Determination Of Cerebral Blood Flow Research Articles

Genetic deletion of hormone-sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet-induced obesity on memory.

Hormone-sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet-induced obesity. HSL-/-, HSL+/-, and HSL+/+ mice of either sex were fed high-fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild-type mice. CBF was positively correlated with lectin-stained vessel density. HSL deletion did not exacerbate HFD-induced microgliosis in the hippocampus and hypothalamus. HSL-/- mice showed preserved memory performance when compared to wild-type mice, and HSL deletion did not significantly aggravate HFD-induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD-induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet-induced obesity. While HSL-/- mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD-induced neuroinflammation and memory dysfunction.

Neuro-SPECT: On the development and function of brain emission tomography in the Copenhagen area.

This review describes the development of single-photon emission tomography (SPECT) in the Copenhagen area under the leadership of the internationally renown scientist, Niels A. Lassen, and the history leading up to construction of the tomograph. Measurements of global cerebral blood flow (CBF) in the 1940s and 1950s were performed by Kety & Schmidt and Lassen & Munck. Determination of regional cerebral blood flow (rCBF) by intra-arterial injection of 133 Xe and measurement with a 254-multicrystal scintillation detector and a computer system was a major step forward in the study of physiology and pathophysiology of cortical cerebral blood flow. Tomography with radioisotope ligands, including non-invasive administration, was advanced in different centres during the 1970s. An emission tomograph, the Tomomatic 64, was developed as a result of a multidisciplinary Danish and international collaboration. It was the first emission tomograph to provide dynamic data that could produce cross-sectional rCBF images. The present description of the construction and function of the Tomomatic 64 includes comparison with other contemporary and later brain-dedicated SPECT systems. Basic and clinical application of the Tomomatic 64 in Copenhagen resulted in several hundred important scientific publications and improved diagnostics for patients with a variety of neurological disorders. It is concluded that the development of the Tomomatic 64 was a major step forward in the study and examination of rCBF and brain function related to several brain disorders, in addition to vascular diseases.

A mathematical model of cerebral blood flow control in anaemia and hypoxia.

The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli. A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired. The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia. A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model simulation assesses the physiological plausibility of some currently hypothesized cerebral blood flow control mechanisms in hypoxia and anaemia, and also examines the impact of anaemia and hypoxia on brain hypoxia. In addition, carbon dioxide is examined for its impact on brain hypoxia in the context of concomitant changes associated with anaemia and hypoxia. The model calculations are based on a single compartment of brain tissue with constant metabolism and perfusion pressure, as well as previously developed equations describing oxygen and carbon dioxide carriage in blood. Experimental data are used to develop the control equations for cerebral blood flow regulation. The interactive model illustrates that there are clear interactions of anaemia, hypoxia and carbon dioxide in the determination of cerebral blood flow and brain tissue oxygen tension. In both anaemia and hypoxia, cerebral blood flow increases to maintain oxygen delivery, with brain hypoxia increasing when cerebral blood flow control mechanisms are impaired. Hypocapnia superimposes its effects, increasing brain hypoxia. Hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, and this effect is exacerbated when blood flow regulation is degraded by conditions that negatively impact cerebrovascular control. Differences in brain hypoxia in anaemia and hypoxia suggest that brain oxygen tension is not a plausible sensor for cerebral blood flow control.

Dual-contrast pCASL using simultaneous gradient-echo/spin-echo multiband EPI

A 2D gradient-echo EPI is commonly employed for arterial spin labeling (ASL) readout to achieve fast whole brain coverage measurements. However, such a readout suffers from susceptibility artifacts induced by magnetic field inhomogeneities. To reduce these susceptibility effects, single–shot spin-echo EPI was proposed to be used for acquisitions in continuous ASL (CASL). To minimize functional and physiological variations, a gradient-echo (GE)/spin-echo (SE) dual-echo EPI readout of the CASL sequence is needed for a comparison between GE- and SE-based determination of cerebral blood flow (CBF). In this study, we employed a simultaneous GE/SE multiband EPI as the readout of a pseudo-CASL (pCASL) sequence. Motor cortex activations derived from a finger-tapping task and functional networks from resting state fMRI were compared for both GE and SE contrasts. Direct comparison of SE and GE contrasts revealed that GE ASL provides an improved sensitivity of functional activity in finger-tapping and in resting-state imaging. SE ASL, on the other hand, suffered less from susceptibility artifacts induced by magnetic field inhomogeneities and pulsatile flow artifacts.

Simulation at Incomplete Acquisition on Stress-rest Cerebral Blood Flow Quantitative Values One Day Method

The QSPECT dual table autoradiography (DTARG) method can be used for quantitative determination of cerebral blood flow. We verified the influence on quantitative values obtained for cerebral blood flow in the case when usual acquisition was impossible and evaluated those values. Results obtained with an acquisition time of 30 min were considered to be true values, and the correlation and consistency with results of other times were evaluated. Values obtained with a shortened acquisition time showed a high correlation with the true value. As for consistency, there were differences among the various data collection intervals. Nevertheless, regardless of the use of a shortened acquisition time and the data acquisition interval, values obtained with the QSPECT program showed a high correlation with the true value. Based on our findings showing a high correlation, a quantitative evaluation of cerebral blood flow can be performed with the QSPECT DTARG method, even with complications, such as examination interruption, thus, it is considered to be a flexible method.

Assessment of glioma response to radiotherapy using 3D pulsed-continuous arterial spin labeling and 3D segmented volume

BackgroundGliomas are the most common primary brain tumors in adults, in some cases, radiotherapy may be the preferred treatment option especially for elderly people who cannot endure surgery. Therefore, it is necessary to evaluate the effects of radiotherapy on glioma. Arterial spin labeling (ASL) is an MR imaging technique that allows for a quantitative determination of cerebral blood flow (CBF) noninvasively. Tumor volume is still an important determinant for evaluating treatment response. The purpose of this study was to investigate the relationship between the tumor perfusion parameters and tumor volume and assess the effects of radiotherapy on glioma using pulsed-continuous arterial spin labeling (pcASL) technique. Methods35 patients with gliomas, histologically classified as low-grade group (n=16) and high-grade group (n=19), treated with radiotherapy only or before using other therapies were included in this study. MR examinations, including T1 weighted image and pcASL, were performed before and 4, 8, 12, 16 weeks after radiotherapy. Regional CBF of normal tissue, mean tumor blood flow (TBFmean), maximum tumor blood flow (TBFmax), and tumor volume were evaluated at each time point. Both the percentage change in CBF (CBF ratio), TBFmean (TBFmean ratio), TBFmax (TBFmax ratio) and the percentage change in tumor volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and CBF ratio, TBFmean ratio, TBFmax ratio was assessed using linear regression analysis and Pearson’s correlation. ResultsThe TBFmean and TBFmax of high-grade gliomas were significantly higher than that of low-grade group. In high-grade group, a strong correlation was demonstrated between the tumor volume and the TBFmax before radiotherapy (R2=0.35, rs=0.59, p<0.05). There was also a significant correlation between the TBFmax before radiotherapy and the tumor volume ratio before and 8 weeks after radiotherapy (R2=0.56, rs=−0.74, p<0.05). ConclusionThe TBFmax measured using pcASL could assess tumoral grade and also could become a potential tool for evaluating the therapeutic effects of radiation.

Quantitative cerebral blood flow with bolus tracking perfusion MRI: Measurements in porcine model and comparison with PET

We recently presented a method for the quantitative measurement of the arterial input function which allows for determination of absolute cerebral blood flow (CBF) values without adjustable parameters. The aim of the present work is to estimate absolute CBF values by using this new technique and to compare it with the gold standard for cerebral perfusion, H(2)(15)O positron emission tomography. Pigs (13) were comparatively investigated by each method performing multiple measurement runs. The reproducibility of both methods was assessed by a voxel-wise correlation of repeated measurements. An intersubject evaluation was performed on median whole-brain CBF estimates. The mean CBF (MRI) was 20±4mL/100g/min for gray matter, the mean CBF (positron emission tomography) was 24±6mL/100g/min for gray and white matter. The reproducibility for MRI correlated with r = 0.85 and P<0.0001, for positron emission tomography with r = 0.76 and P<0.0001. The correlation for the median whole-brain CBF in MRI and positron emission tomography was r = 0.60 and P = 0.04. The proposed method allows for determination of quantitative CBF without normalization factors. The relatively low estimates of absolute CBF most likely results from the higher age of the pigs as compared to other studies. The intermediate correlation between both methods is caused by physiological intraindividual fluctuations of the CBF and by a limited reproducibility of both methods.

Three‐dimensional whole‐brain perfusion quantification using pseudo‐continuous arterial spin labeling MRI at multiple post‐labeling delays: accounting for both arterial transit time and impulse response function

Measurement of the cerebral blood flow (CBF) with whole-brain coverage is challenging in terms of both acquisition and quantitative analysis. In order to fit arterial spin labeling-based perfusion kinetic curves, an empirical three-parameter model which characterizes the effective impulse response function (IRF) is introduced, which allows the determination of CBF, the arterial transit time (ATT) and T(1,eff). The accuracy and precision of the proposed model were compared with those of more complicated models with four or five parameters through Monte Carlo simulations. Pseudo-continuous arterial spin labeling images were acquired on a clinical 3-T scanner in 10 normal volunteers using a three-dimensional multi-shot gradient and spin echo scheme at multiple post-labeling delays to sample the kinetic curves. Voxel-wise fitting was performed using the three-parameter model and other models that contain two, four or five unknown parameters. For the two-parameter model, T(1,eff) values close to tissue and blood were assumed separately. Standard statistical analysis was conducted to compare these fitting models in various brain regions. The fitted results indicated that: (i) the estimated CBF values using the two-parameter model show appreciable dependence on the assumed T(1,eff) values; (ii) the proposed three-parameter model achieves the optimal balance between the goodness of fit and model complexity when compared among the models with explicit IRF fitting; (iii) both the two-parameter model using fixed blood T1 values for T(1,eff) and the three-parameter model provide reasonable fitting results. Using the proposed three-parameter model, the estimated CBF (46 ± 14 mL/100 g/min) and ATT (1.4 ± 0.3 s) values averaged from different brain regions are close to the literature reports; the estimated T(1,eff) values (1.9 ± 0.4 s) are higher than the tissue T1 values, possibly reflecting a contribution from the microvascular arterial blood compartment.

Imaging of the appearance time of cerebral blood using [15O]H2O PET for the computation of correct CBF

BackgroundQuantification of cerebral blood flow (CBF) is important for the understanding of normal and pathologic brain physiology. Positron emission tomography (PET) with H215O (or C15O2) can quantify CBF and apply kinetic analyses, including autoradiography (ARG) and the basis function methods (BFM). These approaches, however, are sensitive to input function errors such as the appearance time of cerebral blood (ATB), known as the delay time. We estimated brain ATB in an image-based fashion to correct CBF by accounting for differences in computed CBF values using three different analyses: ARG and BFM with and without fixing the partition coefficient.MethodsSubject groups included those with no significant disorders, those with elevated cerebral blood volume, and those with reduced CBF. All subjects underwent PET examination, and CBF was estimated using the three analyses. The ATB was then computed from the differences of the obtained CBF values, and ATB-corrected CBF values were computed. ATB was also estimated for regions of interest (ROIs) of multiple cortical regions. The feasibility of the present method was tested in a simulation study.ResultsThere were no significant differences in the obtained ATB between the image- and ROI-based methods. Significantly later appearance was found in the cerebellum compared to other brain regions for all groups. In cortical regions where CBF was reduced due to occlusive lesions, the ATB was 0.2 ± 1.2 s, which was significantly delayed relative to the contralateral regions. A simulation study showed that the ATB-corrected CBF was less sensitive to errors in input function, and noise on the tissue curve did not enhance the degree of noise on ATB-corrected CBF image.ConclusionsThis study demonstrates the potential utility of visualizing the ATB in the brain, enabling the determination of CBF with less sensitivity to error in input function.

Effect of cyclodextrin complexation on the in vivo disposition of the brain imaging radiopharmaceutical 99mTechnetium ethyl cysteinate dimer (99mTc-ECD).

The brain imaging radiopharmaceutical, 99mTechnetium ethyl cysteinate dimer (99mTc-ECD, 99mTc-bicisate) is the most recent addition to the available set of radiopharmaceuticals for measuring cerebral blood flow. Ideally radiotracers should be trapped in the brain long enough so that their distribution can be quantitated and should demonstrate good spatial resolution. Furthermore, the stability (chemical and metabolic) and bioavailability of radiopharmaceuticals have in general proved to be a challenge during development and clinical administration. In view of these challenges and background, this study with 99mTc-ECD is presented. The aims of this research program were to develop novel approaches to improve the chemical and metabolic stability and the bioavailability of 99mTc-ECD across the blood brain barrier for cerebral blood flow determinations, using the well known non-human primate in vivo baboon model. These aims were addressed by investigating the influence of cyclodextrin--99mTc-ECD complexation on normal cerebral blood flow patterns, using two different cyclodextrins, i.e., gamma-cyclodextrin (CAS 17465-86-0) and beta-trimethylcyclodextrin (CAS 55216-11-0). The effect of incubation of 99mTc-ECD (with or without cyclodextrin complexation) in plasma, on metabolic esterase action, was also investigated. Possible protection against plasma esterase by acetylcholine (CAS 51-84-3) of 99mTc-ECD was further determined. The current study has shown that cyclodextrin complexation of 99mTc-ECD indeed offers a useful approach to improve the stability of the radiopharmaceutical against peripheral metabolism. The acetylcholine shows also potential to protect 99mTc-ECD. However, it is clear from the current data that the choice of cyclodextrin is of utmost importance, as has been observed from significantly reduced the bioavailability of 99mTc-ECD when complexed with beta-trimethylcyclodextrin. The plasma incubation procedures showed that gamma-cyclodextrin offers protection with only slightly reduced bioavailability. This study has indicated that novel approaches, such as cyclodextrin technologies, indeed show potential to modify the performance in its currently available 99mTc-ECD form.

The brain at work

Our understanding of the cerebral blood flow (CBF) response to exercise has evolved dramatically over some 20 years in parallel with the advent of new methods to measure brain perfusion in humans. Previously, the Kety–Schmidt method was the only method available for evaluation of CBF in humans. The outflow from the brain through the internal jugular vein was taken to represent CBF and no change was found during exercise, probably because the spinal veins become more important when humans are upright as is the case for most exercise studies (Ide & Secher, 2000). As a consequence, it was often considered that exercise was the exception for which cerebral ‘activation’ (and maybe thinking?) was not required. Yet, with the introduction of methods that evaluate brain tissue flow (133Xenon-clearance) or inflow to the brain through the common or, ideally the internal carotic artery, an ∼20% increase in CBF during mild- to moderate-intensity dynamic exercise was observed. The CBF then levels out or maybe decreases when exercise becomes intense, with the decrease in the arterial carbon dioxide tension accompanying the exponential increase in ventilation. Thus CBF, and indeed cerebral oxygenation responses during incremental exercise, were hypothesised to follow an inverted U-shaped curve. The vast majority of human studies have applied a transcranial Doppler (TCD) approach to evaluate changes in CBF during exercise. Although this approach has the advantage that it can be used during high-intensity dynamic exercise of a large muscle mass, when using the TCD technique one must assume that the diameter of the isonated artery does not change. This assumption has become universally accepted although TCD was introduced by R. Aaslid (1984) to detect vasospasm after neurosurgical procedures. In support of the supposition that the diameter of the isonated artery at the base of the brain (often the middle cerebral artery (MCA)) remains constant during exercise, an inverted U-shape response to incremental exercise is detected with the TCD, and the magnitude of the increase in mean flow velocity is similar to that determined by other estimates of CBF (∼20%). In contrast, the diameter of the MCA increases in response to hypoxia (Wilson et al. 2011) and constricts in response to the administration of the α1-adrenergic receptor agonist phenylephrine (Ogoh et al. 2011), indicating that there is a need for new ambulatory methods for the evaluation of CBF. In a recent issue of The Journal of Physiology, Vogiatzis et al. (2011) introduced a new method using near-infrared spectroscopy to detect CBF (in the frontal lobe) during progressive exercise after bolus injection of idocyanine green, with and without hypoxia, in trained cyclists. It is comforting that the inverted U-shape CBF response to incremental exercise is confirmed by this initiative, and that the validity of the method is supported by an increase in CBF during hypoxia. Yet, as mentioned by the authors, the determined CBF is unreasonably low (23 ml min−1 100 g−1) compared to a normal value of ∼50 ml min−1 100 g−1 and the increase with CBF during exercise is twice as large as normally found. Near-infrared light has to pass through the skin and the scalp to reach the frontal lobe and the authors consider that the low skin (and scalp) blood flow could influence the result. Accordingly, it would be of value if this method for determination of CBF were repeated during exercise after skin blood flow is eliminated, e.g. by cooling the skin or after the administration of phenylephrine (Ogoh et al. 2011). The TCD technique has been invaluable for the development in understanding the brain at work both under normoxic and hypoxic conditions; however, it is problematic that the TCD evaluation of CBF is expressed as a velocity. Such a limitation may be surmounted by using near-infrared spectroscopy to determine CBF during exercise (Vogiatzis et al. 2011), although the extent of the influence of skin blood flow must be established. Similarly, flow in basal cerebral arteries may be evaluated by duplex ultrasound (Wilson et al. 2011) as it is established for peripheral arteries. Accordingly, we now have two additional methods available to take the evaluation of CBF during hypoxic exercise to new heights and the study by Vogiatzis et al. (2011) provides support to the notion that exercise in hypoxia is limited by cerebral oxygen supply and brain oxygenation.

Phase-Contrast Magnetic Resonance Angiography Measurements of Global Cerebral Blood Flow in the Neonate

Cerebral blood flow (CBF) alterations are important in pathogenesis of neonatal ischemic/hemorrhagic brain damage. In clinical practice, estimation of neonatal CBF is mostly based on Doppler-measured blood flow velocities in major intracranial arteries. Using phase-contrast magnetic resonance angiography (PC-MRA), global CBF can be estimated, but there is limited neonatal experience. The objective of this study was to gain experience with PC-MRA for the determination of global CBF in neonates. In infants eligible for MRI, PC-MRA global CBF was determined by measuring volume blood flow in both internal carotid arteries (ICAs) and basilar artery (BA). Thirty newborns (GA, 25.7-42.1 wk; weight, 1050-5858 g; postconceptional age, 225-369 d) were investigated. Total PC-MRA CBF ranged from 27 to 186 mL/min. Significant correlations between PC-MRA CBF and postconceptional age and weight were detected. When calculating PC-MRA measured CBF per kilogram body weight, brain perfusion was about stable over the range of postconceptional ages and ranged between 11 and 48 mL/min/kg (median, 25 mL/min/kg). In conclusion, neonatal PC-MRA CBF seems to be a useful technique to estimate noninvasive CBF.

Nonhuman Primate Positron Emission Tomography Neuroimaging in Drug Abuse Research

Positron emission tomography (PET) neuroimaging in nonhuman primates has led to significant advances in our current understanding of the neurobiology and treatment of stimulant addiction in humans. PET neuroimaging has defined the in vivo biodistribution and pharmacokinetics of abused drugs and related these findings to the time course of behavioral effects associated with their addictive properties. With novel radiotracers and enhanced resolution, PET neuroimaging techniques have also characterized in vivo drug interactions with specific protein targets in the brain, including neurotransmitter receptors and transporters. In vivo determinations of cerebral blood flow and metabolism have localized brain circuits implicated in the effects of abused drugs and drug-associated stimuli. Moreover, determinations of the predisposing factors to chronic drug use and long-term neurobiological consequences of chronic drug use, such as potential neurotoxicity, have led to novel insights regarding the pathology and treatment of drug addiction. However, similar approaches clearly need to be extended to drug classes other than stimulants. Although dopaminergic systems have been extensively studied, other neurotransmitter systems known to play a critical role in the pharmacological effects of abused drugs have been largely ignored in nonhuman primate PET neuroimaging. Finally, the study of brain activation with PET neuroimaging has been replaced in humans mostly by functional magnetic resonance imaging (fMRI). There has been some success in implementing pharmacological fMRI in awake nonhuman primates. Nevertheless, the unique versatility of PET imaging will continue to complement the systems-level strengths of fMRI, especially in the context of nonhuman primate drug abuse research.

Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m

Upon ascent to high altitude, cerebral blood flow (CBF) rises substantially before returning to sea-level values. The underlying mechanisms for these changes are unclear. We examined three hypotheses: (1) the balance of arterial blood gases upon arrival at and across 2 weeks of living at 5050 m will closely relate to changes in CBF; (2) CBF reactivity to steady-state changes in CO2 will be reduced following this 2 week acclimatisation period, and (3) reductions in CBF reactivity to CO2 will be reflected in an augmented ventilatory sensitivity to CO2. We measured arterial blood gases, middle cerebral artery blood flow velocity (MCAv, index of CBF) and ventilation () at rest and during steady-state hyperoxic hypercapnia (7% CO2) and voluntary hyperventilation (hypocapnia) at sea level and then again following 2–4, 7–9 and 12–15 days of living at 5050 m. Upon arrival at high altitude, resting MCAv was elevated (up 31 ± 31%; P < 0.01; vs. sea level), but returned to sea-level values within 7–9 days. Elevations in MCAv were strongly correlated (R2= 0.40) with the change in ratio (i.e. the collective tendency of arterial blood gases to cause CBF vasodilatation or constriction). Upon initial arrival and after 2 weeks at high altitude, cerebrovascular reactivity to hypercapnia was reduced (P < 0.05), whereas hypocapnic reactivity was enhanced (P < 0.05 vs. sea level). Ventilatory response to hypercapnia was elevated at days 2–4 (P < 0.05 vs. sea level, 4.01 ± 2.98 vs. 2.09 ± 1.32 l min−1 mmHg−1). These findings indicate that: (1) the balance of arterial blood gases accounts for a large part of the observed variability (∼40%) leading to changes in CBF at high altitude; (2) cerebrovascular reactivity to hypercapnia and hypocapnia is differentially affected by high-altitude exposure and remains distorted during partial acclimatisation, and (3) alterations in cerebrovascular reactivity to CO2 may also affect ventilatory sensitivity.

Regional cerebral blood flow in healthy volunteers measured by the graph plot method with iodoamphetamine SPECT

The graph plot method, a technique that uses N-isopropyl-(123)I-p-iodoamphetamine (IMP) and single photon emission computed tomography (SPECT) for non-invasive measurement of regional cerebral blood flow (CBF), has been developed and applied in the clinical setting, although it has been performed without obtaining normal CBF values in normal, healthy subjects. The aim of this study was to measure normal regional CBF in older healthy subjects with IMP SPECT and the graph plot method. Eleven healthy volunteers (mean age: 63.5 ± 8.9 years; six males and five females) were recruited and regional CBF was measured using IMP SPECT and the graph plot method. The averaged global CBF was 45.4 ml/100 g/min. The distribution of regional CBF was almost homogenous in the cortices. There was no significant correlation between the global CBF and age in subjects aged 50-80 years. We used the IMP graph plot method to measure regional CBF in normal healthy subjects, without arterial blood sampling, and obtained compatible CBF values. This method is non-invasive and convenient for determination of regional CBF in the clinical setting.

Development of a fluorescent microsphere technique for rapid histological determination of cerebral blood flow

The purpose of this study was to develop a more efficient fluorescent microsphere method to facilitate the rapid use of the histological technique and to enable its use in large tissue regions. Using fluorescent plate/slide imaging technology and automated detection and analysis software, we were able to rapidly image, detect, and count 3 separate microsphere colors in 200 μm thick tissue sections from piglet brain. In resting newborn piglets ( n = 6) on isoflurane anesthesia, we measured a median total cerebral blood flow (CBF) of 105 ml/min/100 g (range 27–206 ml/min/100 g). Compared with other FM analysis methods, our method reduces the time required to determine blood flow, improves accuracy in lipid-rich tissues and large tissue regions and, unlike the radiolabeled microsphere method, can be combined with histological analysis.

Evaluation of cerebral infarctions of the carotid area by an intravenous 133Xenon and 99mTechnetium method.

Quantitative determinations of regional cerebral blood flow (rCBFf, rCBFm) and volume (rCBV), transfer time (rCTT) and fast compartmental weight (Wf) were performed in 34 patients with infarctions of the carotid area by a 133Xe and 99mTc intravenous injection method. The results were compared with clinical signs and electroencephalographic (EEG) findings. A significant difference was found between the lesion side and the control side in all the parameters except rCBV. This difference increased with the severity of the infarction and age of the patients. The difference between the two sides was especially great in the patients with totally occluded internal carotid artery. A slight diaschisis could be observed in the present infarction group. An almost significant reduction on the "normal side" was seen in Wf. In order to assess the reciprocal influence of all the different blood flow parameters, the difference index (DI): Formula: (see text) was calculated, where delta i = the difference between the two sides in one parameter expressed in percent. This proved to be abnormal in 80% of the patients. The atraumatic isotope technique employed offers a good opportunity for the quantitative evaluation of hemodynamics in cerebral infarction and serves as an aid in the diagnosis of infarction.

Regional cerebral oxygen utilization and blood flow in normal man using oxygen-15 and positron emission tomography.

Quantitative determination of regional cerebral blood flow (rCBF), regional cerebral oxygen utilization (rCMRO2) and regional oxygen extraction ratio (rOER) was performed in 11 normal volunteers by an oxygen 15 inhalation method and positron emission tomography. Regional values comparable with figures from the literature have been obtained. This non-invasive approach offers the possibility of a simultaneous quantitative evaluation of these physiological parameters in health and disease.

Variability in Pediatric Brain Death Determination and Documentation in Southern California

Because the concept of brain death is difficult to define and to apply, we hypothesized that significant variability exists in pediatric brain death determination and documentation. Children (0-18 years of age) for whom death was determined with neurologic criteria between January 2000 and December 2004, in southern California, were included. Medical charts were reviewed for documented performance of 14 specific elements derived from the 1987 brain death guidelines and confirmatory testing. A total of 51.2% of children (142 of 277 children) referred to OneLegacy became organ donors. Care locations varied, including PICUs (68%), adult ICUs (29%), and other (3%). One patient was <7 days, 6 were 7 days to 2 months, 22 were 2 months to 1 year, and 113 were >1 year of age. The number of brain death examinations performed was 0 (4 patients), 2 (122 patients), 3 (14 patients), or 4 (2 patients). Recommended intervals between examinations were followed for 18% of patients >1 year of age and for no younger patients. A mean of only 5.5 of 14 examination elements were completed by neurologists and pediatric intensivists and 5.8 by neurosurgeons. No apnea testing was recorded in 60% of cases, and inadequate PaCO(2) increase occurred in more than one half. Cerebral blood flow determination was performed as a confirmatory test 74% of the time (83 of 112 cases), compared with 26% (29 of 112 cases) for electroencephalography alone. Children suffering brain death are cared for in various locations by a diverse group of specialists. Clinical practice varies greatly from established guidelines, and documentation is incomplete for most patients. Physicians rely on cerebral blood flow measurements more than electroencephalography for confirmatory testing. Codifying clinical and testing criteria into a checklist could lend uniformity and enhance the quality and rigor of this crucial determination.

Brain Imaging and Behavior: Progress and Opportunities

The emergence of advanced noninvasive medical imaging directed toward the in vivo investigation of the human brain has revolutionized the study of brain behavior relationships in healthy individuals as well as in those with illnesses affecting neural structure and function. Computer-assisted tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) are landmark technical advances that forever changed the clinical neuroscience disciplines of neurology, neurosurgery, psychiatry and neuropsychology, as well as radiology itself, as they entered widespread use during the 1970s (CT) and 1980s (PET and MRI). These tools were rapidly applied to clinical research studies of major brain disorders from strokes and tumors to dementia and schizophrenia. In the post-millennial era, high field MRI now yields unprecedented information about brain morphology with spatial resolution at the millimeter or sub-millimeter scale. Numerous MR techniques can be tuned to reveal particular normal or lesional tissue contrast. T2-weighted and fluidattenuated inversion recovery MR scans have become an accepted surrogate marker for quantifying demyelinating lesion burden in patients with multiple sclerosis in clinical trials and are also widely used to quantify microvascular lesion burden. These techniques have also been used to study cognitive correlates of specific brain disorders. MR and PET are moving toward becoming accepted biomarkers for detection and treatment monitoring in Alzheimer’s disease and other dementias. Fluorodeoxyglucose PET assessment of metabolism was recently approved by Medicare for use in the differential diagnosis of dementia in complex or ambiguous cases. Advanced molecular imaging probes targeting specific receptors, transporters or pathophysiological features of disease also show great promise for early diagnosis and as a biomarker for treatment response. These and other related tools will play a major role in the new era of personalized medicine. A remarkable recent example is the advent of ligands for in vivo labeling of brain amyloid, a key molecular hallmark of Alzheimer’s disease involved in plaque formation. Use of blood oxygen level dependent contrast functional MRI (fMRI) to assess brain activation patterns has been enormously successful as a research tool since the milestone studies in the early 1990s. Arterial spin labeling fMRI techniques now permit quantitative determination of cerebral blood flow without ionizing radiation. Evidence of fMRI’s maturity is the recent provision of a current procedural terminology code for reimbursement when used as a clinically indicated mapping procedure for neurosurgical planning. Clinical fMRI continues to advance, for example, in combination with transient disruption approaches such as repetitive transcranial magnetic stimulation and intraoperative stimulation mapping. MR spectroscopy and spectroscopic imaging address the neurochemical composition of brain tissue. Magnetic resonance spectroscopic imaging is now capable of rapidly generating quantitative maps of major metabolites that serve as markers for neuronal integrity and also yield information regarding metabolism, membrane breakdown and inflammation. Another remarkable MR technique, diffusion weighted imaging, can reveal acute strokes as they are evolving and influence treatment strategy in near real time. A related technique, diffusion tensor imaging (DTI), permits visualization of fiber tracts indicating the location and integrity of connectivity patterns within major neural circuits subserving Brain Imaging and Behavior (2007) 1:1–2 DOI 10.1007/s11682-007-9005-0