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1.  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
2.  Autoregulation after ischaemic stroke 
Journal of hypertension  2009;27(11):2218-2222.
Absent outcome data from randomized clinical trials, management of hypertension in acute ischaemic stroke remains controversial. Data from human participants have failed to resolve the question whether cerebral blood flow (CBF) in the peri-infarct region will decrease due to impaired autoregulation when systemic mean arterial pressure (MAP) is rapidly reduced.
Nine participants, 1–11 days after hemispheric ischaemic stroke, with systolic blood pressure more than 145 mmHg, underwent baseline PET measurements of regional CBF. Intravenous nicardipine infusion was then used to rapidly reduce mean arterial pressure 16 ± 7 mmHg and CBF measurement was repeated.
Compared with the contralateral hemisphere, there were no significant differences in the percent change in CBF in the infarct (P = 0.43), peri-infarct region (P = 1.00) or remainder of the ipsilateral hemisphere (P = 0.50). Two participants showed CBF reductions of greater than 19% in both hemispheres.
In this study, selective regional impairment of CBF autoregulation in the infarcted hemisohere to reduced systemic blood pressure was not a characteristic of acute cerebral infarction. Reductions in CBF did occur in some individuals, but it was bihemispheric phenomenon that likely was due to an upward shift of the autoregulatory curve as a consequence of chronic hypertension. These results indicate individual monitoring of changes in global CBF, such as with bedside transcranial Doppler, may be useful to determine individual safe limits when MAP is lowered in the setting of acute ischaemic stroke. The benefit of such an approach can only be demonstrated by clinical trials demonstrating improved patient outcome.
PMCID: PMC2888663  PMID: 19644387
autoregulation; blood pressure; cerebral infarction; cerebrovascular circulation
3.  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
4.  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
5.  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
6.  Continuous Cerebral Blood Flow Autoregulation Monitoring in Patients Undergoing Liver Transplantation 
Neurocritical care  2012;17(1):77-84.
Clinical monitoring of cerebral blood flow (CBF) autoregulation in patients undergoing liver transplantation may provide a means for optimizing blood pressure to reduce the risk of brain injury. The purpose of this pilot project is to test the feasibility of autoregulation monitoring with transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) in patients undergoing liver transplantation and to assess changes that may occur perioperatively.
We performed a prospective observational study in 9 consecutive patients undergoing orthotopic liver transplantation. Patients were monitored with TCD and 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. Both Mx and COx were averaged and compared during the dissection phase, anhepatic phase, first 30 mins of reperfusion, and remaining reperfusion phase. Impaired autoregulation was defined as Mx ≥ 0.4.
Autoregulation was impaired in one patient during all phases of surgery, in two patients during the anhepatic phase, and in one patient during reperfusion. Impaired autoregulation was associated with a MELD score > 15 (p=0.015) and postoperative seizures or stroke (p<0.0001). Analysis of Mx categorized in 5-mmHg bins revealed that MAP at the lower limit of autoregulation (MAP when Mx increased to ≥ 0.4) ranged between 40 and 85 mmHg. Average Mx and average COx were significantly correlated (p=0.0029). The relationship between COx and Mx remained when only patients with bilirubin > 1.2 mg/dL were evaluated (p=0.0419). There was no correlation between COx and baseline bilirubin (p=0.2562) but MELD score and COx were correlated (p=0.0458). Average COx was higher for patients with a MELD score > 15 (p=0.073) and for patients with a neurologic complication than for patients without neurologic complications (p=0.0245).
These results suggest that autoregulation is impaired in patients undergoing liver transplantation, even in the absence of acute, fulminant liver failure. Identification of patients at risk for neurologic complications after surgery may allow for prompt neuroprotective interventions, including directed pressure management.
PMCID: PMC3748944  PMID: 22644887
7.  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
8.  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
9.  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
10.  Cerebral Blood Flow Dynamics and Head-of-Bed Changes in the Setting of Subarachnoid Hemorrhage 
BioMed Research International  2013;2013:640638.
Head-of-bed (HOB) elevation is usually restricted in patients with aneurysmal subarachnoid hemorrhage (SAH). The goal of this study is to correlate HOB changes (0° and 90°) with cerebral blood flow using transcranial Doppler (TCD) and thermal diffusion probe in SAH patients. Thirteen patients with SAH were prospectively enrolled in the study. Eight patients underwent placement of a thermal diffusion probe for regional CBF measurement. CBF values were measured with the patients in flat (0°) and upright sitting positions (90°) at days 3, 7, and 10. The average increase in blood flow velocity when changing HOB from 0° to 90° was 7.8% on day 3, 0.1% on day 7, and 13.1% on day 10. The middle cerebral artery had the least changes in velocity. The average regional CBF measurement was 22.7 ± 0.3 mL/100 g/min in the supine position and 23.6 ± 9.1 mg/100 g/min in the sitting position. The changes were not statistically significant. None of the patients developed clinical cerebral vasospasm. Changing HOB position in the setting of SAH did not significantly affect cerebral or regional blood flow. These data suggest that early mobilization should be considered given the detrimental effects of prolonged bed rest.
PMCID: PMC3859207  PMID: 24371827
11.  Cerebrovascular Autoregulation in Pediatric Moyamoya Disease 
Paediatric anaesthesia  2013;23(6):547-556.
Moyamoya syndrome carries a high risk of cerebral ischemia, and impaired cerebrovascular autoregulation may play a critical role. Autoregulation indices derived from near-infrared spectroscopy (NIRS) may clarify hemodynamic goals that conform to the limits of autoregulation.
The aims of this pilot study were to determine whether the NIRS-derived indices could identify blood pressure ranges that optimize autoregulation and whether autoregulatory function differs between anatomic sides in patients with unilateral vasculopathy.
Pediatric patients undergoing indirect surgical revascularization for moyamoya were enrolled sequentially. NIRS-derived autoregulation indices, the cerebral oximetry index (COx) and the hemoglobin volume index (HVx), were calculated intraoperatively and postoperatively to measure autoregulatory function. The 5-mmHg ranges of optimal mean arterial blood pressure (MAPOPT) with best autoregulation and the lower limit of autoregulation (LLA) were identified.
Of seven enrolled patients (aged 2–16 years), six had intraoperative and postoperative autoregulation monitoring and one had only intraoperative monitoring. Intraoperative MAPOPT was identified in six (86%) of seven patients with median values of 60–80 mmHg. Intraoperative LLA was identified in three (43%) patients at 55–65 mmHg. Postoperative MAPOPT was identified in six (100%) of six patients with median values of 70–90 mmHg. Patients with unilateral disease had higher intraoperative HVx (p=0.012) on the side with vasculopathy.
NIRS-derived indices may identify hemodynamic goals that optimize autoregulation in pediatric moyamoya.
PMCID: PMC3648623  PMID: 23506446
Pediatric; neurosurgery; moyamoya; cerebrovascular; autoregulation
12.  Noninvasive Autoregulation Monitoring in a Swine Model of Pediatric Cardiac Arrest 
Anesthesia and Analgesia  2012;114(4):825-836.
Cerebrovascular autoregulation after resuscitation has not been well studied in an experimental model of pediatric cardiac arrest. Furthermore, developing noninvasive methods of monitoring autoregulation using near-infrared spectroscopy (NIRS) would be clinically useful in guiding neuroprotective hemodynamic management after pediatric cardiac arrest. We tested the hypotheses that the lower limit of autoregulation (LLA) would shift to a higher arterial blood pressure between 1 and 2 days of recovery after cardiac arrest and that the LLA would be detected by NIRS-derived indices of autoregulation in a swine model of pediatric cardiac arrest. We also tested the hypothesis that autoregulation with hypertension would be impaired after cardiac arrest.
Data on LLA were obtained from neonatal piglets that had undergone hypoxic-asphyxic cardiac arrest and recovery for 1 day (n=8) or 2 days (n=8), or that had undergone sham surgery with 2 days of recovery (n=8). Autoregulation with hypertension was examined in a separate cohort of piglets that underwent hypoxic-asphyxic cardiac arrest (n=5) or sham surgery (n=5) with 2 days of recovery. After the recovery period, piglets were reanesthetized, and autoregulation was monitored by standard laser-Doppler flowmetry and autoregulation indices derived from NIRS (the cerebral oximetry [COx] and hemoglobin volume [HVx] indices). The LLA was determined by decreasing blood pressure through inflation of a balloon catheter in the inferior vena cava. Autoregulation during hypertension was evaluated by inflation of an aortic balloon catheter.
The LLAs were similar between sham-operated piglets and piglets that recovered for 1 or 2 days after arrest. The NIRS-derived indices accurately detected the LLA determined by laser-Doppler flowmetry. The area under the curve of the receiver operator characteristic curve for cerebral oximetry index was 0.91 at 1 day and 0.92 at 2 days after arrest. The area under the curve for hemoglobin volume index was 0.92 and 0.89 at the respective time points. During induced hypertension, the static rate of autoregulation, defined as the percent change in cerebrovascular resistance divided by the percent change in cerebral perfusion pressure, was not different between postarrest and sham-operated piglets. At 2 days recovery from arrest, piglets exhibited neurobehavioral deficits and histologic neuronal injury.
In a swine model of pediatric hypoxic-asphyxic cardiac arrest with confirmed brain damage, the LLA did not differ 1 and 2 days after resuscitation. The NIRS-derived indices accurately detected the LLA compared to laser-Doppler flow measurements at those time points. Autoregulation remained functional during hypertension.
PMCID: PMC3310318  PMID: 22314692
13.  Relationship between oxygen supply and cerebral blood flow assessed by transcranial Doppler and near – infrared spectroscopy in healthy subjects during breath – holding 
Breath – holding (BH) is a suitable method for inducing cerebral vasomotor reactivity (VMR). The assessment of VMR is of clinical importance for the early detection of risk conditions and for the follow-up of disabled patients. Transcranial Doppler ultrasonography (TCD) is used to measure cerebral blood flow velocity (CBFV) during BH, whereas near-infrared spectroscopy (NIRS) measures the concentrations of the oxygenated (O2Hb) and reduced (CO2Hb) hemoglobin. The two techniques provide circulatory and functional-related parameters. The aim of the study is the analysis of the relationship between oxygen supply and CBFV as detected by TCD and NIRS in healthy subjects performing BH.
20 healthy subjects (15 males and 5 females, age 33 ± 4.5 years) underwent TCD and NIRS examination during voluntary breath – holding. VMR was quantified by means of the breath-holding index (BHI). We evaluated the BHI based on mean CBFV, O2Hb and CO2Hb concentrations, relating the baseline to post-stimulus values. To quantify VMR we also computed the slope of the linear regression line of the concentration signals during BH. From the NIRS signals we also derived the bidimensional representation of VMR, plotting the instantaneous O2Hb concentration vs the CO2Hb concentration during the BH phase. Two subjects, a 30 years old current smoker female and a 63 years old male with a ischemic stroke event at the left middle cerebral artery, were tested as case studies.
The BHI for the CBFV was equal to 1.28 ± 0.71 %/s, the BHI for the O2Hb to 0.055 ± 0.037 μmol/l/s and the BHI for CO2Hb to 0.0006 ± 0.0019 μmol/l/s, the O2Hb slope was equal to 0.15 ± 0.09 μmol/l/s and the CO2Hb slope to 0.09 ± 0.04 μmol/l/s. There was a positive correlation between the CBFV and the O2Hb increments during BH (r = 0.865). The bidimensional VMR pattern shows common features among healthy subjects that are lost in the control studies.
We show that healthy subjects present a common VMR pattern when counteracting cerebral blood flow perturbations induced by voluntary BH. The proposed methodology allows for the monitoring of changes in the VMR pattern, hence it could be used for assessing the efficacy of neurorehabilitation protocols.
PMCID: PMC1544341  PMID: 16854224
14.  No effect of low-dose statins treatment on cerebral blood flow in humans with atherosclerotic cerebrovascular disease 
Animal studies have suggested that the reduction in stroke risk observed with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) therapy is owing to an increase in basal cerebral blood flow (CBF). The purpose of the study was to determine if statin therapy was associated with increased CBF in humans with cerebrovascular atherosclerotic disease. Quantitative measurements of CBF were obtained on study entry in 97 patients with carotid artery occlusion enrolled in a prospective study of cerebral hemodynamics and stroke risk. This study represents a post hoc analysis of CBF measurements based on whether patients were receiving statin therapy at the time of CBF measurement. Global and regional CBF (including hemispheric, basal ganglia, and arterial borderzones), and baseline clinical, epidemiologic, and laboratory stroke risk factors were compared between the two groups. Nineteen of the 97 patients were on a statin agent on study entry. The statin group was younger, had significantly lower LDL levels and included more women. Statin therapy was not associated with higher baseline values of CBF in global or regional analyses. Mean middle cerebral artery territory CBF (±s.d.) ipsilateral to the occluded carotid artery was 37.6±12.7 mL/100 g min for the statin group (n = 19) compared with 38.6±12.7 mL/100 g min for the nonstatin group (n = 78). Contralateral values were 42.9±13.5 and 44.2±13.3 mL/100 g min for the statin and nonstatin groups, respectively. We conclude that the stroke risk reduction observed with statin therapy in humans likely involves mechanisms other than an increased basal CBF.
PMCID: PMC2680545  PMID: 17356563
atherosclerosis; CBF measurements; cerebral hemodynamics; cerebrovascular disease
15.  Cerebral blood flow velocity changes during upright positioning in bed after acute stroke: an observational study 
BMJ Open  2013;3(8):e002960.
National guidelines recommend mobilisation in bed as early as possible after acute stroke. Little is known about the influence of upright positioning on real-time cerebral flow variables in patients with stroke. We aimed to assess whether cerebral blood flow velocity (CBFV) changes significantly after upright positioning in bed in the acute stroke phase.
Observational study.
47 patients with acute ischaemic stroke measured in the subacute phase after symptom onset and 20 healthy controls.
Primary and secondary outcome measures
We recorded postural changes in bilateral transcranial Doppler (primary outcome) and simultaneously recorded near-infrared spectroscopy, end-tidal CO2, non-invasive blood pressure data and changes in neurological status (secondary outcomes).
Postures included the supine, half sitting (45°), sitting (70°) and Trendelenburg (−15°) positions. Using multilevel analyses, we compared postural changes between hemispheres, outcome groups (using modified Rankin Scale) as well as between patients and healthy controls.
The mean patient age was 62±15 years and median National Institute of Health Stroke Scale score on admission was 7 (IQR 5–14). Mean proportional CBFV changes on sitting were not significantly different between healthy controls and affected hemispheres in patients with stroke. No significant differences were found between affected and unaffected stroke hemispheres and between patients with unfavourable and favourable outcomes. During upright positioning, no neurological worsening or improvement was observed in any of the patients.
No indications were found that upright positioning in bed in mild to moderately affected patients with stroke compromises flow and (frontal)oxygenation significantly during the subacute phase of stroke. Supine or Trendelenburg positioning does not seem to augment real-time flow variables.
PMCID: PMC3752059  PMID: 23945730
16.  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
17.  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
18.  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
19.  Regional Ischemic Vulnerability of the Brain to Hypoperfusion: The Need for Location Specific CT Perfusion Thresholds in Acute Stroke Patients 
To characterize the spatial pattern of cerebral ischemic vulnerability to hypoperfusion in stroke patients.
We included 90 patients who underwent admission CT perfusion (CTP) and MRI within 12 hours of ischemic stroke onset. Infarcted brain lesions (“core”) were segmented from admission diffusion-weighted-imaging (DWI), and - along with the CTP parameter maps - coregistered onto MNI-152 brain space, which was parcellated into 125 mirror cortical and subcortical regions per hemisphere. We tested the hypothesis that the percent infarction increment per unit relative cerebral blood flow (rCBF) reduction differs statistically between regions using regression analysis to assess the interaction between regional rCBF and region variables. Next, for each patient, a “vulnerability index” (VI) map was constructed with voxel values equaling the product of that voxel’s rCBF and infarction probability (derived from the MNI-152-transformed, binary, segmented DWI lesions). Voxel-based rCBF threshold for core was determined within the upper 20th percentile of VI map voxel values.
Different regions had different percent infarction increase per unit rCBF reduction (p=0.001). The caudate body, putamen, insular ribbon, paracentral lobule, precentral, middle and inferior frontal gyri had the highest ischemic vulnerability to hypoperfusion. A voxel-based rCBF threshold of <0.42 optimally distinguished infarct core in the highly-vulnerable regions, whereas rCBF <0.16 distinguished core in the remainder of the brain.
We demonstrated regional ischemic vulnerability of the brain to hypoperfusion in acute stroke patients. Location specific - rather than whole-brain - rCBF thresholds may provide a more accurate metric for estimating infarct core using CTP maps.
PMCID: PMC3090217  PMID: 21493917
Stroke; Compute tomography; Magnetic resonance imaging
20.  Bedside assessment of cerebral perfusion reductions in patients with acute ischaemic stroke by near-infrared spectroscopy and indocyanine green 
Objective: To detect perfusion reductions in patients with acute cerebral infarcts using near-infrared spectroscopy (NIRS) with indocyanine green (ICG) as tracer.
Methods: Kinetics of an intravenous bolus of ICG were monitored by NIRS in 13 patients with acute infarction in the territory of the middle cerebral artery (mean (SD) age, 62.2 (13.0) years) and 12 controls (64.2 (9.1) years) at 2.8 (2.8) days after onset. NIRS optodes were placed bitemporally, with an interoptode distance of 4–5 cm. Absolute concentration changes in ICG were calculated. The following were assessed: time to peak, maximum ICG concentration, time interval between 0% and 100% maximum ICG concentration (interval), rise time (time between 10% and 90% ICG maximum), slope (maximum Δ ICG/interval), and blood flow index (BFI = maximum Δ ICG/rise time) of each hemisphere. Intraindividual differences were calculated between the two hemispheres.
Results: Patients with ischaemic stroke had increased time to peak (p<0.01), interval (p<0.01), and rise time (p<0.01), while maximum ICG concentration (p<0.03), slope (p<0.01), and BFI (p<0.01) were diminished at the site of infarction compared with the unaffected hemisphere. In stroke patients, intraindividual differences in time to peak (p<0.001), interval (p<0.001), rise time (p = 0.001), maximum ICG concentration (p<0.02), slope (p<0.001), and BFI (p<0.001) were greater than in the controls, with excellent sensitivity and specificity for Δ time to peak (100% and 100%, respectively) and Δ time interval (100% and 91.7%).
Conclusions: Measurement of interhemispheric differences in ICG kinetics by NIRS detects perfusion reductions in patients with acute middle cerebral artery infarction. This non-invasive bedside test is rapid, repeatable, without major side effects, and avoids transportation of critically ill patients.
PMCID: PMC1757454  PMID: 14707304
21.  Predicting the Limits of Cerebral Autoregulation During Cardiopulmonary Bypass 
Anesthesia and Analgesia  2011;114(3):503-510.
Mean arterial blood pressure (MAP) targets are empirically chosen during cardiopulmonary bypass (CPB). We have previously shown that near-infrared spectroscopy (NIRS) can be used clinically for monitoring cerebral blood flow autoregulation. The hypothesis of this study was that real-time autoregulation monitoring using NIRS-based methods is more accurate for delineating the MAP at the lower limit of autoregulation (LLA) during CPB than empiric determinations based on age, preoperative history, and preoperative blood pressure.
Two hundred thirty-two patients undergoing coronary artery bypass graft and/or valve surgery with CPB underwent transcranial Doppler monitoring of the middle cerebral arteries and NIRS monitoring. A continuous, moving Pearson's correlation coefficient was calculated between MAP and cerebral blood flow velocity, and between MAP and NIRS data to generate mean velocity index and cerebral oximeter index. When autoregulated, there is no correlation between cerebral blood flow and MAP (i.e., mean velocity and cerebral oximetry indices approach 0); when MAP is below the LLA, mean velocity and cerebral oximetry indices approach 1. The LLA was defined as the MAP where mean velocity index increased with declining MAP to ≥ 0.4. Linear regression was performed to assess the relation between preoperative systolic blood pressure, MAP, MAP in 10% decrements from baseline, and average cerebral oximetry index with MAP at the LLA.
The MAP at the LLA was 66 mmHg (95% prediction interval, 43 to 90 mmHg) for the 225 patients in which this limit was observed. There was no relationship between preoperative MAP and the LLA (p = 0.829) after adjusting for age, gender, prior stroke, diabetes, and hypertension, but a cerebral oximetry index value of >0.5 was associated with the LLA (p=0.022). The LLA could be identified with cerebral oximetry index in 219 (94.4%) patients. The mean difference in the LLA for mean velocity index versus cerebral oximetry index was −0.2±10.2 mmHg (95%CI, −1.5 to 1.2 mmHg). Preoperative systolic blood pressure was associated with a higher LLA (p=0.046) but only for those with systolic blood pressure ≤160 mmHg.
There is a wide range of MAP at the LLA in patients during CPB making estimating this target difficult. Real-time monitoring of autoregulation with cerebral oximetry index may provide a more rational means for individualizing MAP during CPB.
PMCID: PMC3288415  PMID: 22104067
22.  Cerebral Hemodynamic Responses to Acupuncture in Migraine Patients: A Systematic Review 
We review the literature conjoining acupuncture, migraine, and cerebral hemodynamics. To do so, we searched PubMed in March 2013 for studies investigating cerebral hemodynamics with functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), transcranial Doppler (TCD) ultrasound, and other tools in migraineurs, acupuncture recipients, and migraineurs receiving acupuncture. Our search identified 1321 distinct articles – acupuncture (n = 463), migraine (n = 866), and both (n = 8). Only three (n = 3) satisfied our inclusion criteria. Based on these three, we found the following: (1) Acupuncture may positively influence not just dynamic, but also static cerebral autoregulation during the interictal phase, depending on the intervals between sessions of acupuncture as dose units. (2) TCD can detect pretreatment differences between responders and non-responders to acupuncture, which may be predictive of clinical response. (3) “Point-through-point” needling (at angles connecting acupoints) may be clinically superior to standard acupuncture, thus needling angles may affect treatment effectiveness. None of the reviewed articles investigated patient responses during migraine attack. Although the 2009 Cochrane review affirmed acupuncture as effective prophylaxis for migraine, few studies investigated the cerebrovascular aspects – only analyzing arterial blood flow, but not microcirculation. Future research is warranted in monitoring brain tissue oxygenation to investigate acupuncture as both a preventive and abortive treatment for migraine, varying the type and dose interval and analyzing variations in clinical response.
PMCID: PMC3925002  PMID: 24716180
Acupuncture; Cerebral autoregulation; Cerebral hemodynamics; Migraine; Transcranial doppler sonography
23.  Does the resting state connectivity have hemispheric asymmetry? A near-infrared spectroscopy study 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.05.092.
Near-infrared spectroscopy (NIRS) is a novel technology for low-cost noninvasive brain imaging suitable for use in virtually all subject and patient populations. Numerous studies of brain functional connectivity using fMRI, and recently NIRS, suggest new tools for the assessment of cognitive functions during task performance and the resting state (RS). We analyzed functional connectivity and its possible hemispheric asymmetry measuring coherence of optical signals at low frequencies (0.01-0.1 Hz) in the prefrontal cortex in 13 right-handed (RH) and 2 left-handed (LH) healthy subjects at rest (4-8 min) using a continuous-wave NIRS instrument CW5 (TechEn, Milford, MA). Two optical probes were placed bilaterally over the inferior frontal gyrus (IFG) and the middle frontal gyrus (MFG) using anatomical landmarks of the 10-20 system. As a result, 28 optical channels (14 for each hemisphere) were recorded for changes in oxygenated (HbO) and de-oxygenated (HbR) hemoglobin. Global physiological signals (respiratory and cardiac) were removed using Principal and Independent Component Analyses. Inter-channel coherences for HbO and HbR signals were calculated using Morlet wavelets along with correlation coefficients. Connectivity matrices showed specific patterns of connectivity which was higher within each anatomical region (IFG and MFG) and between hemispheres (e.g., left IFG <-> right IFG) than between IFG and MFG in the same hemisphere. Laterality indexes were calculated as t-values for the ‘left > right’ comparisons of intrinsic connectivity within each regional group of channels in each subject. Regardless of handedness, the group average laterality indexes were negative thus revealing significantly higher connectivity in the right hemisphere in the majority of RH subjects and in both LH subjects. The analysis of Granger Causality between hemispheres has also shown a greater flow of information from the right to the left hemisphere which may point to an important role of the right hemisphere in the resting state. These data encourage further exploration of the NIRS connectivity and its application for the analysis of hemispheric relationships within the functional architecture of the brain.
PMCID: PMC3869394  PMID: 23721726
Near-infrared spectroscopy; Brain hemodynamics; Functional connectivity; Resting state; Prefrontal cortex; Hemispheric asymmetry
24.  Functional near-infrared spectroscopy for the assessment of overt reading 
Brain and Behavior  2012;2(6):825-837.
Functional near-infrared spectroscopy (fNIRS) has become increasingly established as a promising technique for monitoring functional brain activity. To our knowledge, no study has yet used fNIRS to investigate overt reading of irregular words and nonwords with a full coverage of the cerebral regions involved in reading processes. The aim of our study was to design and validate a protocol using fNIRS for the assessment of overt reading. Twelve healthy French-speaking adults underwent one session of fNIRS recording while performing an overt reading of 13 blocks of irregular words and nonwords. Reading blocks were separated by baseline periods during which participants were instructed to fixate a cross. Sources (n = 55) and detectors (n = 16) were placed bilaterally over frontal, temporal, parietal, and occipital regions. Two wavelengths were used: 690 nm, more sensitive to deoxyhemoglobin (HbR) concentration changes, and 830 nm, more sensitive to oxyhemoglobin (HbO) concentration changes. For all participants, total hemoglobin (HbT) concentrations (HbO + HbR) were significantly higher than baseline for both irregular word and nonword reading in the inferior frontal gyri, the middle and superior temporal gyri, and the occipital cortices bilaterally. In the temporal gyri, although the difference was not significant, [HbT] values were higher in the left hemisphere. In the bilateral inferior frontal gyri, higher [HbT] values were found in nonword than in irregular word reading. This activation could be related to the grapheme-to-phoneme conversion characterizing the phonological pathway of reading. Our findings confirm that fNIRS is an appropriate technique to assess the neural correlates of overt reading.
PMCID: PMC3500469  PMID: 23170245
Adults; irregular words; lexical reading; nonwords; optical imaging; phonological reading; reading aloud
25.  Arterial Input Function Placement for Accurate CT Perfusion Map Construction in Acute Stroke 
AJR. American journal of roentgenology  2010;194(5):1330-1336.
The objective of our study was to evaluate the effect of varying arterial input function (AIF) placement on the qualitative and quantitative CT perfusion parameters.
Retrospective analysis of CT perfusion data was performed on 14 acute stroke patients with a proximal middle cerebral artery (MCA) clot. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were constructed using a systematic method by varying only the AIF placement in four positions relative to the MCA clot including proximal and distal to the clot in the ipsilateral and contralateral hemispheres. Two postprocessing software programs were used to evaluate the effect of AIF placement on perfusion parameters using a delay-insensitive deconvolution method compared with a standard deconvolution method.
One hundred sixty-eight CT perfusion maps were constructed for each software package. Both software programs generated a mean CBF at the infarct core of < 12 mL/100 g/min and a mean CBV of < 2 mL/100 g for AIF placement proximal to the clot in the ipsilateral hemisphere and proximal and distal to the clot in the contralateral hemisphere. For AIF placement distal to the clot in the ipsilateral hemisphere, the mean CBF significantly increased to 17.3 mL/100 g/min with delay-insensitive software and to 19.4 mL/100 g/min with standard software (p < 0.05). The mean MTT was significantly decreased for this AIF position. Furthermore, this AIF position yielded qualitatively different parametric maps, being most pronounced with MTT and CBF. Overall, CBV was least affected by AIF location.
For postprocessing of accurate quantitative CT perfusion maps, laterality of the AIF location is less important than avoiding AIF placement distal to the clot as detected on CT angiography. This pitfall is less severe with deconvolution-based software programs using a delay-insensitive technique than with those using a standard deconvolution method.
PMCID: PMC3744327  PMID: 20410422

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