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author:("yoph, Arjun")
1.  Fiber Optic Monitoring of Spinal Cord Hemodynamics in Experimental Aortic Occlusion 
Anesthesiology  2015;123(6):1362-1373.
Spinal cord ischemia occurs frequently during thoracic aneurysm repair. Current methods to detect ischemia, based upon electrophysiology techniques, are indirect, non-specific, and temporally slow. Here we report the testing of a spinal cord blood flow and oxygenation monitor, based on Diffuse Correlation and Optical Spectroscopies, during aortic occlusion in a sheep model.
Testing was carried out in sixteen Dorset sheep. Sensitivity in detecting spinal cord blood flow and oxygenation changes during aortic occlusion, pharmacologically induced hypotension and hypertension, and physiologically induced hypoxia/hypercarbia were assessed. Accuracy of the Diffuse Correlation Spectroscopy measurements was determined via comparison to microsphere blood flow measurements. Precision was assessed through repeated measurements in response to pharmacologic interventions.
The fiber optic probe can be placed percutaneously, and is capable of continuously measuring spinal cord blood flow and oxygenation preoperatively, intraoperatively, and postoperatively. The device is sensitive to spinal cord blood flow and oxygenation changes associated with aortic occlusion, immediately detecting a fall in blood flow (−65 ± 32%, n=32) and blood oxygenation (−17 ± 13%, n=11) in 100% of trials. Comparison of spinal cord blood flow measurements by the device with microsphere measurements led to a correlation of R2=0.49, p<0.01 and the within-sheep coefficient of variation was 9.69%. Finally, Diffuse Correlation Spectroscopy is temporally more sensitive to ischemic interventions than motor evoked potentials.
The first generation spinal fiber optic monitoring device offers a novel and potentially important step forward in the monitoring of spinal cord ischemia.
PMCID: PMC4679520  PMID: 26418696
Ischemia; Spinal Cord; Aneurysm; Aortic; Perioperative Care
2.  Continuous cerebral hemodynamic measurement during deep hypothermic circulatory arrest 
Biomedical Optics Express  2016;7(9):3461-3470.
While survival of children with complex congenital heart defects has improved in recent years, roughly half suffer neurological deficits suspected to be related to cerebral ischemia. Here we report the first demonstration of optical diffuse correlation spectroscopy (DCS) for continuous and non-invasive monitoring of cerebral microvascular blood flow during complex human neonatal or cardiac surgery. Comparison between DCS and Doppler ultrasound flow measurements during deep hypothermia, circulatory arrest, and rewarming were in good agreement. Looking forward, DCS instrumentation, alone and with NIRS, could provide access to flow and metabolic biomarkers needed by clinicians to adjust neuroprotective therapy during surgery.
PMCID: PMC5030024  PMID: 27699112
(170.3890) Medical optics instrumentation; (170.6935) Tissue characterization
3.  Pressure modulation algorithm to separate cerebral hemodynamic signals from extracerebral artifacts 
Neurophotonics  2015;2(3):035004.
We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm’s ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.
PMCID: PMC4524732  PMID: 26301255
diffuse correlation spectroscopy; near-infrared spectroscopy; functional brain imaging; cerebral blood flow monitoring; stroke
4.  Fast blood flow monitoring in deep tissues with real-time software correlators 
Biomedical Optics Express  2016;7(3):776-797.
We introduce, validate and demonstrate a new software correlator for high-speed measurement of blood flow in deep tissues based on diffuse correlation spectroscopy (DCS). The software correlator scheme employs standard PC-based data acquisition boards to measure temporal intensity autocorrelation functions continuously at 50 – 100 Hz, the fastest blood flow measurements reported with DCS to date. The data streams, obtained in vivo for typical source-detector separations of 2.5 cm, easily resolve pulsatile heart-beat fluctuations in blood flow which were previously considered to be noise. We employ the device to separate tissue blood flow from tissue absorption/scattering dynamics and thereby show that the origin of the pulsatile DCS signal is primarily flow, and we monitor cerebral autoregulation dynamics in healthy volunteers more accurately than with traditional instrumentation as a result of increased data acquisition rates. Finally, we characterize measurement signal-to-noise ratio and identify count rate and averaging parameters needed for optimal performance.
PMCID: PMC4866455  PMID: 27231588
(030.0030) Coherence and statistical optics; (030.5290) Photon statistics; (030.5260) Photon counting; (170.3880) Medical and biological imaging; (170.1610) Clinical applications; (110.4153) Motion estimation and optical flow; (170.2655) Functional monitoring and imaging; (170.1470) Blood or tissue constituent monitoring; (290.4210) Multiple scattering; (170.5270) Photon density waves; (170.6510) Spectroscopy, tissue diagnostics; (170.6480) Spectroscopy, speckle
5.  Time-to-Surgery and Pre-operative Cerebral Hemodynamics Predict Post-operative White Matter Injury in Neonates with Hypoplastic Left Heart Syndrome 
Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately half of the HLHS survivors exhibit neurobehavioral symptoms believed to be associated with this injury, though the exact timing of the injury is not known.
Neonates with HLHS were recruited for pre- and post-operative monitoring of cerebral oxygen saturation (ScO2), cerebral oxygen extraction fraction (OEF), and cerebral blood flow (CBF) using two non-invasive optical-based techniques, namely diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomical magnetic resonance imaging (MRI) scans were performed prior to and approximately one week after surgery in order to quantify the extent and timing of the acquired white matter injury. Risk factors for developing new or worsened white matter injury were assessed using uni- and multi-variate logistic regression.
Thirty-seven neonates with HLHS were studied. In a univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time-to-surgery (p=0.0003). In a multivariate model, longer time between birth and surgery (i.e., time-to-surgery), delayed sternal closure, and higher pre-operative CBF were predictors of post-operative white matter injury. Additionally, longer time-to-surgery and higher pre-operative CBF on morning of surgery were correlated with lower ScO2 (p=0.03 and p=0.05) and higher OEF (p=0.05 and p=0.05).
Longer time-to-surgery is associated with new post-operative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation may decrease the likelihood of acquiring postoperative white matter injury.
PMCID: PMC4254035  PMID: 25109755
7.  Diffuse correlation spectroscopy for measurement of cerebral blood flow: future prospects 
Neurophotonics  2014;1(1):011009.
Diffuse correlation spectroscopy (DCS) is an emerging optical modality used to measure cortical cerebral blood flow. This outlook presents a brief overview of the technology, summarizing the advantages and limitations of the method, and describing its recent applications to animal, adult, and infant cohorts. At last, the paper highlights future applications where DCS may play a pivotal role individualizing patient management and enhancing our understanding of neurovascular coupling, activation, and brain development.
PMCID: PMC4292799  PMID: 25593978
cerebral blood flow; biomedical optics; spectroscopy; medical imaging
8.  Continuous Optical Monitoring of Cerebral Hemodynamics during Head-of-Bed Manipulation in Brain-Injured Adults 
Neurocritical care  2014;20(3):443-453.
Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering.
Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 minutes at each position. Patient and control response differences were assessed.
rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P<0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3% ± 28.2%, P=0.938). rCBF increased in controls (18.6% ± 9.4%, P<0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R=0.40, P<0.001), but not intracranial pressure.
DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.
PMCID: PMC3883971  PMID: 23653267
Diffuse correlation spectroscopy; Near-infrared spectroscopy; Diffuse optical spectroscopy; Head-of-bed; Cerebral blood flow; Neurocritical care; Cerebral hemodynamics
9.  Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures 
Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology.
In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology.
The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = −0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments.
Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0578-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4487833  PMID: 26013572
10.  Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients during Head of Bed Manipulation 
Background and Purpose
A primary goal of acute ischemic stroke (AIS) management is to maximize perfusion in the affected region and surrounding ischemic penumbra. However, interventions to maximize perfusion, such as flat head-of-bed (HOB) positioning, are currently prescribed empirically. Bedside monitoring of cerebral blood flow (CBF) allows the effects of interventions such as flat HOB to be monitored, and may ultimately be used to guide clinical management.
Cerebral perfusion was measured during head of bed (HOB) manipulations in 17 patients with unilateral acute ischemic stroke affecting large cortical territories in the anterior circulation. Simultaneous measurements of frontal CBF and arterial flow velocity were performed with diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. Results were analyzed in the context of available clinical data and a previous study.
Frontal CBF, averaged over the patient cohort, decreased by 17% (p=0.034) and 15% (p=0.011) in the ipsilesional and contralesional hemispheres, respectively, when HOB was changed from flat to 30°. Significant (cohort-averaged) changes in blood velocity were not observed. Individually, varying responses to HOB manipulation were observed, including paradoxical increases in CBF with increasing HOB angle. Clinical features, stroke volume, and distance to the optical probe could not explain this paradoxical response.
A lower HOB angle results in an increase in cortical CBF without a significant change in arterial flow velocity in AIS, but there is variability across patients in this response. Bedside CBF monitoring with DCS provides a potential means to individualize interventions designed to optimize CBF in AIS.
PMCID: PMC4006296  PMID: 24652308
stroke; perfusion; near-infrared spectroscopy; cerebral hemodynamics; head-of-bed manipulation
11.  Blood Flow Reduction in Breast Tissue due to Mammographic Compression 
Academic radiology  2014;21(2):151-161.
Rationale and objectives
This study measures hemodynamic properties such as blood flow and hemoglobin concentration and oxygenation in the healthy human breast under a wide range of compressive loads. Because many breast-imaging technologies derive contrast from the deformed breast, these load-dependent vascular responses affect contrast agent–enhanced and hemoglobin-based breast imaging.
Diffuse optical and diffuse correlation spectroscopies were used to measure the concentrations of oxygenated and deoxygenated hemoglobin, lipid, water, and microvascular blood flow during axial breast compression in the parallel-plate transmission geometry.
Significant reductions (P < .01) in total hemoglobin concentration (~30%), blood oxygenation (~20%), and blood flow (~87%) were observed under applied pressures (forces) of up to 30 kPa (120 N) in 15 subjects. Lipid and water concentrations changed <10%.
Imaging protocols based on injected contrast agents should account for variation in tissue blood flow due to mammographic compression. Similarly, imaging techniques that depend on endogenous blood contrasts will be affected by breast compression during imaging.
PMCID: PMC4393946  PMID: 24439328
Mammographic compression; breast cancer; blood flow; breast imaging; diffuse optics
12.  Cerebral oxygen metabolism in neonates with congenital heart disease quantified by MRI and optics 
Neonatal congenital heart disease (CHD) is associated with altered cerebral hemodynamics and increased risk of brain injury. Two novel noninvasive techniques, magnetic resonance imaging (MRI) and diffuse optical and correlation spectroscopies (diffuse optical spectroscopy (DOS), diffuse correlation spectroscopy (DCS)), were employed to quantify cerebral blood flow (CBF) and oxygen metabolism (CMRO2) of 32 anesthetized CHD neonates at rest and during hypercapnia. Cerebral venous oxygen saturation (SvO2) and CBF were measured simultaneously with MRI in the superior sagittal sinus, yielding global oxygen extraction fraction (OEF) and global CMRO2 in physiologic units. In addition, microvascular tissue oxygenation (StO2) and indices of microvascular CBF (BFI) and CMRO2 (CMRO2i) in the frontal cortex were determined by DOS/DCS. Median resting-state MRI-measured OEF, CBF, and CMRO2 were 0.38, 9.7 mL/minute per 100 g and 0.52 mL O2/minute per 100 g, respectively. These CBF and CMRO2 values are lower than literature reports for healthy term neonates (which are sparse and quantified using different methods) and resemble values reported for premature infants. Comparison of MRI measurements of global SvO2, CBF, and CMRO2 with corresponding local DOS/DCS measurements demonstrated strong linear correlations (R2=0.69, 0.67, 0.67; P<0.001), permitting calibration of DOS/DCS indices. The results suggest that MRI and optics offer new tools to evaluate cerebral hemodynamics and metabolism in CHD neonates.
PMCID: PMC3948119  PMID: 24326385
cerebral blood flow; cerebral hemodynamics; diffuse optics; MRI; near-infrared spectroscopy; neonatal ischemia
13.  Diffuse correlation spectroscopy for non-invasive, micro-vascular cerebral blood flow measurement 
NeuroImage  2013;85(0 1):51-63.
Diffuse correlation spectroscopy (DCS) uses the temporal fluctuations of near-infrared (NIR) light to measure cerebral blood flow (CBF) non-invasively. Here, we provide a brief history of DCS applications in brain with an emphasis on the underlying physical ideas, common instrumentation and validation. Then we describe recent clinical research that employs DCS-measured CBF as a biomarker of patient well-being, and as an indicator of hemodynamic and metabolic response to functional stimuli.
PMCID: PMC3991554  PMID: 23770408
diffuse correlation spectroscopy; cerebral blood flow; functional neuroimaging; diffuse optics; near-infrared spectroscopy; cerebral metabolic rate of oxygen extraction; ischemic stroke; neurocritical care; neonatalogy
14.  The Challenge of Connecting the Dots in the B.R.A.I.N 
Neuron  2013;80(2):10.1016/j.neuron.2013.09.008.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts, and discuss likely technological deliverables and neuroscience progress.
PMCID: PMC3864648  PMID: 24139032
15.  Noninvasive Optical Quantification of Cerebral Venous Oxygen Saturation in Humans 
Academic radiology  2014;21(2):162-167.
Rationale and Objectives
Cerebral oxygen extraction, defined as the difference between arterial and venous oxygen saturations (SaO2 and SvO2), is a critical parameter for managing intensive care patients at risk for neurological collapse. Although quantification of SaO2 is easily performed with pulse oximetry or moderately invasive arterial blood draws in peripheral vessels, cerebral SvO2 is frequently not monitored because of the invasiveness and risk associated with obtaining jugular bulb or super vena cava (SVC) blood samples.
Materials and Methods
In this study, near-infrared spectroscopy (NIRS) was used to noninvasively measure cerebral SvO2 in anesthetized and mechanically ventilated pediatric patients (n = 10). To quantify SvO2, the NIRS signal component that fluctuates at the respiration frequency is isolated. This respiratory component is dominated by the venous portion of the interrogated vasculature. The NIRS measurements of SvO2 were validated against the clinical gold standard: invasively measured oxygen saturations from SVC blood samples. This technique was also applied in healthy volunteers (n = 5) without mechanical ventilation to illustrate its potential for use in healthy populations with natural airways.
Ten pediatric patients with pulmonary hypertension were studied. In these patients, SvO2 in the SVC exhibited good agreement with NIRS-measured SvO2 (R2 = 0.80, P = .001, slope = 1.16 ± 0.48). Furthermore, in the healthy adult volunteers, mean (standard deviation) NIRS-measured SvO2 was 79.4 (6.8)%. This value is in good agreement with the expected average central venous saturation reported in literature.
Respiration frequency-selected NIRS can noninvasively quantify cerebral SvO2. This bedside technique can be used to help assess brain health in neurologically unstable patients.
PMCID: PMC4126245  PMID: 24439329
Near-infrared spectroscopy; cerebral venous oxygenation; pediatrics; validation; noninvasive
16.  Towards non-invasive characterization of breast cancer and cancer metabolism with diffuse optics 
PET clinics  2013;8(3):10.1016/j.cpet.2013.04.004.
We review recent developments in diffuse optical imaging and monitoring of breast cancer, i.e. optical mammography. Optical mammography permits non-invasive, safe and frequent measurement of tissue hemodynamics oxygen metabolism and components (lipids, water, etc.), the development of new compound indices indicative of the risk and malignancy, and holds potential for frequent non-invasive longitudinal monitoring of therapy progression.
PMCID: PMC3826963  PMID: 24244206
Diffuse Optical Tomography; Diffuse Optical Spectroscopy; Metabolic Imaging; Blood Flow; Breast Cancer; Neo-adjuvant chemotherapy
17.  Optically Measured Microvascular Blood Flow Contrast of Malignant Breast Tumors 
PLoS ONE  2014;9(6):e99683.
Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS), a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval) tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92–2.63); tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94–2.66), and using normal tissue in the contralateral breast was 2.27 (1.90–2.70). Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography.
PMCID: PMC4072684  PMID: 24967878
18.  Neurovascular coupling varies with level of global cerebral ischemia in a rat model 
In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses.
PMCID: PMC3597370  PMID: 23032485
cerebral hemodynamics; evoked potentials; global ischemia; intrinsic optical imaging; neurovascular coupling
19.  Optical Monitoring and Detection of Spinal Cord Ischemia 
PLoS ONE  2013;8(12):e83370.
Spinal cord ischemia can lead to paralysis or paraparesis, but if detected early it may be amenable to treatment. Current methods use evoked potentials for detection of spinal cord ischemia, a decades old technology whose warning signs are indirect and significantly delayed from the onset of ischemia. Here we introduce and demonstrate a prototype fiber optic device that directly measures spinal cord blood flow and oxygenation. This technical advance in neurological monitoring promises a new standard of care for detection of spinal cord ischemia and the opportunity for early intervention. We demonstrate the probe in an adult Dorset sheep model. Both open and percutaneous approaches were evaluated during pharmacologic, physiological, and mechanical interventions designed to induce variations in spinal cord blood flow and oxygenation. The induced variations were rapidly and reproducibly detected, demonstrating direct measurement of spinal cord ischemia in real-time. In the future, this form of hemodynamic spinal cord diagnosis could significantly improve monitoring and management in a broad range of patients, including those undergoing thoracic and abdominal aortic revascularization, spine stabilization procedures for scoliosis and trauma, spinal cord tumor resection, and those requiring management of spinal cord injury in intensive care settings.
PMCID: PMC3865183  PMID: 24358279
21.  Optical malignancy parameters for monitoring progression of breast cancer neoadjuvant chemotherapy 
Biomedical Optics Express  2012;4(1):105-121.
We introduce and demonstrate use of a novel, diffuse optical tomography (DOT) based breast cancer signature for monitoring progression of neoadjuvant chemotherapy. This signature, called probability of malignancy, is obtained by statistical image analysis of total hemoglobin concentration, blood oxygen saturation, and scattering coefficient distributions in the breast tomograms of a training-set population with biopsy-confirmed breast cancers. A pilot clinical investigation adapts this statistical image analysis approach for chemotherapy monitoring of three patients. Though preliminary, the study shows how to use the malignancy parameter for separating responders from partial-responders and demonstrates the potential utility of the methodology compared to traditional DOT quantification schemes.
PMCID: PMC3539198  PMID: 23304651
(170.3830) Mammography; (170.3880) Medical and biological imaging; (170.1610) Clinical applications; (170.6510) Spectroscopy, tissue diagnostics
Treatment-induced apoptosis of cancer cells is one goal of cancer therapy. Interestingly, more heat is generated by mitochondria during apoptosis, especially the uncoupled apoptotic state,1,2 compared to the resting state. In this case study, we explore these thermal effects by longitudinally measuring temperature variations in a breast lesion of a pathological complete responder during neadjuvant chemotherapy (NAC). Diffuse Optical Spectroscopic Imaging (DOSI) was employed to derive absolute deep tissue temperature using subtle spectral features of the water peak at 975 nm.3 A significant temperature increase was observed in time windows during the anthracycline and cyclophosphamide (AC) regimen but in not paclitaxel and bevacizumab regimen. Hemoglobin concentration changes generally did not follow temperature, suggesting that the measured temperature increases were likely due to mitochondrial uncoupling rather than a direct vascular effect. A simultaneous increase of tissue oxygen saturation with temperature was also observed, suggesting that oxidative stress also contributes to apoptosis. Although preliminary, this study indicates that longitudinal DOSI tissue temperature monitoring provides information that can improve our understanding of the mechanisms of tissue response during NAC.
PMCID: PMC3296557  PMID: 22408653
23.  O2 Regulates Skeletal Muscle Progenitor Differentiation through Phosphatidylinositol 3-Kinase/AKT Signaling 
Molecular and Cellular Biology  2012;32(1):36-49.
Skeletal muscle stem/progenitor cells, which give rise to terminally differentiated muscle, represent potential therapies for skeletal muscle diseases. Delineating the factors regulating these precursors will facilitate their reliable application in human muscle repair. During embryonic development and adult regeneration, skeletal muscle progenitors reside in low-O2 environments before local blood vessels and differentiated muscle form. Prior studies established that low O2 levels (hypoxia) maintained muscle progenitors in an undifferentiated state in vitro, although it remained unclear if progenitor differentiation was coordinated with O2 availability in vivo. In addition, the molecular signals linking O2 to progenitor differentiation are incompletely understood. Here we show that the muscle differentiation program is repressed by hypoxia in vitro and ischemia in vivo. Surprisingly, hypoxia can significantly impair differentiation in the absence of hypoxia-inducible factors (HIFs), the primary developmental effectors of O2. In order to maintain the undifferentiated state, low O2 levels block the phosphatidylinositol 3-kinase/AKT pathway in a predominantly HIF1α-independent fashion. O2 deprivation affects AKT activity by reducing insulin-like growth factor I receptor sensitivity to growth factors. We conclude that AKT represents a key molecular link between O2 and skeletal muscle differentiation.
PMCID: PMC3255700  PMID: 22006022
24.  Two-Photon Absorption Properties of Proquinoidal D-A-D and A-D-A Quadrupolar Chromophores 
The journal of physical chemistry. A  2011;115(22):5525-5539.
We report the synthesis, one- and two-photon absorption spectroscopy, fluorescence, and electrochemical properties of a series of quadrupolar molecules that feature proquinoidal π-aromatic acceptors. These quadrupolar molecules possess either donor-acceptor-donor (D–A–D) or acceptor-donor-acceptor (A–D–A) electronic motifs, and feature 4-N,N-dihexylaminophenyl, 4-dodecyloxyphenyl, 4-(N,N-dihexylamino)benzo[c][1,2,5]thiadiazolyl or 2,5-dioctyloxyphenyl electron donor moieties and benzo[c][1,2,5]thiadiazole (BTD) or 6,7-bis(3’,7’-dimethyloctyl)[1,2,5]thiadiazolo[3,4-g]quinoxaline (TDQ) electron acceptor units. These conjugated structures are highly emissive in nonpolar solvents and exhibit large spectral red-shifts of their respective lowest energy absorption bands relative to analogous reference compounds that incorporate phenylene components in place of BTD and TDQ moieties. BTD-based D-A-D and A-D-A chromophores exhibit increasing fluorescence emission red-shifts, and a concomitant decrease of the fluorescence quantum yield (Φf) with increasing solvent polarity; these data indicate that electronic excitation augments benzothiadiazole electron density via an internal charge transfer mechanism. The BTD- and TDQ-containing structures exhibit blue-shifted two-photon absorption (TPA) spectra relative to their corresponding one-photon absorption (OPA) spectra, and display high TPA cross-sections (>100 GM) within these spectral windows. D-A-D and A-D-A structures that feature more extensive conjugation within this series of compounds exhibit larger TPA cross-sections consistent with computational simulation. Factors governing TPA properties of these quadrupolar chromophores are discussed within the context of a three-state model.
PMCID: PMC3121192  PMID: 21568299
25.  Tumor Blood Flow Differs between Mouse Strains: Consequences for Vasoresponse to Photodynamic Therapy 
PLoS ONE  2012;7(5):e37322.
Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies.
PMCID: PMC3356280  PMID: 22624014

Results 1-25 (43)