With the causes of perinatal brain injuries still unclear and the probable role of hemodynamic instability in their etiology, bedside monitoring of neonatal cerebral hemodynamics with standard values as a function of age are needed. In this study, we combined quantitative frequency domain near infrared spectroscopy (FD-NIRS) measures of cerebral tissue oxygenation (StO 2 ) and cerebral blood volume (CBV) with diffusion correlation spectroscopy (DCS) measures of a cerebral blood flow index (CBF ix ) to test the validity of the CBV-CBF relationship in premature neonates and to estimate cerebral metabolic rate of oxygen (rCMRO 2 ) with or without the CBF ix measurement. We measured 11 premature neonates (28-34 weeks gestational age) without known neurological issues, once a week from one to six weeks of age. In nine patients, cerebral blood velocities from the middle cerebral artery were collected by transcranial Doppler (TCD) and compared with DCS values. Results show a steady decrease in StO 2 during the first six weeks of life while CBV remains stable, and a steady increase in CBF ix . rCMRO 2 estimated from FD-NIRS remains constant but shows wide interindividual variability. rCMRO 2 calculated from FD-NIRS and DCS combined increased by 40% during the first six weeks of life with reduced interindividual variability. TCD and DCS values are positively correlated. In conclusion, FD-NIRS combined with DCS offers a safe and quantitative bedside method to assess CBV, StO 2 , CBF, and rCMRO 2 in the premature brain, facilitating individual follow-up and comparison among patients. A stable CBV-CBF relationship may not be valid for premature neonates.

Purpose:To explore the optical and physiologic properties of normal and lesion-bearing breasts by using a combined optical and digital breast tomosynthesis (DBT) imaging system. Materials and Methods:Institutional review board approval and patient informed consent were obtained for this HIPAA-compliant study. Combined optical and tomosynthesis imaging analysis was performed in 189 breasts from 125 subjects (mean age, 56 years 6 13 [standard deviation]), including 138 breasts with negative fi ndings and 51 breasts with lesions. Threedimensional (3D) maps of total hemoglobin concentration (Hb T ), oxygen saturation (S O 2 ), and tissue reduced scattering coeffi cients were interpreted by using the coregistered DBT images. Paired and unpaired t tests were performed between various tissue types to identify signifi cant differences. Results:The estimated average bulk Hb T from 138 normal breasts was 19.2 m mol/L. The corresponding mean SO 2 was 0.73, within the range of values in the literature. A linear correlation ( R = 0.57, P , .0001) was found between Hb T and the fi broglandular volume fraction derived from the 3D DBT scans. Optical reconstructions of normal breasts revealed structures corresponding to chest-wall muscle, fi broglandular, and adipose tissues in the Hb T , SO 2 , and scattering images. In 26 malignant tumors of 0.6-2.5 cm in size, Hb T was signifi cantly greater than that in the fibroglandular tissue of the same breast ( P = .0062). Solid benign lesions ( n = 17) and cysts ( n = 8) had signifi cantly lower Hb T contrast than did the malignant lesions ( P = .025 and P = .0033, respectively). Conclusion:The optical and DBT images were structurally consistent. The malignant tumors and benign lesions demonstrated different Hb T and scattering contrasts, which can potentially be exploited to reduce the false-positive rate of conventional mammography and unnecessary biopsies. BREAST IMAGING: Combined Optical and X-ray Tomosynthesis Breast Imaging Fang et al cancers and the reduction of the number of biopsies of benign lesions, compared with stand-alone conventional mammography.Our purpose was to explore the optical and physiologic properties of normal and lesion-bearing breasts by using a combined optical and DBT imaging system. Materials and MethodsThe experimental protocols were approved by the institutional review board (Massachusetts General Hospital), and written informed consent was obtained from all subjects. The study was compliant with Health Insurance Portability and Accountability Act guidelines. Imaging InstrumentationA photograph of the combined optical and DBT imaging system and probes is shown in Figures E1 and E2 (online). The detailed confi guration of the imaging physiologic parameters, such as the concentrations of oxygenated hemoglobin (Hb O ), deoxygenated hemoglobin (Hb R ), water, and lipids ( 16 ). With DOT, nearinfrared lasers, either radiofrequencymodulated, continuous-wave or pulsed, are used to probe tissue structure noninvasively ( 13,17 ). The concentrations of the tissue ...

Continuum methods were used to calculate the electrostatic contributions of charged and polar side chains to the overall stability of a small 41-residue helical protein, the peripheral subunit-binding domain. The results of these calculations suggest several residues that are destabilizing, relative to hydrophobic isosteres. One position was chosen to test the results of these calculations. Arg8 is located on the surface of the protein in a region of positive electrostatic potential. The calculations suggest that Arg8 makes a significant, unfavorable electrostatic contribution to the overall stability. The experiments described in this paper represent the first direct experimental test of the theoretical methods, taking advantage of solid-phase peptide synthesis to incorporate approximately isosteric amino acid substitutions. Arg8 was replaced with norleucine (Nle), an amino acid that is hydrophobic and approximately isosteric, or with alpha-amino adipic acid (Aad), which is also approximately isosteric but oppositely charged. In this manner, it is possible to isolate electrostatic interactions from the effects of hydrophobic and van der Waals interactions. Both Arg8Nle and Arg8Aad are more thermostable than the wild-type sequence, testifying to the validity of the calculations. These replacements led to stability increases at 52.6 degrees C, the T(m) of the wild-type, of 0.86 and 1.08 kcal mol(-)(1), respectively. The stability of Arg8Nle is particularly interesting as a rare case in which replacement of a surface charge with a hydrophobic residue leads to an increase in the stability of the protein.

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) are two diffuse optical technologies for brain imaging that are sensitive to changes in hemoglobin concentrations and blood flow, respectively. Measurements for both modalities are acquired on the scalp, and therefore hemodynamic processes in the extracerebral vasculature confound the interpretation of cortical hemodynamic signals. The sensitivity of NIRS to the brain versus the extracerebral tissue and the contrast-to-noise ratio (CNR) of NIRS to cerebral hemodynamic responses have been well characterized, but the same has not been evaluated for DCS. This is important to assess in order to understand their relative capabilities in measuring cerebral physiological changes. We present Monte Carlo simulations on a head model that demonstrate that the relative brain-to-scalp sensitivity is about three times higher for DCS (0.3 at 3 cm) than for NIRS (0.1 at 3 cm). However, because DCS has higher levels of noise due to photon-counting detection, the CNR is similar for both modalities in response to a physiologically realistic simulation of brain activation. Even so, we also observed higher CNR of the hemodynamic response during graded hypercapnia in adult subjects with DCS than with NIRS.

Abstract. Diffuse correlation spectroscopy (DCS) measurements of blood flow rely on the sensitivity of the temporal autocorrelation function of diffusively scattered light to red blood cell (RBC) mean square displacement (MSD). For RBCs flowing with convective velocity v RBC , the autocorrelation is expected to decay exponentially with ðv RBC τÞ 2 , where τ is the delay time. RBCs also experience shear-induced diffusion with a diffusion coefficient D shear and an MSD of 6D shear τ. Surprisingly, experimental data primarily reflect diffusive behavior. To provide quantitative estimates of the relative contributions of convective and diffusive movements, we performed Monte Carlo simulations of light scattering through tissue of varying vessel densities. We assumed laminar vessel flow profiles and accounted for shear-induced diffusion effects. In agreement with experimental data, we found that diffusive motion dominates the correlation decay for typical DCS measurement parameters. Furthermore, our model offers a quantitative relationship between the RBC diffusion coefficient and absolute tissue blood flow. We thus offer, for the first time, theoretical support for the empirically accepted ability of the DCS blood flow index (BF i ) to quantify tissue perfusion. We find BF i to be linearly proportional to blood flow, but with a proportionality modulated by the hemoglobin concentration and the average blood vessel diameter. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

The prospective multi-center ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a Diffuse Optical Spectroscopic Imaging (DOSI)-derived imaging endpoint, the Tissue Optical Index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine and delivered to 6 institutions where 60 subjects with newly-diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to 4 times during NAC treatment: baseline, one-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor to normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from −82% to 321%, with a median of −36%. Using pCR as the reference standard and receiver-operating characteristic curve methodology, %TOITN AUC was 0.60 (95% CI 0.39 to 0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI 0.63 to 1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction.

To date, the majority of neurovascular coupling studies focused on the thalamic afferents' activity in layer IV and the corresponding large spiking activity as responsible for functional hyperemia. This paper highlights the role of the secondary and late cortico-cortical transmission in neurovascular coupling. Simultaneous scalp electroencephalography (EEG) and diffuse optical imaging (DOI) measurements were obtained during multiple conditions of event-related electrical forepaw stimulation in 33 male Sprague-Dawley rats divided into 6 groups depending on the maintaining anesthetic -alpha-chloralose, pentobarbital, ketamine-xylazine, fentanyl-droperidol, isoflurane, or propofol. The somatosensory evoked potentials (SEP) were decomposed into four components and the question of which best predicts the hemodynamic responses was investigated. Results of the linear regression analysis show that the hemodynamic response is best correlated with the secondary and late cortico-cortical transmissions and not with the initial thalamic input activity in layer IV. Baseline cerebral blood flow (CBF) interacts with neural activity and influences the evoked hemodynamic responses. Finally, neurovascular coupling appears to be the same across all anesthetics used.

In this paper, we report new progress in developing the instrument and software platform of a combined X-ray mammography/diffuse optical breast imaging system. Particularly, we focus on system validation using a series of balloon phantom experiments and the optical image analysis of 49 healthy patients. Using the finite-element method for forward modeling and a regularized Gauss-Newton method for parameter reconstruction, we recovered the inclusions inside the phantom and the hemoglobin images of the human breasts. An enhanced coupling coefficient estimation scheme was also incorporated to improve the accuracy and robustness of the reconstructions. The recovered average total hemoglobin concentration (HbT) and oxygen saturation (SO2) from 68 breast measurements are 16.2 μm and 71%, respectively, where the HbT presents a linear trend with breast density. The low HbT value compared to literature is likely due to the associated mammographic compression. From the spatially co-registered optical/X-ray images, we can identify the chest-wall muscle, fatty tissue, and fibroglandular regions with an average HbT of 20.1±6.1 μm for fibroglandular tissue, 15.4±5.0 μm for adipose, and 22.2±7.3 μm for muscle tissue. The differences between fibroglandular tissue and the corresponding adipose tissue are significant (p < 0.0001). At the same time, we recognize that the optical images are influenced, to a certain extent, by mammographical compression. The optical images from a subset of patients show composite features from both tissue structure and pressure distribution. We present mechanical simulations which further confirm this hypothesis.