Coupling between cerebral blood flow and cerebral blood volume: Contributions of different vascular compartments

A better understanding of the coupling between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is vital for furthering our understanding of the BOLD response. The aim of this study was to measure CBF‐CBV coupling in different vascular compartments during neural activation. Three haemodynamic parameters were measured during a visual stimulus. Look‐Locker flow‐sensitive alternating inversion recovery was used to measure changes in CBF and arterial CBV (CBV_a) using sequence parameters optimized for each contrast. Changes in total CBV (CBV_tot) were measured using a gadolinium‐based contrast agent technique. Haemodynamic changes were extracted from a region of interest based on voxels that were activated in the CBF experiments. The CBF‐CBV_tot coupling constant α_tot was measured as 0.16 ± 0.14 and the CBF‐CBV_a coupling constant α_a was measured as 0.65 ± 0.24. Using a two‐compartment model of the vasculature (arterial and venous), the change in venous CBV (CBV_v) was predicted for an assumed value of baseline arterial and venous blood volume. These results will enhance the accuracy and reliability of applications that rely on models of the BOLD response, such as calibrated BOLD.     

Quantitative agreement between [15O]H2O PET and model free QUASAR MRI‐derived cerebral blood flow and arterial blood volume

The purpose of this study was to assess whether there was an agreement between quantitative cerebral blood flow (CBF) and arterial cerebral blood volume (CBVA) measurements by [¹⁵O]H₂O positron emission tomography (PET) and model‐free QUASAR MRI. Twelve healthy subjects were scanned within a week in separate MRI and PET imaging sessions, after which quantitative and qualitative agreement between both modalities was assessed for gray matter, white matter and whole brain region of interests (ROI). The correlation between CBF measurements obtained with both modalities was moderate to high (r²: 0.28–0.60, P < 0.05), although QUASAR significantly underestimated CBF by 30% (P < 0.001). CBV_A was moderately correlated (r²: 0.28–0.43, P < 0.05), with QUASAR yielding values that were only 27% of the [¹⁵O]H₂O‐derived values (P < 0.001). Group‐wise voxel statistics identified minor areas with significant contrast differences between [¹⁵O]H₂O PET and QUASAR MRI, indicating similar qualitative CBV_A and CBF information by both modalities. In conclusion, the results of this study demonstrate that QUASAR MRI and [¹⁵O]H₂O PET provide similar CBF and CBV_A information, but with systematic quantitative discrepancies. Copyright © 2016 John Wiley & Sons, Ltd.     

Measurement of absolute arterial cerebral blood volume in human brain without using a contrast agent

Arterial cerebral blood volume (CBV_a) is a vital indicator of tissue perfusion and vascular reactivity. We extended the recently developed inflow vascular‐space‐occupancy (iVASO) MRI technique, which uses spatially selective inversion to suppress the signal from blood flowing into a slice, with a control scan to measure absolute CBV_a using cerebrospinal fluid (CSF) for signal normalization. Images were acquired at multiple blood nulling times to account for the heterogeneity of arterial transit times across the brain, from which both CBV_a and arterial transit times were quantified. Arteriolar CBV_a was determined separately by incorporating velocity‐dependent bipolar crusher gradients. Gray matter (GM) CBV_a values (n = 11) were 2.04 ± 0.27 and 0.76 ± 0.17 ml blood/100 ml tissue without and with crusher gradients (b = 1.8 s/mm²), respectively. Arterial transit times were 671 ± 43 and 785 ± 69 ms, respectively. The arterial origin of the signal was validated by measuring its T₂, which was within the arterial range. The proposed approach does not require exogenous contrast agent administration, and provides a non‐invasive alternative to existing blood volume techniques for mapping absolute CBV_a in studies of brain physiology and neurovascular diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

Influence of intravenously administered catecholamines on cerebral oxygen consumption and blood flow in the rat

In order to study effects of catecholamines on cerebral oxygen consumption (CMRo₂) and blood flow (CBF), rats maintained on 75 % N₂O and 25 % O₂, were infused i.v. with noradrenaline (2, 5, or 8 μpg. kg^-1. min^-1) or adrenaline (2 or 8, μg. kg^-1.min^-1) for 10 min before CBF and CMR_oz were measured. In about 50% of animals infused with 2–8, μg. kg^-1 min^-1 of noradrenaline, CMRo_z (and CBF) rose. However, there was no dose-dependent response, and CMRo₂, did not exceed 150% of control. The effects of noradrenaline in a dose of 5 μg. kg^-l. min^-1 on CMRo₂, and CBF were blocked by propranolol (2.5μg.kg^-1). In animals infused with adrenaline (8 μg.kg^-1.min^-1) CMRo₂, was doubled and, in many, CBF rose 4- to 6-fold. It is concluded that, when given in sufficient amounts, catecholamines have pronounced effects on cerebral metabolism and blood flow, the effects of adrenaline on CMRo₂, and CBF resembling those observed in status epilepticus.     

Blood oxygenation level-dependent (BOLD) total and extravascular signal changes and ΔR2* in human visual cortex at 1.5, 3.0 and 7.0 T

The characterisation of the extravascular (EV) contribution to the blood oxygenation level‐dependent (BOLD) effect is important for understanding the spatial specificity of BOLD contrast and for modelling approaches that aim to extract quantitative metabolic parameters from the BOLD signal. Using bipolar crusher gradients, total (b = 0 s/mm²) and predominantly EV (b = 100 s/mm²) gradient echo BOLD ΔR₂* and signal changes (ΔS/S) in response to visual stimulation (flashing checkerboard; f = 8 Hz) were investigated sequentially (within < 3 h) at 1.5, 3.0 and 7.0 T in the same subgroup of healthy volunteers (n = 7) and at identical spatial resolutions (3.5 × 3.5 × 3.5 mm³). Total ΔR₂* (z‐score analysis) values were ?0.61 ± 0.10 s^?1 (1.5 T), ?0.74 ± 0.05 s^?1 (3.0 T) and ?1.37 ± 0.12 s^?1 (7.0 T), whereas EV ΔR₂* values were ?0.28 ± 0.07 s^?1 (1.5 T), ?0.52 ± 0.07 s^?1 (3.0 T) and ?1.25 ± 0.11 s^?1 (7.0 T). Although EV ΔR₂* increased linearly with field, as expected, it was found that EV ΔS/S increased less than linearly with field in a manner that varied with TE choice. Furthermore, unlike ΔR₂*, total and EV ΔS/S did not converge at 7.0 T. These trends were similar whether a z‐score analysis or occipital lobe‐based region‐of‐interest approach was used for voxel selection. These findings suggest that calibrated BOLD approaches may benefit from an EV ΔR₂* measurement as opposed to a ΔS/S measurement at a single TE. Copyright © 2010 John Wiley & Sons, Ltd.     

Relationship between baseline cerebral blood flow and vascular responses to changes in PaCO2 measured by positron emission tomography in humans: implication of inter-individual variations of cerebral vascular tone

Aim: Inter‐individual variations in normal human cerebral blood flow (CBF) at rest condition have been reported. Inter‐individual variation of cerebral vascular tone is considered to contribute to this, and several determinants of cerebral vascular tone have been proposed. In the present study, the relationship between CBF and cerebral vascular tone to inter‐individual variation at rest condition was investigated using positron emission tomography (PET). Methods: CBF was measured using PET with H₂¹⁵O in each of 20 healthy subjects (20–28 years) under three conditions: at rest (baseline), during hypercapnia and during hypocapnia. The vascular response to change in P_aCO₂ was calculated as the percentage changes in CBF per absolute change in P_aCO₂ in response to hypercapnia and hypocapnia. Results: A significant negative correlation between baseline CBF and the vascular response to hypocapnia was observed in the thalamus, temporal cortex, parietal cortex, occipital cortex and cerebral cortex (P < 0.05). A trend towards negative correlation between baseline CBF and the vascular response to hypocapnia was observed in the cerebellum and putamen (P < 0.1). A significant negative correlation between baseline CBF and the vascular response to hypercapnia was observed in the occipital cortex (P < 0.05). No significant correlation was observed between baseline CBF and haemoglobin concentration, and P_aCO₂. Conclusion: These findings support the assumption that cerebral vascular tone might incline towards vasoconstriction and vasodilatation when baseline CBF is low and high between individuals respectively. Although several determinants of cerebral vascular tone have been proposed, the mechanism of such inter‐individual differences in cerebral vascular tone is unknown.     

Technical considerations on the validity of blood oxygenation level‐dependent‐based MR assessment of vascular deoxygenation

A blood oxygenation level‐dependent (BOLD)‐based apparent relative oxygen extraction fraction (rOEF) as a semi‐quantitative marker of vascular deoxygenation has recently been introduced in clinical studies of patients with glioma and stroke, yielding promising results. These rOEF measurements are based on independent quantification of the transverse relaxation times T₂ and T₂* and relative cerebral blood volume (rCBV). Simulations demonstrate that small errors in any of the underlying measures may result in a large deviation of the calculated rOEF. Therefore, we investigated the validity of such measurements. For this, we evaluated the quantitative measurements of T₂ and T₂* at 3 T in a gel phantom, in healthy subjects and in healthy tissue of patients with brain tumors. We calculated rOEF maps covering large portions of the brain from T₂, T₂* and rCBV [routinely measured in patients using dynamic susceptibility contrast (DSC)], and obtained rOEF values of 0.63 ± 0.16 and 0.90 ± 0.21 in healthy‐appearing gray matter (GM) and white matter (WM), respectively; values of about 0.4 are usually reported. Quantitative T₂ mapping using the fast, clinically feasible, multi‐echo gradient spin echo (GRASE) approach yields significantly higher values than much slower multiple single spin echo (SE) experiments. Although T₂* mapping is reliable in magnetically homogeneous tissues, uncorrectable macroscopic background gradients and other effects (e.g. iron deposition) shorten T₂*. Cerebral blood volume (CBV) measurement using DSC and normalization to WM yields robust estimates of rCBV in healthy‐appearing brain tissue; absolute quantification of the venous fraction of CBV, however, is difficult to achieve. Our study demonstrates that quantitative measurements of rOEF are currently biased by inherent difficulties in T₂ and CBV quantification, but also by inadequacies of the underlying model. We argue, however, that standardized, reproducible measurements of apparent T₂, T₂* and rCBV may still allow the estimation of a meaningful apparent rOEF, which requires further validation in clinical studies. Copyright © 2014 John Wiley & Sons, Ltd.     

Using microbubbles as an MRI contrast agent for the measurement of cerebral blood volume

The susceptibility differences at the gas–liquid interface of microbubbles (MBs) allow their use as an intravascular susceptibility contrast agent for in vivo MRI. However, the characteristics of MBs are very different from those of the standard gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DPTA) contrast agent, including the size distribution and hemodynamic properties, which could influence MRI outcomes. Here, we investigate quantitatively the correlation between the relative cerebral blood volume (rCBV) derived from Gd‐DTPA (rCBV_Gd) and the MB‐induced susceptibility effect (ΔR₂*_MB) by conventional dynamic susceptibility contrast MRI (DSC‐MRI). Custom‐made MBs had a mean diameter of 0.92 µm and were capable of inducing 4.68 ± 3.02% of the maximum signal change (MSC). The MB‐associated ΔR₂*_MB was compared with rCBV_Gd in 16 rats on 4.7‐T MRI. We observed a significant effect of the time to peak (TTP) on the correlation between ΔR₂*_MB and rCBV_Gd, and also found a noticeable dependence between TTP and MSC. Our findings suggest that MBs with longer TTPs can be used for the estimation of rCBV by DSC‐MRI, and emphasize the critical effect of TTP on MB‐based contrast MRI. Copyright © 2013 John Wiley & Sons, Ltd.     

Near-infrared spectrophotometry determined brain oxygenation during fainting

During orthostatic hypotension we evaluated whether presyncopal symptoms relate to a reduced brain oxygenation. Nine subjects performed 50° head-up tilt for 1 h and eight subjects were followed during 2 h of supine rest and during 1 h of 10° head-down tilt. Cerebral perfusion was assessed by transcranial Doppler determined middle cerebral artery blood velocity (MCA v_mean), while brain blood oxygenation was assessed by near-infrared spectrophotometry determined concentration changes for oxygenated (ΔHbO₂) and deoxygenated haemoglobin and brain cell oxygenation by the oxidized cytochrome c concentration (ΔCytO₂). During head-up tilt, six volunteers developed presyncopal symptoms and mean arterial pressure (88 (78–103) to 68 (57–79) mmHg; median and range), heart rate (96 (72–111) to 65 (50–107) beats min^?1), MCA v_mean (59 (51–82) to 41 (29–56) cm s^?1), ΔHbO₂ (by ?5.3 (?3.0 to ?14.8) μmol l^?1) and ΔCytO₂ were reduced (by ?0.2 (?0.1 to ?0.4) μmol l^?1; P < 0.05). During tilt down the cardiovascular variables recovered immediately and ΔHbO₂ increased to 2.2 (?0.9–12.0) mmol L^?1 above the resting value and also ΔCytO₂ recovered. In the nonsyncopal head-up tilted subjects as in the controls, blood pressure, heart rate, MCA v_mean and brain oxygenation indices remained stable. The results suggest that during orthostasis, presyncopal symptoms relate not only to cerebral hypoperfusion but also to reduced brain oxygenation.     

Quantitative characterization of hemodynamic properties and vasculature dysfunction of high-grade gliomas

Aberrations in tumor and peritumoral vasculature may not be distinguishable by cerebral blood flow (CBF) or cerebral blood volume (CBV) alone. The relationships between CBF and CBV were examined to estimate vasculature-specific hemodynamic characteristics. Twenty glioma patients were studied with dynamic susceptibility T2*-weighted MRI [(dynamic contrast-enhanced magnetic resonance imaging (DSC-MRI)] before and during week 1 and 3 of radiotherapy (RT). CBF and CBV were calculated from DSC-MRI, and relationships between the two were evaluated: the physiological measure of mean transit time (MTT) = CBV/CBF; empirical fitting using the power law CBV = constant x (CBF)(beta). Three different tissue types were assessed: the Gd-enhancing tumor volume (GEV); non-enhanced abnormal tissue located beyond GEV but within the abnormal hyperintense region on FLAIR images (NEV); normal tissue in the hemisphere contralateral to the tumor (CNT). The effects of tissue types, CBV magnitudes (low, medium and high), before and during RT, on MTT and beta were analyzed by analysis of variance (ANOVA). The MTT and beta for the three tissue types were significantly different (p < 0.009). MTT increased from CNT (1.60 s) to NEV (1.93 s) to GEV (2.28 s) (p < 0.0005). beta was significantly greater in GEV (1.079) and NEV (1.070) than in CNT (1.025). Beta increased with increasing CBV magnitude while MTT was independent of CBV magnitude. There was a significant decrease in MTT of NEV and GEV during week 3 of RT compared with pre-RT values for all CBV magnitudes. There was a significant increase in beta during RT in the tumor and peritumor. Progressive abnormalities in vasculature and hemodynamic characteristics of the vascular bed were delineated, with significant disorder in the tumor but mild abnormality in peritumoral tissue.     

A Method for Determining Blood Flow and Oxygen Consumption in the Rat Brain

Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo₂) were measured in rats under nitrous oxide anaesthesia, using a ¹³³Xenon modification of the Kety and Schmidt inert gas technique with sampling of cerebral venous blood from the retroglenoid vein. Extracerebral contamination of the venous blood sampled was studied by comparing the rates at which the activity of ¹³³Xenon decreased in blood and tissues. Contamination was avoided by gentle compression of the contralateral retroglenoid vein during sampling. CBF and CMRo₂ of the rat brain were 80±2 and 7.6 ± 0.2 ml·(100 g)^-1, min^-1, respectively. These values are about 25% lower than those previously obtained for cerebral cortical tissue under similar conditions. Induced hypercapnia (Paco₂ about 70 mm Hg) or hypocapnia (Paco² 15–20 mm Hg) gave rise to expected changes in CBF but did not alter CMRo² The CMRo² of the rat brain is at least twice that of the human brain. This species difference, which is similar to that previously reported for the oxygen uptake of cerebral tissue in vitro, probably reflects on inverse relationship between brain weight and neuronal packing density.     

Cerebral blood flow response to acute hypoxic hypoxia

Hypoxic hypoxia (inspiratory hypoxia) stimulates an increase in cerebral blood flow (CBF) maintaining oxygen delivery to the brain. However, this response, particularly at the tissue level, is not well characterised. This study quantifies the CBF response to acute hypoxic hypoxia in healthy subjects. A 20‐min hypoxic (mean P_ETo ₂ = 52 mmHg) challenge was induced and controlled by dynamic end‐tidal forcing whilst CBF was measured using pulsed arterial spin labelling perfusion MRI. The rate constant, temporal delay and magnitude of the CBF response were characterised using an exponential model for whole‐brain and regional grey matter. Grey matter CBF increased from 76.1 mL/100 g/min (95% confidence interval (CI) of fitting: 75.5 mL/100 g/min, 76.7 mL/100 g/min) to 87.8 mL/100 g/min (95% CI: 86.7 mL/100 g/min, 89.6 mL/100 g/min) during hypoxia, and the temporal delay and rate constant for the response to hypoxia were 185 s (95% CI: 132 s, 230 s) and 0.0035 s^–1 (95% CI: 0.0019 s^–1, 0.0046 s^–1), respectively. Recovery from hypoxia was faster with a delay of 20 s (95% CI: –38 s, 38 s) and a rate constant of 0.0069 s^–1 (95% CI: 0.0020 s^–1, 0.0103 s^–1). R₂*, an index of blood oxygenation obtained simultaneously with the CBF measurement, increased from 30.33 s^–1 (CI: 30.31 s^–1, 30.34 s^–1) to 31.48 s^–1 (CI: 31.47 s^–1, 31.49 s^–1) with hypoxia. The delay and rate constant for changes in R₂* were 24 s (95% CI: 21 s, 26 s) and 0.0392 s^–1 (95% CI: 0.0333 s^–1, 0.045 s^–1 ), respectively, for the hypoxic response, and 12 s (95% CI: 10 s, 13 s) and 0.0921 s^–1 (95% CI: 0.0744 s^–1, 0.1098 s^–1/) during the return to normoxia, confirming rapid changes in blood oxygenation with the end‐tidal forcing system. CBF and R₂* reactivity to hypoxia differed between subjects, but only R₂* reactivity to hypoxia differed significantly between brain regions. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

Cerebral blood volume estimation by ferumoxytol‐enhanced steady‐state MRI at 9.4 T reveals microvascular impact of α1‐adrenergic receptor antibodies

Cerebrovascular abnormality is frequently accompanied by cognitive dysfunctions, such as dementia. Antibodies against the α₁‐adrenoceptor (α₁‐AR) can be found in patients with Alzheimer's disease with cerebrovascular disease, and have been shown to affect the larger vessels of the brain in rodents. However, the impact of α₁‐AR antibodies on the cerebral vasculature remains unclear. In the present study, we established a neuroimaging method to measure the relative cerebral blood volume (rCBV) in small rodents with the ultimate goal to detect changes in blood vessel density and/or vessel size induced by α₁‐AR antibodies. For this purpose, mapping of R₂* and R₂ was performed using MRI at 9.4 T, before and after the injection of intravascular iron oxide particles (ferumoxytol). The change in the transverse relaxation rates (ΔR₂*, ΔR₂) showed a significant rCBV decrease in the cerebrum, cortex and hippocampus of rats (except hippocampal ΔR₂), which was more pronounced for ΔR₂* than for ΔR₂. Immunohistological analyses confirmed that the α₁‐AR antibody induced blood vessel deficiencies. Our findings support the hypothesis that α₁‐AR antibodies lead to cerebral vessel damage throughout the brain, which can be monitored by MRI‐derived rCBV, a non‐invasive neuroimaging method. This demonstrates the value of rCBV estimation by ferumoxytol‐enhanced MRI at 9.4 T, and further underlines the significance of this antibody in brain diseases involving vasculature impairments, such as dementia. Copyright © 2014 John Wiley & Sons, Ltd.     

Near‐infrared spectroscopy determined brain and muscle oxygenation during exercise with normal and resistive breathing

To elevate effects of carbon dioxide (CO₂) retention by way of an increased respiratory load during submaximal exercise (150 W), the concentration changes of oxy‐ (ΔHbO₂) and deoxy‐haemoglobin (ΔHb) of active muscles and the brain were determined by near‐infrared spectroscopy (NIRS) in eight healthy males. During exercise, pulmonary ventilation increased to 33 (28–40) L min^–1 (median with range) with no effect of a moderate breathing resistance (reduction of the pneumotach diameter from 30 to 14 and 10 mm). The end‐tidal CO₂ pressure (P_ETCO ₂) increased from 45 (42–48) to 48 (46–58) mmHg with a reduction of only 1% in the arterial haemoglobin O₂ saturation (S_aO ₂). During control exercise (normal breathing resistance), muscle and brain ΔHbO₂ were not different from the resting levels, and only the leg muscle ΔHb increased (4 (–2–10) μM , P < 0.05). Moderate resistive breathing increased ΔHbO₂ of the intercostal and vastus lateralis muscles to 6 ± (–5–14) and 1 (–7–9) μM (P < 0.05), respectively, while muscle ΔHb was not affected. Cerebral ΔHbO₂ and ΔHb became elevated to 6 (1–15) and 1 (–1–6) μM by resistive breathing (P < 0.05). Resistive breathing caused an increased concentration of oxygenated haemoglobin in active muscles and in the brain. The results indicate that CO₂ influences blood flow to active skeletal muscle although its effect appears to be smaller than for the brain.     

In vivo quantification of hyperoxic arterial blood water T1

Normocapnic hyperoxic and hypercapnic hyperoxic gas challenges are increasingly being used in cerebrovascular reactivity (CVR) and calibrated functional MRI experiments. The longitudinal arterial blood water relaxation time (T_1a) change with hyperoxia will influence signal quantification through mechanisms relating to elevated partial pressure of plasma‐dissolved O₂ (pO₂) and increased oxygen bound to hemoglobin in arteries (Y_a) and veins (Y_v). The dependence of T_1a on Y_a and Y_v has been elegantly characterized ex vivo; however, the combined influence of pO₂, Y_a and Y_v on T_1a in vivo under normal ventilation has not been reported. Here, T_1a is calculated during hyperoxia in vivo by a heuristic approach that evaluates T₁‐dependent arterial spin labeling (ASL) signal changes to varying gas stimuli. Healthy volunteers (n = 14; age, 31.5 ± 7.2 years) were scanned using pseudo‐continuous ASL in combination with room air (RA; 21% O₂/79% N₂), hypercapnic normoxic (HN; 5% CO₂/21% O₂/74% N₂) and hypercapnic hyperoxic (HH; 5% CO₂/95% O₂) gas administration. HH T_1a was calculated by requiring that the HN and HH cerebral blood flow (CBF) change be identical. The HH protocol was then repeated in patients (n = 10; age, 61.4 ± 13.3 years) with intracranial stenosis to assess whether an HH T_1a decrease prohibited ASL from being performed in subjects with known delayed blood arrival times. Arterial blood T_1a decreased from 1.65 s at baseline to 1.49 ± 0.07 s during HH. In patients, CBF values in the affected flow territory for the HH condition were increased relative to baseline CBF values and were within the physiological range (RA CBF = 36.6 ± 8.2 mL/100 g/min; HH CBF = 45.2 ± 13.9 mL/100 g/min). It can be concluded that hyperoxic (95% O₂) 3‐T arterial blood T_1aHH = 1.49 ± 0.07 s relative to a normoxic T_1a of 1.65 s. Copyright © 2015 John Wiley & Sons, Ltd.     

Investigation of the BOLD and CBV fMRI responses to somatosensory stimulation in awake marmosets (Callithrix jacchus)

Understanding the spatiotemporal features of the hemodynamic response function (HRF) to brain stimulation is essential for the correct application of neuroimaging methods to study brain function. Here, we investigated the spatiotemporal evolution of the blood oxygen level‐dependent (BOLD) and cerebral blood volume (CBV) HRF in conscious, awake marmosets (Callithrix jacchus), a New World non‐human primate with a lissencephalic brain and with growing use in biomedical research. The marmosets were acclimatized to head fixation and placed in a 7‐T magnetic resonance imaging (MRI) scanner. Somatosensory stimulation (333‐μs pulses; amplitude, 2 mA; 64 Hz) was delivered bilaterally via pairs of contact electrodes. A block design paradigm was used in which the stimulus duration increased in pseudo‐random order from a single pulse up to 256 electrical pulses (4 s). For CBV measurements, 30 mg/kg of ultrasmall superparamagnetic ironoxide particles (USPIO) injected intravenously, were used. Robust BOLD and CBV HRFs were obtained in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2) and caudate at all stimulus conditions. In particular, BOLD and CBV responses to a single 333‐μs‐long stimulus were reliably measured, and the CBV HRF presented shorter onset time and time to peak than the BOLD HRF. Both the size of the regions of activation and the peak amplitude of the HRFs grew quickly with increasing stimulus duration, and saturated for stimulus durations greater than 1 s. Onset times in S1 and S2 were faster than in caudate. Finally, the fine spatiotemporal features of the HRF in awake marmosets were similar to those obtained in humans, indicating that the continued refinement of awake non‐human primate models is essential to maximize the applicability of animal functional MRI studies to the investigation of human brain function.     

BOLD fMRI and hemodynamic responses to somatosensory stimulation in anesthetized mice: spontaneous breathing vs. mechanical ventilation

Mouse functional MRI (fMRI) has been of great interest due to the abundance of transgenic models. Due to a mouse's small size, spontaneous breathing has often been used. Because the vascular physiology affecting fMRI might not be controlled normally, its effects on functional responses were investigated with optical intrinsic signal (OIS) imaging and 9.4 T BOLD fMRI. Three conditions were tested in C57BL/6 mice: spontaneous breathing under ketamine and xylazine anesthesia (KX), mechanical ventilation under KX, and mechanical ventilation under isoflurane. Spontaneous breathing under KX induced an average pCO₂ of 83 mmHg, whereas a mechanical ventilation condition achieved a pCO₂ of 37‐41 mmHg within a physiological range. The baseline diameter of arterial and venous vessels was only 7%‐9% larger with spontaneous breathing than with mechanical ventilation under KX, but it was much smaller than that in normocapnic isoflurane‐anesthetized mice. Three major functional studies were performed. First, CBV‐weighted OIS and arterial dilations to 4‐second forepaw stimulation were rapid and larger at normocapnia than hypercapnia under KX, but very small under isoflurane. Second, CBV‐weighted OIS and arterial dilations by vasodilator acetazolamide were measured for investigating vascular reactivity and were larger in the normocapnic condition than in the hypercapnic condition under KX. Third, evoked OIS and BOLD fMRI responses in the contralateral mouse somatosensory cortex to 20‐second forepaw stimulation were faster and larger in the mechanical ventilation than spontaneous breathing. BOLD fMRI peaked at the end of the 20‐second stimulation under hypercapnic spontaneous breathing, and at ~9 seconds under mechanical ventilation. The peak amplitude of BOLD fMRI was 2.2% at hypercapnia and ~3.4% at normocapnia. Overall, spontaneous breathing induces sluggish reduced hemodynamic and fMRI responses, but it is still viable for KX anesthesia due to its simplicity, noninvasiveness, and well‐localized BOLD activity in the somatosensory cortex.     

A comparison of pulse oximetry and cerebral oxygenation in children with severe sleep apnea–hypopnea syndrome: a pilot study

Near infrared spectroscopy (NIRS) has been used to assess the impact of obstructive sleep apnea–hypopnea syndrome (OSAHS) on cerebral oxygenation. However, the relationship between the variations in the cerebral tissue oxygen saturation (ΔTOI) and pulse oximetry (ΔSpO₂) has not been assessed in children with OSAHS. Consecutive clinically stable children with severe OSAHS [apnea–hypopnea index (AHI) >15 events h⁻¹] diagnosed during a night‐time polygraphy with simultaneous recording of cerebral oxygenation with NIRS (NIRO‐200NX, Hamamatsu Photonics KK) were included between September 2015 and June 2016. Maximal ΔSpO₂ (SpO₂ drop from the value preceding desaturation to nadir) and concomitant variations in transcutaneous carbon dioxide (ΔPtcCO₂), maximal ΔTOI and maximal variations in cerebral oxygenated (O₂Hb) and deoxygenated (HHb) haemoglobin were reported. The relationships between ΔSpO₂, ΔPtcCO₂ and ΔTOI, ΔO₂Hb and ΔHHb were investigated. The data from five children (three boys, aged 9.6 ± 6.7 years, AHI 16–91 events h⁻¹) were analysed. Strong correlations were found between ΔSpO₂ and ΔTOI (r = 0.887, P < 0.001), but also with ΔO₂Hb and ΔHHb with a particular pattern in the youngest child with a dark skin pigmentation. Mean ΔSpO₂ was 20 ± 17% and mean ΔTOI was 8 ± 7%. Maximal ΔSpO₂ of approximately 70% were coupled with ΔTOI of no more than 35%. ΔPtcCO₂ correlated only weakly with the cerebral oxygenation indexes. This pilot study shows a strong relationship between pulse oximetry and cerebral oxygenation in children with OSAHS, with lower changes in TOI compared to SpO₂. Future studies should address the clinical impact of respiratory events on cerebral oxygenation and its consequences.     

Comparison of relative cerebral blood flow maps using pseudo-continuous arterial spin labeling and single photon emission computed tomography

Pseudo‐continuous arterial spin labeling (PCASL) MRI is a relatively new arterial spin labeling technique and has the potential to extend the cerebral blood flow (CBF) measurement to all tissue types, including white matter. However, the arterial transit time (δ_a) for white matter is not well established and a limited number of reports using multi‐delay methods have yielded inconsistent findings. In this study, we used a different approach and measured white matter δ_a (mean ± standard deviation, 1541 ± 173 ms) by determining the arrival times of exogenous contrast agent in a bolus tracking experiment. The data also confirmed δ_a of gray matter to be 912 ± 209 ms. In the second part of this study, we used these parameters in PCASL kinetic models and compared relative CBF (rCBF, with respect to the whole brain) maps with those measured using a single photon emission computed tomography (SPECT) technique. It was found that the use of tissue‐specific δ_a in the PCASL model was helpful in improving the correspondence between the two modalities. On a regional level, the gray/white matter CBF ratios were 2.47 ± 0.39 and 2.44 ± 0.18 for PCASL and SPECT, respectively. On a single‐voxel level, the variance between the modalities was still considerable, with an average rCBF difference of 0.27. Copyright © 2011 John Wiley & Sons, Ltd.     

Acute effects of acetazolamide on cerbral blood flow in man

We have followed the time course of the effect of the carbonic anhydrase inhibitor acetazolamide injected i. v. in unanesthetized healthy human beings. The dose administered was 500 mg as a bolus. Cerebral blood flow (CBF) was measured continuously before, during and after the injection, using a pulsed ultrasound doppler system, which measured the instantaneous mean velocity across the lumen of the internal carotid artery, just below its entrance into the skull. Ventilation, heart-rate, end-expiratory PCO₂- arterial PCO₂, pH and systemic blood pressure was also measured. We found that acetazolamide caused a rise in CBF which could be detected as early as 2 min after the injection. A maximal average response of 75% increase in CBF was seen after 25 min. The half-time of the declining phase of the response was 95 min. There were no systematic differences in the CO₂ reactivities, given as ACBF/ΔPACO₂ in % of CBF at normocapnia, before and after acetazolamide injection, regardless of the absolute PACO₂ level. The present dose of the drug caused no change in ventilation, alveolar and arterial PCO₂ or in arterial blood pH indicating that the carbonic anhydrase was not fully inhibited. Our observations show that acetazolamide nevertheless caused a rapid vasodilation in the brain and over a wide range of PCO₂′s. We suggest that this agent has a local vasodilator effect on the cerebral arterioles, unrelated to its specific effects as a carbonic anhydrase inhibitor.