optics. One of the critical points in MC simulations is to define the new photon direction after each scattering event. One of the most popular solutions is to use the Henyey-Greenstein phase function or some linear combinations of it. In this note, we demonstrate that randomly generating the angle defining the new direction of a photon after a collision, by means of the Henyey-Greenstein phase function, is not equivalent to generating the cosine of this angle, as is classically done. In practice, it is demonstrated that for a nearly isotropic medium (asymmetry parameter g approximately 0) this discrepancy is not large, however for an anisotropic medium as is typically found in vivo (e.g. g = 0.98) the two methods give completely different results.

A review is presented of recent advances in optical imaging and spectroscopy and the use of light for addressing breast cancer issues. Spectroscopic techniques offer the means to characterize tissue components and obtain functional information in real time. Three-dimensional optical imaging of the breast using various illumination and signal collection schemes in combination with image reconstruction algorithms may provide a new tool for cancer detection and treatment monitoring.

Angiogenesis, the formation of blood vessels, is a process whereby capillary sprout are formed in response to external stimuli. We model the tumor induced angiogenesis on keys events such of migratory response of endothelial cells to tumor angiogenic factors and the local cell interaction with the extracellular matrix (ECM). We consider the ECM medium as a statistically inhomogeneous two-phase random medium. Numerical simulations of the model are presented. Using this model, we will compare the influence of ECM distribution on vascular network formation. By developing mathematical models of angiogenesis, we hope to provide a deeper insight into the mechanisms underlying angiogenesis.

Three quantitative and non-invasive techniques were used to monitor angiogenesis in Kaposi's sarcoma patients: thermography, laser Doppler imaging (LDI), and near-infrared spectroscopy. Before and after combination cytotoxic and anti-angiogenesis therapy, blood volume, oxygenated hemoglobin, temperature, and blood flow were analyzed. These three techniques are objective, easy to perform, and appear to be very sensitive in assessing changes in the lesions upon administration of therapy.

We analyse the effect on scattered photons of anomalous optical inclusions in a turbid slab with otherwise uniform properties. Our motivation for doing so is that inclusions affect scattering contrast used to quantify optical properties found from transmitted light intensity measured in transillumination experiments. The analysis is based on a lattice random walk formalism which takes into account effects of both positive and negative deviations of the scattering coefficient from that of the bulk. Our simulations indicate the existence of a qualitative difference between the effects of these two types of perturbations. In the case of positive perturbations the time delay is found to be proportional to the square of the size of the inclusion while for negative perturbations the time delay is a linear function of its volume.