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1.  Effects of acetazolamide on the micro- and macro-vascular cerebral hemodynamics: a diffuse optical and transcranial doppler ultrasound study 
Biomedical Optics Express  2010;1(5):1443-1459.
Acetazolamide (ACZ) was used to stimulate the cerebral vasculature on ten healthy volunteers to assess the cerebral vasomotor reactivity (CVR). We have combined near infrared spectroscopy (NIRS), diffuse correlation spectroscopy (DCS) and transcranial Doppler (TCD) technologies to non-invasively assess CVR in real-time by measuring oxy- and deoxy-hemoglobin concentrations, using NIRS, local cerebral blood flow (CBF), using DCS, and blood flow velocity (CBFV) in the middle cerebral artery, using TCD. Robust and persistent increases in oxy-hemoglobin concentration, CBF and CBFV were observed. A significant agreement was found between macro-vascular (TCD) and micro-vascular (DCS) hemodynamics, between the NIRS and TCD data, and also within NIRS and DCS results. The relative cerebral metabolic rate of oxygen, rCMRO2, was also determined, and no significant change was observed. Our results showed that the combined diffuse optics-ultrasound technique is viable to follow (CVR) and rCMRO2 changes in adults, continuously, at the bed-side and in real time.
PMCID: PMC3018112  PMID: 21258561
(170.3660) Light propagation in tissues; (170.3890) Medical optics instrumentation; (170.6480) Spectroscopy, speckle; (170.7170) Ultrasound; (290.4210) Multiple scattering
2.  Noninvasive Measurement of Cerebral Blood Flow and Blood Oxygenation Using Near-Infrared and Diffuse Correlation Spectroscopies in Critically Brain-Injured Adults 
Neurocritical care  2010;12(2):173-180.
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care
3.  Early postoperative changes in cerebral oxygen metabolism following neonatal cardiac surgery: Effects of surgical duration 
The early postoperative period following neonatal cardiac surgery is a time of increased risk for brain injury, yet the mechanisms underlying this risk are unknown. To understand these risks more completely, we quantified changes in postoperative cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral blood flow (CBF) compared with preoperative levels by using noninvasive optical modalities.
Diffuse optical spectroscopy and diffuse correlation spectroscopy were used concurrently to derive cerebral blood flow and oxygen utilization postoperatively for 12 hours. Relative changes in CMRO2, OEF, and CBF were quantified with reference to preoperative data. A mixed-effect model was used to investigate the influence of total support time and deep hypothermic circulatory arrest duration on relative changes in CMRO2, OEF, and CBF.
Relative changes in CMRO2, OEF, and CBF were assessed in 36 patients, 21 with single-ventricle defects and 15 with 2-ventricle defects. Among patients with single-ventricle lesions, deep hypothermic circulatory arrest duration did not affect relative changes in CMRO2, CBF, or OEF (P > .05). Among 2-ventricle patients, total support time was not a significant predictor of relative changes in CMRO2 or CBF (P > .05), although longer total support time was associated significantly with greater increases in relative change of postoperative OEF (P = .008).
Noninvasive diffuse optical techniques were used to quantify postoperative relative changes in CMRO2, CBF, and OEF for the first time in this observational pilot study. Pilot data suggest that surgical duration does not account for observed variability in the relative change in CMRO2, and that more comprehensive clinical studies using the new technology are feasible and warranted to elucidate these issues further.
PMCID: PMC3658109  PMID: 23111021
4.  Intracranial microprobe for evaluating neuro-hemodynamic coupling in unanesthetized human neocortex 
Journal of neuroscience methods  2009;179(2):208-218.
Measurement of the blood-oxygen-level dependent (BOLD) response with fMRI has revolutionized cognitive neuroscience and is increasingly important in clinical care. The BOLD response reflects changes in deoxy-hemoglobin concentration, blood volume, and blood flow. These hemodynamic changes ultimately result from neuronal firing and synaptic activity, but the linkage between these domains is complex, poorly understood, and may differ across species, cortical areas, diseases, and cognitive states. We describe here a technique that can measure neural and hemodynamic changes simultaneously from cortical microdomains in waking humans. We utilize a “laminar optode,” a linear array of microelectrodes for electrophysiological measures paired with a micro-optical device for hemodynamic measurements. Optical measurements include laser Doppler to estimate cerebral blood flow as well as point spectroscopy to estimate oxy- and deoxy-hemoglobin concentrations. The microelectrode array records local field potential gradients (PG) and multi-unit activity (MUA) at 24 locations spanning the cortical depth, permitting estimation of population trans-membrane current flows (Current Source Density, CSD) and population cell firing in each cortical lamina. Comparison of the laminar CSD/MUA profile with the origins and terminations of cortical circuits allows activity in specific neuronal circuits to be inferred and then directly compared to hemodynamics. Access is obtained in epileptic patients during diagnostic evaluation for surgical therapy. Validation tests with relatively well-understood manipulations (EKG, breath-holding, cortical electrical stimulation) demonstrate the expected responses. This device can provide a new and robust means for obtaining detailed, quantitative data for defining neurovascular coupling in awake humans.
PMCID: PMC2680793  PMID: 19428529
microelectrode; BOLD; oxygenation; hemodynamics; neuro-hemodynamic coupling; breath-hold; electrocardiogram; cortical electrical stimulation
5.  Calibration of diffuse correlation spectroscopy with a time-resolved near-infrared technique to yield absolute cerebral blood flow measurements 
Biomedical Optics Express  2011;2(7):2068-2081.
A primary focus of neurointensive care is the prevention of secondary brain injury, mainly caused by ischemia. A noninvasive bedside technique for continuous monitoring of cerebral blood flow (CBF) could improve patient management by detecting ischemia before brain injury occurs. A promising technique for this purpose is diffuse correlation spectroscopy (DCS) since it can continuously monitor relative perfusion changes in deep tissue. In this study, DCS was combined with a time-resolved near-infrared technique (TR-NIR) that can directly measure CBF using indocyanine green as a flow tracer. With this combination, the TR-NIR technique can be used to convert DCS data into absolute CBF measurements. The agreement between the two techniques was assessed by concurrent measurements of CBF changes in piglets. A strong correlation between CBF changes measured by TR-NIR and changes in the scaled diffusion coefficient measured by DCS was observed (R2 = 0.93) with a slope of 1.05 ± 0.06 and an intercept of 6.4 ± 4.3% (mean ± standard error).
PMCID: PMC3130590  PMID: 21750781
(170.1470) Blood or tissue constituent monitoring; (170.3660) Light propagation in tissues; (170.3890) Medical optics instrumentation
6.  Post traumatic brain perfusion SPECT analysis using reconstructed ROI maps of radioactive microsphere derived cerebral blood flow and statistical parametric mapping 
Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets.
The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM).
A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM.
The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques.
PMCID: PMC2311288  PMID: 18312639
7.  Noninvasive Optical Measures of CBV, StO2, CBF Index, and rCMRO2 in Human Premature Neonates’ Brains in the First Six Weeks of Life 
Human brain mapping  2010;31(3):341-352.
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 (StO2) and cerebral blood volume (CBV) with diffusion correlation spectroscopy (DCS) measures of a cerebral blood flow index (CBFix) to test the validity of the CBV-CBF relationship in premature neonates and to estimate cerebral metabolic rate of oxygen (rCMRO2) with or without the CBFix 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 StO2 during the first six weeks of life while CBV remains stable, and a steady increase in CBFix. rCMRO2 estimated from FD-NIRS remains constant but shows wide interindividual variability. rCMRO2 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, StO2, CBF, and rCMRO2 in the premature brain, facilitating individual follow-up and comparison among patients. A stable CBV-CBF relationship may not be valid for premature neonates.
PMCID: PMC2826558  PMID: 19650140
premature neonates; brain hemodynamics; near-infrared spectroscopy; diffuse correlation spectroscopy; cerebral blood flow; cerebral oxygen consumption; brain development
8.  Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single ventricle physiology 
Pediatric research  2013;73(5):668-673.
Sodium bicarbonate (NaHCO3) is a common treatment for metabolic acidemia, however little definitive information exists regarding its treatment efficacy and cerebral hemodynamic effects. This pilot observational study quantifies relative changes in cerebral blood flow (rCBF) and oxy and deoxy-hemoglobin concentrations (ΔHbO2 and ΔHb) due to bolus administration of NaHCO3 in patients with mild base deficits.
Infants and children with hypoplastic left heart syndrome (HLHS) were recruited prior to cardiac surgery. NaHCO3 was given as needed for treatment of base deficit. Diffuse optical spectroscopies were employed for 15 minutes post-injection to non-invasively monitor ΔHb, ΔHbO2 and rCBF relative to baseline prior to NaHCO3 administration.
Twenty-two anesthetized and mechanically ventilated HLHS patients (1 day to 4 years old) received a median (interquartile range) dose of 1.1 (0.8, 1.8) mEq/kg NaHCO3 administered intravenously over 10–20 seconds to treat a base deficit of −4 (−6, −3) mEq/l. NaHCO3 caused significant dose-dependent increases in rCBF, however population averaged ΔHb or Δ4HbO2 compared to controls were not significant.
Dose-dependent increases in cerebral blood flow (CBF) caused by bolus NaHCO3 are an important consideration in vulnerable populations wherein risk of rapid CBF fluctuations does not outweigh the benefit of treating a base deficit.
PMCID: PMC3724528  PMID: 23403802
9.  Regional and Hemispheric Asymmetries of Cerebral Hemodynamic and Oxygen Metabolism in Newborns 
Cerebral Cortex (New York, NY)  2012;23(2):339-348.
Understanding the evolution of regional and hemispheric asymmetries in the early stages of life is essential to the advancement of developmental neuroscience. By using 2 noninvasive optical methods, frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy, we measured cerebral hemoglobin oxygenation (SO2), blood volume (CBV), an index of cerebral blood flow (CBFi), and the metabolic rate of oxygen (CMRO2i) in the frontal, temporal, and parietal regions of 70 premature and term newborns. In concordance with results obtained using more invasive imaging modalities, we verified both hemodynamic (CBV, CBFi, and SO2) and metabolic (CMRO2i) parameters were greater in the temporal and parietal regions than in the frontal region and that these differences increased with age. In addition, we found that most parameters were significantly greater in the right hemisphere than in the left. Finally, in comparing age-matched males and females, we found that males had higher CBFi in most cortical regions, higher CMRO2i in the frontal region, and more prominent right–left CBFi asymmetry. These results reveal, for the first time, that we can detect regional and hemispheric asymmetries in newborns using noninvasive optical techniques. Such a bedside screening tool may facilitate early detection of abnormalities and delays in maturation of specific cortical areas.
PMCID: PMC3584954  PMID: 22328446
brain development; cerebral asymmetry; diffuse correlation spectroscopy; near-infrared spectroscopy; newborns
10.  Calibrating the BOLD signal during a motor task using an extended fusion model incorporating DOT, BOLD and ASL data 
Neuroimage  2012;61(4):1268-1276.
Multimodal imaging improves the accuracy of the localization and the quantification of brain activation when measuring different manifestations of the hemodynamic response associated with cerebral activity. In this study, we incorporated cerebral blood flow (CBF) changes measured with arterial spin labeling (ASL), Diffuse Optical Tomography (DOT) and blood oxygen level-dependent (BOLD) recordings to reconstruct changes in oxy- (ΔHbO2) and deoxyhemoglobin (ΔHbR). Using the Grubb relation between relative changes in CBF and cerebral blood volume (CBV), we incorporated the ASL measurement as a prior to the total hemoglobin concentration change (ΔHbT). We applied this ASL fusion model to both synthetic data and experimental multimodal recordings during a 2-sec finger-tapping task. Our results show that the new approach is very powerful in estimating ΔHbO2 and ΔHbR with high spatial and quantitative accuracy. Moreover, our approach allows the computation of baseline total hemoglobin concentration (HbT0) as well as of the BOLD calibration factor M on a single subject basis. We obtained an average HbT0 of 71 μM, an average M value of 0.18 and an average increase of 13 % in cerebral metabolic rate of oxygen (CMRO2), all of which are in agreement with values previously reported in the literature. Our method yields an independent measurement of M, which provides an alternative measurement to validate the hypercapnic calibration of the BOLD signal.
PMCID: PMC3376222  PMID: 22546318
fNIRS; fMRI; ASL; CMRO2; BOLD calibration; multimodal imaging
11.  Quantitative investigation of the effect of the extra-cerebral vasculature in diffuse optical imaging: a simulation study 
Biomedical Optics Express  2011;2(3):680-695.
Diffuse optical imaging (DOI) is a non invasive technique allowing the recovery of hemodynamic changes in the brain. Due to the diffusive nature of photon propagation in turbid media and the fact that cerebral tissues are located around 1.5 cm under the adult human scalp, DOI measurements are subject to partial volume errors. DOI measurements are also sensitive to large pial vessels because oxygenated and deoxygenated hemoglobin are the dominant chromophores in the near infrared window. In this study, the effect of the extra-cerebral vasculature in proximity of the sagittal sinus was investigated for its impact on DOI measurements simulated over the human adult visual cortex. Numerical Monte Carlo simulations were performed on two specific models of the human head derived from magnetic resonance imaging (MRI) scans. The first model included the extra-cerebral vasculature in which constant hemoglobin concentrations were assumed while the second did not. The screening effect of the vasculature was quantified by comparing recovered hemoglobin changes from each model for different optical arrays and regions of activation. A correction factor accounting for the difference between the recovered and the simulated hemoglobin changes was computed in each case. The results show that changes in hemoglobin concentration are better estimated when the extra-cerebral vasculature is modeled and the correction factors obtained in this case were at least 1.4-fold lower. The effect of the vasculature was also examined in a high-density diffuse optical tomography configuration. In this case, the difference between changes in hemoglobin concentration recovered with each model was reduced down to 10%.
PMCID: PMC3047372  PMID: 21412472
(170.3660) Light propagation in tissues; (110.3080) Infrared imaging; (170.5280) Photon migration
12.  Direct measurement of tissue blood flow and metabolism with diffuse optics 
Diffuse optics has proven useful for quantitative assessment of tissue oxy- and deoxyhaemoglobin concentrations and, more recently, for measurement of microvascular blood flow. In this paper, we focus on the flow monitoring technique: diffuse correlation spectroscopy (DCS). Representative clinical and pre-clinical studies from our laboratory illustrate the potential of DCS. Validation of DCS blood flow indices in human brain and muscle is presented. Comparison of DCS with arterial spin-labelled MRI, xenon-CT and Doppler ultrasound shows good agreement (0.50
PMCID: PMC3263785  PMID: 22006897
diffuse correlation spectroscopy; blood flow; cerebral blood flow; oxygen metabolism; brain; cancer
Experimental neurology  2010;227(1):79-88.
Rotational inertial forces are thought to be the underlying mechanism for most severe brain injuries. However, little is known about the effect of head rotation direction on injury outcomes, particularly in the pediatric population. Neonatal piglets were subjected to a single non-impact head rotation in the horizontal, coronal, or sagittal direction, and physiological and histopathological responses were observed. Sagittal rotation produced the longest duration of unconsciousness, highest incidence of apnea, and largest intracranial pressure increase, while coronal rotation produced little change, and horizontal rotation produced intermediate and variable derangements. Significant cerebral blood flow reductions were observed following sagittal but not coronal or horizontal injury compared to sham. Subarachnoid hemorrhage, ischemia, and brainstem pathology were observed in the sagittal and horizontal groups but not in a single coronal animal. Significant axonal injury occurred following both horizontal and sagittal rotations. For both groups, the distribution of injury was greater in the frontal and parietotemporal lobes than in the occipital lobes, frequently occurred in the absence of ischemia, and did not correlate with regional cerebral blood flow reductions. We postulate that these direction-dependent differences in injury outcomes are due to differences in tissue mechanical loading produced during head rotation.
PMCID: PMC3021173  PMID: 20875409
animal models; brain ischemia; brain trauma; cerebral blood flow; neuropathology; subarachnoid hemorrhage
Biomedical Optics Express  2012;3(11):2761-2770.
We present a broad-band, continuous-wave spectral approach to quantify the baseline optical properties of tissue and changes in the concentration of a chromophore, which can assist to quantify the regional blood flow from dynamic contrast-enhanced near-infrared spectroscopy data. Experiments were conducted on phantoms and piglets. The baseline optical properties of tissue were determined by a multi-parameter wavelength-dependent data fit of a photon diffusion equation solution for a homogeneous medium. These baseline optical properties were used to find the changes in Indocyanine green concentration time course in the tissue. The changes were obtained by fitting the dynamic data at the peak wavelength of the chromophore absorption, which were used later to estimate the cerebral blood flow using a bolus tracking method.
PMCID: PMC3493236  PMID: 23162714
(300.6340) Spectroscopy, infrared; (290.5820) Scattering measurements; (290.1990) Diffusion
Epileptic events elicit a large focal increase in cerebral blood flow (CBF) to perfuse metabolically active neurons in the focus. Conflicting data exists, however, on whether hemoglobin saturation increases or decreases in the focus and surrounding cortex, and whether CBF increases globally or is decreased in adjacent areas. How these hemodynamic events correlate with actual changes in tissue oxygenation is also not known. Using laser Doppler flowmetry, oxygen microsensors and intrinsic optical imaging spectroscopy, we demonstrate that the dip in hemoglobin in the focus correlates with a profound but temporary decrease in tissue oxygenation in spite of a large increase in cerebral blood flow (CBF). Furthermore, CBF simultaneously decreases in the cortex immediately adjacent to the focus. These events are then replaced with a longer duration, less focal increase in CBF, CBV and hyperoxygenation, the duration of which correlates with the duration of the seizure. These findings raise the question of whether transient focal hypoxia and vascular steal might contribute to progressive deleterious effects of chronic epilepsy on the adult and developing brain. Possible mechanisms based on recent astrocyte-based models of neurovascular coupling are discussed. Implications for functional magnetic resonance imaging of epileptic events are discussed.
PMCID: PMC2745405  PMID: 19261877
Cerebral blood flow; cerebral cortex; epilepsy; optical imaging; seizure; tissue oxygen
Optics Express  2011;19(21):20301-20315.
Occlusions of bilateral common carotid arteries (bi-CCA) in mice are popular models for the investigation of transient forebrain ischemia. Currently available technologies for assessing cerebral blood flow (CBF) and oxygenation in ischemic mice have limitations. This study tests a novel near-infrared diffuse correlation spectroscopy (DCS) flow-oximeter for monitoring both CBF and cerebral oxygenation in mice undergoing repeated transient forebrain ischemia. Concurrent flow measurements in a mouse brain were first conducted for validation purposes; DCS measurement was found highly correlated with laser Doppler measurement (R2 = 0.94) and less susceptible to motion artifacts. With unique designs in experimental protocols and fiber-optic probes, we have demonstrated high sensitivities of DCS flow-oximeter in detecting the regional heterogeneity of CBF responses in different hemispheres and global changes of both CBF and cerebral oxygenation across two hemispheres in mice undergoing repeated 2-minute bi-CCA occlusions over 5 days. More than 75% CBF reductions were found during bi-CCA occlusions in mice, which may be considered as a threshold to determine a successful bi-CCA occlusion. With the progress of repeated 2-minute bi-CCA occlusions over days, a longitudinal decline in the magnitudes of CBF reduction was observed, indicating the brain adaptation to cerebral ischemia through the repeated preconditioning.
PMCID: PMC3495871  PMID: 21997041
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle
Little is known about cerebral blood flow, cerebral blood volume (CBV), oxygenation, and oxygen consumption in the premature newborn brain. We combined quantitative frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation (SO2) and CBV with diffusion correlation spectroscopy measures of cerebral blood flow index (BFix) to determine the relationship between these measures, gestational age at birth (GA), and chronological age. We followed 56 neonates of various GA once a week during their hospital stay. We provide absolute values of SO2 and CBV, relative values of BFix, and relative cerebral metabolic rate of oxygen (rCMRO2) as a function of postmenstrual age (PMA) and chronological age for four GA groups. SO2 correlates with chronological age (r=−0.54, P value ⩽0.001) but not with PMA (r=−0.07), whereas BFix and rCMRO2 correlate better with PMA (r=0.37 and 0.43, respectively, P value ⩽0.001). Relative CMRO2 during the first month of life is lower when GA is lower. Blood flow index and rCMRO2 are more accurate biomarkers of the brain development than SO2 in the premature newborns.
PMCID: PMC3293111  PMID: 22027937
brain hemodynamic development; cerebral oxygen consumption; diffuse correlation spectroscopy; frequency-domain near-infrared spectroscopy; premature neonates
Modern non-invasive brain imaging techniques utilize changes in cerebral blood flow, volume and oxygenation that accompany brain activation. However, stimulus-evoked hemodynamic responses display considerable inter-trial variability even when identical stimuli are presented and the sources of this variability are poorly understood. One of the sources of this response variation could be ongoing spontaneous hemodynamic fluctuations. To investigate this issue, 2-dimensional optical imaging spectroscopy was used to measure cortical hemodynamics in response to sensory stimuli in anesthetized rodents. Pre-stimulus cortical hemodynamics displayed spontaneous periodic fluctuations and as such, data from individual stimulus presentation trials were assigned to one of four groups depending on the phase angle of pre-stimulus hemodynamic fluctuations and averaged. This analysis revealed that sensory evoked cortical hemodynamics displayed distinctive response characteristics and magnitudes depending on the phase angle of ongoing fluctuations at stimulus onset. To investigate the origin of this phenomenon, “null-trials” were collected without stimulus presentation. Subtraction of phase averaged “null trials” from their phase averaged stimulus-evoked counterparts resulted in four similar time series that resembled the mean stimulus-evoked response. These analyses suggest that linear superposition of evoked and ongoing cortical hemodynamic changes may be a property of the structure of inter-trial variability.
PMCID: PMC2938927  PMID: 20844602
optical-imaging; brain-imaging; barrel cortex; spontaneous fluctuations
Optics express  2009;17(5):3884-3902.
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
PMCID: PMC2724658  PMID: 19259230
Neurological research  2010;32(10):1033-1040.
Traumatic brain injury (TBI) causes an early reduction of cerebral blood flow (CBF). The purpose was to study cerebrovascular endothelial function by examining the reactivity of cerebral vessels to L-arginine.
Fifty-one patients with severe TBI were prospectively studied by measuring cerebral hemodynamics before and after the administration of L-arginine, 300 mg/kg at 12 hrs and at 48 hrs after injury. These hemodynamic measurements, using transcranial Doppler techniques, included internal carotid flow volume as an estimate of hemispheric cerebral blood flow, flow velocity in intracranial vessels, CO2 reactivity, and dynamic pressure autoregulation using thigh cuff deflation and carotid compression methods. Changes in the hemodynamics with L-arginine administration were analyzed using a general linear mixed model.
L-arginine produced no change in mean arterial pressure, intracranial pressure, or brain oxygenation. Overall, L-arginine induced an 11.3% increase in internal carotid artery flow volume (p= .0190). This increase was larger at 48 hrs than at 12 hrs (p= .0045), and tended to be larger in the less injured hemisphere at both time periods. The response of flow velocity in the intracranial vessels was similar, but smaller differences with administration of L-arginine were observed. There was a significant improvement in CO2 reactivity with L-arginine, but no change in dynamic pressure autoregulation.
The low response of the cerebral vessels to L-arginine at 12 hrs post-injury with improvement at 48hrs suggests that dysfunction of cerebrovascular endothelium plays a role in the reduced CBF observed after TBI.
PMCID: PMC2958228  PMID: 20712924
cerebral autoregulation; endothelial dysfunction; L-arginine; nitric oxide; traumatic brain injury
Biomedical Optics Express  2013;4(7):978-994.
A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.
PMCID: PMC3704102  PMID: 23847725
(170.3880) Medical and biological imaging; (170.2655) Functional monitoring and imaging; (170.3660) Light propagation in tissues; (170.6480) Spectroscopy, speckle
Optical imaging of changes in total hemoglobin concentration (HbT), cerebral blood volume (CBV), and hemoglobin oxygen saturation (SO2) provides a means to investigate brain hemodynamic regulation. However, high-resolution transcranial imaging remains challenging. In this study, we applied a novel functional photoacoustic microscopy technique to probe the responses of single cortical vessels to left forepaw electrical stimulation in mice with intact skulls. Functional changes in HbT, CBV, and SO2 in the superior sagittal sinus and different-sized arterioles from the anterior cerebral artery system were bilaterally imaged with unambiguous 36 × 65-μm2 spatial resolution. In addition, an early decrease of SO2 in single blood vessels during activation (i.e., ‘the initial dip') was observed. Our results indicate that the initial dip occurred specifically in small arterioles of activated regions but not in large veins. This technique complements other existing imaging approaches for the investigation of the hemodynamic responses in single cerebral blood vessels.
PMCID: PMC3367230  PMID: 22472612
cerebral blood volume; forepaw electrical stimulation; hemodynamic response; hemoglobin oxygen saturation; total hemoglobin concentration; transcranial photoacoustic microscopy
Biomedical Optics Express  2012;3(2):259-272.
This study explored using a novel diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively monitor blood flow and oxygenation changes in head and neck tumors during radiation delivery. A fiber-optic probe connected to the DCS flow-oximeter was placed on the surface of the radiologically/clinically involved cervical lymph node. The DCS flow-oximeter in the treatment room was remotely operated by a computer in the control room. From the early measurements, abnormal signals were observed when the optical device was placed in close proximity to the radiation beams. Through phantom tests, the artifacts were shown to be caused by scattered x rays and consequentially avoided by moving the optical device away from the x-ray beams. Eleven patients with head and neck tumors were continually measured once a week over a treatment period of seven weeks, although there were some missing data due to the patient related events. Large inter-patient variations in tumor hemodynamic responses were observed during radiation delivery. A significant increase in tumor blood flow was observed at the first week of treatment, which may be a physiologic response to hypoxia created by radiation oxygen consumption. Only small and insignificant changes were found in tumor blood oxygenation, suggesting that oxygen utilizations in tumors during the short period of fractional radiation deliveries were either minimal or balanced by other effects such as blood flow regulation. Further investigations in a large patient population are needed to correlate the individual hemodynamic responses with the clinical outcomes for determining the prognostic value of optical measurements.
PMCID: PMC3269843  PMID: 22312579
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle
Journal of Korean Medical Science  2000;15(2):203-210.
In this study, we tested the hypothesis that decreased cerebral perfusion pressure (CPP) induces cerebral ischemia and worsen brain damage in neonatal bacterial meningitis. Meningitis was induced by intracisternal injection of 10(9) colony forming units of Escherichia coli in 21 newborn piglets. Although CPP decreased significantly at 8 hr after bacterial inoculation, deduced hemoglobin (HbD), measured as an index of changes in cerebral blood flow by near infrared spectroscopy, did not decrease significantly. In correlation analyses, CPP showed significant positive correlation with brain ATP and inverse correlation with brain lactate levels. CPP also correlated positively with HbD and oxidized cytochrome aa3 (Cyt aa3) by near infrared spectroscopy. However, CPP did not show significant correlation with cerebral cortical cell membrane Na+,K+-ATPase activity, nor with levels of lipid peroxidation products. In summary, decreased CPP observed in this study failed to induce cerebral ischemia and further brain injury, indicating that cerebrovascular autoregulation is intact during the early phase of experimental neonatal bacterial meningitis.
PMCID: PMC3054608  PMID: 10803699
Critical Care Medicine  2012;40(8):2400-2406.
Cerebral perfusion pressure (CPP) less than 40 mm Hg following pediatric traumatic brain injury (TBI) has been associated with increased mortality independent of age, and current guidelines recommend maintaining CPP between 40–60 mm Hg. Although adult TBI studies have observed an increased risk of complications associated with targeting a CPP > 70, we hypothesize that targeting a CPP of 70 mm Hg with the use of phenylephrine early after injury in the immature brain will be neuroprotective.
Animals were randomly assigned to injury with CPP = 70 mm Hg (CPP70) or CPP = 40 mm Hg (CPP40). Diffuse TBI was produced by a single rapid rotation of the head in the axial plane. Cerebral microdialysis, brain tissue oxygen, intracranial pressure, and cerebral blood flow (CBF) were measured 30 min – 6 h post-injury. One hour after injury, CPP was manipulated with the vasoconstrictor phenylephrine. Animals were euthanized 6 h post-TBI, brains fixed, and stained to assess regions of cell injury and axonal dysfunction.
University center.
21 four week-old female swine.
Measurements and Main Results
Augmentation of CPP to 70 mm Hg resulted in no change in axonal dysfunction, but significantly smaller cell injury volumes at 6 hours post injury compared to CPP40 (1.1% vs. 7.4%, p < 0.05). Microdialysis lactate/pyruvate ratios were improved at CPP70 compared to CPP40. CBF was higher in the CPP70 group but did not reach statistical significance. Phenylephrine was well tolerated and there were no observed increases in serum lactate or intracranial pressure in either group.
Targeting a CPP of 70 mm Hg resulted in a greater reduction in metabolic crisis and cell injury volumes compared to a CPP of 40 mm Hg in an immature swine model. Early aggressive CPP augmentation to a CPP of 70 mm Hg in pediatric TBI before severe intracranial hypertension has the potential to be neuroprotective, and further investigations are needed.
PMCID: PMC3400930  PMID: 22809910
pediatric head injury; cerebral perfusion pressure; phenylephrine; neuroprotection; swine; cerebral blood flow

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