- Email: [email protected]
Microvascular versus Macrovascular Cerebral Vasomotor Reactivity in Patients with Severe Internal Carotid Artery Stenosis or Occlusion
Microvascular versus Macrovascular Cerebral Vasomotor Reactivity in Patients with Severe Internal Carotid Artery Stenosis or Occlusion Peyman Zirak, PhD, Raquel Delgado-Mederos, MD, PhD, Lavinia Dinia, MD, bregas, MD, PhD, Turgut Durduran, PhD Joan Martı-Fa Rationale and Objectives: In patients with severe internal carotid artery steno-occlusive lesions (ISOL), impaired cerebrovascular reactivity (CVR) is predictive of future ischemic stroke (IS) or transient ischemic attack (TIA). Therefore, the evaluation of CVR in ISOL patients may be a means to evaluate the risk for IS/TIA and decide on an intervention. Our aim was (1) to explore the feasibility of concurrent near-infrared spectroscopy (NIRS-DOS), diffuse correlation spectroscopy, and transcranial Doppler for CVR assessment in ISOL patients, and (2) to compare macrovascular and microvascular CVR in ISOL patients and explore its potential for IS/TIA risk stratification. Materials and Methods: Twenty-seven ISOL patients were recruited. The changes in continuous microvascular and macrovascular hemodynamics upon acetazolamide injection were used to determine CVR. Results: Oxyhemoglobin (HbO2, by near-infrared spectroscopy), microvascular cerebral blood flow (CBF, by diffuse correlation spectroscopy) and CBF velocity (by transcranial Doppler) showed significant increases upon acetazolamide injection in all subjects (P < .03). Only macrovascular CVR (P = .024) and none of the microvascular measures were significantly dependent on the presence of ISOL. In addition, while CBF was significantly correlated with HbO2, neither of these microvascular measures correlated with macrovascular CBF velocity. Conclusions: We demonstrated the simultaneous, continuous, and noninvasive evaluation of CVR at both the microvasculature and macrovasculature. We found that macrovascular CVR response depends on the presence of ISOL, whereas the microvascular CVR did not significantly depend on the ISOL presence, possibly due to the role of collaterals other than those of the circle of Willis. The concurrent microvascular and macrovascular CVR measurement in the ISOL patients might improve future IS/TIA risk assessment. Key Words: Diffuse correlation spectroscopy; near-infrared spectroscopy; cerebrovascular reactivity; internal carotid artery stenosis. ªAUR, 2014
Acad Radiol 2014; 21:168–174 ncies Foto niques, Mediterranean Technology Park, 08860 ICFO- Institut de Cie Castelldefels, Barcelona, Spain (P.Z., T.D.); and Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (R.D.-M., L.D., J.M.F.). Received August 9, 2013; accepted October 14, 2013. Sources of Cellex Barcelona, Marie Curie Funding: This work was funded by Fundacio IRG (FP7, RPTAMON; PI09/00557), Institute de Salud Carlos III (DOMMON, CERCA FIS), Ministerio de Economia y Competitividad, Institucio (DOCNEURO), Generalitat de Catalunya, European Regional Development Fund (FEDER/ERDF), and LASERLAB (BIOPTICHAL, FP7) and Photonics4Life (FP7) consortia. Dedication: We dedicate this manuscript to the memory of late Dr Britton Chance, with whom one of the authors (T.D.) has had years of interactions on the role of diffuse correlation spectroscopy for neurological applications. His encouragement, critical mind, and decades of experience have inspired all of us. Disclosures: One of the authors (T.D.) is a coinventor in a patent involving DCS/NIRS technology. Part of the DCS technology is now commercialized by a company (Hemophotonics S.L), but T.D. currently does not receive any royalties or has not any other financial relations with the company. The other authors have no conflicting financial or ethical issues to disclose. Address correspondence to: P.Z. e-mail: [email protected] ªAUR, 2014 http://dx.doi.org/10.1016/j.acra.2013.10.010
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evere stenosis or occlusion of the internal carotid artery (ICA) increases the risk of subsequent ischemic stroke (IS) and transient ischemic attack (TIA) (1). Moreover, patients with severe internal carotid artery stenoocclusive lesions (ISOL) are found to be at a particularly higher risk of imminent stroke events when autoregulatory vasodilation capacity of the cerebral terminal arterioles in response to a reduced perfusion pressure, or cerebrovascular reactivity (CVR), is impaired (2–5). Thus, to aid in the decision of the suitable treatment, such as carotid revascularization versus drug therapy, the assessment of CVR has been proposed by several authors as a screening method to stratify ISOL patients based on their assumed risk of future IS or TIA (6). CVR is normally evaluated by measuring the maximum vasodilation capacity of cerebral vasculature. The maximum vasodilation is induced by introducing a potent vasodilatory stimulus, most commonly CO2, inhalation or acetazolamide (ACZ) infusion. Consequent cerebrovascular changes are then followed by a method capable of measuring microvascular
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cerebral blood flow (CBF), blood oxygen saturation, blood volume, or macrovascular cerebral blood flow velocity (CBFV). Many modalities such as positron emission tomography, xenon-enhanced computed tomography (Xe-CT), continuous arterial spin labeling magnetic resonance imaging, single-photon emission CT, transcranial Doppler (TCD), and near-infrared spectroscopy (NIRS-DOS) have been used to evaluate the CVR of ISOL patients (7). In clinics, however, a large number of studies on the role of CVR on subsequent IS/TIA are limited to TCD (macrovascular) since currently available clinical technologies for microvascular CVR assessment are complex and costly and involve patient transport, and ionizing radiation (e.g., positron emission tomography and Xe-CT). Some studies have found correlations between macrovascular CVR measured by TCD and internal carotid artery (ICA) patency, symptom history and IS/TIA risks (8,9). Nevertheless, since the microvascular CVR measures also reflect the efficiency of the collateral vasculature in compensating for blood flow deficiency due to stenosis or occlusion of the ipsilateral ICA, they are believed to be more individualized indicators of CVR condition (10). As a consequence, a bedside noninvasive and relatively simple technology for microvascular CVR assessment would be desirable (1) for more precise IS/TIA risk assessment according to the status of collateral circulation and hemodynamic response of the cerebral vasculature, and (2) based on the proposed risk, to facilitate a decision on the appropriate therapies. Such a bedside and noninvasive modality could also be used after large trials to end the current debate on the significance of CVR function on the precise selection of subgroup of ISOL patients who would benefit from therapies like extracranial/intracranial bypass surgery (11). In this study, we have applied a novel hybrid diffuse optical technology for real-time bedside assessment of microvascular CVR based on simultaneous microvascular CBF and oxygenation measurements (12). The hybrid diffuse optical monitor consisted of two diffuse optical modalities: diffuse correlation spectroscopy (DCS) and NIRS-DOS. DCS (13–15) measures the microvascular CBF continuously, at the patient bedside without any need for exogenous markers and has been extensively validated in vivo (15,16). The blood oxygenation and blood volume changes in the brain were followed by NIRS-DOS. Concurrently, we have also assessed the bilateral CBFV (macrovascular) by TCD. The normal CVR response range available for DCS/NIRS-DOS hybrid diffuse optics technique was established in our previous study (17), where we have applied a similar methodology to healthy volunteers and found a significant agreement between microvascular and macrovascular CVR. We also demonstrated the potential of the combined DCS/NIRS-DOS technique for cerebral metabolic rate of oxygen assessment. Here, our main goals were to demonstrate the potential of hybrid diffuse optics for noninvasive bedside assessment of microvascular CVR and to compare the bilateral CVR responses in anterior middle cerebral artery (MCA) territory (microvascular) and at the MCA trunk (macrovascular) in the presence of
severe ISOL by a relatively simple technique. Finally, we classified our CVR findings according to the presence of normal CVR or its total absence, and, since our measures were continuous, we assessed the temporal properties of the response in both the microvasculature and macrovasculature.
MATERIALS AND METHODS Subjects
The population was selected from patients with symptomatic and asymptomatic steno-occlusive ICA disease who were referred to the neurovascular laboratory at the hospital de la Santa Creu i Sant Pau, Barcelona, Spain for carotid artery ultrasound examination. The patients were approached for recruitment in the study if they had a unilateral or bilateral severe $70% stenosis or occlusion of the ICA as determined by published criteria using a carotid artery ultrasound (multifrequency linear array transducer; Aplio-XG, Toshiba, Tochigi, Japan) (18). In these patients, the ICA stenosis or occlusion was further confirmed by magnetic resonance angiography (MRA), CT angiography (CTA), and/or digital subtraction angiography (DSA) according to North American Symptomatic Carotid Endarterectomy Trial criteria (19). Patients were excluded if they had an inadequate temporal bone window for sufficient TCD examination or the evidence of an additional intracranial stenosis of the carotid siphon, the MCA, or the anterior cerebral artery. Patients were asked to avoid coffee, antihypertensive drugs, and smoking on the day of measurement. Information about demographic and vascular risk factors such as age, gender, history of smoking, hypertension, diabetes, hypercholesterolemia, and previously diagnosed coronary heart disease and vascular peripheral disease were recorded. The study was approved by the institutional ethics committee at the hospital de la Santa Creu i Sant Pau. Diffuse Optics and TCD Protocol
The measurement protocol, instrumentation, optode design, and analysis methods are explained in detail in our previous work (17). Briefly, relative changes in oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) concentration were followed by a custom-made frequency domain NIRS-DOS device (95230 Imagent, ISS, Champaign, IL, USA) with 16 lasers at 690 nm, 785 nm, and 830 nm and two photomultipliers for detection. The relative microvascular CBF was measured by DCS at the patient’s bedside (15). The optical fibers were placed on the right and left side of the forehead of subjects approximately 1 cm above the eyebrows and as far away as possible from the midline (17). The CBFV in the right and left MCA were obtained by TCD (MultiDop-T, DWL Elektronische Systeme, Singe, Germany). Two probes in a range-gated and pulsed-wave mode at 2 MHz and at a depth 169
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of 50 10 mm were applied over the temporal bone by use of a standard head-frame (Diamon, DWL). The optical and ultrasound measures were recorded from 5 minutes before (baseline period) to 20 minutes after ACZ bolus (1 g ACZ/ 10 ml saline). Heart rate and blood pressure (BP) were followed every 3 minutes by use of an autoinflated BP monitor (OMRON, Kyoto, Japan). Analysis
The optical and ultrasound data are analyzed according to our previous study (17), in which we applied a similar protocol for healthy volunteers. The HbO2 and Hb concentrations (by NIRS-DOS), CBF (by DCS), and CBFV (by TCD) data at each time point were compared to the average values of the first five minutes before ACZ injection (baseline period indicated by subscript ‘‘bl’’). These relative measures were then represented as DHbO2 and DHb with D indicating difference, rCBF (rCBF ¼ ðDCBF þ CBFbl Þ=CBFbl ), and rCBFV (rCBFV ¼ ðDCBFV þ CBFVbl Þ=CBFVbl ) where r indicates a ratio. Data with large noise content and/or obvious artifacts due to probe movement were discarded from further analysis. The average DHbO2, DHb, rCBF and rCBFV values from minutes 14 to 16 after ACZ bolus were considered as the maximal change (‘‘final values’’) in response to the ACZ injection. The standard deviation (STD) of the measurement points over the same time period (minutes 14 to 16) was also calculated for all subjects. These STD values were then averaged over all subjects to define a discrimination threshold. We have classified the data as ‘‘responsive’’ (if average (STD 2) < final value) or ‘‘nonresponsive’’ (if average (STD 2) > final value). The median and interquartile range (IQR) of the final values are reported separately for normal (no stenosis or stenosis <50%) and ISOL (stenosis >70% or occlusion) hemispheres. The percent microvascular and macrovascular CVR values (DCS-CVR and TCD-CVR, respectively) were reported as ðCVRDCS ¼ ðrCBF 1Þ 100Þ and ðCVRTCD ¼ ðrCBFV 1Þ 100Þ. Because bilateral hemodynamic data were obtained from all subjects, the data for each patient was considered as two arteries/hemispheres (i.e., a right and a left artery/hemisphere). In addition to the final values, the area under the rCBF, rCBFV, DHbO2, and DHb curves from the start of ACZ injection to 14 minutes after the injection were also calculated and used to compare the cumulative microvascular and macrovascular CVR and oxygenation changes over stenosis and normal sides/arteries. A linear-mixed model (LME) was used to account for important covariates and minimize individual patient bias on TCD-CVR, DCS-CVR, and oxygenation data. In these models, the patient ID represented the random effect, whereas ISOL, symptom history, and other demographic and clinical characteristics represented fixed effects. Kendall’s rank corre170
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TABLE 1. Demographic and Clinical Characteristics of the Population Included for the Analysis Parameter Total no. of subjects Total no. of hemispheres Male Age, (mean STD years) Degree of ICA stenosis 0%–49% 70%–99% Occluded Laterality of stenosis Unilateral steno-occlusion Bilateral steno-occlusion Presenting events Symptomatic arteries Transient ischemic attack Ischemic stroke Asymptomatic arteries Other conditions Smoker Diabetic Hypercholesterol Hypertension
Number 20 33 16 (80%) 64.6 9.7 12 (36%) 14 (43%) 7 (21%) 16 (80%) 4 (20%) 8 (24%) 1 7 25 (76%) 6 (30%) 8 (40%) 12 (60%) 16 (80%)
Data are given as number of subjects and percentage of the total included subjects [No. (%)].
lation coefficient (t; a number between 1 and 1 with 1 showing the perfect correlation, which indicates the ratio of the difference of concordance and nonconcordance pairs to the total number of pairs) was used to test the statistical dependence (correlation) between different variables (20). Moreover, the significance of the changes before and after ACZ bolus was determined by Wilcoxon test. It should be noted that due to the involvement of patients with bilateral ISOL, paired statistical analysis methods to compare the ISOL and normal sides/arteries were not applicable. All statistical evaluations were accomplished by R package with 95% confidence interval (CI) (21).
RESULTS Twenty-seven patients with ISOL were recruited and completed the measurements. After excluding the data with movement artifacts and/or large noise content, the data from one or both hemispheres of 20 patients were used for further statistical analysis. From these 40 hemispheres, data for 6 hemispheres with large noise content and a side of one subject with stenosis degree between 50% and 70% (since it was neither severe stenosis nor normal case according to our criteria) were discarded, leaving data for 33 hemispheres for further statistical analysis. Table 1 details the clinical characteristics of the studied population. The BP and heart rate did not show a significant change upon ACZ bolus injection (P = .59 and P = .41, respectively).
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Figure 1. Individual and average results for all included patients showing changes of (a,b) the DCS-CVR (microvascular CVR, DCS data) and (c,d) the TCD-CVR (macrovascular CVR, TCD data); due to acetazolamide administration. (a,c) Plotting the flow changes for affected sides (ICA stenosis $70%). (b,d) Flow changes for normal sides (ICA stenosis <50%). Vertical bold lines show the start and end of the ACZ injection. The data between the vertical dashed lines have been averaged and used for further analysis. The lineconnected circles and the error bars are average and STD data at 1-minute intervals. (Color version of the figure is available online.)
The individual changes in DCS-CVR and TCD-CVR as well as their average time course after ACZ bolus are depicted in Figure 1. Similarly, Figure 2 represents the individual and average changes of HbO2 and Hb concentrations upon ACZ injection. Table 2 shows DCS-CVR, TCD-CVR, and Hb and HbO2 values according to the presence or absence of ISOL. We have found significant increases for HbO2, rCBF, and rCBFV values over ISOL and normal sides of all studied patients (P < .02). Hb concentration only marginally decreased for affected sides (P = .054) but not for normal sides (P = .26). Statistical comparisons based on mean of final values (instead of median of final values) led to similar results. Noticeably, the results of LME on DCS-CVR, TCDCVR, DHbO2, and DHb indicated that only TCD-CVR (macrovascular measure) was associated with ISOL (P = .024). There was no significant dependence on ISOL for microvascular measures (DCS-CVR, DHbO2, and DHb, P > .16). Furthermore, no microvascular and/or macrovascular measure (TCD-CVR, DCS-CVR, DHbO2, or DHb) showed significant dependence on the symptom history of the arteries (P > .18). Moreover, based on Kendall rank correlation test, there was no correlation between TCDCVR and DHbO2 (P = .064, t = 0.29 for ISOL and P = .94, t = 0.03 for normal sides) or DCS-CVR (P = .38, t = 0.14 for ISOL and P = .54, t = 0.15 for normal sides) where local parameters (DHbO2 and DCS-CVR) showed a significant correlation with HbO2 for both affected (P = .026, t = 0.35) and normal (P < .001, t = 0.64) sides. The LME test on the area under DCS-CVR, TCD-CVR, DHbO2, and DHb curves similarly revealed a significant
dependence between TCD-CVR and ISOL presence (P = .021) and no significant dependence between the DCS-CVR and DHb and DHbO2 with ISOL (P > .05, or no improvement in models with ISOL as the fixed effect). However, the LME based on area under the curve for DHbO2 depended on the ISOL presence (P = .03). Moreover, no significant dependence was found between the symptom history and DCS-CVR, TCD-CVR, DHbO2, and DHb (P > .05). Kendall rank correlation test resulted in no correlation between the area under the TCD-CVR and DCS-CVR (P = .14, t = 0.24 for ISOL and P = .54, t = 0.15 for normal sides) and the TCD-CVR and DHbO2 (P = .065, t = 0.29 for ISOL and P = 1, t = 0 for normal sides) and significant correlation between the DCS-CVR and DHbO2 (P = .031, t = 0.49 for ISOL and P = .009, t = 0.41 for normal sides). As depicted in Figures 1 and 2, a considerable variation on the CVR responses among individuals was observed for microvascular and macrovascular oxygenation and flow values. As a result and as described in the analysis section, to further investigate the microvascular (DCS-CVR and DHbO2) and macrovascular (TCD-CVR) responses, we have classified them into two ‘‘responsive’’ and ‘‘nonresponsive’’ subgroups. We have observed four distinct response groups: (1) both microvasculature and macrovasculature were nonresponsive, (2) macrovasculature, but not microvasculature, was responsive, (3) both microvasculature and macrovasculature were responsive, and (4) microvasculature, but not macrovasculature, was responsive. Table 3 shows these four groups and lists the occurrences for each group. 171
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Figure 2. Individual and average results for all included patients showing changes of (a,b) the DHbO2 (oxyhemoglobin, NIRSDOS data), (c,d) the DHb (deoxyhemoglobin, NIRS-DOS data), upon acetazolamide bolus. (a,c) Oxygenation changes for affected sides (ICA stenosis $70%). (b,d) Oxygenation changes for normal sides (ICA stenosis <50%). Vertical bold lines show the start and end of the ACZ injection. The data between the vertical dashed lines have been averaged and used for further analysis. The line-connected circles and the error bars are average and STD data at 1-minute intervals. (Color version of the figure is available online.)
TABLE 2. Median (Interquartile Range [IQR]), and P Values for Optical and Ultrasound Data ISOL Side Parameter DHbO2, mmol/L DHb, mmol/L CVRDCS, % CVRTCD, %
TABLE 3. MCA CVR (TCD-CVR) Versus Local CVR (DCS-CVR) and DHbO2
Normal Side
Median
IQR
Median
IQR
3.7* 0.4 20* 10.7*
2.3 to 8.3 1.2 to 0.1 14.3 to 25.1 6.8 to 27.5
7.7* 0.5 26.1* 27.8*
5.4 to 12 1.8 to 0.7 13.9 to 32 19 to 42.7
*Observed change is statistically significant (P < .05, Wilcoxon test).
Parameter Responsive by DCS Nonresponsive by DCS Responsive by NIRSDOS, DHbO2 Nonresponsive by NIRS-DOS, DHbO2
Responsive by TCD
Nonresponsive by TCD
15 (45) 5 (15) 13 (39)
10 (30) 3 (9) 4 (12)
7 (21)
9 (27)
Data are indicated as the number of hemispheres/arteries and as percentage of the total [No. (%)].
DISCUSSION We have compared the CVR response assessed with TCD (TCD-CVR) with the local brain tissue CVR assessed with DCS (DCS-CVR) for ISOL patients. Furthermore, using NIRS-DOS, we have simultaneously followed the changes of brain blood oxygenation and blood volume (Table 2). All the subjects were able to complete the study indicating the feasibility and practicality of the method for future larger studies. Improved tissue-probe interface (for both TCD and optics) can further lower the data rejection rate. Our primary finding was that while TCD-CVR measures (macrovascular) were significantly dependent on ISOL, DCSCVR and DHbO2 (microvascular measures) did not show significant dependence on ISOL presence (Table 2). Similarly, several others have reported such varying CVR responses at the presence of ISOL. Brauer et al (22) and Pindzola et al (23) reported that microvascular CVR (assessed by 172
Xe-CT) and that of macrovasculature (measured by TCD) were not correlated for ISOL patients. They have attributed the differences between the two CVR responses to the fact that, in the presence of ISOL, the collaterals other than those of the circle of Willis such as pial and retrograde ophthalmic collaterals may supply the blood to the MCA territory. This idea is further supported with smaller MCA territories found for ISOL patients with arterial spin labeling magnetic resonance imaging (24) and increased collateral circulation with progressive degrees of carotid stenosis (25). Thus, it is reasonable to expect that the CVR calculated from CBFV at the MCA trunk does not agree with the local CVR response when the MCA is no longer the primary route of blood supply to the probed tissue volume. On the other hand, while our microvascular oxygenation measures (NIRS-DOS data) did not correlate with
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macrovascular TCD data, they showed a significant correlation with microvascular flow data (DCS-CVR) at both severe stenosis and normal sides. This finding is notable since NIRSDOS and DCS are two optical modalities that are measured and analyzed independently to track the microvascular oxygenation and flow at the same brain tissue compartment. It further supports the hypothesis that the observed disagreements in our microvascular and macrovascular measures truly reflect the differences between global and local cerebral hemodynamic responses at the presence of ISOL. Similar correlations between local oxygenation and local flow changes were also observed in previous studies for ISOL patients (26). The selection of a heterogeneous patient population was a deliberate choice that allowed us to compare patients with different levels of ICA stenosis or occlusion in one or both of their ICAs and with different symptom records. However this choice resulted in a wider range of CVR responses in both microvasculature and macrovasculature, which required the arrangement of patient responses into responsive and nonresponsive groups for further analysis (Table 3). On classifying the CVR responses into four categories, inconsistent response groups with responsive microvascular CVR but nonresponsive macrovascular CVR and responsive macrovascular CVR but nonresponsive microvascular CVR emerged in our data, which was also reported by others (22,23). Although the rate of occurrences with a small population size is expected to be strongly dependent on the recruited individuals, some similarities remained, 20% responsive macrovascular/nonresponsive microvascular and 45% nonresponsive macrovascular/responsive microvascular in Pindzola et al (23) compared to 15% responsive macrovascular/nonresponsive microvascular and 30% nonresponsive macrovascular/responsive microvascular in this work. It should be noted that considering our relatively small population size no conclusion can be made on the prognostic value of nonresponsive microvascular and/or macrovascular CVR and their occurrences. However, these results show that the presence of local cerebrovascular disorders as ISOL might lead to the diverse microvascular and macrovascular CVR responses and suggests future larger studies to determine the prognostic values of concurrent microvascular and macrovascular CVR evaluation. The hybrid method is readily providing the cerebral tissue oxygenation changes in addition to microvascular flow that could lead to a more precise cerebral hemodynamic stratification (see Table 3). However, due to our population size, further division of responses based on microvascular flow and oxygenation changes is beyond our statistical power. The benefits of hybrid diffuse optics method should be weighed against its limitations. One potential error is the sensitivity to extracerebral and superficial changes. Since it was shown previously that the superficial tissues do not significantly change for ACZ challenge (27) and we have previously found a good agreement between TCD and DCS measures on healthy subjects (17), we do not expect a major problem due to the changes in superficial tissue.
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24. Bokkers R, van Osch M, van der Worp H, et al. Symptomatic carotid artery stenosis: impairment of cerebral autoregulation measured at the brain tissue level with arterial spin-labeling MR imaging. Radiology 2010; 256: 201–208. 25. Henderson R, Eliasziw M, Fox A, et al. Angiographically defined collateral circulation and risk of stroke in patients with severe carotid artery stenosis. Stroke 2000; 31:128–132. 26. Yamaguchi H, Yamauchi H, Hazama S, et al. Correlation between cerebral oxygen metabolism and cerebral blood flow simultaneously measured before and after acetazolamide administration. J Biomed Optics 1999; 4: 418. 27. Tachtsidis I, Tisdall M, Delpy D, et al. Measurement of cerebral tissue oxygenation in young healthy volunteers during acetazolamide provocation: a transcranial Doppler and near-infrared spectroscopy investigation. Oxygen Transport to Tissue XXIX; Advances In Experimental Medicine And Biology 2008; 614:389–396.
Acad Radiol 2014; 21:168–174 ncies Foto niques, Mediterranean Technology Park, 08860 ICFO- Institut de Cie Castelldefels, Barcelona, Spain (P.Z., T.D.); and Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (R.D.-M., L.D., J.M.F.). Received August 9, 2013; accepted October 14, 2013. Sources of Cellex Barcelona, Marie Curie Funding: This work was funded by Fundacio IRG (FP7, RPTAMON; PI09/00557), Institute de Salud Carlos III (DOMMON, CERCA FIS), Ministerio de Economia y Competitividad, Institucio (DOCNEURO), Generalitat de Catalunya, European Regional Development Fund (FEDER/ERDF), and LASERLAB (BIOPTICHAL, FP7) and Photonics4Life (FP7) consortia. Dedication: We dedicate this manuscript to the memory of late Dr Britton Chance, with whom one of the authors (T.D.) has had years of interactions on the role of diffuse correlation spectroscopy for neurological applications. His encouragement, critical mind, and decades of experience have inspired all of us. Disclosures: One of the authors (T.D.) is a coinventor in a patent involving DCS/NIRS technology. Part of the DCS technology is now commercialized by a company (Hemophotonics S.L), but T.D. currently does not receive any royalties or has not any other financial relations with the company. The other authors have no conflicting financial or ethical issues to disclose. Address correspondence to: P.Z. e-mail: [email protected] ªAUR, 2014 http://dx.doi.org/10.1016/j.acra.2013.10.010
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evere stenosis or occlusion of the internal carotid artery (ICA) increases the risk of subsequent ischemic stroke (IS) and transient ischemic attack (TIA) (1). Moreover, patients with severe internal carotid artery stenoocclusive lesions (ISOL) are found to be at a particularly higher risk of imminent stroke events when autoregulatory vasodilation capacity of the cerebral terminal arterioles in response to a reduced perfusion pressure, or cerebrovascular reactivity (CVR), is impaired (2–5). Thus, to aid in the decision of the suitable treatment, such as carotid revascularization versus drug therapy, the assessment of CVR has been proposed by several authors as a screening method to stratify ISOL patients based on their assumed risk of future IS or TIA (6). CVR is normally evaluated by measuring the maximum vasodilation capacity of cerebral vasculature. The maximum vasodilation is induced by introducing a potent vasodilatory stimulus, most commonly CO2, inhalation or acetazolamide (ACZ) infusion. Consequent cerebrovascular changes are then followed by a method capable of measuring microvascular
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cerebral blood flow (CBF), blood oxygen saturation, blood volume, or macrovascular cerebral blood flow velocity (CBFV). Many modalities such as positron emission tomography, xenon-enhanced computed tomography (Xe-CT), continuous arterial spin labeling magnetic resonance imaging, single-photon emission CT, transcranial Doppler (TCD), and near-infrared spectroscopy (NIRS-DOS) have been used to evaluate the CVR of ISOL patients (7). In clinics, however, a large number of studies on the role of CVR on subsequent IS/TIA are limited to TCD (macrovascular) since currently available clinical technologies for microvascular CVR assessment are complex and costly and involve patient transport, and ionizing radiation (e.g., positron emission tomography and Xe-CT). Some studies have found correlations between macrovascular CVR measured by TCD and internal carotid artery (ICA) patency, symptom history and IS/TIA risks (8,9). Nevertheless, since the microvascular CVR measures also reflect the efficiency of the collateral vasculature in compensating for blood flow deficiency due to stenosis or occlusion of the ipsilateral ICA, they are believed to be more individualized indicators of CVR condition (10). As a consequence, a bedside noninvasive and relatively simple technology for microvascular CVR assessment would be desirable (1) for more precise IS/TIA risk assessment according to the status of collateral circulation and hemodynamic response of the cerebral vasculature, and (2) based on the proposed risk, to facilitate a decision on the appropriate therapies. Such a bedside and noninvasive modality could also be used after large trials to end the current debate on the significance of CVR function on the precise selection of subgroup of ISOL patients who would benefit from therapies like extracranial/intracranial bypass surgery (11). In this study, we have applied a novel hybrid diffuse optical technology for real-time bedside assessment of microvascular CVR based on simultaneous microvascular CBF and oxygenation measurements (12). The hybrid diffuse optical monitor consisted of two diffuse optical modalities: diffuse correlation spectroscopy (DCS) and NIRS-DOS. DCS (13–15) measures the microvascular CBF continuously, at the patient bedside without any need for exogenous markers and has been extensively validated in vivo (15,16). The blood oxygenation and blood volume changes in the brain were followed by NIRS-DOS. Concurrently, we have also assessed the bilateral CBFV (macrovascular) by TCD. The normal CVR response range available for DCS/NIRS-DOS hybrid diffuse optics technique was established in our previous study (17), where we have applied a similar methodology to healthy volunteers and found a significant agreement between microvascular and macrovascular CVR. We also demonstrated the potential of the combined DCS/NIRS-DOS technique for cerebral metabolic rate of oxygen assessment. Here, our main goals were to demonstrate the potential of hybrid diffuse optics for noninvasive bedside assessment of microvascular CVR and to compare the bilateral CVR responses in anterior middle cerebral artery (MCA) territory (microvascular) and at the MCA trunk (macrovascular) in the presence of
severe ISOL by a relatively simple technique. Finally, we classified our CVR findings according to the presence of normal CVR or its total absence, and, since our measures were continuous, we assessed the temporal properties of the response in both the microvasculature and macrovasculature.
MATERIALS AND METHODS Subjects
The population was selected from patients with symptomatic and asymptomatic steno-occlusive ICA disease who were referred to the neurovascular laboratory at the hospital de la Santa Creu i Sant Pau, Barcelona, Spain for carotid artery ultrasound examination. The patients were approached for recruitment in the study if they had a unilateral or bilateral severe $70% stenosis or occlusion of the ICA as determined by published criteria using a carotid artery ultrasound (multifrequency linear array transducer; Aplio-XG, Toshiba, Tochigi, Japan) (18). In these patients, the ICA stenosis or occlusion was further confirmed by magnetic resonance angiography (MRA), CT angiography (CTA), and/or digital subtraction angiography (DSA) according to North American Symptomatic Carotid Endarterectomy Trial criteria (19). Patients were excluded if they had an inadequate temporal bone window for sufficient TCD examination or the evidence of an additional intracranial stenosis of the carotid siphon, the MCA, or the anterior cerebral artery. Patients were asked to avoid coffee, antihypertensive drugs, and smoking on the day of measurement. Information about demographic and vascular risk factors such as age, gender, history of smoking, hypertension, diabetes, hypercholesterolemia, and previously diagnosed coronary heart disease and vascular peripheral disease were recorded. The study was approved by the institutional ethics committee at the hospital de la Santa Creu i Sant Pau. Diffuse Optics and TCD Protocol
The measurement protocol, instrumentation, optode design, and analysis methods are explained in detail in our previous work (17). Briefly, relative changes in oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) concentration were followed by a custom-made frequency domain NIRS-DOS device (95230 Imagent, ISS, Champaign, IL, USA) with 16 lasers at 690 nm, 785 nm, and 830 nm and two photomultipliers for detection. The relative microvascular CBF was measured by DCS at the patient’s bedside (15). The optical fibers were placed on the right and left side of the forehead of subjects approximately 1 cm above the eyebrows and as far away as possible from the midline (17). The CBFV in the right and left MCA were obtained by TCD (MultiDop-T, DWL Elektronische Systeme, Singe, Germany). Two probes in a range-gated and pulsed-wave mode at 2 MHz and at a depth 169
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of 50 10 mm were applied over the temporal bone by use of a standard head-frame (Diamon, DWL). The optical and ultrasound measures were recorded from 5 minutes before (baseline period) to 20 minutes after ACZ bolus (1 g ACZ/ 10 ml saline). Heart rate and blood pressure (BP) were followed every 3 minutes by use of an autoinflated BP monitor (OMRON, Kyoto, Japan). Analysis
The optical and ultrasound data are analyzed according to our previous study (17), in which we applied a similar protocol for healthy volunteers. The HbO2 and Hb concentrations (by NIRS-DOS), CBF (by DCS), and CBFV (by TCD) data at each time point were compared to the average values of the first five minutes before ACZ injection (baseline period indicated by subscript ‘‘bl’’). These relative measures were then represented as DHbO2 and DHb with D indicating difference, rCBF (rCBF ¼ ðDCBF þ CBFbl Þ=CBFbl ), and rCBFV (rCBFV ¼ ðDCBFV þ CBFVbl Þ=CBFVbl ) where r indicates a ratio. Data with large noise content and/or obvious artifacts due to probe movement were discarded from further analysis. The average DHbO2, DHb, rCBF and rCBFV values from minutes 14 to 16 after ACZ bolus were considered as the maximal change (‘‘final values’’) in response to the ACZ injection. The standard deviation (STD) of the measurement points over the same time period (minutes 14 to 16) was also calculated for all subjects. These STD values were then averaged over all subjects to define a discrimination threshold. We have classified the data as ‘‘responsive’’ (if average (STD 2) < final value) or ‘‘nonresponsive’’ (if average (STD 2) > final value). The median and interquartile range (IQR) of the final values are reported separately for normal (no stenosis or stenosis <50%) and ISOL (stenosis >70% or occlusion) hemispheres. The percent microvascular and macrovascular CVR values (DCS-CVR and TCD-CVR, respectively) were reported as ðCVRDCS ¼ ðrCBF 1Þ 100Þ and ðCVRTCD ¼ ðrCBFV 1Þ 100Þ. Because bilateral hemodynamic data were obtained from all subjects, the data for each patient was considered as two arteries/hemispheres (i.e., a right and a left artery/hemisphere). In addition to the final values, the area under the rCBF, rCBFV, DHbO2, and DHb curves from the start of ACZ injection to 14 minutes after the injection were also calculated and used to compare the cumulative microvascular and macrovascular CVR and oxygenation changes over stenosis and normal sides/arteries. A linear-mixed model (LME) was used to account for important covariates and minimize individual patient bias on TCD-CVR, DCS-CVR, and oxygenation data. In these models, the patient ID represented the random effect, whereas ISOL, symptom history, and other demographic and clinical characteristics represented fixed effects. Kendall’s rank corre170
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TABLE 1. Demographic and Clinical Characteristics of the Population Included for the Analysis Parameter Total no. of subjects Total no. of hemispheres Male Age, (mean STD years) Degree of ICA stenosis 0%–49% 70%–99% Occluded Laterality of stenosis Unilateral steno-occlusion Bilateral steno-occlusion Presenting events Symptomatic arteries Transient ischemic attack Ischemic stroke Asymptomatic arteries Other conditions Smoker Diabetic Hypercholesterol Hypertension
Number 20 33 16 (80%) 64.6 9.7 12 (36%) 14 (43%) 7 (21%) 16 (80%) 4 (20%) 8 (24%) 1 7 25 (76%) 6 (30%) 8 (40%) 12 (60%) 16 (80%)
Data are given as number of subjects and percentage of the total included subjects [No. (%)].
lation coefficient (t; a number between 1 and 1 with 1 showing the perfect correlation, which indicates the ratio of the difference of concordance and nonconcordance pairs to the total number of pairs) was used to test the statistical dependence (correlation) between different variables (20). Moreover, the significance of the changes before and after ACZ bolus was determined by Wilcoxon test. It should be noted that due to the involvement of patients with bilateral ISOL, paired statistical analysis methods to compare the ISOL and normal sides/arteries were not applicable. All statistical evaluations were accomplished by R package with 95% confidence interval (CI) (21).
RESULTS Twenty-seven patients with ISOL were recruited and completed the measurements. After excluding the data with movement artifacts and/or large noise content, the data from one or both hemispheres of 20 patients were used for further statistical analysis. From these 40 hemispheres, data for 6 hemispheres with large noise content and a side of one subject with stenosis degree between 50% and 70% (since it was neither severe stenosis nor normal case according to our criteria) were discarded, leaving data for 33 hemispheres for further statistical analysis. Table 1 details the clinical characteristics of the studied population. The BP and heart rate did not show a significant change upon ACZ bolus injection (P = .59 and P = .41, respectively).
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Figure 1. Individual and average results for all included patients showing changes of (a,b) the DCS-CVR (microvascular CVR, DCS data) and (c,d) the TCD-CVR (macrovascular CVR, TCD data); due to acetazolamide administration. (a,c) Plotting the flow changes for affected sides (ICA stenosis $70%). (b,d) Flow changes for normal sides (ICA stenosis <50%). Vertical bold lines show the start and end of the ACZ injection. The data between the vertical dashed lines have been averaged and used for further analysis. The lineconnected circles and the error bars are average and STD data at 1-minute intervals. (Color version of the figure is available online.)
The individual changes in DCS-CVR and TCD-CVR as well as their average time course after ACZ bolus are depicted in Figure 1. Similarly, Figure 2 represents the individual and average changes of HbO2 and Hb concentrations upon ACZ injection. Table 2 shows DCS-CVR, TCD-CVR, and Hb and HbO2 values according to the presence or absence of ISOL. We have found significant increases for HbO2, rCBF, and rCBFV values over ISOL and normal sides of all studied patients (P < .02). Hb concentration only marginally decreased for affected sides (P = .054) but not for normal sides (P = .26). Statistical comparisons based on mean of final values (instead of median of final values) led to similar results. Noticeably, the results of LME on DCS-CVR, TCDCVR, DHbO2, and DHb indicated that only TCD-CVR (macrovascular measure) was associated with ISOL (P = .024). There was no significant dependence on ISOL for microvascular measures (DCS-CVR, DHbO2, and DHb, P > .16). Furthermore, no microvascular and/or macrovascular measure (TCD-CVR, DCS-CVR, DHbO2, or DHb) showed significant dependence on the symptom history of the arteries (P > .18). Moreover, based on Kendall rank correlation test, there was no correlation between TCDCVR and DHbO2 (P = .064, t = 0.29 for ISOL and P = .94, t = 0.03 for normal sides) or DCS-CVR (P = .38, t = 0.14 for ISOL and P = .54, t = 0.15 for normal sides) where local parameters (DHbO2 and DCS-CVR) showed a significant correlation with HbO2 for both affected (P = .026, t = 0.35) and normal (P < .001, t = 0.64) sides. The LME test on the area under DCS-CVR, TCD-CVR, DHbO2, and DHb curves similarly revealed a significant
dependence between TCD-CVR and ISOL presence (P = .021) and no significant dependence between the DCS-CVR and DHb and DHbO2 with ISOL (P > .05, or no improvement in models with ISOL as the fixed effect). However, the LME based on area under the curve for DHbO2 depended on the ISOL presence (P = .03). Moreover, no significant dependence was found between the symptom history and DCS-CVR, TCD-CVR, DHbO2, and DHb (P > .05). Kendall rank correlation test resulted in no correlation between the area under the TCD-CVR and DCS-CVR (P = .14, t = 0.24 for ISOL and P = .54, t = 0.15 for normal sides) and the TCD-CVR and DHbO2 (P = .065, t = 0.29 for ISOL and P = 1, t = 0 for normal sides) and significant correlation between the DCS-CVR and DHbO2 (P = .031, t = 0.49 for ISOL and P = .009, t = 0.41 for normal sides). As depicted in Figures 1 and 2, a considerable variation on the CVR responses among individuals was observed for microvascular and macrovascular oxygenation and flow values. As a result and as described in the analysis section, to further investigate the microvascular (DCS-CVR and DHbO2) and macrovascular (TCD-CVR) responses, we have classified them into two ‘‘responsive’’ and ‘‘nonresponsive’’ subgroups. We have observed four distinct response groups: (1) both microvasculature and macrovasculature were nonresponsive, (2) macrovasculature, but not microvasculature, was responsive, (3) both microvasculature and macrovasculature were responsive, and (4) microvasculature, but not macrovasculature, was responsive. Table 3 shows these four groups and lists the occurrences for each group. 171
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Figure 2. Individual and average results for all included patients showing changes of (a,b) the DHbO2 (oxyhemoglobin, NIRSDOS data), (c,d) the DHb (deoxyhemoglobin, NIRS-DOS data), upon acetazolamide bolus. (a,c) Oxygenation changes for affected sides (ICA stenosis $70%). (b,d) Oxygenation changes for normal sides (ICA stenosis <50%). Vertical bold lines show the start and end of the ACZ injection. The data between the vertical dashed lines have been averaged and used for further analysis. The line-connected circles and the error bars are average and STD data at 1-minute intervals. (Color version of the figure is available online.)
TABLE 2. Median (Interquartile Range [IQR]), and P Values for Optical and Ultrasound Data ISOL Side Parameter DHbO2, mmol/L DHb, mmol/L CVRDCS, % CVRTCD, %
TABLE 3. MCA CVR (TCD-CVR) Versus Local CVR (DCS-CVR) and DHbO2
Normal Side
Median
IQR
Median
IQR
3.7* 0.4 20* 10.7*
2.3 to 8.3 1.2 to 0.1 14.3 to 25.1 6.8 to 27.5
7.7* 0.5 26.1* 27.8*
5.4 to 12 1.8 to 0.7 13.9 to 32 19 to 42.7
*Observed change is statistically significant (P < .05, Wilcoxon test).
Parameter Responsive by DCS Nonresponsive by DCS Responsive by NIRSDOS, DHbO2 Nonresponsive by NIRS-DOS, DHbO2
Responsive by TCD
Nonresponsive by TCD
15 (45) 5 (15) 13 (39)
10 (30) 3 (9) 4 (12)
7 (21)
9 (27)
Data are indicated as the number of hemispheres/arteries and as percentage of the total [No. (%)].
DISCUSSION We have compared the CVR response assessed with TCD (TCD-CVR) with the local brain tissue CVR assessed with DCS (DCS-CVR) for ISOL patients. Furthermore, using NIRS-DOS, we have simultaneously followed the changes of brain blood oxygenation and blood volume (Table 2). All the subjects were able to complete the study indicating the feasibility and practicality of the method for future larger studies. Improved tissue-probe interface (for both TCD and optics) can further lower the data rejection rate. Our primary finding was that while TCD-CVR measures (macrovascular) were significantly dependent on ISOL, DCSCVR and DHbO2 (microvascular measures) did not show significant dependence on ISOL presence (Table 2). Similarly, several others have reported such varying CVR responses at the presence of ISOL. Brauer et al (22) and Pindzola et al (23) reported that microvascular CVR (assessed by 172
Xe-CT) and that of macrovasculature (measured by TCD) were not correlated for ISOL patients. They have attributed the differences between the two CVR responses to the fact that, in the presence of ISOL, the collaterals other than those of the circle of Willis such as pial and retrograde ophthalmic collaterals may supply the blood to the MCA territory. This idea is further supported with smaller MCA territories found for ISOL patients with arterial spin labeling magnetic resonance imaging (24) and increased collateral circulation with progressive degrees of carotid stenosis (25). Thus, it is reasonable to expect that the CVR calculated from CBFV at the MCA trunk does not agree with the local CVR response when the MCA is no longer the primary route of blood supply to the probed tissue volume. On the other hand, while our microvascular oxygenation measures (NIRS-DOS data) did not correlate with
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macrovascular TCD data, they showed a significant correlation with microvascular flow data (DCS-CVR) at both severe stenosis and normal sides. This finding is notable since NIRSDOS and DCS are two optical modalities that are measured and analyzed independently to track the microvascular oxygenation and flow at the same brain tissue compartment. It further supports the hypothesis that the observed disagreements in our microvascular and macrovascular measures truly reflect the differences between global and local cerebral hemodynamic responses at the presence of ISOL. Similar correlations between local oxygenation and local flow changes were also observed in previous studies for ISOL patients (26). The selection of a heterogeneous patient population was a deliberate choice that allowed us to compare patients with different levels of ICA stenosis or occlusion in one or both of their ICAs and with different symptom records. However this choice resulted in a wider range of CVR responses in both microvasculature and macrovasculature, which required the arrangement of patient responses into responsive and nonresponsive groups for further analysis (Table 3). On classifying the CVR responses into four categories, inconsistent response groups with responsive microvascular CVR but nonresponsive macrovascular CVR and responsive macrovascular CVR but nonresponsive microvascular CVR emerged in our data, which was also reported by others (22,23). Although the rate of occurrences with a small population size is expected to be strongly dependent on the recruited individuals, some similarities remained, 20% responsive macrovascular/nonresponsive microvascular and 45% nonresponsive macrovascular/responsive microvascular in Pindzola et al (23) compared to 15% responsive macrovascular/nonresponsive microvascular and 30% nonresponsive macrovascular/responsive microvascular in this work. It should be noted that considering our relatively small population size no conclusion can be made on the prognostic value of nonresponsive microvascular and/or macrovascular CVR and their occurrences. However, these results show that the presence of local cerebrovascular disorders as ISOL might lead to the diverse microvascular and macrovascular CVR responses and suggests future larger studies to determine the prognostic values of concurrent microvascular and macrovascular CVR evaluation. The hybrid method is readily providing the cerebral tissue oxygenation changes in addition to microvascular flow that could lead to a more precise cerebral hemodynamic stratification (see Table 3). However, due to our population size, further division of responses based on microvascular flow and oxygenation changes is beyond our statistical power. The benefits of hybrid diffuse optics method should be weighed against its limitations. One potential error is the sensitivity to extracerebral and superficial changes. Since it was shown previously that the superficial tissues do not significantly change for ACZ challenge (27) and we have previously found a good agreement between TCD and DCS measures on healthy subjects (17), we do not expect a major problem due to the changes in superficial tissue.
Since transcranial optical measures were carried through the forehead, there is a chance that optical and TCD measurements result from different vascular territories (anterior cerebral artery versus MCA territories), which could lead to the discrepancies when a local pathology is present. A future probe design could accommodate other regions of the head to explore their utility. Here, we have demonstrated a real-time, bedside hybrid optical technique capable of direct and continuous measurement of microvascular oxygenation and blood flow that could readily accompany other available clinical modalities. A larger prospective study of CVR responses at both microvascular and macrovascular levels is needed to reveal the possible benefits of concurrent microvascular and macrovascular CVR measurement to more accurately select ISOL patients at higher future risk of IS/TIA and for subsequent therapy planning. REFERENCES 1. Barnett H, Taylor D, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415–1425. 2. Gupta A, Chazen JL, Hartman M, et al. Cerebrovascular reserve and stroke risk in patients with carotid stenosis or occlusion: A systematic review and meta-analysis. Stroke 2012; 43:2884–2891. 3. Gibbs J, Leenders K, Wise R, et al. Evaluation of cerebral perfusion reserve in patients with carotid-artery occlusion. Lancet 1984; 323:310–314. 4. Kistler J, Ropper A, Heros R. Therapy of ischemic cerebral vascular disease due to atherothrombosis. N Engl J Med 1984; 311:27–34. 5. Caplan L, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55:1475. 6. Markus H, Cullinane M. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001; 124:457–467. nek K, et al. Can we identify patients with carotid 7. Herzig R, Hlustık P, Urba occlusion who would benefit from EC/IC bypass? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2004; 148:119–122. 8. Vernieri F, Tibuzzi F, Pasqualetti P, et al. Transcranial Doppler and nearinfrared spectroscopy can evaluate the hemodynamic effect of carotid artery occlusion. Stroke 2004; 35:64–70. 9. Russell S, Woo H, Siller K, et al. Evaluating middle cerebral artery collateral blood flow reserve using acetazolamide transcranial Doppler ultrasound in patients with carotid occlusive disease. Surg Neurol 2008; 70: 466–470. 10. Ozgur HT, Walsh TK, Masaryk A, et al. Correlation of cerebrovascular reserve as measured by acetazolamide-challenged SPECT with angiographic flow patterns and intra- or extracranial arterial stenosis. Am J Neuroradiol 2001; 22:928–936. 11. Romano JG, Liebeskind DS. Revascularization of collaterals for hemodynamic stroke insight on pathophysiology from the Carotid Occlusion Surgery Study. Stroke 2012; 43:1988–1991. 12. T Durduran, AG Yodh, Diffuse correlation spectroscopy for noninvasive, microvascular cerebral blood flow measurement, NeuroImage, 2013 in Press. 13. Boas D, Campbell L, Yodh A. Scattering and imaging with diffusing temporal field correlations. Phys Rev Lett 1995; 75:1855–1858. 14. Boas DA, Yodh AG. Spatially varying dynamical properties of turbid media probed with diffusing temporal light correlation. J Opt Soc Am A 1997; 14: 192–215. 15. Durduran T, Choe R, Baker W, et al. Diffuse optics for tissue monitoring and tomography. Rep Progr Phys 2010; 73:076701. 16. Mesquita R, Durduran T, Yu G, et al. Direct measurement of tissue blood flow and metabolism with diffuse optics. Phil Trans R Soc 2011; 369: 4390–4406. bregas J, et al. Effects of acetazol17. Zirak P, Delgado-Mederos R, Martı-Fa amide on the microand macrovascular cerebral hemodynamics: a diffuse optical and transcranial Doppler ultrasound study. Biomed Opt Exp 2010; 1:1443–1459.
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24. Bokkers R, van Osch M, van der Worp H, et al. Symptomatic carotid artery stenosis: impairment of cerebral autoregulation measured at the brain tissue level with arterial spin-labeling MR imaging. Radiology 2010; 256: 201–208. 25. Henderson R, Eliasziw M, Fox A, et al. Angiographically defined collateral circulation and risk of stroke in patients with severe carotid artery stenosis. Stroke 2000; 31:128–132. 26. Yamaguchi H, Yamauchi H, Hazama S, et al. Correlation between cerebral oxygen metabolism and cerebral blood flow simultaneously measured before and after acetazolamide administration. J Biomed Optics 1999; 4: 418. 27. Tachtsidis I, Tisdall M, Delpy D, et al. Measurement of cerebral tissue oxygenation in young healthy volunteers during acetazolamide provocation: a transcranial Doppler and near-infrared spectroscopy investigation. Oxygen Transport to Tissue XXIX; Advances In Experimental Medicine And Biology 2008; 614:389–396.