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1.  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
2.  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
3.  Quantification of the cortical contribution to the NIRS signal over the motor cortex using concurrent NIRS-fMRI measurements 
Neuroimage  2011;59(4):3933-3940.
Near-Infrared Spectroscopy (NIRS) measures the functional hemodynamic response occuring at the surface of the cortex. Large pial veins are located above the surface of the cerebral cortex. Following activation, these veins exhibit oxygenation changes but their volume likely stays constant. The back-reflection geometry of the NIRS measurement renders the signal very sensitive to these superficial pial veins. As such, the measured NIRS signal contains contributions from both the cortical region as well as the pial vasculature. In this work, the cortical contribution to the NIRS signal was investigated using (1) Monte Carlo simulations over a realistic geometry constructed from anatomical and vascular MRI and (2) multimodal NIRS-BOLD recordings during motor stimulation. A good agreement was found between the simulations and the modeling analysis of in vivo measurements. Our results suggest that the cortical contribution to the deoxyhemoglobin signal change (ΔHbR) is equal to 16–22% of the cortical contribution to the total hemoglobin signal change (ΔHbT). Similarly, the cortical contribution of the oxyhemoglobin signal change (ΔHbO) is equal to 73–79% of the cortical contribution to the ΔHbT signal. These results suggest that ΔHbT is far less sensitive to pial vein contamination and therefore, it is likely that the ΔHbT signal provides better spatial specificity and should be used instead of ΔHbO or ΔHbR to map cerebral activity with NIRS. While different stimuli will result in different pial vein contributions, our finger tapping results do reveal the importance of considering the pial contribution.
PMCID: PMC3279595  PMID: 22036999
NIRS-fMRI; Pial vasculature; Balloon Model; Monte Carlo simulations
4.  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
5.  Cerebral hemodynamic and ventilatory responses to hypoxia, hypercapnia, and hypocapnia during 5 days at 4,350 m 
This study investigated the changes in cerebral near-infrared spectroscopy (NIRS) signals, cerebrovascular and ventilatory responses to hypoxia and CO2 during altitude exposure. At sea level (SL), after 24 hours and 5 days at 4,350 m, 11 healthy subjects were exposed to normoxia, isocapnic hypoxia, hypercapnia, and hypocapnia. The following parameters were measured: prefrontal tissue oxygenation index (TOI), oxy- (HbO2), deoxy- and total hemoglobin (HbTot) concentrations with NIRS, blood velocity in the middle cerebral artery (MCAv) with transcranial Doppler and ventilation. Smaller prefrontal deoxygenation and larger ΔHbTot in response to hypoxia were observed at altitude compared with SL (day 5: ΔHbO2−0.6±1.1 versus −1.8±1.3 μmol/cmper mm Hg and ΔHbTot 1.4±1.3 versus 0.7±1.1 μmol/cm per mm Hg). The hypoxic MCAv and ventilatory responses were enhanced at altitude. Prefrontal oxygenation increased less in response to hypercapnia at altitude compared with SL (day 5: ΔTOI 0.3±0.2 versus 0.5±0.3% mm Hg). The hypercapnic MCAv and ventilatory responses were decreased and increased, respectively, at altitude. Hemodynamic responses to hypocapnia did not change at altitude. Short-term altitude exposure improves cerebral oxygenation in response to hypoxia but decreases it during hypercapnia. Although these changes may be relevant for conditions such as exercise or sleep at altitude, they were not associated with symptoms of acute mountain sickness.
PMCID: PMC3887348  PMID: 24064493
altitude illness; carbon dioxide; cerebral hemodynamic; near-infrared spectroscopy; oxygenation
6.  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
7.  Improving Dynamic Susceptibility Contrast MRI Measurement of Quantitative Cerebral Blood Flow using Corrections for Partial Volume and Nonlinear Contrast Relaxivity: a Xenon CT Comparative Study 
To test whether dynamic susceptibility contrast MRI-based CBF measurements are improved with arterial input function (AIF) partial volume (PV) and nonlinear contrast relaxivity correction, using a gold-standard CBF method, xenon computed tomography (xeCT).
Materials and Methods
18 patients with cerebrovascular disease underwent xeCT and MRI within 36 hrs. PV was measured as the ratio of the area under the AIF and the venous output function (VOF) concentration curves. A correction was applied to account for the nonlinear relaxivity of bulk blood (BB). Mean CBF was measured with both techniques and regression analyses both within and between patients were performed.
Mean xeCT CBF was 43.3±13.7 ml/100g/min (mean±SD). BB correction decreased CBF by a factor of 4.7±0.4, but did not affect precision. The least-biased CBF measurement was with BB but without PV correction (45.8±17.2 ml/100 g/min, coefficient of variation [COV]=32%). Precision improved with PV correction, although absolute CBF was mildly underestimated (34.3±10.8 ml/100 g/min, COV=27%). Between patients correlation was moderate even with both corrections (R=0.53).
Corrections for AIF PV and nonlinear BB relaxivity improve bolus MRI-based CBF maps. However, there remain challenges given the moderate between-patient correlation, which limit diagnostic confidence of such measurements in individual patients.
PMCID: PMC2851938  PMID: 19787719
magnetic resonance imaging; perfusion; computed tomography; xenon CT; cerebral blood flow; quantitation; stroke; cerebrovascular disease; dynamic susceptibility contrast
8.  CBF Measurements using Multidelay Pseudocontinuous and Velocity-Selective Arterial Spin Labeling in Patients with Long Arterial Transit Delays: Comparison with Xenon CT CBF 
To test the theory that velocity-selective arterial spin labeling (VSASL) is insensitive to transit delay.
Materials and Methods
Cerebral blood flow (CBF) was measured in ten Moyamoya disease patients using xenon CT (xeCT) and MR imaging, which included multiple pseudo-continuous ASL (pcASL) with different post-label delays, VSASL, and dynamic susceptibility contrast (DSC) imaging. Correlation coefficient, root-mean-square difference, mean CBF error between ASL and gold-standard xeCT CBF measurements as well the dependence of this error on transit delay (TD) as estimated by DSC time-to-peak of the residue function (Tmax) were determined.
For pcASL with different PLD, CBF measurement with short PLD (1.5–2 s) had the strongest correlations with xeCT; VSASL had a lower but still significant correlation with a mean coefficient of 0.55. We noted the theoretically predicted dependence of CBF error on Tmax and on PLD for pcASL; VSASL CBF measurements had the least dependence of the error on TD. We also noted effects suggesting that the location of the label decay (blood vs. tissue) impacted the measurement, which was worse for pcASL than for VSASL.
We conclude that VSASL is less sensitive to TD than conventional ASL techniques and holds promise for CBF measurements in cerebrovascular diseases with slow flow.
PMCID: PMC3368036  PMID: 22359345
ASL; VSASL; perfusion; Moyamoya; Xenon CT; DSC
9.  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
10.  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
11.  Changes in cerebral blood flow after acetazolamide: an experimental study comparing near-infrared spectroscopy and SPECT 
Background and purpose
It is important to find a reliable and bedside method, which can estimate the cerebral blood flow (CBF) of patients in clinical settings. Estimation of CBF by calculating a blood flow index (BFI) using continuous wave near-infrared spectroscopy (CW-NIRS) and indocyanine green (ICG) as an iv tracer has been proposed to be a feasible and promising method. To validate if the BFI method can detect relative changes in CBF we compared data with the established method 133Xenon single photon emission computer tomography (133Xe-SPECT).
Ten healthy subjects were investigated before and after a bolus of acetazolamide. NIRS data were obtained using a multi source detector separation configuration in order to assess a corrected BFI (BFIcorr) value, which attempts to eliminate contamination of skin blood flow.
Data obtained showed no significant correlation between CBF changes measured by 133Xe-SPECT and BFIcorr (0.133, P = 0.732). After acetazolamide, a 49% increase in CBF was detected using the 133Xe-SPECT method, whereas no changes in any ICG variables were observed after acetazolamide.
The study shows that it is not possible to obtain reliable BFI data, which reflect changes in CBF after acetazolamide infusion, using the CW-NIRS and ICG method.
PMCID: PMC2782727  PMID: 19236469
acetazolamide; blood flow index; cerebral blood flow; indocyanine green; near-infrared spectroscopy; single photon emission computer tomography
12.  Near-infrared spectroscopy measurement of the pulsatile component of cerebral blood flow and volume from arterial oscillations 
Journal of biomedical optics  2007;12(1):014033.
We describe a near-infrared spectroscopy (NIRS) method to noninvasively measure relative changes in the pulsate components of cerebral blood flow (pCBF) and volume (pCBV) from the shape of heartbeat oscillations. We present a model that is used and data to show the feasibility of the method. We use a continuous-wave NIRS system to measure the arterial oscillations originating in the brains of piglets. Changes in the animals' CBF are induced by adding CO2 to the breathing gas. To study the influence of scalp on our measurements, comparative, invasive measurements are performed on one side of the head simultaneously with noninvasive measurements on the other side. We also did comparative measurements of CBF using a laser Doppler system to validate the results of our method. The results indicate that for sufficient source-detector separation, the signal contribution of the scalp is minimal and the measurements are representative of the cerebral hemodynamics. Moreover, good correlation between the results of the laser Doppler system and the NIRS system indicate that the presented method is capable of measuring relative changes in CBF. Preliminary results show the potential of this NIRS method to measure pCBF and pCBV relative changes in neonatal pigs.
PMCID: PMC2637815  PMID: 17343508
cerebral blood flow; cerebral blood volume; near-infrared spectroscopy; arterial oscillations
13.  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
14.  Investigation of Frontal Lobe Activation with fNIRS and Systemic Changes During Video Gaming 
Frontal lobe activation caused by tasks such as videogames can be investigated using multichannel near-infrared spectroscopy (fNIRS), sometimes called optical topography. The aims of this study are to investigate the effects of video gaming (fighting and puzzle games) in the brain and the systemic physiology and to determine whether systemic responses during the gaming task are associated with the measurement of localised cerebral haemodynamic changes as measured by fNIRS. We used a continuous-wave 8-channel fNIRS system to measure the changes in concentration of oxy-haemoglobin (HbO2) and deoxy-haemoglobin (HHb) and changes in total haemoglobin (ΔtHb = ΔHbO2 + ΔHHb) over the frontal lobe in 30 healthy volunteers. The Portapres system was used to measure mean blood pressure (MBP) and heart rate (HR), and a laser Doppler was employed to measure the changes in scalp blood flow (or flux). Even though we observed significant changes in systemic variables during gaming, in particular in scalp flow, we also managed to see localised activation patterns over the frontal polar (FP1) region. However, in some channels over the frontal lobe, we also observed significant correlations between the HbO2 and systemic variables.
PMCID: PMC4038001  PMID: 23852481
15.  Oscillations in Cerebral Haemodynamics in Patients with Falciparum Malaria 
Spontaneous oscillations in cerebral haemodynamics studied with near-infrared spectroscopy (NIRS), become impaired in several pathological conditions. We assessed the spectral characteristics of these oscillations in 20 patients with falciparum malaria admitted to Ispat General Hospital, Rourkela, India. Monitoring included continuous frontal lobe NIRS recordings within 24 h of admission (Day 0), together with single measurements of a number of clinical and chemical markers recorded on admission. Seven patients returned for follow-up measurements on recovery (FU). A 2,048 sampling-point segment of oxygenated haemoglobin concentration ([ΔHbO2]) data was subjected to Fourier analysis per patient, and power spectral density was derived over the very low frequency (VLF: 0.02–0.04 Hz), low frequency (LF: 0.04–0.15 Hz) and high frequency (HF: 0.15–0.4 Hz) bands. At Day 0, VLF spectral power was 21.1 ± 16.4, LF power 7.2 ± 4.6 and HF power 2.6 ± 5.0, with VLF power being statistically significantly higher than LF and HF (P < 0.005). VLF power tended to decrease in the severely ill patients and correlated negatively with heart rate (r = 0.57, P < 0.01), while LF power correlated positively with aural body temperature (r = 0.49, P < 0.05). In all but one of the patients who returned for FU measurements, VLF power increased after recovery. This may be related to autonomic dysfunction in severe malaria, a topic of little research to date. The present study demonstrated that application of NIRS in a resource-poor setting is feasible and has potential as a research tool.
PMCID: PMC4038006  PMID: 22879021
16.  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
17.  Cerebral near-infrared spectroscopy as a measure of nociceptive evoked activity in critically ill infants 
Due to the subtlety or absence of predictable, objective signs of pain in critically ill infants, health care professionals must often rely on observations of behavioural or nonspecific physiological signals. Although parameters such as heart rate or blood pressure could be regarded as relatively more objective or quantifiable measures than behavioural signals, they are often unstable and generally nonspecific. However, reducing inaccuracies in pain assessment and misinterpretation of pain intensity may be facilitated by new techniques that shed light on the cerebral responses to pain that could be measured directly. Near-infrared spectroscopy is one such technique that has been used to detect subtle changes in the concentrations of oxygenated and deoxygenated hemoglobin in the brains of preterm and term infants in response to stressful and/or painful stimuli. Following a review of cortical pain responses, this article provides an overview of near-infrared spectroscopy technology and its use in functional activation studies in critically ill infants, and its potential applications in clinical settings and pain research.
Signs of pain may be subtle or absent in a critically ill infant. The complex nature of pain may further obscure its identification and measurement. Because the use of monitoring and neuroimaging techniques has become more common in pain research, an understanding of these specialized technologies is important. Near-infrared spectroscopy (NIRS) is a noninvasive technique for monitoring tissue hemodynamics and oxygenation. There are indications that NIRS is capable of detecting the cerebral hemodynamic changes associated with sensory stimuli, including pain, in infants. These developments suggest that NIRS may play an important role in research focusing on pain perception in critically ill infants. The present review briefly describes the cortical responses to noxious stimuli, which parallel cerebral hemodynamic responses to various stimuli. This is followed by an overview of NIRS technology including a summary of the literature on functional studies that have used NIRS in infants. Current NIRS techniques have well-recognized limitations that must be considered carefully during the measurement and interpretation of the signals. Nonetheless, until more advanced NIRS techniques emerge, the current devices have strengths that should be exploited.
PMCID: PMC3206783  PMID: 22059205
Infants; Near-infrared spectroscopy; Neurodiagostic technique; Nociception; Pain
18.  Cerebral Blood Flow Autoregulation Is Preserved After Continuous Flow Left Ventricular Assist Device Implantation 
To compare cerebral blood flow (CBF) autoregulation in patients undergoing continuous flow left ventricular assist device (LVAD) implantation with that in patients undergoing coronary artery bypass graft (CABG) surgery.
Prospective, observational, controlled study.
Academic medical center.
Fifteen patients undergoing LVAD insertion and 10 patients undergoing CABG surgery.
Measurements and Main Results
Cerebral autoregulation was monitored with transcranial Doppler and near-infrared spectroscopy (NIRS). A continuous, Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity, and between MAP and NIRS data rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Mx and COx approach zero when autoregulation is intact (no correlation between CBF and MAP), but approach 1 when autoregulation is impaired. Mx was lower during and immediately after cardiopulmonary bypass (CPB) in the LVAD group than it was in the CABG surgery patients, indicating better preserved autoregulation. Based on COx monitoring, autoregulation tended to be better preserved in the LVAD group than in the CABG group immediately after surgery (p=0.0906). On postoperative day 1, COx was lower in LVAD patients than in CABG surgery patients, again indicating preserved CBF autoregulation (p=0.0410). Based on COx monitoring, 3 (30%) of the CABG patients had abnormal autoregulation (COx ≥ 0.3) on the first postoperative day but none of the LVAD patients had this abnormality (p=0.037).
These data suggest that CBF autoregulation is preserved during and immediately after surgery in patients undergoing LVAD insertion.
PMCID: PMC3490198  PMID: 23122299
19.  Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety 
Many studies have reported beneficial effects from the application of near-infrared (NIR) light photobiomodulation (PBM) to the body, and one group has reported beneficial effects applying it to the brain in stroke patients. We have reported that the measurement of a patient's left and right hemispheric emotional valence (HEV) may clarify data and guide lateralized treatments. We sought to test whether a NIR treatment could 1. improve the psychological status of patients, 2. show a relationship between immediate psychological improvements when HEV was taken into account, and 3. show an increase in frontal pole regional cerebral blood flow (rCBF), and 4. be applied without side effects.
We gave 10 patients, (5 M/5 F) with major depression, including 9 with anxiety, 7 with a past history of substance abuse (6 with an opiate abuse and 1 with an alcohol abuse history), and 3 with post traumatic stress disorder, a baseline standard diagnostic interview, a Hamilton Depression Rating Scale (HAM-D), a Hamilton Anxiety Rating Scale (HAM-A), and a Positive and Negative Affect Scale (PANAS). We then gave four 4-minute treatments in a random order: NIR to left forehead at F3, to right forehead at F4, and placebo treatments (light off) at the same sites. Immediately following each treatment we repeated the PANAS, and at 2-weeks and at 4-weeks post treatment we repeated all 3 rating scales. During all treatments we recorded total hemoglobin (cHb), as a measure of rCBF with a commercial NIR spectroscopy device over the left and the right frontal poles of the brain.
At 2-weeks post treatment 6 of 10 patients had a remission (a score ≤ 10) on the HAM-D and 7 of 10 achieved this on the HAM-A. Patients experienced highly significant reductions in both HAM-D and HAM-A scores following treatment, with the greatest reductions occurring at 2 weeks. Mean rCBF across hemispheres increased from 0.011 units in the off condition to 0.043 units in the on condition, for a difference of 0.032 (95% CI: -0.016, 0.080) units, though this result did not reach statistical significance. Immediately after treatment the PANAS improved to a significantly greater extent with NIR "on" relative to NIR "off" when a hemisphere with more positive HEV was treated than when one with more negative HEV was treated. We observed no side effects.
This small feasibility study suggests that NIR-PBM may have utility for the treatment of depression and other psychiatric disorders and that double blind randomized placebo-controlled trials are indicated.
Trial registration Identifier: NCT00961454
PMCID: PMC2796659  PMID: 19995444
20.  Risks for impaired cerebral autoregulation during cardiopulmonary bypass and postoperative stroke 
BJA: British Journal of Anaesthesia  2012;109(3):391-398.
Impaired cerebral autoregulation may predispose patients to cerebral hypoperfusion during cardiopulmonary bypass (CPB). The purpose of this study was to identify risk factors for impaired autoregulation during coronary artery bypass graft, valve surgery with CPB, or both and to evaluate whether near-infrared spectroscopy (NIRS) autoregulation monitoring could be used to identify this condition.
Two hundred and thirty-four patients were monitored with transcranial Doppler and NIRS. A continuous, moving Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and cerebral blood flow (CBF) velocity, and between MAP and NIRS data, to generate the mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Functional autoregulation is indicated by an Mx and COx that approach zero (no correlation between CBF and MAP); impaired autoregulation is indicated by an Mx and COx approaching 1. Impaired autoregulation was defined as an Mx ≥0.40 at all MAPs during CPB.
Twenty per cent of patients demonstrated impaired autoregulation during CPB. Based on multivariate logistic regression analysis, time-averaged COx during CPB, male gender, , CBF velocity, and preoperative aspirin use were independently associated with impaired CBF autoregulation. Perioperative stroke occurred in six of 47 (12.8%) patients with impaired autoregulation compared with five of 187 (2.7%) patients with preserved autoregulation (P=0.011).
Impaired CBF autoregulation occurs in 20% of patients during CPB. Patients with impaired autoregulation are more likely than those with functional autoregulation to have perioperative stroke. Non-invasive monitoring autoregulation may provide an accurate means to predict impaired autoregulation.
Clinical trials registration. (NCT00769691).
PMCID: PMC3415287  PMID: 22661748
cardiac surgery; cardiopulmonary bypass; cerebral autoregulation; stroke
21.  Regional cerebral blood flow of patients with focal epilepsy studied using xenon enhanced CT brain scanning. 
Stable xenon-enhanced X-ray computed tomography (XeCT) was used to measure the regional cerebral blood flow (rCBF) of 12 patients with drug resistant partial epilepsy and a marked unilateral focus on electroencephalography (EEG). Interictal mean rCBF of fixed regions of interest (ROIs) was reduced by 25% in the cortex of the epileptogenic cerebral lobe compared with the same regions on the contralateral side (p less than 0.02). Six control scans showed a mean side to side cortical difference in rCBF of 14%, whereas the epileptogenic focus was associated with a reduction in the cortical rCBF of greater than 30% in six out of the 12 patients. In an additional patient with partial epilepsy XeCT demonstrated significant focal hypoperfusion when interictal EEGs and conventional CT scans showed no abnormalities.
PMCID: PMC1032598  PMID: 3125306
22.  Feasibility of NIRS in the Neurointensive Care Unit: A Pilot Study in Stroke Using Physiological Oscillations 
Neurocritical care  2009;11(2):288-295.
Near-infrared spectroscopy (NIRS) is a non-invasive, real-time bedside modality sensitive to changes in cerebral perfusion and oxygenation and is highly sensitive to physiological oscillations at different frequencies. However, the clinical feasibility of NIRS remains limited, partly due to concerns regarding NIRS signal quantification, which relies on mostly arbitrary assumptions on hemoglobin concentrations and tissue layers. In this pilot study comparing stroke patients to healthy controls, we explored the utility of the interhemispheric correlation coefficient (IHCC) during physiological oscillations in detecting asymmetry in hemispheric microvascular hemodynamics.
Using bi-hemispheric continuous-wave NIRS, 12 patients with hemispheric strokes and 9 controls were measured prospectively. NIRS signal was band-pass filtered to isolate cardiac (0.7–3 Hz) and respiratory (0.15–0.7 Hz) oscillations. IHCCs were calculated in both oscillation frequency bands. Using Fisher’s Z-transform for non-Gaussian distributions, the IHCC during cardiac and respiratory oscillations were compared between both groups.
Nine patients and nine controls had data of sufficient quality to be included in the analysis. The IHCCs during cardiac and respiratory oscillations were significantly different between patients versus controls (cardiac 0.79 ± 0.18 vs. 0.94 ± 0.07, P = 0.025; respiratory 0.24 ± 0.28 vs. 0.59 ± 0.3; P = 0.016).
Computing the IHCC during physiological cardiac and respiratory oscillations may be a new NIRS analysis technique to quantify asymmetric microvascular hemodynamics in stroke patients in the neurocritical care unit. It allows each subject to serve as their own control obviating the need for arbitrary assumptions on absolute hemoglobin concentration. Future clinical applications may include rapid identification of patients with ischemic brain injury in the pre-hospital setting. This promising new analysis technique warrants further validation.
PMCID: PMC2782535  PMID: 19649749
Near-infrared spectroscopy; Cerebrovascular disease; Stroke; Critical care
23.  Noninvasive optical characterization of muscle blood flow, oxygenation, and metabolism in women with fibromyalgia 
Arthritis Research & Therapy  2012;14(6):R236.
Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.
Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily increasing from 20 to 70% maximal voluntary isometric contraction (MVIC). For the cuff occlusion protocol, forearm arterial blood flow was occluded via a tourniquet on the upper arm for 3 minutes. Leg or arm muscle hemodynamics, including relative blood flow (rBF), oxy- and deoxy-hemoglobin concentration ([HbO2] and [Hb]), total hemoglobin concentration (THC) and blood oxygen saturation (StO2), were continuously monitored throughout protocols using a custom-built hybrid diffuse optical instrument that combined a commercial near-infrared oximeter for tissue oxygenation measurements and a custom-designed diffuse correlation spectroscopy (DCS) flowmeter for tissue blood flow measurements. Relative oxygen extraction fraction (rOEF) and oxygen consumption rate (rVO2) were calculated from the measured blood flow and oxygenation data. Post-manipulation (fatiguing exercise or cuff occlusion) recovery in muscle hemodynamics was characterized by the recovery half-time, a time interval from the end of manipulation to the time that tissue hemodynamics reached a half-maximal value.
Subjects with FM had similar hemodynamic and metabolic response/recovery patterns as healthy controls during exercise and during arterial occlusion. However, tissue rOEF during exercise in subjects with FM was significantly lower than in healthy controls, and the half-times of oxygenation recovery (Δ[HbO2] and Δ[Hb]) were significantly longer following fatiguing exercise and cuff occlusion.
Our results suggest an alteration of muscle oxygen utilization in the FM population. This study demonstrates the potential of using combined diffuse optical spectroscopies (i.e., NIRS/DCS) to comprehensively evaluate tissue oxygen and flow kinetics in skeletal muscle.
PMCID: PMC3674608  PMID: 23116302
24.  A temporal comparison of BOLD, ASL, and NIRS hemodynamic responses to motor stimuli in adult humans 
NeuroImage  2005;29(2):368-382.
In this study, we have preformed simultaneous near-infrared spectroscopy (NIRS) along with BOLD (blood oxygen level dependent) and ASL (arterial spin labeling)-based fMRI during an event-related motor activity in human subjects in order to compare the temporal dynamics of the hemodynamic responses recorded in each method. These measurements have allowed us to examine the validity of the biophysical models underlying each modality and, as a result, gain greater insight into the hemodynamic responses to neuronal activation. Although prior studies have examined the relationships between these two methodologies through similar experiments, they have produced conflicting results in the literature for a variety of reasons. Here, by employing a short-duration, event-related motor task, we have been able to emphasize the subtle temporal differences between the hemodynamic parameters with a high contrast-to-noise ratio. As a result of this improved experimental design, we are able to report that the fMRI measured BOLD response is more correlated with the NIRS measure of deoxy-hemoglobin (R = 0.98; P < 10−20) than with oxy-hemoglobin (R = 0.71), or total hemoglobin (R = 0.53). This result was predicted from the theoretical grounds of the BOLD response and is in agreement with several previous works [Toronov, V.A.W., Choi, J.H., Wolf, M., Michalos, A., Gratton, E., Hueber, D., 2001. “Investigation of human brain hemodynamics by simultaneous near-infrared spectroscopy and functional magnetic resonance imaging.” Med. Phys. 28 (4) 521–527; MacIntosh, B.J., Klassen, L.M., Menon, R.S., 2003. “Transient hemodynamics during a breath hold challenge in a two part functional imaging study with simultaneous near-infrared spectroscopy in adult humans.” NeuroImage 20 1246– 1252; Toronov, V.A.W., Walker, S., Gupta, R., Choi, J.H., Gratton, E., Hueber, D., Webb, A., 2003. “The roles of changes in deoxyhemoglobin concentration and regional cerebral blood volume in the fMRI BOLD signal” Neuroimage 19 (4) 1521– 1531]. These data have also allowed us to examine more detailed measurement models of the fMRI signal and comment on the roles of the oxygen saturation and blood volume contributions to the BOLD response. In addition, we found high correlation between the NIRS measured total hemoglobin and ASL measured cerebral blood flow (R = 0.91; P < 10−10) and oxy-hemoglobin with flow (R = 0.83; P < 10−05) as predicted by the biophysical models. Finally, we note a significant amount of cross-modality, correlated, inter-subject variability in amplitude change and time-to-peak of the hemodynamic response. The observed co-variance in these parameters between subjects is in agreement with hemodynamic models and provides further support that fMRI and NIRS have similar vascular sensitivity.
PMCID: PMC2692693  PMID: 16303317
Near-infrared spectroscopy; BOLD; ASL; Multimodality comparison
25.  Somatosensory evoked changes in cerebral oxygen consumption measured non-invasively in premature neonates 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.01.035.
The hemodynamic functional response is used as a reliable marker of neuronal activity in countless studies of brain function and cognition. In newborns and infants, however, conflicting results have appeared in the literature concerning the typical response, and there is little information on brain metabolism and functional activation. Measurement of all hemodynamic components and oxygen metabolism is critical for understanding neurovascular coupling in the developing brain.
To this end, we combined multiple near infrared spectroscopy techniques to measure oxy- and deoxy-hemoglobin concentrations, cerebral blood volume (CBV), and relative cerebral blood flow (CBF) in the somatosensory cortex of 6 preterm neonates during passive tactile stimulation of the hand. By combining these measures we estimated relative changes in the cerebral metabolic rate of oxygen consumption (rCMRO2).
CBF starts increasing immediately after stimulus onset, and returns to baseline before blood volume. This is consistent with the model of pre-capillary arteriole active dilation driving the CBF response, with a subsequent CBV increase influenced by capillaries and veins dilating passively to accommodate the extra blood. rCMRO2 estimated using the steady-state formulation shows a biphasic pattern: an increase immediately after stimulus onset, followed by a post-stimulus undershoot due to blood flow returning faster to baseline than oxygenation. However, assuming a longer mean transit time from the arterial to the venous compartment, due to the immature vascular system of premature infants, reduces the post-stimulus undershoot and increases the flow/consumption ratio to values closer to adult values reported in the literature.
We are the first to report changes in local rCBF and rCMRO2 during functional activation in preterm infants. The ability to measure these variables in addition to hemoglobin concentration changes is critical for understanding neurovascular coupling in the developing brain, and for using this coupling as a reliable functional imaging marker in neonates.
PMCID: PMC3686986  PMID: 23370052
Oxygen metabolism; functional activation; premature neonates; somatosensory cortex; near infrared spectroscopy; diffusion correlation spectroscopy

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