Hemoglobin signal network mapping reveals novel indicators for precision medicine.

Precision medicine currently relies on a mix of deep phenotyping strategies to guide more individualized healthcare. Despite being widely available and information-rich, physiological time-series measures are often overlooked as a resource to extend insights gained from such measures. Here we have explored resting-state hemoglobin measures applied to intact whole breasts for two subject groups - women with confirmed breast cancer and control subjects - with the goal of achieving a more detailed assessment of the cancer phenotype from a non-invasive measure. Invoked is a novel ordinal partition network method applied to multivariate measures that generates a Markov chain, thereby providing access to quantitative descriptions of short-term dynamics in the form of several classes of adjacency matrices. Exploration of these and their associated co-dependent behaviors unexpectedly reveals features of structured dynamics, some of which are shown to exhibit enzyme-like behaviors and sensitivity to recognized molecular markers of disease. Thus, findings obtained strongly indicate that despite the use of a macroscale sensing method, features more typical of molecular-cellular processes can be identified. Discussed are factors unique to our approach that favor a deeper depiction of tissue phenotypes, its extension to other forms of physiological time-series measures, and its expected utility to advance goals of precision medicine.

Endurance Exercise Enhances Emotional Valence and Emotion Regulation.

Acute exercise consistently benefits both emotion and cognition, particularly cognitive control. We evaluated acute endurance exercise influences on emotion, domain-general cognitive control and the cognitive control of emotion, specifically cognitive reappraisal. Thirty-six endurance runners, defined as running at least 30 miles per week with one weekly run of at least 9 miles (21 female, age 18-30 years) participated. In a repeated measures design, participants walked at 57% age-adjusted maximum heart rate (HRmax; range 51%-63%) and ran at 70% HRmax (range 64%-76%) for 90 min on two separate days. Participants completed measures of emotional state and the Stroop test of domain-general cognitive control before, every 30 min during and 30 min after exercise. Participants also completed a cognitive reappraisal task (CRT) after exercise. Functional near-infrared spectroscopy (fNIRS) tracked changes in oxygenated and deoxygenated hemoglobin (O2Hb and dHb) levels in the prefrontal cortex (PFC). Results suggest that even at relatively moderate intensities, endurance athletes benefit emotionally from running both during and after exercise and task-related PFC oxygenation reductions do not appear to hinder prefrontal-dependent cognitive control.

Hemoglobin state-flux: A finite-state model representation of the hemoglobin signal for evaluation of the resting state and the influence of disease.

SUMMARY: In this report we introduce a weak-model approach for examination of the intrinsic time-varying properties of the hemoglobin signal, with the aim of advancing the application of functional near infrared spectroscopy (fNIRS) for the detection of breast cancer, among other potential uses. The developed methodology integrates concepts from stochastic network theory with known modulatory features of the vascular bed, and in doing so provides access to a previously unrecognized dense feature space that is shown to have promising diagnostic potential. Notable features of the methodology include access to this information solely from measures acquired in the resting state, and analysis of these by treating the various components of the hemoglobin (Hb) signal as a co-varying interacting system. APPROACH: The principal data-transform kernel projects Hb state-space trajectories onto a coordinate system that constitutes a finite-state representation of covariations among the principal elements of the Hb signal (i.e., its oxygenated (ΔoxyHb) and deoxygenated (ΔdeoxyHb) forms and the associated dependent quantities: total hemoglobin (ΔtotalHb = ΔoxyHb + ΔdeoxyHb), hemoglobin oxygen saturation (ΔHbO2Sat = 100Δ(oxyHb/totalHb)), and tissue-hemoglobin oxygen exchange (ΔHbO2Exc = ΔdeoxyHb-ΔoxyHb)). The resulting ten-state representation treats the evolution of this signal as a one-space, spatiotemporal network that undergoes transitions from one state to another. States of the network are defined by the algebraic signs of the amplitudes of the time-varying components of the Hb signal relative to their temporal mean values. This assignment produces several classes of coefficient arrays, most with a dimension of 10×10. BIOLOGICAL MOTIVATION: Motivating our approach is the understanding that effector mechanisms that modulate blood delivery to tissue operate on macroscopic scales, in a spatially and temporally varying manner. Also recognized is that this behavior is sensitive to nonlinear actions of these effectors, which include the binding properties of hemoglobin. Accessible phenomenology includes measures of the kinetics and probabilities of network dynamics, which we treat as surrogates for the actions of feedback mechanisms that modulate tissue-vascular coupling. FINDINGS: Qualitative and quantitative features of this space, and their potential to serve as markers of disease, have been explored by examining continuous-wave fNIRS 3D tomographic time series obtained from the breasts of women who do and do not have breast cancer. Inspection of the coefficient arrays reveals that they are governed predominantly by first-order rate processes, and that each array class exhibits preferred structure that is mainly independent of the others. Discussed are strategies that may serve to extend evaluation of the accessible feature space and how the character of this information holds potential for development of novel clinical and preclinical uses.

Improving the analysis of near-infrared spectroscopy data with multivariate classification of hemodynamic patterns: a theoretical formulation and validation.

OBJECTIVE: The statistical analysis of functional near infrared spectroscopy (fNIRS) data based on the general linear model (GLM) is often made difficult by serial correlations, high inter-subject variability of the hemodynamic response, and the presence of motion artifacts. In this work we propose to extract information on the pattern of hemodynamic activations without using any a priori model for the data, by classifying the channels as 'active' or 'not active' with a multivariate classifier based on linear discriminant analysis (LDA). APPROACH: This work is developed in two steps. First we compared the performance of the two analyses, using a synthetic approach in which simulated hemodynamic activations were combined with either simulated or real resting-state fNIRS data. This procedure allowed for exact quantification of the classification accuracies of GLM and LDA. In the case of real resting-state data, the correlations between classification accuracy and demographic characteristics were investigated by means of a Linear Mixed Model. In the second step, to further characterize the reliability of the newly proposed analysis method, we conducted an experiment in which participants had to perform a simple motor task and data were analyzed with the LDA-based classifier as well as with the standard GLM analysis. MAIN RESULTS: The results of the simulation study show that the LDA-based method achieves higher classification accuracies than the GLM analysis, and that the LDA results are more uniform across different subjects and, in contrast to the accuracies achieved by the GLM analysis, have no significant correlations with any of the demographic characteristics. Findings from the real-data experiment are consistent with the results of the real-plus-simulation study, in that the GLM-analysis results show greater inter-subject variability than do the corresponding LDA results. SIGNIFICANCE: The results obtained suggest that the outcome of GLM analysis is highly vulnerable to violations of theoretical assumptions, and that therefore a data-driven approach such as that provided by the proposed LDA-based method is to be favored.

Hemodynamic correlates of spontaneous neural activity measured by human whole-head resting state EEG+fNIRS.

The brains of awake, resting human subjects display spontaneously occurring neural activity patterns whose magnitude is typically many times greater than those triggered by cognitive or perceptual performance. Evoked and resting state activations affect local cerebral hemodynamic properties through processes collectively referred to as neurovascular coupling. Its investigation calls for an ability to track both the neural and vascular aspects of brain function. We used scalp electroencephalography (EEG), which provided a measure of the electrical potentials generated by cortical postsynaptic currents. Simultaneously we utilized functional near-infrared spectroscopy (NIRS) to continuously monitor hemoglobin concentration changes in superficial cortical layers. The multi-modal signal from 18 healthy adult subjects allowed us to investigate the association of neural activity in a range of frequencies over the whole-head to local changes in hemoglobin concentrations. Our results verified the delayed alpha (8-16Hz) modulation of hemodynamics in posterior areas known from the literature. They also indicated strong beta (16-32Hz) modulation of hemodynamics. Analysis revealed, however, that beta modulation was likely generated by the alpha-beta coupling in EEG. Signals from the inferior electrode sites were dominated by scalp muscle related activity. Our study aimed to characterize the phenomena related to neurovascular coupling observable by practical, cost-effective, and non-invasive multi-modal techniques.

Enhanced resting-state dynamics of the hemoglobin signal as a novel biomarker for detection of breast cancer.

PURPOSE: The work presented here demonstrates an application of diffuse optical tomography (DOT) to the problem of breast-cancer diagnosis. The potential for using spatial and temporal variability measures of the hemoglobin signal to identify useful biomarkers was studied. METHODS: DOT imaging data were collected using two instrumentation platforms the authors developed, which were suitable for exploring tissue dynamics while performing a simultaneous bilateral exam. For each component of the hemoglobin signal (e.g., total, oxygenated), the image time series was reduced to eight scalar metrics that were affected by one or more dynamic properties of the breast microvasculature (e.g., average amplitude, amplitude heterogeneity, strength of spatial coordination). Receiver-operator characteristic (ROC) analyses, comparing groups of subjects with breast cancer to various control groups (i.e., all noncancer subjects, only those with diagnosed benign breast pathology, and only those with no known breast pathology), were performed to evaluate the effect of cancer on the magnitudes of the metrics and of their interbreast differences and ratios. RESULTS: For women with known breast cancer, simultaneous bilateral DOT breast measures reveal a marked increase in the resting-state amplitude of the vasomotor response in the hemoglobin signal for the affected breast, compared to the contralateral, noncancer breast. Reconstructed 3D spatial maps of observed dynamics also show that this behavior extends well beyond the tumor border. In an effort to identify biomarkers that have the potential to support clinical aims, a group of scalar quantities extracted from the time series measures was systematically examined. This analysis showed that many of the quantities obtained by computing paired responses from the bilateral scans (e.g., interbreast differences, ratios) reveal statistically significant differences between the cancer-positive and -negative subject groups, while the corresponding measures derived from individual breast scans do not. ROC analyses yield area-under-curve values in the 77%-87% range, depending on the metric, with sensitivity and specificity values ranging from 66% to 91%. An interesting result is the initially unexpected finding that the hemodynamic-image metrics are only weakly dependent on the tumor burden, implying that the DOT technique employed is sensitive to tumor-induced changes in the vascular dynamics of the surrounding breast tissue as well. Computational modeling studies serve to identify which properties of the vasomotor response (e.g., average amplitude, amplitude heterogeneity, and phase heterogeneity) principally determine the values of the metrics and their codependences. Findings from the modeling studies also serve to clarify the influence of spatial-response heterogeneity and of system-design limitations, and they reveal the impact that a complex dependence of metric values on the modeled behaviors has on the success in distinguishing between cancer-positive and -negative subjects. CONCLUSIONS: The authors identified promising hemoglobin-based biomarkers for breast cancer from measures of the resting-state dynamics of the vascular bed. A notable feature of these biomarkers is that their spatial extent encompasses a large fraction of the breast volume, which is mainly independent of tumor size. Tumor-induced induction of nitric oxide synthesis, a well-established concomitant of many breast cancers, is offered as a plausible biological causal factor for the reported findings.

On the geometry dependence of differential pathlength factor for near-infrared spectroscopy. I. Steady-state with homogeneous medium.

This work analytically examines some dependences of the differential pathlength factor (DPF) for steady-state photon diffusion in a homogeneous medium on the shape, dimension, and absorption and reduced scattering coefficients of the medium. The medium geometries considered include a semi-infinite geometry, an infinite-length cylinder evaluated along the azimuthal direction, and a sphere. Steady-state photon fluence rate in the cylinder and sphere geometries is represented by a form involving the physical source, its image with respect to the associated extrapolated half-plane, and a radius-dependent term, leading to simplified formula for estimating the DPFs. With the source-detector distance and medium optical properties held fixed across all three geometries, and equal radii for the cylinder and sphere, the DPF is the greatest in the semi-infinite and the smallest in the sphere geometry. When compared to the results from finite-element method, the DPFs analytically estimated for 10 to 25 mm source­detector separations on a sphere of 50 mm radius with µa=0.01 mm(−1) and µ's=1.0 mm(−1) are on average less than 5% different. The approximation for sphere, generally valid for a diameter≥20 times of the effective attenuation pathlength, may be useful for rapid estimation of DPFs in near-infrared spectroscopy of an infant head and for short source­detector separation.

Feasibility of near-infrared spectroscopic tomography for intraoperative functional cerebral monitoring: a primate study.

OBJECTIVE: The wide-ranging manipulations to the cardiovascular system that frequently occur during cardiac surgery can expose the brain to variations in its blood supply that could prove deleterious. As a first step to developing a resource suitable for monitoring such changes, we detected the hemodynamic events induced in the brain of a primate model, using high-density near-infrared spectroscopy combined with tomographic reconstruction methods and validated the findings using established radiologic and histologic techniques. METHODS: Continuous monitoring of the relative changes in the components of the cerebral hemoglobin signal was performed using high-density near-infrared spectroscopy (270 source-detector channel array) in anesthetized bonnet macaques with the brain exposed to induced ischemia and other acute events. A comparative analysis (exact binomial test) applied to reconstructed 3-dimensional images before and after the events and between cerebral hemispheres, combined with postprocedure magnetic resonance imaging, and postmortem histopathologic examination of the macaques' brains was performed to document and validate the spatial features revealed by the optical findings. RESULTS: Relative changes in the measured and calculated components of the hemoglobin signal, in response to the performed manipulations, revealed substantial concurrence among the reconstructed 3-dimensional images, magnetic resonance imaging of the macaques' brains, and postmortem histopathologic examination findings. Concurrence was seen when the manipulated hemoglobin concentration and associated oxygenation levels were either increased or decreased, and whether they were bilateral or restricted to a specified hemisphere. CONCLUSIONS: Continuous near-infrared spectroscopy tomography has been shown to accurately capture and localize cerebral ischemia, vasodilatation, and hemorrhage in primates in real time. These findings are directly applicable to clinical intraoperative functional cerebral monitoring.

A programmable laboratory testbed in support of evaluation of functional brain activation and connectivity.

An important determinant of the value of quantitative neuroimaging studies is the reliability of the derived information, which is a function of the data collection conditions. Near infrared spectroscopy (NIRS) and electroencelphalography are independent sensing domains that are well suited to explore principal elements of the brain's response to neuroactivation, and whose integration supports development of compact, even wearable, systems suitable for use in open environments. In an effort to maximize the translatability and utility of such resources, we have established an experimental laboratory testbed that supports measures and analysis of simulated macroscopic bioelectric and hemodynamic responses of the brain. Principal elements of the testbed include 1) a programmable anthropomorphic head phantom containing a multisignal source array embedded within a matrix that approximates the background optical and bioelectric properties of the brain, 2) integrated translatable headgear that support multimodal studies, and 3) an integrated data analysis environment that supports anatomically based mapping of experiment-derived measures that are directly and not directly observable. Here, we present a description of system components and fabrication, an overview of the analysis environment, and findings from a representative study that document the ability to experimentally validate effective connectivity models based on NIRS tomography.

Optomechanical imaging system for breast cancer detection.

Imaging studies of the breast comprise three principal sensing domains: structural, mechanical, and functional. Combinations of these domains can yield either additive or wholly new information, depending on whether one domain interacts with the other. In this report, we describe a new approach to breast imaging based on the interaction between controlled applied mechanical force and tissue hemodynamics. Presented is a description of the system design, performance characteristics, and representative clinical findings for a second-generation dynamic near-infrared optical tomographic breast imager that examines both breasts simultaneously, under conditions of rest and controlled mechanical provocation. The expected capabilities and limitations of the developed system are described in relation to the various sensing domains for breast imaging.

Digital optical tomography system for dynamic breast imaging.

Diffuse optical tomography has shown promising results as a tool for breast cancer screening and monitoring response to chemotherapy. Dynamic imaging of the transient response of the breast to an external stimulus, such as pressure or a respiratory maneuver, can provide additional information that can be used to detect tumors. We present a new digital continuous-wave optical tomography system designed to simultaneously image both breasts at fast frame rates and with a large number of sources and detectors. The system uses a master-slave digital signal processor-based detection architecture to achieve a dynamic range of 160 dB and a frame rate of 1.7 Hz with 32 sources, 64 detectors, and 4 wavelengths per breast. Included is a preliminary study of one healthy patient and two breast cancer patients showing the ability to identify an invasive carcinoma based on the hemodynamic response to a breath hold.

Using co-variations in the Hb signal to detect visual activation: a near infrared spectroscopic imaging study.

The premise of this report is that functional Near Infrared Spectroscopy (fNIRS) imaging data contain valuable physiological information that can be extracted by using analysis techniques that simultaneously consider the components of the measured hemodynamic response [i.e., levels of oxygenated, deoxygenated and total hemoglobin (oxyHb, deoxyHb and totalHb, respectively)]. We present an algorithm for examining the spatiotemporal co-variations among the Hb components, and apply it to the data obtained from a demonstrational study that employed a well-established visual stimulation paradigm: a contrast-reversing checkerboard. Our results indicate that the proposed method can identify regions of tissue that participate in the hemodynamic response to neuronal activation, but are distinct from the areas identified by conventional analyses of the oxyHb, deoxyHb and totalHb data. A discussion is provided that compares these findings to other recent studies using fNIRS techniques.

Event-related fast optical signal in a rapid object recognition task: improving detection by the independent component analysis.

Noninvasive recording of fast optical signals presumably reflecting neuronal activity is a challenging task because of a relatively low signal-to-noise ratio. To improve detection of those signals in rapid object recognition tasks, we used the independent component analysis (ICA) to reduce "global interference" (heartbeat and contribution of superficial layers). We recorded optical signals from the left prefrontal cortex in 10 right-handed participants with a continuous-wave instrument (DYNOT, NIRx, Brooklyn, NY). Visual stimuli were pictures of urban, landscape and seashore scenes with various vehicles as targets (target-to-non-target ratio 1:6) presented at ISI=166 ms or 250 ms. Subjects mentally counted targets. Data were filtered at 2-30 Hz and artifactual components were identified visually (for heartbeat) and using the ICA weight matrix (for superficial layers). Optical signals were restored from the ICA components with artifactual components removed and then averaged over target and non-target epochs. After ICA processing, the event-related response was detected in 70%-100% of subjects. The refined signal showed a significant decrease from baseline within 200-300 ms after targets and a slight increase after non-targets. The temporal profile of the optical signal corresponded well to the profile of a "differential ERP response", the difference between targets and non-targets which peaks at 200 ms in similar object detection tasks. These results demonstrate that the detection of fast optical responses with continuous-wave instruments can be improved through the ICA method capable to remove noise, global interference and the activity of superficial layers. Fast optical signals may provide further information on brain processing during higher-order cognitive tasks such as rapid categorization of objects.

The design and characterization of a digital optical breast cancer imaging system.

Optical imaging has the potential to play a major role in breast cancer screening and diagnosis due to its ability to image cancer characteristics such as angiogenesis and hypoxia. A promising approach to evaluate and quantify these characteristics is to perform dynamic imaging studies in which one monitors the hemodynamic response to an external stimulus, such as a valsalva maneuver. It has been shown that the response to such stimuli shows MARKED differences between cancerous and healthy tissues. The fast imaging rates and large dynamic range of digital devices makes them ideal for this type of imaging studies. Here we present a digital optical tomography system designed specifically for dynamic breast imaging. The instrument uses laser diodes at 4 different near-infrared wavelengths with 32 sources and 128 silicon photodiode detectors.

Image correction algorithm for functional three-dimensional diffuse optical tomography brain imaging.

We outline a computationally efficient image correction algorithm, which we have applied to diffuse optical tomography (DOT) image time series derived from a magnetic resonance imaging (MRI)-based brain model. Results show that the algorithm increases spatial resolution, decreases spatial bias, and only modestly reduces temporal accuracy for noise levels typically seen in experiment, and produces results comparable to image reconstructions that incorporate information from MRI priors. We demonstrate that this algorithm has robust performance in the presence of noise, background heterogeneity, irregular external and internal boundaries, and error in the initial guess. However, the algorithm introduces artifacts when the absorption and scattering coefficients of the reference medium are overestimated--a situation that is easily avoided in practice. The considered algorithm offers a practical approach to improving the quality of images from time-series DOT, even without the use of MRI priors.

Image correction scheme applied to functional diffuse optical tomography scattering images.

We have extended our investigation on the use of a linear algorithm for enhancing the accuracy of diffuse optical tomography (DOT) images, to include spatial maps of the diffusion coefficient. The results show that the corrected images are markedly improved in terms of estimated size, spatial resolution, two-object resolving power, and quantitative accuracy. These image-enhancing effects are significant at expected levels of diffusion-coefficient contrast in tissue and noise levels typical of experimental DOT data. Overall, the types and magnitudes of image-enhancing effects obtained here are qualitatively similar to those seen in previous studies on mu(a) perturbations. The implications for practical implementations of DOT time-series imaging are discussed.

Image quality improvement via spatial deconvolution in optical tomography: time-series imaging.

We present the fourth in a series of studies devoted to the issue of improving image quality in diffuse optical tomography (DOT) by using a spatial deconvolution operation that seeks to compensate for the information-blurring property of first-order perturbation algorithms. Our earlier reports consider only static target media. Here we report spatial deconvolution applied to media with time-varying optical properties, as a model of tissue dynamics resulting from varying metabolic demand and modulation of the vascular bed. Issues under study include the influence of deconvolution on the accuracy of the recovered temporal and spatial information. The impact of noise is also explored, and techniques for ameliorating its information-degrading effects are examined. At low noise levels (i.e, < or = 5% of the time-varying signal amplitude), spatial deconvolution markedly improves the accuracy of recovered information. Temporal information is more seriously degraded by noise than is spatial information, and the impact of noise increases with the complexity of the time-varying signal. These effects, however, can be significantly reduced using simple noise suppression techniques (e.g., low-pass filtering). Results suggest that the deconvolution scheme should provide considerable enhancement of the quality of spatiotemporal information recovered from dynamic DOT techniques applied to tissue studies.

Improved accuracy of reconstructed diffuse optical tomographic images by means of spatial deconvolution: two-dimensional quantitative characterization.

Systematic characterization studies are presented, relating to a previously reported spatial deconvolution operation that seeks to compensate for the information-blurring property of first-order perturbation algorithms for diffuse optical tomography (DOT) image reconstruction. In simulation results that are presented, this deconvolution operation has been applied to two-dimensional DOT images reconstructed by solving a first-order perturbation equation. Under study was the effect on algorithm performance of control parameters in the measurement (number and spatial distribution of sources and detectors, presence of noise, and presence of systematic error), target (medium shape; and number, location, size, and contrast of inclusions), and computational (number of finite-element-method mesh nodes, length of filter-generating linear system, among others) parameter spaces associated with computation and the use of the deconvolution operators. Substantial improvements in reconstructed image quality, in terms of recovered inclusion location, size, and contrast, are found in all cases. A finding of practical importance is that the method is robust to appreciable differences between the optical coefficients of the media used for filter generation and those of the target media to which the filters are subsequently applied.

Design and implementation of dynamic near-infrared optical tomographic imaging instrumentation for simultaneous dual-breast measurements.

Dynamic near-infrared optical tomographic measurement instrumentation capable of simultaneous bilateral breast imaging, having a capability of four source wavelengths and 32 source-detector fibers for each breast, is described. The system records dynamic optical data simultaneously from both breasts, while verifying proper optical fiber contact with the tissue through implementation of automatic schemes for evaluating data integrity. Factors influencing system complexity and performance are discussed, and experimental measurements are provided to demonstrate the repeatability of the instrumentation. Considerations in experimental design are presented, as well as techniques for avoiding undesirable measurement artifacts, given the high sensitivity and dynamic range (1:10(9)) of the system. We present exemplary clinical results comparing the measured physiologic response of a healthy individual and of a subject with breast cancer to a Valsalva maneuver.

Spatial deconvolution technique to improve the accuracy of reconstructed three-dimensional diffuse optical tomographic images.

A straightforward spatial deconvolution operation is presented that seeks to invert the information-blurring property of first-order perturbation algorithms for diffuse optical tomography (DOT) image reconstruction. The method that was developed to generate these deconvolving operators, or filters, was conceptually based on the frequency-encoding process used in magnetic resonance imaging. The computation of an image-correcting filter involves the solution of a large system of linear equations, in which known true distributions and the corresponding recovered distributions are compared. Conversely, application of a filter involves only a simple matrix multiplication. Simulation results show that application of this deconvolution operation to three-dimensional DOT images reconstructed by the solution of a first-order perturbation equation (Born approximation) can yield marked enhancement of image quality. In the examples considered, use of image-correcting filters produces obvious improvements in image quality, in terms of both location and mirco(a) of the inclusions. The displacements between the true and recovered locations of an inclusion's centroid location are as small as 1 mm, in an 8-cm-diameter medium with 1.5-cm-diameter inclusions, and the peak value of the recovered micro(a) for the inclusions deviates from the true value by as little as 5%.