Quantitative techniques have been derived for the measurement of global cerebral blood flow, cerebral blood volume, its response to changing arterial carbon dioxide tension and mixed cerebral venous saturation in the human newborn undergoing intensive care. Normal ranges have been established and significant disturbances of cerebral oxygenation and perfusion have been demonstrated in a variety of pathological conditions. Recently, absolute cerebral deoxyhaemoglobin concentration has been obtained in the newborn using second differential spectroscopy. When combined with the measurement of total cerebral haemoglobin concentration, the mean saturation of cerebral blood (SmcO2) may be obtained, allowing global cerebral oxygenation to be determined continuously in the intensive care unit. Marked changes in the concentrations of cerebral oxy- and deoxyhaemoglobin have been observed in foetuses undergoing labour. Measurements of SmcO2 from the foetal brain prior to delivery have shown the expected close correlation with acid-base status at birth. Although movement artefact remains a theoretical risk during uterine contractions, preliminary measurements of optical path length by intensity-modulated spectroscopy have demonstrated only small fluctuations. In future the clinical application of time, phase and spatially resolved spectroscopy is likely to improve both the quantitative accuracy and the regional specificity of physiological measurements in the foetal and neonatal brain.
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
diffuse correlation spectroscopy (DCS); diffuse reflectance spectroscopy (DRS); cerebral hemodynamics; cerebral blood flow; traumatic brain injury; near—infrared spectroscopy (NIRS)
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care
Advances in medical and surgical care of the high-risk neonate have led to increased survival. A significant number of these neonates suffer from neurodevelopmental delays and failure in school. The focus of clinical research has shifted to understanding events contributing to neurological morbidity in these patients. Assessing changes in cerebral oxygenation and regulation of cerebral blood flow (CBF) is important in evaluating the status of the central nervous system. Traditional CBF imaging methods fail for both ethical and logistical reasons. Optical near infrared spectroscopy (NIRS) is increasingly being used for bedside monitoring of cerebral oxygenation and blood volume in both very low birth weight infants and neonates with congenital heart disease. Although trends in CBF may be inferred from changes in cerebral oxygenation and/or blood volume, NIRS does not allow a direct measure of CBF in these populations. Two relatively new modalities, arterial spin-labeled perfusion magnetic resonance imaging and optical diffuse correlation spectroscopy, provide direct, noninvasive measures of cerebral perfusion suitable for the high-risk neonates. Herein we discuss the instrumentation, applications, and limitations of these noninvasive imaging techniques for measuring and/or monitoring CBF.
infant cerebral blood flow; CBF; arterial spin labeled perfusion; MRI; PVL; optical spectroscopy
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.
premature neonates; brain hemodynamics; near-infrared spectroscopy; diffuse correlation spectroscopy; cerebral blood flow; cerebral oxygen consumption; brain development
Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.
Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily increasing from 20 to 70% maximal voluntary isometric contraction (MVIC). For the cuff occlusion protocol, forearm arterial blood flow was occluded via a tourniquet on the upper arm for 3 minutes. Leg or arm muscle hemodynamics, including relative blood flow (rBF), oxy- and deoxy-hemoglobin concentration ([HbO2] and [Hb]), total hemoglobin concentration (THC) and blood oxygen saturation (StO2), were continuously monitored throughout protocols using a custom-built hybrid diffuse optical instrument that combined a commercial near-infrared oximeter for tissue oxygenation measurements and a custom-designed diffuse correlation spectroscopy (DCS) flowmeter for tissue blood flow measurements. Relative oxygen extraction fraction (rOEF) and oxygen consumption rate (rVO2) were calculated from the measured blood flow and oxygenation data. Post-manipulation (fatiguing exercise or cuff occlusion) recovery in muscle hemodynamics was characterized by the recovery half-time, a time interval from the end of manipulation to the time that tissue hemodynamics reached a half-maximal value.
Subjects with FM had similar hemodynamic and metabolic response/recovery patterns as healthy controls during exercise and during arterial occlusion. However, tissue rOEF during exercise in subjects with FM was significantly lower than in healthy controls, and the half-times of oxygenation recovery (Δ[HbO2] and Δ[Hb]) were significantly longer following fatiguing exercise and cuff occlusion.
Our results suggest an alteration of muscle oxygen utilization in the FM population. This study demonstrates the potential of using combined diffuse optical spectroscopies (i.e., NIRS/DCS) to comprehensively evaluate tissue oxygen and flow kinetics in skeletal muscle.
This review describes the diffusion model for light transport in tissues and the medical applications of diffuse light. Diffuse optics is particularly useful for measurement of tissue hemodynamics, wherein quantitative assessment of oxy- and deoxy-hemoglobin concentrations and blood flow are desired. The theoretical basis for near-infrared or diffuse optical spectroscopy (NIRS or DOS, respectively) is developed, and the basic elements of diffuse optical tomography (DOT) are outlined. We also discuss diffuse correlation spectroscopy (DCS), a technique whereby temporal correlation functions of diffusing light are transported through tissue and are used to measure blood flow. Essential instrumentation is described, and representative brain and breast functional imaging and monitoring results illustrate the workings of these new tissue diagnostics.
Ischemia is a common and deleterious secondary injury following traumatic brain injury (TBI). A great challenge for the treatment of TBI patients in the neurointensive care unit (NICU) is to detect early signs of ischemia in order to prevent further advancement and deterioration of the brain tissue. Today, several imaging techniques are available to monitor cerebral blood flow (CBF) in the injured brain such as positron emission tomography (PET), single-photon emission computed tomography, xenon computed tomography (Xenon-CT), perfusion-weighted magnetic resonance imaging (MRI), and CT perfusion scan. An ideal imaging technique would enable continuous non-invasive measurement of blood flow and metabolism across the whole brain. Unfortunately, no current imaging method meets all these criteria. These techniques offer snapshots of the CBF. MRI may also provide some information about the metabolic state of the brain. PET provides images with high resolution and quantitative measurements of CBF and metabolism; however, it is a complex and costly method limited to few TBI centers. All of these methods except mobile Xenon-CT require transfer of TBI patients to the radiological department. Mobile Xenon-CT emerges as a feasible technique to monitor CBF in the NICU, with lower risk of adverse effects. Promising results have been demonstrated with Xenon-CT in predicting outcome in TBI patients. This review covers available imaging methods used to monitor CBF in patients with severe TBI.
cerebral blood flow; brain injury; neurointensive care; Xenon-CT; imaging
Traumatic brain injury is a major cause of mortality and morbidity worldwide. It can be worsened by secondary injury particularly with hypoxia or hypotension. Current prehospital guidelines emphasise regular measurement of peripheral oxygen saturation and blood pressure but there is no monitor in use to provide direct information relating to blood flow or oxygen delivery to the brain tissue. This prospective cohort study will assess the utility of near-infrared spectroscopy monitoring in prehospital medicine in demonstrating injury, pathophysiology and associations with long-term functional outcomes.
A prospective cohort study will be conducted in prehospital services where physician/paramedic teams respond rapidly to patients suffering significant traumatic injuries. A study observer accompanying the clinical team will apply non-invasive near-infrared spectroscopy tissue oximetry using a Nonin EQUANOX 7610 Regional Oximetry monitor (TM Nonin Medical, Inc.). This will be applied to patients with traumatic injuries less than 30 minutes old requiring transport. Measurements will be taken at two sites on the forehead and one on the forearm. Clinical teams will be blinded to all monitoring values. Near-infrared spectroscopy tissue oximetry parameters of oxyhaemoglobin%, deoxyhaemoglobin%, total tissue haemoglobin index and regional oxygen saturation will be recorded. Separate statistical analysis relating to time spent with cerebral regional oxygen saturation values < 45% and time series analysis will be performed to demonstrate associations with acute phase outcomes including injuries seen on cerebral imaging, and long-term functional outcomes measured by Glasgow Outcome Score and Extended Glasgow Outcome Score will then be undertaken.
This prospective cohort study will demonstrate associations evident from the earliest stages of prehospital treatment between near-infrared spectroscopy tissue oximetry values and both acute and long-term outcomes of patients suffering traumatic injuries. This may provide the basis for future interventional studies utilising near-infrared spectroscopy tissue oximetry to guide prehospital trauma care.
This trial is registered with the Australian and New Zealand Clinical Trials Registry. The registration number is ACTRN12611001124921.
Traumatic brain injury; Near-infrared spectroscopy; Prehospital
Neonatal congenital heart disease (CHD) is associated with altered cerebral hemodynamics and increased risk of brain injury. Two novel noninvasive techniques, magnetic resonance imaging (MRI) and diffuse optical and correlation spectroscopies (diffuse optical spectroscopy (DOS), diffuse correlation spectroscopy (DCS)), were employed to quantify cerebral blood flow (CBF) and oxygen metabolism (CMRO2) of 32 anesthetized CHD neonates at rest and during hypercapnia. Cerebral venous oxygen saturation (SvO2) and CBF were measured simultaneously with MRI in the superior sagittal sinus, yielding global oxygen extraction fraction (OEF) and global CMRO2 in physiologic units. In addition, microvascular tissue oxygenation (StO2) and indices of microvascular CBF (BFI) and CMRO2 (CMRO2i) in the frontal cortex were determined by DOS/DCS. Median resting-state MRI-measured OEF, CBF, and CMRO2 were 0.38, 9.7 mL/minute per 100 g and 0.52 mL O2/minute per 100 g, respectively. These CBF and CMRO2 values are lower than literature reports for healthy term neonates (which are sparse and quantified using different methods) and resemble values reported for premature infants. Comparison of MRI measurements of global SvO2, CBF, and CMRO2 with corresponding local DOS/DCS measurements demonstrated strong linear correlations (R2=0.69, 0.67, 0.67; P<0.001), permitting calibration of DOS/DCS indices. The results suggest that MRI and optics offer new tools to evaluate cerebral hemodynamics and metabolism in CHD neonates.
cerebral blood flow; cerebral hemodynamics; diffuse optics; MRI; near-infrared spectroscopy; neonatal ischemia
Murine hindlimb ischemia is a useful model for investigation of the mechanisms of peripheral arterial disease and for understanding the role of endothelial cells and generic factors affecting vascular regeneration or angiogenesis. To date, important research with these models has explored tissue reperfusion following ischemia with Laser Doppler methods, methods which provide information about superficial (~mm) vascular regeneration. In this work, we employ diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) in mice after hindlimb ischemia. We hypothesize that vascular re-growth is not uniform in tissue, and therefore, since diffuse optical methods are capable of probing deep tissues, that the diffuse optics approach will provide a more complete picture of the angiogenesis process throughout the whole depth profile of the limb. Besides increased depth penetration, the combined measurements of DCS and DOS enable all-optical, noninvasive, longitudinal monitoring of tissue perfusion and oxygenation that reveals the interplay between these hemodynamic parameters during angiogenesis. Control mice were found to reestablish 90% of perfusion and oxygen consumption during this period, but oxygen saturation in the limb only partially recovered to about 30% of its initial value. The vascular recovery of mice with endothelial cell-specific deletion of HIF-2α was found to be significantly impaired relative to control mice, indicating that HIF-2α is important for endothelial cell functions in angiogenesis. Comparison of DOS/DCS measurements to parallel measurements in the murine models using Laser Doppler Flowmetry reveal differences in the reperfusion achieved by superficial versus deep tissue during neoangiogenesis; findings from histological analysis of blood vessel development were further correlated with these differences. In general, the combination of DCS and DOS enables experimenters to obtain useful information about oxygenation, metabolism, and perfusion throughout the limb. The results establish diffuse optics as a practical noninvasive method to evaluate the role of transcription factors, such as the endothelial cell-specific HIF-2α, in genetic ally modified mice.
(170.3880) Medical and biological imaging; (170.1420) Biology; (170.3660) Light propagation in tissues; (170.5380) Physiology
Transcranial near-infrared spectroscopy (NIRS) provides an assessment of cerebral oxygen metabolism by monitoring concentration changes in oxidised cytochrome c oxidase Δ[oxCCO]. We investigated the response of Δ[oxCCO] to global changes in cerebral oxygen delivery at different source-detector separations in 16 healthy adults. Hypoxaemia was induced by delivery of a hypoxic inspired gas mix and hypercapnia by addition of 6 % CO2 to the inspired gases. A hybrid optical spectrometer was used to measure frontal cortex light absorption and scattering at discrete wavelengths and broadband light attenuation at 20, 25, 30 and 35 mm. Without optical scattering changes, a decrease in cerebral oxygen delivery, resulting from the reduction in arterial oxygen saturation during hypoxia, led to a decrease in Δ[oxCCO]. In contrast, Δ[oxCCO] increased when cerebral oxygen delivery increased due to increased cerebral blood flow during hypercapnia. In both cases the magnitude of the Δ[oxCCO] response increased from the detectors proximal (measuring superficial tissue layers) to the detectors distal (measuring deep tissue layers) to the broadband light source. We conclude that the Δ[oxCCO] response to hypoxia and hypercapnia appears to be dependent on penetration depth, possibly reflecting differences between the intra- and extracerebral tissue concentration of cytochrome c oxidase.
The aim of the study was to better understand blood-flow changes in large arteries and microvessels during the first 15 minutes of reflow in a P7 rat model of arterial occlusion. Blood-flow changes were monitored by using ultrasound imaging with sequential Doppler recordings in internal carotid arteries (ICAs) and basilar trunk. Relative cerebral blood flow (rCBF) changes were obtained by using laser speckle Doppler monitoring. Tissue perfusion was measured with [14C]-iodoantipyrine autoradiography. Cerebral energy metabolism was evaluated by mitochondrial oxygen consumption. Gradual increase in mean blood-flow velocities illustrated a gradual perfusion during early reflow in both ICAs. On ischemia, the middle cerebral artery (MCA) territory presented a residual perfusion, whereas the caudal territory remained normally perfused. On reflow, speckle images showed a caudorostral propagation of reperfusion through anastomotic connections, and a reduced perfusion in the MCA territory. Autoradiography highlighted the caudorostral gradient, and persistent perfusion in ventral and medial regions. These blood-flow changes were accompanied by mitochondrial respiration impairment in the ipsilateral cortex. Collectively, these data indicate the presence of a primary collateral pathway through the circle of Willis, providing an immediate diversion of blood flow toward ischemic regions, and secondary efficient cortical anastomoses in the immature rat brain.
cerebral ischemia; collateral supply; mitochondria; oxygen consumption; reperfusion
Two major avenues of work converged in the late 1980’s and early 1990’s to give rise to brain perfusion MRI. The development of anatomical brain MRI quickly had as a major goal the generation of angiograms using tricks to label flowing blood in macroscopic vessels. These ideas were aimed at getting information about microcirculatory flow as well. Over the same time course the development of in vivo magnetic resonance spectroscopy had as its primary goal the assessment of tissue function and in particular, tissue energetics. For this the measurement of the delivery of water to tissue was critical for assessing tissue oxygenation and viability. The measurement of the washin/washout of “freely” diffusible tracers by spectroscopic based techniques pointed the way for quantitative approaches to measure regional blood flow by MRI. These two avenues came together in the development of arterial spin labeling (ASL) MRI techniques to measure regional cerebral blood flow. The early use of ASL to measure brain activation to help verify BOLD fMRI led to a rapid development of ASL based perfusion MRI. Today development and applications of regional brain blood flow measurements with ASL continues to be a major area of activity.
Perfusion MRI; magnetization transfer; functional MRI; blood flow tracers
We report the use of a novel hybrid near-infrared spectrometer for the measurement of
optical scattering, pathlength and chromophore concentration in critically ill
patients with brain injury. Ten mechanically ventilated patients with acute brain
injury were studied. In addition to standard neurointensive care monitoring, middle
cerebral artery flow velocity, brain lactate–pyruvate ratio (LPR) and brain tissue
oxygen tension were monitored. The patients were subjected to graded normobaric
hyperoxia (NBH), with the inspired fraction of oxygen increased from baseline to 60%
then 100%. NBH induced significant changes in the concentrations of oxyhaemoglobin,
deoxyhaemoglobin and oxidised–reduced cytochrome c oxidase; these
were accompanied by a corresponding reduction in brain LPR and increase in brain
tissue oxygen tension. No significant change in optical scattering or pathlength was
observed. These results suggest that the measurement of chromophore concentration in
the injured brain is not confounded by changes in optical scattering or pathlength
and that NBH induces an increase in cerebral aerobic metabolism.
Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering.
Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 minutes at each position. Patient and control response differences were assessed.
rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P<0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3% ± 28.2%, P=0.938). rCBF increased in controls (18.6% ± 9.4%, P<0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R=0.40, P<0.001), but not intracranial pressure.
DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.
Diffuse correlation spectroscopy; Near-infrared spectroscopy; Diffuse optical spectroscopy; Head-of-bed; Cerebral blood flow; Neurocritical care; Cerebral hemodynamics
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.
stroke; perfusion; near-infrared spectroscopy; cerebral hemodynamics; head-of-bed manipulation
This article presents a dynamic model that quantifies the temporal evolution of the concentration and oxygen saturation of hemoglobin in tissue, as determined by time-varying hemodynamic and metabolic parameters: blood volume, flow velocity, and oxygen consumption. This multi-compartment model determines separate contributions from arterioles, capillaries, and venules that comprise the tissue microvasculature, and treats them as a complete network, without making assumptions on the details of the architecture and morphology of the microvascular bed. A key parameter in the model is the effective blood transit time through the capillaries and its associated probability of oxygen release from hemoglobin to tissue, as described by a rate constant for oxygen diffusion. The solution of the model in the time domain predicts the signals measured by hemodynamic-based neuroimaging techniques such as functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) in response to brain activation. In the frequency domain, the model yields an analytical solution based on a phasor representation that provides a framework for quantitative spectroscopy of coherent hemodynamic oscillations. I term this novel technique coherent hemodynamics spectroscopy (CHS), and this article describes how it can be used for the assessment of cerebral autoregulation and the study of hemodynamic oscillations resulting from a variety of periodic physiological challenges, brain activation protocols, or physical maneuvers.
Dynamic model; transfer function analysis; phasor; hemoglobin concentration; near-infrared spectroscopy; functional magnetic resonance imaging
Background and Purpose
In focal ischemic cortex, cerebral blood flow autoregulation is impaired, and perfusion passively follows blood pressure variations. Although it is generally agreed that profound hypotension is harmful in acute stroke, the hemodynamic and metabolic impact of increased blood pressure on the ischemic core and penumbra are less well understood. We, therefore, tested whether pharmacologically induced hypertension improves cerebral blood flow and metabolism and tissue outcome in acute stroke using optical imaging with high spatiotemporal resolution.
Cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen were measured noninvasively using simultaneous multispectral reflectance imaging and laser speckle flowmetry during distal middle cerebral artery occlusion in mice. Hypertension was induced by phenylephrine infusion starting 10 or 60 minutes after ischemia to raise blood pressure by 30% for the duration of ischemia; control groups received saline infusion.
Mild induced hypertension rapidly increased cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen in both the core and penumbra and prevented the expansion of cerebral blood flow deficit during 1 hour distal middle cerebral artery occlusion. Induced hypertension also diminished the deleterious effects of periinfarct depolarizations on cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen without altering their frequency. Consistent with this, mild induced hypertension reduced infarct volume by 48% without exacerbating tissue swelling when measured 2 days after 1 hour transient distal middle cerebral artery occlusion.
Our data suggest that mild induced hypertension increases collateral cerebral blood flow and oxygenation and improves cerebral metabolic rate of oxygen in the core and penumbra, supporting its use as bridging therapy in acute ischemic stroke until arterial recanalization is achieved.
cerebral metabolic rate of oxygen; laser speckle flowmetry; middle cerebral artery occlusion; multispectral reflectance imaging; stroke
Cerebral ischemia is the leading cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). Although 70% of the patients show angiographic vasospasm only 30% develop symptomatic vasospasm defined as delayed cerebral ischemia (DCI). Early detection and management of reversible ischemia is of critical importance in patients with SAH. Using a bedside Xenon enhanced computerized tomography (Xenon-CT) scanner makes it possible to measure quantitative regional Cerebral blood flow (CBF) bedside in the neurointensive care setting and intracerebral microdialysis (MD) is a method that offers the possibility to monitor the metabolic state of the brain continuously. Here, we present results from nine SAH patients with both MD monitoring and bedside Xenon-CT measurements. CBF measurements were performed within the first 72 h following bleeding. Six out of nine patients developed DCI at a later stage. Five out of six patients who developed DCI had initial global CBF below 26 ml/100 g/min whereas one had 53 ml/100 g/min. The three patients who did not develop clinical vasospasm all had initial global CBF above 27 ml/100 g/min. High lactate/pyruvate (L/P) ratio was associated with lower CBF values in the area surrounding the catheter. Five out of nine patients had L/P ratio ≥25 and four of these patients had CBF ≤ 22 ml/100 g/min. These preliminary results suggest that patients with initially low global CBF on Xenon-CT may be more likely to develop DCI. Initially low global CBF was accompanied with metabolic disturbances determined by the MD. Most importantly, pathological findings on the Xenon-CT and MD could be observed before any clinical signs of DCI. Combining bedside Xenon-CT and MD was found to be useful and feasible. Further studies are needed to evaluate if DCI can be detected before any other signs of DCI to prevent progress to infarction.
cerebral blood flow; subarachnoid hemorrhage; neurointensive care; Xenon-CT; imaging; vasospasm; microdialysis
Acute ischemic stroke is common and disabling, but there remains a paucity of acute treatment options and available treatment (thrombolysis) is underutilized. Advanced brain imaging, designed to identify viable hypoperfused tissue (penumbra), could target treatment to a wider population. Existing magnetic resonance imaging and computed tomography-based technologies are not widely used pending validation in ongoing clinical trials. T2* oxygen challenge magnetic resonance imaging, by providing a more direct readout of tissue viability, has the potential to identify more patients likely to benefit from thrombolysis – irrespective of time from stroke onset – and patients within and beyond the 4·5 h thrombolysis treatment window who are unlikely to benefit and are at an increased risk of hemorrhage.
This study employs serial multimodal imaging and voxel-based analysis to develop optimal data processing for T2* oxygen challenge penumbra assessment. Tissue in the ischemic hemisphere is compartmentalized into penumbra, ischemic core, or normal using T2* oxygen challenge (single threshold) or T2* oxygen challenge plus cerebral blood flow (dual threshold) data. Penumbra defined by perfusion imaging/apparent diffusion coefficient mismatch (dual threshold) is included for comparison.
Permanent middle cerebral artery occlusion was induced in male Sprague-Dawley rats (n = 6) prior to serial multimodal imaging: T2* oxygen challenge, diffusion-weighted and perfusion imaging (cerebral blood flow using arterial spin labeling).
Across the different methods evaluated, T2* oxygen challenge combined with perfusion imaging most closely predicted 24 h infarct volume. Penumbra volume declined from one to four-hours post-stroke: mean ± SD, 77 ± 44 to 49 ± 37 mm3 (single T2* oxygen challenge-based threshold); 55 ± 41 to 37 ± 12 mm3 (dual T2* oxygen challenge/cerebral blood flow); 84 ± 64 to 42 ± 18 mm3 (dual cerebral blood flow/apparent diffusion coefficient), as ischemic core grew: 155 ± 37 to 211 ± 36 mm3 (single apparent diffusion coefficient threshold); 178 ± 56 to 205 ± 33 mm3 (dual T2* oxygen challenge/cerebral blood flow); 139 ± 30 to 168 ± 38 mm3 (dual cerebral blood flow/apparent diffusion coefficient). There was evidence of further lesion growth beyond four-hours (T2-defined edema-corrected infarct, 231 ± 19 mm3).
In conclusion, T2* oxygen challenge combined with perfusion imaging has advantages over alternative magnetic resonance imaging techniques for penumbra detection by providing serial assessment of available penumbra based on tissue viability.
ischemic penumbra; neuroimaging; oxygen challenge; T2* MRI
Brain damage is universal in the rare survivor of unwitnessed cardiac arrest. Non-pulsatile-controlled cerebral reperfusion offsets this damage, but may simultaneously cause brain oedema when delivered at the required the high mean perfusion pressure. This study analyses pulsatile perfusion first in control pigs and then using controlled reperfusion after prolonged normothermic brain ischaemia (simulating unwitnessed arrest) to determine if it might provide a better method of delivery for brain reperfusion.
Initial baseline studies during isolated brain perfusion in 12 pigs (six non-pulsatile and six pulsatile) examined high (750 cc/min) then low (450 cc/min) fixed flow before and after transient (30 s) ischaemia, while measuring brain vascular resistance and oxygen metabolism. Twelve subsequent pigs underwent 30 min of normothermic global brain ischaemia followed by either uncontrolled reperfusion with regular blood (n = 6) or pulsatile-controlled reperfusion (n = 6) before unclamping brain inflow vessels. Functional neurological deficit score (NDS; score: 0, normal; 500, brain death) was evaluated 24 h post-reperfusion.
High baseline flow rates with pulsatile and non-pulsatile perfusion before and after transient ischaemia maintained normal arterial pressures (90–100 mmHg), surface oxygen levels IN Vivo Optical Spectroscopy (INVOS) and oxygen uptake. In contrast, oxygen uptake fell after 30 s ischaemia at 450 cc/min non-pulsatile flow, but improved following pulsatile perfusion, despite its delivery at lower mean cerebral pressure. Uncontrolled (normal blood) reperfusion after 30 min of prolonged ischaemia, caused negligible INVOS O2 uptake (<10–15%), raised conjugated dienes (CD; 1.75 ± 0.15 A233 mn), one early death, multiple seizures, high NDS (243 ± 16) and extensive cerebral infarcts (2,3,5-triphenyl tetrazolium chloride stain) and oedema (84.1 ± 0.6%). Conversely, pulsatile-controlled reperfusion pigs exhibited normal O2 uptake, low CD levels (1.31 ± 0.07 A233 mn; P < 0.01 versus uncontrolled reperfusion), no seizures and a low NDS (32 ± 14; P < 0.001 versus uncontrolled reperfusion); three showed complete recovery (NDS = 0) and all could sit and eat. Post-mortem brain oedema was minimal (81.1 ± 0.5; P < 0.001 versus uncontrolled reperfusion) and no infarctions occurred.
Pulsatile perfusion lowers cerebral vascular resistance and improves global O2 uptake to potentially offset post-ischaemic oedema following high-pressure reperfusion. The irreversible functional and anatomic damage that followed uncontrolled reperfusion after a 30-min warm global brain ischaemia interval was reversed by pulsatile-controlled reperfusion, as its delivery resulted in consistent near complete neurological recovery and absent brain infarction.
Brain ischaemia; Brain death; Reperfusion; Controlled reperfusion; Neurological recovery; New treatment; Sudden death; Pulsatile perfusion
Hypoxic-ischaemic injury to the brain is an important cause of perinatal death and seems to be the commonest cause of permanent neurodevelopmental disability in newborn infants who survive after intensive care. If this type of brain injury is to be prevented and treatment put on a rational basis, non-invasive methods are required for defining its mechanisms. This review has considered two such methods: magnetic resonance spectroscopy and near infrared spectroscopy. Magnetic resonance spectroscopy is used to measure, in brain tissue, the concentrations of the 'high energy' phosphorus metabolites that are dependent for their synthesis on the processes of oxidative phosphorylation. Intracellular pH can also be measured. Normal maturational changes in the brain have been defined and abnormalities detected in a range of conditions where hypoxic-ischaemic injury was suspected to have occurred. In laboratory animals the acute effects of curtailment of oxygen supply to the brain ('primary' energy failure) have been observed, and the effects of two commonly used treatments, infusions of sodium bicarbonate and glucose, have been tested. After resuscitation of newborn infants from severe intrapartum asphyxia, a latent period has often been noted before energy failure became detectable. This 'secondary' energy failure is due to a variety of damaging reactions initiated by the acute hypoxicischaemic episode and reperfusion of the brain. It is possible that in the future irreversible injury to brain cells following the episode may be prevented or ameliorated by the prompt use of cerebroprotective agents. The extent of abnormalities detected by magnetic resonance spectroscopy has prognostic implications: evidence of severe energy failure in the first days of life was regularly associated with subsequent death or with severe neurodevelopmental impairments. Many technical developments in magnetic resonance spectroscopy are under way, particularly employing proton (1H) spectroscopy, which will allow the intracerebral concentrations of a wide range of metabolites, including neurotransmitters, to be measured. The combination of spectroscopy with magnetic resonance imaging will permit quantitative data to be obtained from selected volumes within the brain. Near infrared spectroscopy is used to make observations at the cotside of the intracerebral concentrations of the chromophores oxyhaemoglobin, deoxyhaemoglobin, and oxidised cytochrome aa3, and it therefore provides information complementary to that obtained by magnetic resonance spectroscopy. Measurements can also be made of cerebral blood flow, cerebral blood volume, and other haemodynamic indices; in addition, the rea
The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic-ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside.
The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia.
In this prospective cohort study, ASL-MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow values (CBF), measured from 1–2 MRI scans for each patient, were compared to mixed venous saturation values (SctO2) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude-integrated electroencephalogram.
Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO2 and CBF in asphyxiated newborns with severe HIE (r = 0.88; p value = 0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO2 and CBF to those with moderate HIE.
NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE.
brain; hypoxic-ischemic encephalopathy; magnetic resonance imaging; newborn; near-infrared spectroscopy; perfusion
Occlusions of bilateral common carotid arteries (bi-CCA) in mice are popular models for the investigation of transient forebrain ischemia. Currently available technologies for assessing cerebral blood flow (CBF) and oxygenation in ischemic mice have limitations. This study tests a novel near-infrared diffuse correlation spectroscopy (DCS) flow-oximeter for monitoring both CBF and cerebral oxygenation in mice undergoing repeated transient forebrain ischemia. Concurrent flow measurements in a mouse brain were first conducted for validation purposes; DCS measurement was found highly correlated with laser Doppler measurement (R2 = 0.94) and less susceptible to motion artifacts. With unique designs in experimental protocols and fiber-optic probes, we have demonstrated high sensitivities of DCS flow-oximeter in detecting the regional heterogeneity of CBF responses in different hemispheres and global changes of both CBF and cerebral oxygenation across two hemispheres in mice undergoing repeated 2-minute bi-CCA occlusions over 5 days. More than 75% CBF reductions were found during bi-CCA occlusions in mice, which may be considered as a threshold to determine a successful bi-CCA occlusion. With the progress of repeated 2-minute bi-CCA occlusions over days, a longitudinal decline in the magnitudes of CBF reduction was observed, indicating the brain adaptation to cerebral ischemia through the repeated preconditioning.
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle