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1.  Effects of acetazolamide on the micro- and macro-vascular cerebral hemodynamics: a diffuse optical and transcranial doppler ultrasound study 
Biomedical Optics Express  2010;1(5):1443-1459.
Acetazolamide (ACZ) was used to stimulate the cerebral vasculature on ten healthy volunteers to assess the cerebral vasomotor reactivity (CVR). We have combined near infrared spectroscopy (NIRS), diffuse correlation spectroscopy (DCS) and transcranial Doppler (TCD) technologies to non-invasively assess CVR in real-time by measuring oxy- and deoxy-hemoglobin concentrations, using NIRS, local cerebral blood flow (CBF), using DCS, and blood flow velocity (CBFV) in the middle cerebral artery, using TCD. Robust and persistent increases in oxy-hemoglobin concentration, CBF and CBFV were observed. A significant agreement was found between macro-vascular (TCD) and micro-vascular (DCS) hemodynamics, between the NIRS and TCD data, and also within NIRS and DCS results. The relative cerebral metabolic rate of oxygen, rCMRO2, was also determined, and no significant change was observed. Our results showed that the combined diffuse optics-ultrasound technique is viable to follow (CVR) and rCMRO2 changes in adults, continuously, at the bed-side and in real time.
PMCID: PMC3018112  PMID: 21258561
(170.3660) Light propagation in tissues; (170.3890) Medical optics instrumentation; (170.6480) Spectroscopy, speckle; (170.7170) Ultrasound; (290.4210) Multiple scattering
2.  Cerebral blood flow during cardiopulmonary bypass in pediatric cardiac surgery: the role of transcranial Doppler – a systematic review of the literature 
Transcranial Doppler Ultrasound (TCD) is a sensitive, real time tool for monitoring cerebral blood flow velocity (CBFV). This technique is fast, accurate, reproducible and noninvasive. In the setting of congenital heart surgery, TCD finds application in the evaluation of cerebral blood flow variations during cardiopulmonary bypass (CPB).
We performed a search on human studies published on the MEDLINE using the keyword "trans cranial Doppler" crossed with "pediatric cardiac surgery" AND "cardio pulmonary by pass", OR deep hypothermic cardiac arrest", OR "neurological monitoring".
Current scientific evidence suggests a good correlation between changes in cbral blood flow and mean cerebral artery (MCA) blood flow velocity. The introduction of Doppler technology has allowed an accurate monitorization of cerebral blood flow (CBF) during circulatory arrest and low-flow CPB. TCD has also been utilized in detecting cerebral emboli, improper cannulation or cross clamping of aortic arch vessels. Limitations of TCD routine utilization are represented by the need of a learning curve and some experience by the operators, as well as the need of implementing CBF informations with, for example, data on brain tissue oxygen delivery and consumption.
In this light, TCD plays an essential role in multimodal neurological monitorization during CPB (Near Infrared Spectroscopy, TCD, processed electro encephalography) that, according to recent studies, can help to significantly improve neurological outcome after cardiac surgery in neonates and pediatric patients.
PMCID: PMC1764902  PMID: 17166253
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.  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
5.  Influence of probe pressure on the diffuse correlation spectroscopy blood flow signal: extra-cerebral contributions 
Biomedical Optics Express  2013;4(7):978-994.
A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.
PMCID: PMC3704102  PMID: 23847725
(170.3880) Medical and biological imaging; (170.2655) Functional monitoring and imaging; (170.3660) Light propagation in tissues; (170.6480) Spectroscopy, speckle
6.  Association of Ultrasonographic Parameters with Subclinical White-Matter Hyperintensities in Hypertensive Patients 
Background and Purpose. Cerebral white matter hyperintensities (WMHs) are regarded as typical MRI expressions of small-vessel disease (SVD) and are common in hypertensive patients. Hypertension induces pathologic changes in macrocirculation and in microcirculation. Changes in microcirculation may lead to SVD of brain and consequently to hypertensive end-organ damage. This damage is regarded the result of interactions between the macrovascular and microvascular levels. We sought to investigate the association of cerebral WMHs with ultrasonographic parameters of cerebral macrocirculation evaluated by carotid duplex ultrasound (CDU) and transcranial doppler (TCD). Subjects and Methods. The study was prospective, cross-sectional and consecutive and included hypertensive patients with brain MRI with WMHs. Patients underwent CDU and TCD. The clinical variables recorded were demographic characteristics (age, gender, race) and vascular risk factors (hypertension, diabetic mellitus, hypercholesterolemia, current smoking, and body mass index). Excluded from the study were patients with history of clinical stroke (including lacunar stroke and hemorrhagic) or transient ischemic attack (either hemispheric or ocular), hemodynamically significant (>50%) extra- or intracranial stenosis, potential sources of cardioembolism, and absent transtemporal windows. WMHs were quantified with the use of a semiquantitative visual rating method. Ultrasound parameters investigated were (1) common carotid artery (CCA) diameter and intima-media thickness, (2) blood flow velocity in the CCA and internal carotid artery (ICA), and (3) blood flow velocity and pulsatility index of middle cerebral artery (MCA). Results. A total of 52 patients fulfilled the study inclusion criteria (mean age 71.4 ± 4.5 years, 54% men, median WMH-score: 20). The only two ultrasound parameters that were independently associated with WMH score in multivariate linear regression models adjusting for demographic characteristics and vascular risk factors were increased mean common carotid artery (CCA) diameter (beta = 0.784, SE = 0.272, P = 0.006, R2 = 23.9%) and increased middle cerebral artery pulsatility index (MCA-PI; beta = 0.262, SE = 0.110, P = 0.025, R2 = 9.0%). Among all ultrasound parameters the highest AUC (areas under the receiver operating characteristic curve) were documented for MCA-PI (AUC = 0.82, 95% CI = 0.68−0.95, P < 0.001) and mean CCA diameter (AUC = 0.80, 95% CI = 0.67−0.92, P < 0.001). Conclusions. Our study showed that in hypertensive individuals with brain SVD the extent of structural changes in cerebral microcirculation as reflected by WMHs burden is associated with the following ultrasound parameters of cerebral macrocirculation: CCA diameter and MCA-PI.
PMCID: PMC3463900  PMID: 23056917
7.  A comparison of transcranial Doppler with near infrared spectroscopy and indocyanine green during hemorrhagic shock: a prospective experimental study 
Critical Care  2006;10(1):R18.
The present study was designed to compare cerebral hemodynamics assessed using the blood flow index (BFI) derived from the kinetics of the tracer dye indocyanine green (ICG) with transcranial Doppler ultrasound (TCD) in an established model of hemorrhagic shock.
After approval from the Animal Investigational Committee, 20 healthy pigs underwent a simulated penetrating liver trauma. Following hemodynamic decompensation, all animals received a hypertonic-isooncotic hydroxyethyl starch solution and either arginine vasopressin or norepinephrine, and bleeding was subsequently controlled. ICG passage through the brain was monitored by near infrared spectroscopy. BFI was calculated by dividing maximal ICG absorption change by rise time. Mean blood flow velocity (FVmean) of the right middle cerebral artery was recorded by TCD. FVmean and BFI were assessed at baseline (BL), at hemodynamic decompensation, and repeatedly after control of bleeding.
At hemodynamic decompensation, cerebral perfusion pressure (CPP), FVmean and BFI dropped compared to BL (mean ± standard deviation; CPP 16 ± 5 mmHg versus 70 ± 16 mmHg; FVmean 4 ± 5 cm·s-1 versus 28 ± 9 cm·s-1; BFI 0.008 ± 0.004 versus 0.02 ± 0.006; p < 0.001). After pharmacological intervention and control of bleeding, FVmean and BFI increased close to baseline values (FVmean 23 ± 9 cm·s-1; BFI 0.02 ± 0.01), respectively. FVmean and BFI were significantly correlated (r = 0.62, p < 0.0001).
FVmean and BFI both reflected the large variations in cerebral perfusion during hemorrhage and after resuscitation and were significantly correlated. BFI is a promising tool to monitor cerebral hemodynamics at the bedside.
PMCID: PMC1550846  PMID: 16507137
8.  Measurement of cerebral blood flow responses to the thigh cuff maneuver: a comparison of TCD with a novel MRI method 
Cerebral autoregulation (CA) describes the mechanism responsible for maintaining cerebral blood flow (CBF) relatively constant, despite changes in mean arterial blood pressure (ABP). This paper introduces a novel method for assessing CA using magnetic resonance imaging (MRI). Images are rapidly and repeatedly acquired using a gradient-echo echo-planar imaging pulse sequence for a period of 4 minutes, during which a transient decrease in ABP is induced by rapid release of bilateral thigh cuffs. The method was validated by comparing the observed MRI signal intensity change with the CBF velocity change in the middle cerebral arteries, as measured by transcranial Doppler (TCD) ultrasound, using a standardized thigh cuff maneuver in both cases. Cross-correlation analysis of the response profiles from the left and right hemispheres showed a greater consistency for MRI measures than for TCD, both for interhemisphere comparisons and for repeated measures. The new MRI method may provide opportunities for assessing regional autoregulatory changes following acute stroke, and in other conditions in which poor autoregulation is implicated.
PMCID: PMC3099636  PMID: 21189480
BOLD; cerebral autoregulation; cerebral blood flow; MRI; transcranial Doppler
9.  Transcranial Doppler Ultrasound: A Review of the Physical Principles and Major Applications in Critical Care 
Transcranial Doppler (TCD) is a noninvasive ultrasound (US) study used to measure cerebral blood flow velocity (CBF-V) in the major intracranial arteries. It involves use of low-frequency (≤2 MHz) US waves to insonate the basal cerebral arteries through relatively thin bone windows. TCD allows dynamic monitoring of CBF-V and vessel pulsatility, with a high temporal resolution. It is relatively inexpensive, repeatable, and portable. However, the performance of TCD is highly operator dependent and can be difficult, with approximately 10–20% of patients having inadequate transtemporal acoustic windows. Current applications of TCD include vasospasm in sickle cell disease, subarachnoid haemorrhage (SAH), and intra- and extracranial arterial stenosis and occlusion. TCD is also used in brain stem death, head injury, raised intracranial pressure (ICP), intraoperative monitoring, cerebral microembolism, and autoregulatory testing.
PMCID: PMC3876587  PMID: 24455270
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 function and cognition in childhood: a systematic review of transcranial doppler studies 
BMC Neurology  2014;14:43.
The contribution of cerebrovascular function to cognitive performance is gaining increased attention. Transcranial doppler (TCD) is portable, reliable, inexpensive and extremely well tolerated by young and clinical samples. It enables measurement of blood flow velocity in major cerebral arteries at rest and during cognitive tasks.
We systematically reviewed evidence for associations between cognitive performance and cerebrovascular function in children (0-18 years), as measured using TCD. A total of 2778 articles were retrieved from PsychInfo, Pubmed, and EMBASE searches and 25 relevant articles were identified.
Most studies investigated clinical groups, where decreased blood flow velocities in infants were associated with poor neurological functioning, and increased blood flow velocities in children with Sickle cell disease were typically associated with cognitive impairment and lower intelligence. Studies were also identified assessing autistic behaviour, mental retardation and sleep disordered breathing. In healthy children, the majority of studies reported cognitive processing produced lateralised changes in blood flow velocities however these physiological responses did not appear to correlate with behavioural cognitive performance.
Poor cognitive performance appears to be associated with decreased blood flow velocities in premature infants, and increased velocities in Sickle cell disease children using TCD methods. However knowledge in healthy samples is relatively limited. The technique is well tolerated by children, is portable and inexpensive. It therefore stands to make a valuable contribution to knowledge regarding the underlying functional biology of cognitive performance in childhood.
PMCID: PMC3975716  PMID: 24602446
Cognition; Infants; Children; Adolescents; Transcranial doppler; Cerebrovascular
12.  Cerebral Autoregulation of Blood Velocity and Volumetric Flow during Steady-State Changes in Arterial Pressure RR 
Hypertension  2013;62(5):973-979.
The validity of using transcranial Doppler (TCD) measurement of cerebral blood flow velocity (CBFV) to assess cerebral autoregulation (CA) still is a concern. This study measured CBFV in the middle cerebral artery (MCA) using TCD and volumetric cerebral blood flow (CBF) in the internal carotid artery (ICA) using color-coded duplex ultrasonography to assess CA during steady-state changes in mean arterial pressure (MAP). Twenty-one healthy adults participated. MAP was changed stepwise by intravenous infusion of sodium nitroprusside and phenylephrine. Changes in CBFV, CBF, cerebrovascular resistance (CVR = MAP/CBF) or resistance index (CVRi = MAP/CBFV) were measured to assess CA by linear regression analysis. The relationship between changes in ICA diameter and MAP was assessed. All values were normalized as percentage changes from baseline. Drug induced changes in MAP were from −26% to 31%. Changes in CBFV and CVRi in response to MAP were linear and the regresssion slopes were similar between MCA and ICA. However, CBF in ICA remained unchanged despite large changes in MAP. Consistently, a steeper slope of changes in CVR relative to CVRi was observed (0.991 vs. 0.804, P < 0.05). The ICA diameter changed inversely in response to MAP (r = −0.418, P < 0.05). These findings indicate that CA can be assessed with TCD mesurements of CBFV and CVRi in MCA. However, it is likely to be underestimated when compared to the measurements of CBF and CVR in ICA. The inverse relationship between changes in ICA diameter and MAP suggests that large cerebral arteries are involved in CA.
PMCID: PMC3893684  PMID: 24041946
cerebral autoregulation; blood pressure; cerebral blood flow; transcranial Doppler; ultrasonography; middle cerebral artery; internal carotid artery
13.  Transcranial Doppler ultrasound blood flow velocity and pulsatility index as systemic indicators for Alzheimer’s disease 
Multiple lines of evidence suggest cardiovascular co-morbidities hasten the onset of Alzheimer’s disease (AD) or accelerate its course.
To evaluate the utility of cerebral vascular physical function/condition parameters as potential systemic indicators of AD, we employed transcranial Doppler (TCD) ultrasound to assess cerebral blood flow and vascular resistance of the 16 arterial segments comprising the circle of Willis and its major tributaries.
Our study revealed decreased arterial mean flow velocity (MFV) and increased pulsatility index (PI) are associated with a clinical diagnosis of presumptive AD. Cerebral blood flow impairment revealed by these parameters reflects the global hemodynamic and structural consequences of a multifaceted disease process yielding diffuse congestive microvascular pathology, increased arterial rigidity, and decreased arterial compliance combined with putative age-associated cardiovascular output declines.
TCD evaluation offers direct physical confirmation of brain perfusion impairment and may ultimately provide a convenient, noninvasive means to assess the efficacy of medical interventions on cerebral blood flow or reveal incipient AD. In the near term, TCD-based direct assessments of brain perfusion may offer the prospect of preventing or mitigating AD simply by revealing patients who would benefit from interventions to improve circulatory system function.
PMCID: PMC3117072  PMID: 21388892
Alzheimer’s disease; transcranial Doppler ultrasonography; cerebral blood flow; brain hypoperfusion; mean flow velocity; pulsatility index
14.  Haemoglobin Oxygen Saturation Is a Determinant of Cerebral Artery Blood Flow Velocity in Children with Sickle Cell Anaemia 
British journal of haematology  2009;145(4):500-505.
Steady-state haemoglobin (Hb) desaturation is a common finding in sickle cell anaemia (Hb SS) that could predispose to stroke by limiting oxygen delivery to the brain. To determine its association with the risk of overt stroke, we examined the relationship between daytime Hb saturation measured by pulse oximetry (SpO2) and cerebral artery blood flow velocity measured by transcranial Doppler ultrasonography (TCD), an established risk factor for overt stroke in Hb SS. We studied 181 children using multivariable models to control for known determinants of TCD velocity, including age, haematocrit, and a measure of stenosis. We found that SpO2 correlated significantly and inversely with TCD velocity in both the right and left middle cerebral arteries. Hb desaturation was associated with increased cerebral artery blood flow velocities and increased odds of abnormal TCD velocities, hence increased risk of stroke. About 5% of the variation in TCD velocity could be ascribed to Hb saturation while controlling for other determinants of TCD velocity. In conclusion, Hb saturation is a determinant of TCD velocity and a risk factor for stroke in children with Hb SS.
PMCID: PMC2737449  PMID: 19344400
sickle cell disease; stroke; risk factor; pulse oximetry; transcranial Doppler ultrasonography
Pediatric blood & cancer  2007;49(3):318-322.
Children with sickle cell disease are at elevated risk of stroke. Risk increases with blood flow velocity in selected cerebral arteries, as measured by transcranial Doppler (TCD) ultrasound and use of TCD to screen these patients is widely recommended. Interpretation of TCD results should be based on knowledge of intra-individual variation in blood flow velocity, information not currently available for sickle cell patients.
Between 1995 and 2002, 4141 subjects, 2–16 years old, with homozygous sickle cell disease or Sβ0-thalasemmia and no history of stroke were screened with TCD, including 2018 subjects screened in one clinical trial (STOP), 1816 screened in another (STOP 2) and 307 screened in an interval ancillary prospective study. The 812 subjects with ≥2 examinations <6 months apart were selected for analysis, including 242 (29.8%) subjects with normal average velocities (i.e. <170 cm/sec), 350 (43.1%) subjects with conditional velocities (i.e. 170–199 cm/sec) and 220 (27.1%) subjects with abnormal velocities (i.e. >200 cm/sec). The intra-subject standard deviation of TCD velocity was estimated from the difference between velocities at the first two eligible examinations on each subject.
An intra-subject standard deviation of 14.9 cm/sec was obtained. Seven (0.9%) subjects had unusually large and unexplained differences between velocities at the two examinations (range of absolute differences: 69–112 cm/sec).
While stroke risk is well demonstrated to increase with increasingly abnormal TCD velocity, given the relatively large intra-subject variability, one TCD examination is generally not sufficient to characterize stroke risk in this patient population.
PMCID: PMC2867598  PMID: 17243135
sickle cell disease; stroke; transcranial Doppler ultrasound
16.  Transcranial Doppler Ultrasound: Technique and Application 
Seminars in neurology  2013;32(4):411-420.
Transcranial Doppler (TCD) ultrasound provides rapid, noninvasive, real-time measures of cerebrovascular function. TCD can be used to measure flow velocity in the basal arteries of the brain to assess relative changes in flow, diagnose focal vascular stenosis, or to detect embolic signals within these arteries. TCD can also be used to assess the physiologic health of a particular vascular territory by measuring blood flow responses to changes in blood pressure (cerebral autoregulation), changes in end-tidal CO2 (cerebral vasoreactivity), or cognitive and motor activation (neurovascular coupling or functional hyperemia). TCD has established utility in the clinical diagnosis of a number of cerebrovascular disorders such as acute ischemic stroke, vasospasm, subarachnoid hemorrhage, sickle cell disease, as well as other conditions such as brain death. Clinical indication and research applications for this mode of imaging continue to expand. In this review, the authors summarize the basic principles and clinical utility of TCD and provide an overview of a few TCD research applications.
PMCID: PMC3902805  PMID: 23361485
transcranial Doppler; cerebral blood flow; ultrasound; cerebrovascular diseases
17.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
18.  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
19.  Impact of kangaroo mother care on cerebral blood flow of preterm infants 
Kangaroo mother care (KMC) has been widely used to improve the care of preterms and low birth weight infants. However, very little is known about cerebral hemodynamics responses in preterm infants during KMC intervention. The aim of this study is to evaluate the changes of cerebral blood flow (CBF) in middle cerebral artery, before and after a 30 minute application of KMC in stable preterm infants.
It is a prospective, pre-post test without a control group study. CBF flow paremeters were measured with Doppler ultrasonography in one middle cerebral artery. Sixty preterm stable infants were assessed before and after 30 min KMC. CBF indices were assessed in different positions before KMC, forty neonates in supine position and 20 in vertical suspension (baby is held vertically away from the skin of his mother). Other dependent variables heart rate and mean arterial blood pressure and Spo2 were also studied before and after KMC.
The mean gestational age of the infants was (32 ± 2 weeks), and mean birth weight was (2080 ± 270 gm). Comparing CBF indices (Pulsatility index and Resistive index) before and after KMC has shown a significant decrease in both Pulsatility index (PI) and Resistive index (RI) after 30 min. KMC, the mean values were (2.0 ± 0.43 vs 1.68 ± 0.33 & 0.81 ± 0.05 vs 0.76 ± 0.06 respectively P < 0.05*) with mean difference (0.32 & 95% CI 0.042-0.41 & 0.05 & 95% CI 0.04 to 0.06 respectively P < 0.05*) and increase in end diastolic velocity & mean velocity 30 min of KMC (10.97 ± 4.63 vs. 15.39 ± 5.66 P < 0.05*& 25.66 ± 10.74 vs. 32.86 ± 11.47 P < 0.05* ) with mean difference (− 4.42 & 95% CI −5.67 to −3.18 and −7.21 & 95% CI - 9.41 to 5.00 respectively). These changes indicate improvement in CBF. No correlation has been found between CBF parameters and studied vital signs or SpO2.
Kangaroo mother care improves cerebral blood flow, thus it might influence the structure and promote development of the premature infant's brain.
PMCID: PMC4234866  PMID: 25391600
Kangaroo mother care; Premature infants; Cerebral blood flow
Because transcranial Doppler TCD is unable to measure arterial diameter, it remains unproven whether the changes in cerebral blood velocity it measures are representative of changes in cerebral blood flow. Our study was designed to compare velocity changes to flow changes measured by two MRI techniques, perfusion MRI and arterial spin labeling, using flavanol-rich cocoa to induce cerebral blood flow changes in healthy volunteers.
We enrolled 20 healthy subjects aged 62 to 80 years (mean 73 years). Each was studied at baseline and after consuming standardized servings of cocoa for 7–14 days.
Changes in middle cerebral artery flow by TCD were significantly correlated with changes in perfusion assessed by gadolinium MRI (r=0.63; p<0.03). Measures with arterial spin labeling showed a stronger correlation with borderline significance.
Changes in flow velocity in the middle cerebral artery associated with drinking cocoa were highly correlated with changes in cerebral blood flow measured by two MRI techniques, using the tracer gadolinium and arterial spin labeling. These results validate Doppler measures of cerebral blood flow velocity as representative assessments of cerebral blood flow.
PMCID: PMC2906813  PMID: 20587424
TCD; cerebral blood flow; MRI; cocoa
21.  Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients during Head of Bed Manipulation 
Background and Purpose
A primary goal of acute ischemic stroke (AIS) management is to maximize perfusion in the affected region and surrounding ischemic penumbra. However, interventions to maximize perfusion, such as flat head-of-bed (HOB) positioning, are currently prescribed empirically. Bedside monitoring of cerebral blood flow (CBF) allows the effects of interventions such as flat HOB to be monitored, and may ultimately be used to guide clinical management.
Cerebral perfusion was measured during head of bed (HOB) manipulations in 17 patients with unilateral acute ischemic stroke affecting large cortical territories in the anterior circulation. Simultaneous measurements of frontal CBF and arterial flow velocity were performed with diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. Results were analyzed in the context of available clinical data and a previous study.
Frontal CBF, averaged over the patient cohort, decreased by 17% (p=0.034) and 15% (p=0.011) in the ipsilesional and contralesional hemispheres, respectively, when HOB was changed from flat to 30°. Significant (cohort-averaged) changes in blood velocity were not observed. Individually, varying responses to HOB manipulation were observed, including paradoxical increases in CBF with increasing HOB angle. Clinical features, stroke volume, and distance to the optical probe could not explain this paradoxical response.
A lower HOB angle results in an increase in cortical CBF without a significant change in arterial flow velocity in AIS, but there is variability across patients in this response. Bedside CBF monitoring with DCS provides a potential means to individualize interventions designed to optimize CBF in AIS.
PMCID: PMC4006296  PMID: 24652308
stroke; perfusion; near-infrared spectroscopy; cerebral hemodynamics; head-of-bed manipulation
22.  Comparison of oxygen-15 PET and transcranial Doppler CO2-reactivity measurements in identifying haemodynamic compromise in patients with symptomatic occlusion of the internal carotid artery 
EJNMMI Research  2012;2:30.
Transcranial Doppler (TCD) CO2-reactivity and oxygen-15 positron emission tomography (PET) have both been used to measure the cerebral haemodynamic state in patients who may have a compromised blood flow. Our purpose was to investigate whether PET and TCD identify the same patients with an impaired flow state of the brain in patients with internal carotid artery (ICA) occlusion.
Patients with recent transient ischaemic attack or minor ischaemic stroke associated with ICA occlusion underwent TCD with measurement of CO2-reactivity and oxygen-15 PET within a median time interval of 6 days.
We included 24 patients (mean age 64 ± 10 years). Seventeen (71%) patients had impaired CO2-reactivity (≤20%), of whom six had absent reactivity (0%) or steal (<0%) in the hemisphere ipsilateral to the ICA occlusion. PET of the perfusion state of the hemisphere ipsilateral to the ICA occlusion demonstrated stage 1 haemodynamic compromise (decreased cerebral blood flow (CBF) or increased cerebral blood volume (CBV) without increased oxygen extraction fraction (OEF)) in 13 patients and stage 2 (increased OEF) in 2 patients. In 12 patients (50%), there was agreement between TCD and PET, indicating haemodynamic compromise in 10 and a normal flow state of the brain in 2 patients. There was no significant correlation between CO2-reactivity and CBF ipsilateral/contralateral hemispheric ratio (r = 0.168, p value = 0.432), OEF ratio (r = −0.242, p value = 0.255), or CBV/CBF ratio (r = −0.368, p value = 0.077).
In patients with symptomatic ICA occlusion, identification of an impaired flow state of the brain by PET and TCD CO2-reactivity shows concordance in only half of the patients.
PMCID: PMC3444322  PMID: 22682265
carotid artery disease; haemodynamic; PET; transcranial Doppler; stroke
23.  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
24.  Effects of aging on the association between cerebrovascular responses to visual stimulation, hypercapnia and arterial stiffness 
Aging is associated with decreased vascular compliance and diminished neurovascular- and hypercapnia-evoked cerebral blood flow (CBF) responses. However, the interplay between arterial stiffness and reduced CBF responses is poorly understood. It was hypothesized that increased cerebral arterial stiffness is associated with reduced evoked responses to both, a flashing checkerboard visual stimulation (i.e., neurovascular coupling), and hypercapnia. To test this hypothesis, 20 older (64 ± 8 year; mean ± SD) and 10 young (30 ± 5 year) subjects underwent a visual stimulation (VS) and a hypercapnic test. Blood velocity through the posterior (PCA) and middle cerebral (MCA) arteries was measured concurrently using transcranial Doppler ultrasound (TCD). Cerebral and systemic vascular stiffness were calculated from the cerebral blood velocity and systemic blood pressure waveforms, respectively. Cerebrovascular (MCA: young = 76 ± 15%, older = 98 ± 19%, p = 0.004; PCA: young = 80 ± 16%, older = 106 ± 17%, p < 0.001) and systemic (young = 59 ± 9% and older = 80 ± 9%, p < 0.001) augmentation indices (AI) were higher in the older group. CBF responses to VS (PCA: p < 0.026) and hypercapnia (PCA: p = 0.018; MCA: p = 0.042) were lower in the older group. A curvilinear model fitted to cerebral AI and age showed AI increases until ~60 years of age, after which the increase levels off (PCA: R2 = 0.45, p < 0.001; MCA: R2 = 0.31, p < 0.001). Finally, MCA, but not PCA, hypercapnic reactivity was inversely related to cerebral AI (MCA: R2 = 0.28, p = 0.002; PCA: R2 = 0.10, p = 0.104). A similar inverse relationship was not observed with the PCA blood flow response to VS (R2 = 0.06, p = 0.174). In conclusion, older subjects had reduced neurovascular- and hypercapnia-mediated CBF responses. Furthermore, lower hypercapnia-mediated blood flow responses through the MCA were associated with increased vascular stiffness. These findings suggest the reduced hypercapnia-evoked CBF responses through the MCA, in older individuals may be secondary to vascular stiffening.
PMCID: PMC3928624  PMID: 24600398
aging; cerebral blood flow; physiology; transcranial doppler; arterial stiffness
25.  Studying cerebral hemodynamics and metabolism using simultaneous near-infrared spectroscopy and transcranial Doppler ultrasound: a hyperventilation and caffeine study 
Physiological Reports  2015;3(4):e12378.
Caffeine is one of the most widely consumed psycho-stimulants in the world, yet little is known about its effects on brain oxygenation and metabolism. Using a double-blind, placebo-controlled, randomized cross-over study design, we combined transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to study caffeine's effect on middle cerebral artery peak blood flow velocity (Vp), brain tissue oxygenation (StO2), total hemoglobin (tHb), and cerebral oxygen metabolism (CMRO2) in five subjects. Hyperventilation-induced hypocapnia served as a control to verify the sensitivity of our measurements. During hypocapnia (∼16 mmHg below resting values), Vp decreased by 40.0 ± 2.4% (95% CI, P < 0.001), while StO2 and tHb decreased by 2.9 ± 0.3% and 2.6 ± 0.4%, respectively (P = 0.003 and P = 0.002, respectively). CMRO2, calculated using the Fick equation, was reduced by 29.3 ± 9% compared to the isocapnic-euoxia baseline (P < 0.001). In the pharmacological experiments, there was a significant decrease in Vp, StO2, and tHb after ingestion of 200 mg of caffeine compared with placebo. There was no significant difference in CMRO2 between caffeine and placebo. Both showed a CMRO2 decline compared to baseline showing the importance of a placebo control. In conclusion, this study showed that profound hypocapnia impairs cerebral oxidative metabolism. We provide new insight into the effects of caffeine on cerebral hemodynamics. Moreover, this study showed that multimodal NIRS/TCD is an excellent tool for studying brain hemodynamic responses to pharmacological interventions and physiological challenges.
PMCID: PMC4425980  PMID: 25907789
Brain; near-infrared spectroscopy; transcranial Doppler ultrasound

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