A Wearable Fiber-Free Optical Sensor for Continuous Monitoring of Cerebral Blood Flow in Freely Behaving Mice.

OBJECTIVE: Wearable technologies for functional brain monitoring in freely behaving subjects can advance our understanding of cognitive processing and adaptive behavior. Existing technologies are lacking in this capability or need procedures that are invasive and/or otherwise impede brain assessments during social behavioral conditions, exercise, and sleep. METHODS: In response a complete system was developed to combine relative cerebral blood flow (rCBF) measurement, O2 and CO2 supplies, and behavior recording for use on conscious, freely behaving mice. An innovative diffuse speckle contrast flowmetry (DSCF) device and associated hardware were miniaturized and optimized for rCBF measurements in small subject applications. The use of this wearable, fiber-free, near-infrared DSCF head-stage/probe allowed no craniotomy, minimally invasive probe implantation, and minimal restraint of the awake animal. RESULTS AND CONCLUSIONS: Significant correlations were found between measurements with the new DSCF design and an optical standard. The system successfully detected rCBF responses to CO2-induced hypercapnia in both anesthetized and freely behaving mice. SIGNIFICANCE: Collecting rCBF and activity information together during natural behaviors provides realistic physiological results and opens the path to exploring their correlations with pathophysiological conditions.

Communicating uncertainty in national security intelligence: Expert and nonexpert interpretations of and preferences for verbal and numeric formats.

Organizations in several domains including national security intelligence communicate judgments under uncertainty using verbal probabilities (e.g., likely) instead of numeric probabilities (e.g., 75% chance), despite research indicating that the former have variable meanings across individuals. In the intelligence domain, uncertainty is also communicated using terms such as low, moderate, or high to describe the analyst's confidence level. However, little research has examined how intelligence professionals interpret these terms and whether they prefer them to numeric uncertainty quantifiers. In two experiments (N = 481 and 624, respectively), uncertainty communication preferences of expert (n = 41 intelligence analysts in Experiment 1) and nonexpert intelligence consumers were elicited. We examined which format participants judged to be more informative and simpler to process. We further tested whether participants treated verbal probability and confidence terms as independent constructs and whether participants provided coherent numeric probability translations of verbal probabilities. Results showed that although most nonexperts favored the numeric format, experts were about equally split, and most participants in both samples regarded the numeric format as more informative. Experts and nonexperts consistently conflated probability and confidence. For instance, confidence intervals inferred from verbal confidence terms had a greater effect on the location of the estimate than the width of the estimate, contrary to normative expectation. Approximately one-fourth of experts and over one-half of nonexperts provided incoherent numeric probability translations for the terms likely and unlikely when the elicitation of best estimates and lower and upper bounds were briefly spaced by intervening tasks.

On measuring agreement with numerically bounded linguistic probability schemes: A re-analysis of data from Wintle, Fraser, Wills, Nicholson, and Fidler (2019).

Across a wide range of domains, experts make probabilistic judgments under conditions of uncertainty to support decision-making. These judgments are often conveyed using linguistic expressions (e.g., x is likely). Seeking to foster shared understanding of these expressions between senders and receivers, the US intelligence community implemented a communication standard that prescribes a set of probability terms and assigns each term an equivalent numerical probability range. In an earlier PLOS ONE article, [1] tested whether access to the standard improves shared understanding and also explored the efficacy of various enhanced presentation formats. Notably, they found that embedding numeric equivalents in text (e.g., x is likely [55-80%]) substantially outperformed the status-quo approach in terms of the percentage overlap between participants' interpretations of linguistic probabilities (defined in terms of the numeric range equivalents they provided for each term) and the numeric ranges in the standard. These results have important prescriptive implications, yet Wintle et al.'s percentage overlap measure of agreement may be viewed as unfairly punitive because it penalizes individuals for being more precise than the stipulated guidelines even when the individuals' interpretations fall perfectly within the stipulated ranges. Arguably, subjects' within-range precision is a positive attribute and should not be penalized in scoring interpretive agreement. Accordingly, in the present article, we reanalyzed Wintle et al.'s data using an alternative measure of percentage overlap that does not penalize in-range precision. Using the alternative measure, we find that percentage overlap is substantially elevated across conditions. More importantly, however, the effects of presentation format and probability level are highly consistent with the original study. By removing the ambiguity caused by Wintle et al.'s unduly punitive measure of agreement, these findings buttress Wintle et al.'s original claim that the methods currently used by intelligence organizations are ineffective at coordinating the meaning of uncertainty expressions between intelligence producers and intelligence consumers. Future studies examining agreement between senders and receivers are also encouraged to reflect carefully on the most appropriate measures of agreement to employ in their experiments and to explicate the bases for their methodological choices.

Improving Probability Judgment in Intelligence Analysis: From Structured Analysis to Statistical Aggregation.

As in other areas of expert judgment, intelligence analysis often requires judging the probability that hypotheses are true. Intelligence organizations promote the use of structured methods such as "Analysis of Competing Hypotheses" (ACH) to improve judgment accuracy and analytic rigor, but these methods have received little empirical testing. In this experiment, we pitted ACH against a factorized Bayes's theorem (FBT) method, and we examined the value of recalibration (coherentization) and aggregation methods for improving the accuracy of probability judgment. Analytic techniques such as ACH and FBT were ineffective in improving accuracy and handling correlated evidence, and ACH in fact decreased the coherence of probability judgments. In contrast, statistical postanalytic methods (i.e., coherentization and aggregation) yielded large accuracy gains. A wide range of methods for instantiating these techniques were tested. The interactions among the factors considered suggest that prescriptive theorists and interventionists should examine the value of ensembles of judgment-support methods.

Noncontact 3-D Speckle Contrast Diffuse Correlation Tomography of Tissue Blood Flow Distribution.

Recent advancements in near-infrared diffuse correlation techniques and instrumentation have opened the path for versatile deep tissue microvasculature blood flow imaging systems. Despite this progress there remains a need for a completely noncontact, noninvasive device with high translatability from small/testing (animal) to large/target (human) subjects with trivial application on both. Accordingly, we discuss our newly developed setup which meets this demand, termed noncontact speckle contrast diffuse correlation tomography (nc_scDCT). The nc_scDCT provides fast, continuous, portable, noninvasive, and inexpensive acquisition of 3-D tomographic deep (up to 10 mm) tissue blood flow distributions with straightforward design and customization. The features presented include a finite-element-method implementation for incorporating complex tissue boundaries, fully noncontact hardware for avoiding tissue compression and interactions, rapid data collection with a diffuse speckle contrast method, reflectance-based design promoting experimental translation, extensibility to related techniques, and robust adjustable source and detector patterns and density for high resolution measurement with flexible regions of interest enabling unique application-specific setups. Validation is shown in the detection and characterization of both high and low contrasts in flow relative to the background using tissue phantoms with a pump-connected tube (high) and phantom spheres (low). Furthermore, in vivo validation of extracting spatiotemporal 3-D blood flow distributions and hyperemic response during forearm cuff occlusion is demonstrated. Finally, the success of instrument feasibility in clinical use is examined through the intraoperative imaging of mastectomy skin flap.

Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes.

This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (µs') at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

Alignment of sources and detectors on breast surface for noncontact diffuse correlation tomography of breast tumors.

Noncontact diffuse correlation tomography (ncDCT) is an emerging technology for 3D imaging of deep tissue blood flow distribution without distorting hemodynamic properties. To adapt the ncDCT for imaging in vivo breast tumors, we designed a motorized ncDCT probe to scan over the breast surface. A computer-aided design (CAD)-based approach was proposed to create solid volume mesh from arbitrary breast surface obtained by a commercial 3D camera. The sources and detectors of ncDCT were aligned on the breast surface through ray tracing to mimic the ncDCT scanning with CAD software. The generated breast volume mesh along with the boundary data of ncDCT at the aligned source and detector pairs were used for finite-element-method-based flow image reconstruction. We evaluated the accuracy of source alignments on mannequin and human breasts; largest alignment errors were less than 10% in both tangential and radial directions of scanning. The impact of alignment errors (assigned 10%) on the tumor reconstruction was estimated using computer simulations. The deviations of simulated tumor location and blood flow contrast resulted from the alignment errors were 0.77 mm (less than the node distance of 1 mm) and 1%, respectively, which result in minor impact on flow image reconstruction. Finally, a case study on a human breast tumor was conducted and a tumor-to-normal flow contrast was reconstructed, demonstrating the feasibility of ncDCT in clinical application.

Noncontact diffuse correlation tomography of human breast tumor.

Our first step to adapt our recently developed noncontact diffuse correlation tomography (ncDCT) system for three-dimensional (3-D) imaging of blood flow distribution in human breast tumors is reported. A commercial 3-D camera was used to obtain breast surface geometry, which was then converted to a solid volume mesh. An ncDCT probe scanned over a region of interest on the mesh surface and the measured boundary data were combined with a finite element framework for 3-D image reconstruction of blood flow distribution. This technique was tested in computer simulations and in vivo human breasts with low-grade carcinoma. Results from computer simulations suggest that relatively high accuracy can be achieved when the entire tumor is within the sensitive region of diffuse light. Image reconstruction with a priori knowledge of the tumor volume and location can significantly improve the accuracy in recovery of tumor blood flow contrasts. In vivo imaging results from two breast carcinomas show higher average blood flow contrasts (5.9- and 10.9-fold) in the tumor regions compared to the surrounding tissues, which are comparable with previous findings using diffuse correlation spectroscopy. The ncDCT system has the potential to image blood flow distributions in soft and vulnerable tissues without distorting tissue hemodynamics

Speckle contrast diffuse correlation tomography of complex turbid medium flow.

PURPOSE: Developed herein is a three-dimensional (3D) flow contrast imaging system leveraging advancements in the extension of laser speckle contrast imaging theories to deep tissues along with our recently developed finite-element diffuse correlation tomography (DCT) reconstruction scheme. This technique, termed speckle contrast diffuse correlation tomography (scDCT), enables incorporation of complex optical property heterogeneities and sample boundaries. When combined with a reflectance-based design, this system facilitates a rapid segue into flow contrast imaging of larger, in vivo applications such as humans. METHODS: A highly sensitive CCD camera was integrated into a reflectance-based optical system. Four long-coherence laser source positions were coupled to an optical switch for sequencing of tomographic data acquisition providing multiple projections through the sample. This system was investigated through incorporation of liquid and solid tissue-like phantoms exhibiting optical properties and flow characteristics typical of human tissues. Computer simulations were also performed for comparisons. A uniquely encountered smear correction algorithm was employed to correct point-source illumination contributions during image capture with the frame-transfer CCD and reflectance setup. RESULTS: Measurements with scDCT on a homogeneous liquid phantom showed that speckle contrast-based deep flow indices were within 12% of those from standard DCT. Inclusion of a solid phantom submerged below the liquid phantom surface allowed for heterogeneity detection and validation. The heterogeneity was identified successfully by reconstructed 3D flow contrast tomography with scDCT. The heterogeneity center and dimensions and averaged relative flow (within 3%) and localization were in agreement with actuality and computer simulations, respectively. CONCLUSIONS: A custom cost-effective CCD-based reflectance 3D flow imaging system demonstrated rapid acquisition of dense boundary data and, with further studies, a high potential for translatability to real tissues with arbitrary boundaries. A requisite correction was also found for measurements in the fashion of scDCT to recover accurate speckle contrast of deep tissues.

Three-dimensional flow contrast imaging of deep tissue using noncontact diffuse correlation tomography.

This study extended our recently developed noncontact diffuse correlation spectroscopy flowmetry system into noncontact diffuse correlation tomography (ncDCT) for three-dimensional (3-D) flow imaging of deep tissue. A linear array of 15 photodetectors and two laser sources connected to a mobile lens-focusing system enabled automatic and noncontact scanning of flow in a region of interest. These boundary measurements were combined with a finite element framework for DCT image reconstruction implemented into an existing software package. This technique was tested in computer simulations and using a tissue-like phantom with anomaly flow contrast design. The cylindrical tube-shaped anomaly was clearly reconstructed in both simulation and phantom. Recovered and assigned flow contrast changes in anomaly were found to be highly correlated: regression slope = 1.00, R2 = 1.00, and p < 10-5 in simulation and regression slope ≥ 0.97, R2 ≥ 0.96, and p < 10-3 in phantom. These results exhibit promise of our ncDCT technique for 3-D imaging of deep tissue blood flow heterogeneities.

Experimental and theoretical characterization of a lone pair-π complex: water-hexafluorobenzene.

The lone pair-π interaction between H(2)O and C(6)F(6) was studied using matrix isolation infrared spectroscopy and quantum chemical calculations. Co-deposition of H(2)O with C(6)F(6) in a nitrogen matrix at 17 K followed by annealing to 30 K, results in the appearance of multiple new peaks in the infrared spectrum that are shifted from the H(2)O and C(6)F(6) parent absorptions. These peaks only appear when both the H(2)O and C(6)F(6) are present and have been assigned to distinct structures of a 1:1 H(2)O·C(6)F(6) complex. Similar experiments were performed with D(2)O and HDO and the corresponding infrared peaks for the structures of the D(2)O·C(6)F(6) and HDO·C(6)F(6) complexes have also been observed. Theoretical calculations were performed for the H(2)O·C(6)F(6) complex using the B3LYP, MP2, and CCSD(T) methods. Geometry optimizations at the B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVDZ levels of theory located three structural minima, all of which involve the lone pair-π interaction between the H(2)O and the C(6)F(6) ring, but with different relative orientations of the H(2)O and C(6)F(6) subunits. BSSE corrected interaction energies were estimated at the CCSD(T)/aug-cc-pVTZ level and found to be between -11.2 and -12.3 kJ/mol for the three H(2)O·C(6)F(6) structures. Vibrational frequencies for the each of the structures were calculated at the B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVDZ levels. The frequencies calculated with both methods support the assignments of the observed new peaks in the infrared spectra to the structures of the H(2)O·C(6)F(6) complex; however, the B3LYP calculated frequency shifts were found to be in better quantitative agreement with the experimentally observed frequency shifts.

Longitudinal in vivo SPECT/CT imaging reveals morphological changes and cardiopulmonary apoptosis in a rodent model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) has a complex pathogenesis involving both heart and lungs. Animal models can reflect aspects of the human pathology and provide insights into the development and underlying mechanisms of disease. Because of the variability of most animal models of PAH, serial in vivo measurements of cardiopulmonary function, morphology, and markers of pathology can enhance the value of such studies. Therefore, quantitative in vivo SPECT/CT imaging was performed to assess cardiac function, morphology and cardiac perfusion utilizing (201)Thallium ((201)Tl) in control and monocrotaline-treated rats. In addition, lung and heart apoptosis was examined with (99m)Tc-Annexin V ((99m)Tc-Annexin) in these cohorts. Following baseline imaging, rats were injected with saline or monocrotaline (50 mg/kg, i.p.) and imaged weekly for 6 weeks. To assess a therapeutic response in an established pulmonary hypertensive state, a cohort of rats received resveratrol in drinking water (3 mg/kg/day) on days 28-42 post-monocrotaline injection to monitor regression of cardiopulmonary apoptosis. PAH in monocrotaline-treated rats was verified by conventional hemodynamic techniques on day 42 (right ventricular systolic pressure (RSVP) = 66.2 mmHg in monocrotaline vs 28.8 mmHg in controls) and in terms of right ventricular hypertrophy (RV/LVS = 0.70 in monocrotaline vs 0.32 in controls). Resveratrol partially reversed both RVSP (41.4 mmHg) and RV/LVS (0.46), as well as lung edema and RV contractility +dP/dt(max). Serial (99m)Tc-Annexin V imaging showed clear increases in pulmonary and cardiac apoptosis when compared to baseline, which regressed following resveratrol treatment. Monocrotaline induced modest changes in whole-heart perfusion as assessed by (201)TI imaging and cardiac morphological changes consistent with septal deviation and enlarged RV. This study demonstrates the utility of functional in vivo SPECT/CT imaging in rodent models of PAH and further confirms the efficacy of resveratrol in reversing established monocrotaline-induced PAH presumably by attenuation of cardiopulmonary apoptosis.

Influences of tissue absorption and scattering on diffuse correlation spectroscopy blood flow measurements.

In this study we evaluate the influences of optical property assumptions on near-infrared diffuse correlation spectroscopy (DCS) flow index measurements. The optical properties, absorption coefficient (µ(a)) and reduced scattering coefficient (µ(s)'), are independently varied using liquid phantoms and measured concurrently with the flow index using a hybrid optical system combining a dual-wavelength DCS flow device with a commercial frequency-domain tissue-oximeter. DCS flow indices are calculated at two wavelengths (785 and 830 nm) using measured µ(a) and µ(s)' or assumed constant µ(a) and µ(s)'. Inaccurate µ(s)' assumptions resulted in much greater flow index errors than inaccurate µ(a). Underestimated/overestimated µ(s)' from -35%/+175% lead to flow index errors of +110%/-80%, whereas underestimated/overestimated µ(a) from -40%/+150% lead to -20%/+40%, regardless of the wavelengths used. Examination of a clinical study involving human head and neck tumors indicates up to +280% flow index errors resulted from inter-patient optical property variations. These findings suggest that studies involving significant µ(a) and µ(s)' changes should concurrently measure flow index and optical properties for accurate extraction of blood flow information.

Portable optical tissue flow oximeter based on diffuse correlation spectroscopy.

A portable diffuse correlation spectroscopy (DCS) flowmeter has been extended to measure both tissue blood flow and oxygenation (namely, DCS flow oximeter). For validation purposes, calf muscle blood oxygenation during cuff inflation and deflation was measured concurrently using the DCS flow oximeter and a commercial tissue oximeter. The oxygenation traces from the two measurements exhibited similar dynamic responses, and data were highly correlated (r(mean)>0.9, P<10(-5), n=10). The portable, inexpensive, and easy-to-use DCS flow oximeter holds promise for bedside monitoring of tissue blood flow and oxygenation in clinics.

Ab initio study of substituent effects in the interactions of dimethyl ether with aromatic rings.

Ab initio calculations have been used to investigate the interaction energies of dimers of dimethyl ether with benzene, hexafluorobenzene, and several monosubstituted benzenes. The potential energy curves were explored at the MP2/aug-cc-pVDZ level for two basic configurations of the dimers, one in which the oxygen atom of the dimethyl ether was pointed towards the aromatic ring and the other in which the oxygen atom was pointed away from the aromatic ring. Once the optimum intermolecular distances between the dimethyl and the aromatic ring had been determined for each of the dimers in both configurations at the MP2/aug-cc-pVDZ level, single point energy calculations were performed at the MP2/aug-cc-pVTZ level. A CCSD(T) correction term to the energy was determined and this was combined with the MP2/aug-cc-pVTZ energies to estimate the CCSD(T)/aug-cc-pVTZ interaction energies of the dimers. The estimated CCSD(T)/aug-cc-pVTZ interaction energies are predicted to be attractive for all of the dimers in both configurations and dispersion interactions are found to be a large component of the stabilization of the dimers. For the dimers with the dimethyl ether oxygen pointing towards the aromatic ring, the strengths of interaction energies are found to increase as the aromatic ring becomes more electron deficient, while for the dimers with the dimethyl ether oxygen pointing away from the aromatic ring, they increase as the aromatic ring becomes more electron rich. In both cases, the trends can be explained in terms of the electrostatic potentials of the dimethyl ether and the aromatic rings.

Matrix isolation infrared observation of HxSi(N2)y (x = 0, 1, 2 and y = 1, 2) transient species using a 121-nm vacuum ultraviolet photolysis source.

Vacuum ultraviolet photolysis (121.6 nm) of silane in a nitrogen matrix at 12 K leads to the observation of several transient species, which have been characterized using Fourier transform infrared spectroscopy. Four transient species containing silicon and nitrogen have been observed (SiN2, Si(N2)2, HSiN2, and H2SiN2), and one transient species containing only silicon and hydrogen has been observed. The assignment of the infrared bands due to each of these species is accomplished by performing isotopic substitution experiments (SiD4, 15N2, and mixtures with SiH4 and 14N2), matrix annealing experiments, UV-visible photolysis experiments, by comparison with previous experimental matrix isolation frequencies, where available, and for HSiN2 and H2SiN2 by comparison to B3LYP/aug-cc-pVTZ-calculated vibrational frequencies. The observation and infrared assignment of the HSiN2 and H2SiN2 molecules in these experiments is significant in that HSiN2 has not been previously reported in the matrix isolation literature, and H2SiN2 has only been reported once previously by a different route of formation. The energetics of the overall formation pathways for the molecules observed in these experiments is discussed using B3LYP/aug-cc-pVTZ calculations.

Quantitative study of interactions between oxygen lone pair and aromatic rings: substituent effect and the importance of closeness of contact.

Current models describe aromatic rings as polar groups based on the fact that benzene and hexafluorobenzene are known to have large and permanent quadrupole moments. This report describes a quantitative study of the interactions between oxygen lone pair and aromatic rings. We found that even electron-rich aromatic rings and oxygen lone pairs exhibit attractive interactions. Free energies of interactions are determined using the triptycene scaffold and the equilibrium constants were determined by low-temperature 1H NMR spectroscopy. An X-ray structure analysis for one of the model compounds confirms the close proximity between the oxygen and the center of the aromatic ring. Theoretical calculations at the MP2/aug-cc-pVTZ level corroborate the experimental results. The origin of attractive interactions was explored by using aromatic rings with a wide range of substituents. The interactions between an oxygen lone pair and an aromatic ring are attractive at van der Waals' distance even with electron-donating substituents. Electron-withdrawing groups increase the strength of the attractive interactions. The results from this study can be only partly rationalized by using the current models of aromatic system. Electrostatic-based models are consistent with the fact that stronger electron-withdrawing groups lead to stronger attractions, but fail to predict or rationalize the fact that weak attractions even exist between electron-rich arenes and oxygen lone pairs. The conclusion from this study is that aromatic rings cannot be treated as a simple quadrupolar functional group at van der Waals' distance. Dispersion forces and local dipole should also be considered.