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1.  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
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.  Effect of Hyperglycemia on Brain Penetrating Arterioles and Cerebral Blood Flow Before and After Ischemia/Reperfusion 
Translational stroke research  2010;1(2):127-134.
The effect of preexisiting hyperglycemia on cerebral blood flow (CBF) and brain penetrating arterioles before and after 2 h of ischemia and 30 min of reperfusion was determined. Male Wistar rats that were either hyperglycemic (50 mg/kg streptozotocin; n=24) or normoglycemic (n=24) were subjected to transient ischemia by filament occlusion or nonischemic. CBF was measured prior to ischemia using microspheres and during transient ischemia using laser Doppler. Edema was compared by wet/dry weights. Constriction to apamin, TRAM-34, and L-NNA, inhibitors of small- and intermediate-conductance calcium-activated potassium channels (SK and IK) and nitric oxide, were compared in penetrating arterioles from the ischemic hemisphere to investigate changes in basal tone and endothelium-dependent vasodilator responses. Preexisiting hyperglycemia did not affect CBF in non-ischemic animals or after transient ischemia; however, edema was significantly greater. Ischemia and reperfusion caused decreased basal tone in penetrating arterioles similarly in normoglycemic and hyperglycemic animals that was restored by apamin, and further increased by TRAM-34 and L-NNA. The restoration of tone in penetrating arterioles by apamin and TRAM-34 suggests that transient ischemia activates SK and IK channels in penetrating arterioles. This effect of ischemia was not different between normoglycemic and hyperglycemic animals, suggesting that it was related to ischemia and reperfusion rather than hyperglycemia.
PMCID: PMC2886303  PMID: 20563316
Hyperglycemia; Ischemic stroke; Lenticulostriate arterioles; Calcium-activated potassium channels; Cerebral edema
4.  Dynamic spatio-temporal imaging of early reflow in a neonatal rat stroke model 
The aim of the study was to better understand blood-flow changes in large arteries and microvessels during the first 15 minutes of reflow in a P7 rat model of arterial occlusion. Blood-flow changes were monitored by using ultrasound imaging with sequential Doppler recordings in internal carotid arteries (ICAs) and basilar trunk. Relative cerebral blood flow (rCBF) changes were obtained by using laser speckle Doppler monitoring. Tissue perfusion was measured with [14C]-iodoantipyrine autoradiography. Cerebral energy metabolism was evaluated by mitochondrial oxygen consumption. Gradual increase in mean blood-flow velocities illustrated a gradual perfusion during early reflow in both ICAs. On ischemia, the middle cerebral artery (MCA) territory presented a residual perfusion, whereas the caudal territory remained normally perfused. On reflow, speckle images showed a caudorostral propagation of reperfusion through anastomotic connections, and a reduced perfusion in the MCA territory. Autoradiography highlighted the caudorostral gradient, and persistent perfusion in ventral and medial regions. These blood-flow changes were accompanied by mitochondrial respiration impairment in the ipsilateral cortex. Collectively, these data indicate the presence of a primary collateral pathway through the circle of Willis, providing an immediate diversion of blood flow toward ischemic regions, and secondary efficient cortical anastomoses in the immature rat brain.
PMCID: PMC3597373  PMID: 23047273
cerebral ischemia; collateral supply; mitochondria; oxygen consumption; reperfusion
5.  Noninvasive diffuse optical monitoring of head and neck tumor blood flow and oxygenation during radiation delivery 
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
6.  Intracerebral Hemorrhage after Carotid Artery Stenting without Evidence of Hyperperfusion in Positron Emission Tomography 
Interventional Neuroradiology  2007;13(2):191-199.
A 75-year-old man with a recent history of transient left hemiparesis and dysarthria was referred to our hospital. Angiography showed right internal carotid artery (ICA) occlusion and left ICA 89% stenosis. Positron emission tomography (PET) showed decreased cerebral blood flow (CBF), and increased oxygen extraction fraction (OEF) and cerebral blood volume (CBV) in the right hemisphere.
In the left hemisphere, CBV was increased, but CBF and OEF remained normal. One month after the transient ischemic attack, left carotid artery stenting (CAS) was performed without complications. Diffusion-weighted magnetic resonance imaging (MRI) on the day after CAS showed no fresh ischemic lesion. PET on the second day after CAS showed increased CBF and decreased OEF and CBV in the right hemisphere as compared with those before CAS. In the left hemisphere, decreased CBV was observed and CBF was slightly increased as compared with those before CAS.
The postoperative course was uneventful, but on the fifth day after CAS, the patient suddenly showed a focal seizure and right motor weakness. Emergency computed tomography scanning showed massive intracranial hemorrhage with severe brain edema in the left hemisphere. Although CBF study is useful to predict the hyperperfusion syndrome, we cannot disregard the possibility of intracerebral hemorrhage after CAS for carotid artery stenosis when there is no evidence of hyperperfusion on postoperative CBF study.
PMCID: PMC3345483  PMID: 20566149
hyperperfusion, carotid artery stenting, positron emission tomography
7.  Acute treatment with rosuvastatin protects insulin resistant (C57BL/6J ob/ob) mice against transient cerebral ischemia 
The purpose of this study was to investigate the short-term effects of rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on transient, focal cerebral ischemia in C57BL/6J ob/ob mice with insulin resistance (IR). Male ob/ob, lean, or wild-type (WT) mice were treated with RSV (10 mg/kg per day, i.p.) or vehicle for 3 days. Ischemia was induced by 60 mins of middle cerebral artery occlusion (MCAO) and cortical blood flow (CBF) was monitored by laser-Doppler flowmetry. Infarct volumes were measured 24 h after reperfusion. IR mice exhibited a higher infarct volume compared with Lean or WT mice, and RSV reduced infarct volume only in obese mice (40%±3% versus 32%±3%, P < 0.05). Blood cholesterol and insulin levels were elevated in ob/ob mice but were unaffected by RSV. The CBF reductions during MCAO were similar in all groups and were not affected by RSV. Although RSV did not increase cortical endothelial NO synthase (eNOS) levels in the ob/ob mice, it attenuated the increased cortical expression of intracellular adhesion molecule-1 (ICAM-1) after MCAO from ob/ob mice. Thus, RSV protects against stroke in IR mice by a mechanism independent of effects on the lipid profile, CBF, or eNOS but dependent on suppression of post-MCAO ICAM-1 expression.
PMCID: PMC2632795  PMID: 18665182
middle cerebral artery occlusion; cerebral circulation; endothelial nitric oxide synthase; ICAM-1; statins; strokes
8.  Effects of a head-down tilt on cerebral blood flow in mice during bilateral common carotid artery occlusion 
Asian Journal of Neurosurgery  2012;7(4):171-173.
Data on the optimal head position for patients with acute ischemic stroke are unavailable. We evaluated the effects of mild head-down tilt (HDT) on cerebral blood flow (CBF) in mice during bilateral common carotid artery occlusion (BCCAO).
Materials and Methods:
We used mice with BCCAO (35 minutes) and divided these into 2 groups ( n=16): BCCAO at 0°-HDT and 5°-HDT. CBF was measured for both hemispheres with a non-invasive laser Doppler blood perfusion imager. Changes in CBF during BCCAO were examined in both groups.
A significantly greater increase in CBF in both hemispheres was observed in 5°-HDT mice than in 0°-HDT mice (126.1% (8.715)% vs. 102.1% (4.718)%; P=0.0294).
HDT enhanced the increase in CBF in both hemispheres in the mouse BCCAO model. The potential mechanism underlying CBF increase enhanced by HDT during BCCAO warrants further investigation.
PMCID: PMC3613638  PMID: 23559983
Bilateral common carotid artery occlusion; brain infarction; cerebral blood flow; head down; mouse
9.  Oxygen extraction fraction and acetazolamide reactivity in symptomatic carotid artery disease 
Objective: It has been proposed that cerebral blood flow (CBF) response to acetazolamide may be reduced according to the degree of autoregulatory vasodilation in regions with normal oxygen extraction fraction (OEF), whereas the CBF response may be absent in regions with increased OEF where vasodilation may be maximal in response to reduced perfusion pressure. The objective of this study was to test this hypothesis.
Methods: Positron emission tomography (PET) was used to study 30 symptomatic patients with carotid artery steno-occlusive lesions. CBF at baseline and 10 minutes after an intravenous injection of 1 g acetazolamide was measured. The correlation between the change in CBF during acetazolamide administration and the baseline value of OEF in the affected hemisphere was examined.
Results: The baseline OEF value was inversely and non-linearly correlated with the percentage change in CBF during acetazolamide administration (R2 = 0.25, p = 0.02). There was an upward trend of OEF with diminishing acetazolamide response below a critical level around zero response. Acetazolamide response less than 6.65% over baseline (sensitivity 100%, specificity 89%, positive predictive value 50%, negative predictive value 100%) was established as most helpful in predicting abnormally high OEF.
Conclusions: The inverse, non-linear relationship between OEF and CBF response to acetazolamide suggests that these two measurements may not identify haemodynamic impairment in the same patients.
PMCID: PMC1757491  PMID: 14707303
10.  Spatio-temporal dynamics of perfusion and oximetry during ictal discharges in the rat neocortex 
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
11.  Assessment of cerebral haemodynamic reserve: correlation between PET parameters and CO2 reactivity measured by the intravenous 133 xenon injection technique. 
Regional cerebral blood flow (CBF), oxygen utilisation, fractional oxygen extraction (OER) and cerebral blood volume (CBV) were measured by positron emission tomography (PET) in 21 patients with occlusive carotid artery disease. In the same patients, measurements of cerebral CO2 reactivity were performed using the intravenous xenon-133 technique. A significant correlation was found in symptomatic hemispheres between the CBF/CBV ratio and CO2 reactivity. Four patients had significant increases in OER and this was associated with a reduction in CBF/CBV ratio implying exhaustion of haemodynamic reserve. CO2 reactivity was reduced below 1.5% mm Hg in all four cases with raised OER but only in two cases with normal OER. In patients with CO2 reactivities above 1.5% mm Hg, OER was normal in all cases. It is concluded that measurements of CO2 reactivity provide a satisfactory method for assessing cerebral haemodynamic reserve.
PMCID: PMC1033112  PMID: 3145962
12.  Simple model of forebrain ischemia in mouse 
Journal of Neuroscience Methods  2011;204(2):254-261.
The availability of genetically engineered mice allows unraveling the role of specific proteins in mechanisms of ischemic brain injury. Due to the high variability of their vascular anatomy, mouse models of global cerebral ischemia are rather complex. In the present study, we describe a simple model of mouse forebrain ischemia where the bilateral common carotid artery occlusion (BCCO) is combined with isoflurane-induced hypotension. The forebrain ischemia was induced by BCCO that was preceded by increase of the isoflurane level from 1.5% to 5% in the respiratory gases. This caused a decrease of the mean arterial blood pressure (MABP) to about 30 mmHg and the cerebral blood flow dropped to 5% of the control after the BCCO. During the 10 min ischemic period both MABP and CBF remained stable and the reperfusion was induced by reducing the isoflurane level to 0% followed by removal of the carotid clamps. Mice were allowed 1, 2, 3 or 5 days survival followed by histologic analysis. The number of CA1 uninjured neurons was assessed utilizing a stereological approach.
Neurodegeneration was observed at two days after the onset of reperfusion. At 3 days of recovery, about 40% of neurons survived and the cell death did not further increase at 5 days. Degenerative neurons were also detected in the striatum and sporadically in the cortex. This study demonstrates the feasibility of using the described model in mice that can be utilized to examine the effect of new neuroprotective compounds or use transgenic animals to test new hypothesis.
PMCID: PMC3273657  PMID: 22146544
mouse; global cerebral ischemia; model; hypotension; isoflurane; cell death
13.  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
14.  Quantitative cerebral blood flow with Optical Coherence Tomography 
Optics express  2010;18(3):2477-2494.
Absolute measurements of cerebral blood flow (CBF) are an important endpoint in studies of cerebral pathophysiology. Currently no accepted method exists for in vivo longitudinal monitoring of CBF with high resolution in rats and mice. Using three-dimensional Doppler Optical Coherence Tomography and cranial window preparations, we present methods and algorithms for regional CBF measurements in the rat cortex. Towards this end, we develop and validate a quantitative statistical model to describe the effect of static tissue on velocity sensitivity. This model is used to design scanning protocols and algorithms for sensitive 3D flow measurements and angiography of the cortex. We also introduce a method of absolute flow calculation that does not require explicit knowledge of vessel angles. We show that OCT estimates of absolute CBF values in rats agree with prior measures by autoradiography, suggesting that Doppler OCT can perform absolute flow measurements in animal models.
PMCID: PMC2837842  PMID: 20174075
15.  Quantitative cerebral blood flow with Optical Coherence Tomography 
Optics Express  2010;18(3):2477-2494.
Absolute measurements of cerebral blood flow (CBF) are an important endpoint in studies of cerebral pathophysiology. Currently no accepted method exists for in vivo longitudinal monitoring of CBF with high resolution in rats and mice. Using three-dimensional Doppler Optical Coherence Tomography and cranial window preparations, we present methods and algorithms for regional CBF measurements in the rat cortex. Towards this end, we develop and validate a quantitative statistical model to describe the effect of static tissue on velocity sensitivity. This model is used to design scanning protocols and algorithms for sensitive 3D flow measurements and angiography of the cortex. We also introduce a method of absolute flow calculation that does not require explicit knowledge of vessel angles. We show that OCT estimates of absolute CBF values in rats agree with prior measures by autoradiography, suggesting that Doppler OCT can perform absolute flow measurements in animal models.
PMCID: PMC2837842  PMID: 20174075
(110.4500) Optical coherence tomography; (170.3880) Medical and biological imaging; (170.5380) Physiology; (170.1470) Blood or tissue constituent monitoring
16.  Periprocedural Monitoring with Regional Cerebral Oxygen Saturation in Carotid Artery Stenting 
Interventional Neuroradiology  2007;13(Suppl 1):53-57.
Hemodynamic instability during and after carotid artery stenting (CAS) may reduce cerebral blood flow (CBF), leading to cerebral ischemia. To investigate changes in CBF in the periprocedural period, we continuously recorded the regional cerebral oxygen saturation (rSO2) using near-infrared spectroscopy.
In 46 consecutive patients with carotid artery stenosis, rSO2 was continuously recorded during and after CAS. In addition, the patients underwent SPECT to evaluate a change in CBF on the next day after CAS.
Introprocedural bradycardia (heart rate <50 bpm) occurred in 21 patients (46%) including one transient cardiac arrest. Intraprocedural hypotension (systolic blood pressure <80 mmHg) occurred in 18 patients (39%), and 16 of them showed prolonged hypotension. The rSO2 in patients with bradycardia/hypotension during CAS was significantly less than that in patients without them (p<0.01). Moreover, the SPECT on the next day after CAS demonstrated that the ipsilateral CBF in patients with bradycardia/hypotension during CAS significantly more than that in patients without them (p<0.05).
Intraprocedural hemodynamic instability resulted in a significant decrease in rSO2, leading to a possible severe cerebral ischemia. In addition, intraprocedural bradycardia/hypotension might be related with postprodedural hyperperfusion, causing the morbidity and mortality after CAS.
PMCID: PMC3345467  PMID: 20566077
carotid artery stenting, bradycardia, hypotension, oxygen saturation
17.  Interindividual variations of cerebral blood flow, oxygen delivery, and metabolism in relation to hemoglobin concentration measured by positron emission tomography in humans 
Regional cerebral blood flow (CBF) and oxygen metabolism can be measured by positron emission tomography (PET) with 15O-labeled compounds. Hemoglobin (Hb) concentration of blood, a primary determinant of arterial oxygen content (CaO2), influences cerebral circulation. We investigated interindividual variations of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) in relation to Hb concentration in healthy human volunteers (n=17) and in patients with unilateral steno-occlusive disease (n=44). For the patients, data obtained only from the contralateral hemisphere (normal side) were analyzed. The CBF and OEF were inversely correlated with Hb concentration, but CMRO2 was independent of Hb concentration. Oxygen delivery defined as a product of CaO2 and CBF (CaO2 CBF) increased with a rise of Hb concentration. The analysis with a simple oxygen model showed that oxygen diffusion parameter (L) was constant over the range of Hb concentration, indicating that a homeostatic mechanism controlling CBF is necessary to maintain CMRO2. The current findings provide important knowledge to understand the control mechanism of cerebral circulation and to interpret the 15O PET data in clinical practice.
PMCID: PMC2949226  PMID: 20160738
15O PET; CBF; CMRO2; hemoglobin; OEF
18.  Noninvasive Cerebral Perfusion Imaging in High-Risk Neonates 
Seminars in perinatology  2010;34(1):46-56.
Advances in medical and surgical care of the high-risk neonate have led to increased survival. A significant number of these neonates suffer from neurodevelopmental delays and failure in school. The focus of clinical research has shifted to understanding events contributing to neurological morbidity in these patients. Assessing changes in cerebral oxygenation and regulation of cerebral blood flow (CBF) is important in evaluating the status of the central nervous system. Traditional CBF imaging methods fail for both ethical and logistical reasons. Optical near infrared spectroscopy (NIRS) is increasingly being used for bedside monitoring of cerebral oxygenation and blood volume in both very low birth weight infants and neonates with congenital heart disease. Although trends in CBF may be inferred from changes in cerebral oxygenation and/or blood volume, NIRS does not allow a direct measure of CBF in these populations. Two relatively new modalities, arterial spin-labeled perfusion magnetic resonance imaging and optical diffuse correlation spectroscopy, provide direct, noninvasive measures of cerebral perfusion suitable for the high-risk neonates. Herein we discuss the instrumentation, applications, and limitations of these noninvasive imaging techniques for measuring and/or monitoring CBF.
PMCID: PMC2829712  PMID: 20109972
infant cerebral blood flow; CBF; arterial spin labeled perfusion; MRI; PVL; optical spectroscopy
19.  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
20.  Validation of a Stand-Alone Near Infrared Spectroscopy System for Monitoring Cerebral Autoregulation during Cardiac Surgery 
Anesthesia and analgesia  2012;116(1):198-204.
Individualizing arterial blood pressure (ABP) targets during cardiopulmonary bypass (CPB) based on cerebral blood flow (CBF) autoregulation monitoring may provide a more effective means for preventing cerebral hypoperfusion than the current standard of care. Autoregulation can be monitored in real-time with transcranial Doppler (TCD). We have previously demonstrated that near infrared spectroscopy (NIRS) derived regional cerebral oxygen saturation (rScO2) provides a clinically suitable surrogate of CBF for autoregulation monitoring. The purpose of this study was to determine the accuracy of a stand-alone “plug-and-play” investigational system for autoregulation monitoring that uses a commercially available NIRS monitor with TCD methods.
TCD monitoring of middle cerebral artery CBF velocity and NIRS monitoring was performed in 70 patients during CPB. Indices of autoregulation were computed by both a personal computer-based system and an investigational prototype NIRS-based monitor. A moving linear correlation coefficient between slow waves of ABP and CBF velocity (mean velocity index, M×) and between ABP and rScO2 (cerebral oximetry index, CO×) were calculated. When CBF is autoregulated, there is no correlation between CBF and ABP; when CBF is dysregulated, M× and CO× approach 1 (i.e., CBF and ABP are correlated). Linear regression and bias analysis was performed between time-averaged values of M× and CO× derived from the personal computer-based system and from CO× measured with the prototype monitor. Values for M× and CO× were categorized in 5 mmHg bins of ABP for each patient. The lower limit of CBF autoregulation) was defined as the ABP where M× incrementally increased to ≥ 0.4.
There was correlation and good agreement between CO× derived from the prototype monitor and M× (r=0.510, 95% confidence interval [CI], 0.414 to 0.595, p<0.001; bias -0.07 ± 0.19). The correlation and bias between the personal computer-based CO× and CO× from the prototype NIRS monitor were r=0.957, 95% CI, 0.945 to 0.966, p<0.001 and 0.06±0.06, respectively. The average ABP at the lower limit of autoregulation was 63 ± 11 mmHg (95% prediction interval, 52 to 74 mmHg mmHg). While the mean ABP at the CO×-determined lower limit of autoregulation determined with the prototype monitor was statistically different from that determined by M× (59 ± 9 mmHg, 95% prediction interval, 50 to 68 mmHg, p=0.026), the difference is not likely clinically meaningful.
Monitoring CBF autoregulation with an investigational stand-alone NIRS monitor is correlated and in good agreement with TCD based methods. Availability of such a device would allow wide-spread autoregulation monitoring as a means of individualizing ABP targets during CPB.
PMCID: PMC3800185  PMID: 23223100
21.  Transcranial Optical Monitoring of Cerebrovascular Hemodynamics in Acute Stroke Patients 
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
22.  Effect of Chronic Alcohol Consumption on Brain Damage Following Transient Focal Ischemia 
Brain research  2007;1194:73-80.
Chronic alcohol consumption impairs cerebral vasoreactivity, and thus may result in an increase in ischemic brain damage. The goal of this study is to examine the influence of chronic alcohol consumption on transient focal ischemia-induced brain damage. Sprague-Dawley rats were divided into two groups, a control group and an alcohol group. Eight weeks after being fed a liquid diet with or without alcohol, responses of parietal pial arterioles to systemic hypoxia and hypercapnia were measured using a cranial window technique. In separate experiments, rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 hours under ketamine/xylazine or isoflurane anesthesia. Regional cerebral blood flow (rCBF) was monitored through a Laser-Doppler flow probe attached to the lateral aspect of the skull. Neurological evaluation and ischemic lesion were assessed 24-hour after reperfusion. Dilation of pial arterioles in response to hypoxia and hypercapnia was significantly reduced in alcohol-fed rats. Alcohol-fed rats had significantly larger infarct volumes and worse neurological outcomes than nonalcoholfed rats under ketamine/xylazine or isoflurane anesthesia. In addition, rCBF measurement indicated that alcohol-fed rats had less regulatory rebound increase in rCBF after the initial drop in rCBF at the onset of MCAO. Our findings suggest that chronic alcohol consumption exacerbates transient focal ischemia-induced brain damage. Increased ischemic brain damage during alcohol consumption may be related to an impaired cerebral vasoreactivity.
PMCID: PMC2275899  PMID: 18191819
23.  Correlation of Early Reduction in the Apparent Diffusion Coefficient of Water with Blood Flow Reduction During Middle Cerebral Artery Occlusion in Rats 
To determine the relationship between reductions in the apparent diffusion coefficient of water (ADC) and in cerebral blood flow (CBF) during focal ischemia, we used diffusion-weighted magnetic resonance (D-MR) imaging and autoradiographic CBF analysis to examine rats subjected to 30 or 90 min of permanent middle cerebral artery (MCA) occlusion. In the 30-min occlusion group (n = l0), the area with substantially reduced ADC (15% or more below the contralateral level [ADCJ15]) corresponded best to the area with CBF below 25 ml/lOO g/min and was significantly smaller than the area with CBF below 50 m1/100 g/min (CBF50), a level associated with reduced protein synthesis and delayed necrosis (40 ± 13% versus 74 ± 8% of the ischemic hemisphere; P < 0.OOOl). In the 90-min occlusion group (n = 6), the ADC15 area corresponded best to the CBF30 to CBF35 area and was again significantly smaller than the CBF50 area (54 ± 13% versus 73 ± 20%, P < 0.05). Thus, the area of substantially reduced ADC at 30 and 90 min represents only 53% and 74%, respectively, of the tissue at risk for infarction. These findings indicate a potential limitation in using early D-MR imaging to predict stroke outcome.
PMCID: PMC2733355  PMID: 7500876
diffusion-weighted MRI; focal cerebral ischemia; rat; cerebral blood flow
24.  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
25.  The Time of Maximum Post-Ischemic Hyperperfusion Indicates Infarct Growth Following Transient Experimental Ischemia 
PLoS ONE  2013;8(5):e65322.
After recanalization, cerebral blood flow (CBF) can increase above baseline in cerebral ischemia. However, the significance of post-ischemic hyperperfusion for tissue recovery remains unclear. To analyze the course of post-ischemic hyperperfusion and its impact on vascular function, we used magnetic resonance imaging (MRI) with pulsed arterial spin labeling (pASL) and measured CBF quantitatively during and after a 60 minute transient middle cerebral artery occlusion (MCAO) in adult rats. We added a 5% CO2 - challenge to analyze vasoreactivity in the same animals. Results from MRI were compared to histological correlates of angiogenesis. We found that CBF in the ischemic area recovered within one day and reached values significantly above contralateral thereafter. The extent of hyperperfusion changed over time, which was related to final infarct size: early (day 1) maximal hyperperfusion was associated with smaller lesions, whereas a later (day 4) maximum indicated large lesions. Furthermore, after initial vasoparalysis within the ischemic area, vasoreactivity on day 14 was above baseline in a fraction of animals, along with a higher density of blood vessels in the ischemic border zone. These data provide further evidence that late post-ischemic hyperperfusion is a sequel of ischemic damage in regions that are likely to undergo infarction. However, it is transient and its resolution coincides with re-gaining of vascular structure and function.
PMCID: PMC3669346  PMID: 23741488

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