bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional Brain Measurement of Bmax and KD with the Opiate Antagonist Cyclofoxy: Equilibrium Studies in the Conscious Rat
Authors: Kawai R. , Carson R. E. , Dunn B. , Newman A. H. , Rice K. C. , Blasberg R. G.
Published: April 2011

Brain distribution of the opiate receptor antagonist, cyclofoxy (CF), was evaluated at equilibrium in rats. A combination of i.v. injection and constant i.v. infusion was used to administer CF over a wide dose range (2.4–450 nmol/rat). Kinetic simulations and experimental results showed that this administration schedule accomplishes “true” tissue-blood equilibrium of CF within 60 min. To estimate the receptor-ligand binding parameters, we assumed that the CF concentration at the receptor site is identical to that in plasma water at equilibrium, and can be calculated from measured blood data after corrections for radiolabeled metabolites and plasma protein binding. This assumption was supported by CSF and plasma water measurements at equilibrium. Regional KD, Bmax, and a nonspecific tissue binding equilibrium constant ( Keq) were estimated by fitting the tissue and plasma water concentrations to a single receptor model; the estimated values were 1.4–2.9 n M, 15–74 pmol/g of tissue, and 5.2–8.0, respectively. They are in good agreement with previous in vitro measurements (Rothman and McLean, 1988) as well as in vivo estimates from i.v. injection experiments (Sawada et al., 1990 c). The conventional method to estimate the receptor-ligand binding parameters using data from cerebellum to approximate nonspecific tissue binding was found to be unacceptable. Although cerebellum is a brain region with no opiate receptors in rats, small differences in nonspecific tissue binding in different brain regions resulted in significant overestimations of KD and Bmax with this method. Receptor-active and -inactive enantiomers [[18F](-)-CF and [3H](+)-CF)] were simultaneously administered to the same animal and the receptor-bound CF concentration could be accurately measured; this method was used to estimate 5max from a single study in a single animal and has potential for direct application in human studies using positron emission tomography.
Extracellular pH in the Brain during Ischemia: Relationship to the Severity of Lactic Acidosis
Authors: Katsura Kenichiro , Ekholm Anders , Asplund Barbro , Siesjö Bo K.
Published: April 2011

On the basis of data showing a bimodal distribution of values for extracellular pH (pHe), and a discontinuous ΔPco2/Δlactate relationship, Kraig et al. (1986) proposed that H+ is grossly compartmentalized between neurons and glia in the ischemic brain. We measured ΔpHe during ischemia, varying ischemic lactate contents between 9 and 38 mmol kg−1. No bimodal distribution was found, but ΔpHe varied linearly with lactate content. Because we have also failed to record a discontinuous ΔPco2/Δlactate relationship, we conclude that major compartmentation of H+ does not occur during ischemia.
The Effect of Combined Hypoxemia and Cephalic Hypotension on Fetal Cerebral Blood Flow and Metabolism
Authors: Hohimer A. Roger , Chao Conrad R. , Bissonnette John M.
Published: April 2011

The effect of hypoxemia and cephalic hypotension, alone and in combination, on hemispherical CBF and metabolism was examined in seven chronically catheterized fetal sheep. Hypoxemia was induced by lowering the maternal inspired oxygen fraction and cephalic hypotension was generated by partial occlusion of the fetal brachiocephalic artery. CBF was measured with radionuclide-labeled microspheres. During control, the arterial blood oxygen content (Cao2) was 3.2 ± 1.0 (SD) m M and CBF averaged 131 ± 21 (SD) ml min−1 100 g−1. The cephalic perfusion pressure (PP, mean cephalic arterial - sagittal venous) was 40 ± 4 mm Hg and cerebral vascular resistance (CVR, PP/CBF) was 0.31 ± 0.06 mm Hg ml−1 min 100 g. During induced hypoxemia, Cao2 was 1.4 ± 0.7 m M and CBF was elevated to 223 ± 60 ml min−1 100 g−1. PP was not different from control and CVR was lower at 0.19 ± 0.04 mm Hg ml−1 min 100 g, reflecting cerebral vasodilation. With cephalic hypotension alone (PP = 21 ± 4 mm Hg; Cao2 = 3.4 ± 0.9 m M), CBF fell to 83 ± 23 ml min−1 100 g−1 and there was no significant change in CVR (0.26 ± 0.05 mm Hg ml−1 min 100 g). During combined hypoxemia and hypotension (Cao2 = 1.5 ± 0.8 m M and PP = 18 ± 4 mm Hg), CBF was significantly greater than during hypotension alone (100 ± 6 ml min−1 100 g). CVR was 0.19 ± 0.05 mm Hg ml−1 min 100 g, identical to that measured in normotensive hypoxemia and significantly less than found during hypotension alone. Cerebral oxygen consumption was lower during combined hypoxemia and cephalic hypotension than during hypoxemia alone. Cerebral glucose uptake was significantly higher than control in both the hypoxemic and combined hypoxemic-hypotensive conditions. The glucose:oxygen quotient (6 × molar glucose uptake/molar oxygen consumption) was not different from unity during control or hypotension but was 2.31 ± 1.16 and 3.63 ± 1.99 during the hypoxemic and hypoxemic-hypotensive conditions, respectively, suggesting an anaerobic glucose utilization. No significant lactate efflux could be measured in any of these conditions.
Regionally Selective Effects of NMDA Receptor Antagonists against Ischemic Brain Damage in the Gerbil
Authors: Warner Michael A. , Neill Kenneth H. , Nadler J. Victor , Crain Barbara J.
Published: April 2011

This study compared the ability of three N-methyl-D-aspartate (NMDA) receptor antagonists to prevent neuronal degeneration in an animal model of global cerebral ischemia. The model employed is characterized by damage to the striatum, hippocampus, and neocortex. Antagonists were administered to gerbils either before or after a 5-min bilateral carotid occlusion. The intraischemic rectal temperature was either maintained at 36–37°C or allowed to fall passively to 28–32°C. Antagonists and doses tested were 1 and 10 mg/kg of MK-801 (pre- or postischemia), 30 mg/kg of CGS 19755 preischemia, four 25 mg/kg doses of CGS 19755 administered between 0.5 and 6.5 h postischemia, and 40 mg/kg of MDL 27,266 (pre- or postischemia). All three NMDA receptor antagonists exhibited some degree of neuroprotective activity when the carotid occlusion was performed under normothermic conditions. Most of the treatments with antagonist markedly reduced striatal damage. CA1 hippocampal and neocortical pyramidal cells were spared by only three of the treatments, however, and the extent of neuroprotection varied widely from case to case. Toxic doses of antagonist were required to protect CA1 pyramidal cells from ischemic damage. Ischemic damage to hippocampal areas CA2–CA3a and CA4 appeared to be resistant to all of these treatments. Most CA1 pyramidal cells that were protected from degeneration by an NMDA receptor antagonist were histologically abnormal. The neuroprotective effects of MK-801 and intraischemic hypothermia appeared to be additive. MK-801 (10 mg/kg) consistently reduced the postischemic brain temperature, but only the magnitude of hypothermia produced soon after reperfusion correlated with its neuroprotective action. These results suggest that NMDA receptor antagonists are relatively poor neuroprotective agents against a moderately severe ischemic insult.
Measurement of Human Cerebral Blood Flow with [15O]Butanol and Positron Emission Tomography
Authors: Berridge Marc S. , Adler Lee P. , Nelson A. Dennis , Cassidy Emily H. , Muzic Raymond F. , Bednarczyk Edward M. , Miraldi F.
Published: April 2011

Although H215O is widely used for CBF measurement by positron tomography, it underestimates CBF, especially at elevated flow rates. Several tracers, including butanol, overcome this problem, but the short half-life of 15O provides advantages that cause water to remain the tracer of choice. We report the first use and evaluation of 15O–labeled butanol for CBF measurement. Flow measurements made in a similar fashion with water and butanol at 10-min intervals were compared in normal volunteers under resting and hypercapnic conditions. Regional analysis showed good agreement between the tracers at low flows, and significant underestimation of flow by water relative to butanol in regions of elevated flow. The observed relationship between the tracers and the curve-fitted permeability-surface area product for water (133 ml · 100 g−1 · min−1) follow the known relationship between water and true flow. These observations indicate that [15O]-butanol provided accurate measurements of human regional CBF under conditions of elevated perfusion. We conclude that butanol is a convenient and accurate method for routine CBF determination by positron emission tomography.
Mechanism Underlying Protective Effect of MK-801 against NMDA-Induced Neuronal Injury in vivo
Authors: Uematsu Daisuke , Greenberg Joel H. , Araki Nobuo , Reivich Martin
Published: April 2011

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the dihydropyridine calcium antagonist nimodipine on NMDA-induced phenomena were investigated using an in vivo fluorometric technique with indo-1. Indo-1, a fluorescent cytosolic free calcium ([Ca2+]i) indicator, was loaded into the cat cortex approximately 500 μm in depth by super-fusion with the membrane-permeant indo-1 acetoxymethyl ester (indo-1-AM). Changes in [Ca2+]i signals (400 and 506 nm) and reduced nicotinamide adenine dinucleotide (NADH) fluorescence (464 nm) were simultaneously measured directly from the cortex during ultraviolet excitation (340 nm). Superfusion of 100 μM NMDA over the exposed cortex induced an elevation of the [Ca2+]i signal ratio (400/506 nm), biphasic changes in NAD/NADH redox state (initial oxidation followed by progressive reduction), and characteristic changes in the EEG (abrupt depression in amplitude followed by an excitatory pattern of 18–22 Hz poly spikes or sharp waves). These changes were completely blocked by treatment with MK-801 and reduced by nimodipine. The mechanism underlying the protective effects of systemically administered MK-801 on the NMDA-induced neuronal injury was verified in vivo.
Reversible Focal Ischemia in the Rat: Effects of Halothane, Isoflurane, and Methohexital Anesthesia
Authors: Warner David S. , Zhou Jiegang , Ramani Ramachandran , Todd Michael M.
Published: April 2011

Barbiturates and the volatile anesthetic isoflurane reduce CMR to similar values. If the mechanism of barbiturate protection against focal ischemic injury is due to a reduction in cellular energy requirements, then isoflurane should similarly reduce ischemic injury. To evaluate this, spontaneously hypertensive rats underwent 2 h of reversible middle cerebral artery occlusion (MCAO) while receiving deep methohexital, isoflurane, or halothane anesthesia. Ninety-six hours postischemia, neurologic deficits were present but without a difference between groups. Mean ± SD infarct volume, as assessed by triphenyl tetrazolium chloride staining and computerized planimetry, was significantly less in the methohexital group (n = 8; 166 ± 74 mm3) than in either the halothane (n = 9; 249 ± 71 mm3; p < 0.04) or the isoflurane (n = 9; 243 ± 62 mm3; p < 0.03) groups. One possible explanation for the lack of protective effect for isoflurane might be related to its vasodilative properties, which could result in a cerebral vascular steal. To examine this possibility, rats anesthetized with methohexital or isoflurane underwent autoradiographic determination of CBF with or without MCAO. In isoflurane-anesthetized sham rats (n = 5; no ischemia), CBF was approximately three times greater than in methohexital-treated (n = 5) sham rats. During ischemia, although a regional reduction in flow was noted in both anesthetic groups, mean flow remained greater in the isoflurane group. When the ischemic hemisphere was analyzed for percentage of cross-sectional area where flow was <25 ml/100 g/min, significantly less tissue appeared to be at risk for infarction in the isoflurane group (n = 7; 32.9 ± 19.4%) versus the methohexital group (n = 8; 49.1 ± 12.6%; p < 0.05). These results are consistent with the following conclusions: (a) CMR reduction is not a sufficient criterion for anesthetic-mediated brain protection; (b) isoflurane does not cause cerebrovascular steal; and (c) ischemic flow thresholds for infarction are different for methohexital and isoflurane.
Kinetics and Modeling of l-6-[18F]Fluoro-DOPA in Human Positron Emission Tomographic Studies
Authors: Huang Sung-Cheng , Yu Dan-Chu , Barrio Jorge R. , Grafton Scott , Melega William P. , Hoffman John M. , Satyamurthy N. , Mazziotta John C. , Phelps Michael E.
Published: April 2011

Kinetics of l-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) in striatum and cerebellum were measured in 10 normal human subjects with positron emission tomography (PET) from 0 to 120 min after an intravenous bolus injection of the tracer. The time course of the arterial plasma concentrations of the tracer and its metabolites was also assayed biochemically. FDOPA compartmental models that are based on biochemical information were investigated for their consistency with the measured striatal and cerebellar tissue kinetics. A modeling approach was also developed for separating plasma FDOPA and metabolite time-activity curves from the measured total 18F time-activity curve in plasma. Results showed that a model consisting of three separate compartments for tissue FDOPA, tissue 6-[18F]fluorodopamine (FDA) and its metabolites, and tissue l-3,4-dihydroxy-6-[18F]fluoro-3- O-methylphenylalanine (3-OMFD) could describe adequately the striatal kinetics in humans. Based on this model, the FDOPA transport constant across the blood–brain barrier (BBB) ( K1), the FDOPA decarboxylation rate constant ( k3), and the turnover rate constant of FDA and its metabolites ( k4) could be estimated by model fitting to the tissue kinetics and were found for the normal subjects to be 0.031 ± 0.006 ml/min/g (mean ± SD), 0.041 ± 0.015/min, and 0.004 ± 0.002/min, respectively. About 50% of the FDOPA that crossed the BBB from plasma to striatum was decarboxylated. The decarboxylation constant with respect to plasma FDOPA ( K3) was 0.015 ± 0.003 ml/min/g. The BBB transport corresponded to a permeability–surface area product of 0.032 ml/min/g for FDOPA. For 3-OMFD, the BBB transport was 1.7 times faster. The effects of tissue heterogeneity on the FDOPA kinetics and on the estimated model parameters were also investigated. The usefulness and implications of these findings for interpretation of PET FDOPA studies are discussed.
Kinetic Analysis of Central [76Br]Bromolisuride Binding to Dopamine D2 Receptors Studied by PET
Authors: Delforge Jacques , Loc'h Christian , Hantraye Philippe , Stulzaft Oscar , Khalili-Varasteh Marina , Mazière Mariannick , Syrota André , Mazière Bernard
Published: April 2011

The in vivo kinetic analysis of dopamine D2 receptors was obtained in baboon brain using positron emission tomography (PET) and [76Br]bromolisuride ([76Br]BLIS) as radioligand. An injection of a trace amount of [76Br]BLIS was followed 3 h later by an injection of a mixture of [76Br]BLIS and BLIS in the same syringe (coinjection experiment). A third injection performed at 6 h was either an excess of unlabeled ligand (displacement experiment) or a second coinjection. This protocol allowed us to evaluate in the striatum of each animal and after a single experiment the quantity of available receptors ( B′max) and the kinetic parameters including the association and dissociation rate constants ( k+1 VR and k–1, respectively, where VR is the volume of reaction). The cerebellum data were fitted using a model without specific binding. All the parameters were estimated using nonlinear mathematical models of the ligand-receptor interactions including or not including nonspecific binding. The plasma time-concentration curve was used as an input function after correction for the metabolites. An estimate of standard errors was obtained for each PET study and for each identified parameter using the covariance matrix. The average values of B′max and Kd VR were 73 ± 11 pmol/ml tissue and 1.9 ± 0.9 pmol/ml, respectively. The nonspecific binding was identifiable in the experiment where the last injection corresponded to a second coinjection. We found that ∼6% of the striatal binding was nonspecific after a tracer injection of [76Br]-BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.
Rapid Feasibility Studies of Tracers for Positron Emission Tomography: High-Resolution PET in Small Animals with Kinetic Analysis
Authors: Ingvar M. , Eriksson L. , Rogers G. A. , Stone-Elander S. , Widén L.
Published: April 2011

The development of methods for production of a radiotracer for use in human studies with positron emission tomography (PET) is often a time-consuming process of optimizing radiolabelling yields and handling procedures. Sometimes the radiotracer is not the original drug, but rather a derivative with unknown in vivo pharmacological properties. We have developed a fast and simple method of testing putative new PET tracers in vivo in small animals. The procedure has been validated in rats with different PET tracers with known kinetic and pharmacological properties ([2-18F]2-fluoro-2-deoxy-d-glucose, [ N-methyl-11C]Ro 15-1788, and [15O]butanol). The tracer concentration in arterial blood was continuously measured to obtain the brain input function. Following image reconstruction of the scans, time–activity curves of selected regions of interest were generated. Estimations of CMRglc (1.0 ± 0.2 μmol g−1 min−1), CBF (1.4 ± 0.4 ml g−1 min−1) and transport rate constants for [ N-methyl-11C]Ro 15-1788 (K1 = 0.44 ± 0.01 ml g−1 min−1 and k2 = 0.099 ± 0.005 min−1) as well as calculated first pass extraction (0.32 ±0.1) are in reasonable agreement with literature values. Small animal studies require minimal amounts of radioactivity and can be performed without sterility and toxicology tests. They may serve as a preliminary basis for radiation safety calculations because whole body scans can be performed even with a head scanner. The major advantage of this procedure in comparison to ex vivo autoradiography is that very few experiments are necessary to reliably determine the properties of the blood–brain barrier transport of the radiotracer and the possible whole brain receptor binding characteristics.
Prepro-Vasoactive Intestinal Polypeptide-Derived Peptide Sequences in Cerebral Blood Vessels of Rats: On the Functional Anatomy of Metabolic Autoregulation
Authors: Zhang En-Tan , Mikkelsen Jens Damsgaard , Fahrenkrug Jan , Møller Morten , Kronborg Dorte , Lauritzen Martin
Published: April 2011

This study describes the distribution of peptide sequences derived from the prepro-vasoactive intestinal polypeptide (preproVIP) molecule in perivascular nerves of rat brain arteries and arterioles. The peptides were identified by immunohistochemistry using highly specific antibodies. Five peptide sequences (preproVIP 60–76, peptide histidine isoleucine (PHI), preproVIP 111–122, VIP, and preproVIP 156–170) were identified in the perivascular nerves throughout the arterial cerebral circulation. The density of the immunoreactive fibers was highest in the nerves of the larger extracerebral arteries, declining in smaller branching arteries. All peptide sequences were identified in the nerves of small pial arterioles overlying the cortical convexity, whereas capillaries and veins contained no immunoreactive material. Dendritic processes of neocortical neurons immunoreactive for VIP and PHI could be followed towards the brain surface where the processes penetrated into the pial layer, often close to the pial vasculature. Some of the processes were also observed to enter the Virchow-Robin space, close to the arterioles. It is possible that cortical nerve cells containing VIP and PHI release the peptides in the perivascular space during periods of activity and thereby contribute to local vasodilatation associated with changes of neuronal function.
Hemodynamic Consequences of Common Carotid Artery Thrombosis and Thrombogenically Activated Blood in Rats
Authors: Dietrich W. Dalton , Prado Ricardo , Watson Brant D. , Busto Raul , Ginsberg Myron D.
Published: April 2011

We documented the hemodynamic consequences of nonocclusive common carotid artery thrombosis (CCAT) and tested the hypothesis that vasoactive substances capable of altering local CBF (LCBF) are released into the systemic circulation following cerebrovascular injury. Ten minutes after photochemically induced CCAT, an autoradiographic determination of LCBF was conducted with [14C]iodoantipyrine. In blood transfusion studies using donor and recipient rats, a 1-ml sample of thrombogenically activated blood (TAB) collected downstream from the forming thrombus was reinjected into a recipient rat 15 or 60 min before CBF study. A heterogeneous pattern of abnormal LCBF was documented in the ipsilateral hemisphere of CCAT rats and recipient rats receiving TAB 15 min before CBF study. Acute hemodynamic abnormalities included ischemic (< 35% of control) and hyperemic (> 125% of control) foci and more global reductions (50–80% of control) in cortical and subcortical LCBF. Border zone hyperemia exceeding 2.0 ml/g/min was associated with focal sites of severe LCBF reductions. Although recipient rats that received TAB 15 min before CBF study displayed similar hemodynamic abnormalities, LCBF values in 60-min recipient rats were not significantly different from control despite ischemic foci. Humoral factors generated during CCAT appear to be responsible for the acute LCBF consequences of cerebrovascular thrombosis. Vasoactive substances released from a thrombotic site, capable of regionally affecting vascular reactivity in a time-dependent fashion, might be expected to participate in the pathogenesis of transient ischemic attacks and acute stroke.
Hippocampal Damage following Repeated Brief Hypotensive Episodes in the Rat
Authors: Yamauchi Yoichi , Kato Hiroyuki , Kogure Kyuya
Published: April 2011

We examined the brain damage following repeated hypotensive episodes in the rat. Severe hypotension was induced by withdrawal of arterial blood. The MABP was maintained at about 25 mm Hg with isoelectric EEG and the shed blood was retransfused. After 1 week of recovery, histopathological changes were examined. No brain damage was observed after 1 min of isoelectric EEG. Mild neuronal damage to the hippocampal CA1 subfield was seen in some animals after two episodes of 1-min isoelectric EEG at a 1-h interval. Significant and consistent neuronal loss in the hippocampal CA1 subfield was observed after three episodes of 1-min isoelectric EEG. Scattered neuronal damage in the thalamus was additionally seen in some animals. The present study indicates that repeated brief hypotensive episodes produce brain damage depending on the number of episodes, even though no brain damage results when induced as a single insult. This animal model may reproduce hemodynamic transient ischemic attacks in humans.
Modulation of Ornithine Decarboxylase mRNA following Transient Ischemia in the Gerbil Brain
Authors: Dempsey Robert J. , Carney John M. , Kindy Mark S.
Published: April 2011

Ornithine decarboxylase (ODC) is the rate-limiting enzyme that catalyzes the synthesis of polyamines from ornithine and is thought to be involved in the cellular response to growth, differentiation, and stress. Previous studies have demonstrated that transient cerebral ischemia results in an increase in ODC activity and polyamine synthesis. We have used the Mongolian gerbil as a model system to test the hypothesis that the cellular response to ischemia induces a distinct pattern of ODC gene expression. Our results indicate that transient ischemia, induced by bilateral carotid occlusion, elevates ODC mRNA within 1–4 h after reperfusion, which correlates with increased ODC activity and polyamine synthesis. Increased ODC mRNA can be detected in the forebrain, striatum, hippocampus, and midbrain but not the cerebellum, which is not subject to ischemic injury. In contrast, c- fos mRNA increased by 15 min after reperfusion and actin mRNA did not demonstrate alterations in level after ischemia. Pentobarbital prevented the increase in ODC mRNA, whereas the glutamate antagonist MK-801 had no effect on the elevation of ODC gene expression after ischemia. We conclude that the ischemia-induced increase in ODC enzyme activity may be attributed in part to transcriptional activation of the ODC gene.
Graded Postischemic Reoxygenation Ameliorates Inhibition of Cerebral Cortical Protein Synthesis in Dogs
Authors: Burda Jozef , Maršala Martin , Radoňták Jozef , Maršala Jozef
Published: April 2011

The purpose of this study was to determine the effect of normoxic reperfusion and graded postischemic reoxygenation on cerebral protein synthesis in a cell-free system. Ischemia alone produced a relatively small decrease (15–17%) in activity in all the subcellular systems studied. After a 15-min interval of normoxic reperfusion (75–90 mm Hg O2 in arterial blood), a 40% decrease (p < 0.01) in [14C]leucine incorporation was observed. Reoxygenation with hypoxemic blood containing 37.5 mm Hg O2 at 0–5 min and 56 mm Hg O2 at 6–10 min of recirculation followed by 5 min of normoxic reperfusion resulted in a significant increase (p < 0.05) of polypeptide chain synthesis in vitro when compared with normoxic reperfusion. The results obtained by this experimental approach tend to show that graded postischemic reoxygenation could be used as a simple and effective neuroprotective tool that substantially diminishes the secondary postischemic damage in nervous tissue, including the newly synthesized proteins.
Possible Role of Protein Kinase C-Dependent Smooth Muscle Contraction in the Pathogenesis of Chronic Cerebral Vasospasm
Authors: Matsui Tohru , Takuwa Yoh , Johshita Hiroo , Yamashita Kamejiro , Asano Takao
Published: April 2011

In the present study, we investigate the possible role of protein kinase C (PKC)-dependent smooth muscle contraction in cerebral vasospasm following subarachnoid hemorrhage (SAH), employing the beagle “two-hemorrhage” model. The occurrence of chronic vasospasm was angiographically confirmed on day 7 in the basilar artery, which was exposed via the transclival approach. The artery was superfused with aerated Krebs-Henseleit solution containing various agents, and the subsequent changes in the basilar artery diameter were recorded by successive angiography. The preexisting spasm was not ameliorated by local application of neurotransmitter antagonists (atropine, methysergide, phentolamine, and diphenhydramine), calmodulin inhibitors (R24571 and W-7), or a calcium antagonist, nicardipine. However, the application of PKC inhibitors such as H-7 and staurosporine induced significant dilation of the artery. In another experiment, an intrinsic PKC activator, 1,2-diacylglycerol (DAG), in the basilar artery, the CSF, and the cisternal clot of beagles exposed to two hemorrhages was measured on days 1,2,4, 7, and 14 using the DAG kinase method. On days 2, 4, and 7, the DAG content of the basilar artery showed a significant and prolonged increase (150–190% of control), whereas it was unchanged on days 1 and 14. Throughout the experimental period, there was a significant linear correlation between the DAG content and the angiographical diameter of the basilar artery. The above results indicate that SAH leads to an increase in the DAG level within the cerebral artery through an as yet unknown mechanism and that subsequent activation of the PKC-dependent contractile system participates in the occurrence of chronic vasospasm.
Cerebral Blood Flow Reactivity to Changes in Carbon Dioxide Calculated Using End-Tidal versus Arterial Tensions
Authors: Young William L. , Prohovnik Isak , Ornstein Eugene , Ostapkovich Noeleen , Matteo Richard S.
Published: April 2011

We retrospectively examined arterial and endtidal estimations of CO2 tension used to calculate cerebrovascular reactivity in 68 anesthetized patients. CBF was measured using the intravenous 133Xe technique at mean ± SD Paco2 values of 28.2 ± 5.2 and 38.8 ± 4.8 mm Hg. The correlation between all Paco2 and end-tidal Pco2 (Petco2) values was y = 0.85 x −0.49 ( r = 0.93, p = 0.0001). There was a moderate correlation between age and the difference between Paco2 and Petco2 ( y = 0.11 x + 0.79; r = 0.73, p = 0.0001). Cerebrovascular reactivity to changes in CO2 (ml 100 g−1 min−1 mm Hg−1) was similar (p = 0.358) when calculated by using either Paco2 (1.9 ± 0.8) or Petco2 (1.8 ± 0.8) and highly correlated ( y = 0.86 x + 0.23; r = 0.91, p = 0.0001). The CBF response to changes in CO2 tension can be reliably estimated from noninvasive measurement of Petco2.
Regional Cerebral Blood Flow during Spreading Cortical Depression in Conscious Rats
Authors: Duckrow Robert B.
Published: April 2011

Spreading cortical depression (SCD) of EEG activity was induced in one cerebral hemisphere of conscious restrained rats by direct current stimulation of the lateral frontal cortex. Regional CBF was measured using [14C]iodoantipyrine and brain dissection. An early phase of increased CBF was not measured in conscious rats, but an early relative hyperperfusion was measured if the resting CBF was first reduced by treatment with pentobarbital or indomethacin. A long-lasting reduction in CBF was measured in conscious rats following the passage of SCD. This flow reduction resolved after 3 h. In conscious rats, CBF decreased in the striatum and thalamus ipsilateral to the SCD, paralleling the CBF changes occurring in the cortex. The CBF change in these deep structures was abolished by pentobarbital. An early transient increase in regional CBF was measured in the cerebral cortex contralateral to the hemisphere involved with SCD in conscious rats. This early contralateral hyperperfusion was also abolished by pentobarbital or indomethacin but not by atropine or propranolol. The vascular response to SCD in conscious rats differs from that which occurs in anesthetized rats.
Region of Interest Issues: The Relationship between Structure and Function in the Brain
Authors: Mazziotta John C. , Pelizzari Charles C. , Chen George T. , Bookstein Fred L. , Valentino Daniel
Published: April 2011

The comparison of data sets from individual subjects between imaging modalities is necessary in order to evaluate the normal physiologic responses of the brain or the pathophysiological changes that accompany disease states. Similarly, it is critical to compare data between individuals both within and across imaging modalities. In a collaborative project with a number of university groups, we have developed a system that allows for the within-subject alignment and registration of three-dimensional data sets obtained from different modalities for the same individuals. These data make use of proposed criteria for the optimal solution to positron emission tomography image acquisition and analysis originally established through a series of international workshops. The analysis takes into account errors induced by image acquisition, registration, and alignment with regard to scaling, translation, and rotation. Using the principles of morphometrics and homologous landmarks, the between-subject warping of individual brain anatomy to match that of other individuals, groups or an idealized model can be obtained. Resultant information can provide averaged between-subject data for populations of normal individuals or patients with specific neurologic disorders. Such a system, provides the means by which to compare objectively quantitative data between individuals in a highly automated fashion.
Quantitative Comparison of Measurements of Cerebral Glucose Metabolic Rate Made with Two Positron Cameras
Authors: Grady Cheryl L.
Published: April 2011

The rapid progress in PET technology has created the dilemma of how to compare data from old and new tomographs. We examined cerebral metabolic data from two scanners, with different spatial resolutions and methods of attenuation correction, to see if metabolic values from the lower-resolution tomograph (ECAT II) could be adjusted to make them comparable to data from the higher-resolution scanner (Scanditronix PC1024-7B). Nine subjects were scanned on both tomographs after a single injection of [18F]2-fluoro-2-deoxy-D-glucose. Regional and lobar gray matter metabolic rates for glucose were obtained from comparable images from each scanner. Ratios of lobar to global gray matter metabolism also were calculated. Regression coefficients and percent differences were computed to compare ECAT II and PC 1024 data. Two-thirds of the region pairs showed significant regressions, although percent differences were quite variable, with measures of glucose utilization ranging from 30 to 120% higher on the PC 1024 compared to those from the ECAT II. Comparisons of lobar glucose rates between the two machines were less variable (50 to 80%), and ratios differed by only ±5% (except for the temporal ratios). Since there was no simple and consistent relationship between regional metabolic rates on the two tomographs, an overall adjustment of regional ECAT values for comparison to PC1024 values would be impossible. A region-by-region adjustment would be necessary. Lobar ratios are sufficiently similar that direct comparisons might be possible.
Specification and Selection of Regions of Interest (ROIs) in a Computerized Brain Atlas
Authors: Bohm C. , Greitz T. , Seitz R. , Eriksson L.
Published: April 2011

The computerized individually adjustable brain atlas (CBA) has been further developed. The atlas was primarily designed for anatomical localization and quantitative evaluation of data in positron emission tomography (PET), but may also be employed for other neuroimaging modalities, such as transmission computed tomography (CT) and magnetic resonance imaging (MRI). The atlas is based on anatomical information obtained from digitized cryosectioned brains. Using spatially standardized and then averaged MRI images, we demonstrate the high localization accuracy and precision of the brain atlas. This is a prerequisite for obtaining accuracy when using the atlas in the localization and the quantitative evaluation of PET data. The specification and the selection of region of interests (ROIs) by the CBA are presented and discussed.
Statistical Issues in the Analysis of Neuroimages
Authors: Ford I. , McColl J. H. , McCormack A. G. , McCrory S. J.
Published: April 2011

Statistical issues in the analysis of neuroimages are reviewed. These include biological questions of interest, basic problems of measurement and experimental design, normalisation, standardisation and transformation, and statistical methodology. Finally, three data sets are reviewed to illustrate some of the issues raised in the report.
The Spectral Signature Method for the Analysis of PET Brain Images
Authors: Images Brain , Levy A. V. , Laska E. , Brodie J. D. , Volkow N. D. , Wolf A. P.
Published: April 2011

We introduce the concept of the metabolic centroid spectrum as the feature space to characterize the distribution of metabolic activity in three-dimensional brains. The method computes the metabolic centroid of a brain subvolume for each increment of metabolic activity occurring in the whole brain. The result is the metabolic spectral signature, a continuous three-dimensional curve whose shape reflects the distribution of metabolic rates in the brain. The method's sensitivity to metabolic distribution asymmetries is greatly increased over that of the metabolic centroid method, while retaining its advantages; it is almost invariant to head size, head positioning, photon scatter, and the positron emission tomography (PET) camera's full width at half-maximum. It does not require magnetic resonance, computed tomography, or x-ray images. To test the method we analyzed the metabolic PET images of 40 normal subjects and 20 schizophrenics. The results show a unification of several metabolic characteristics of schizophrenic brains, such as laterality, hypofrontality, cortical/subcortical abnormalities, and overall brain hypometabolism, which were identified by different laboratories in separate studies using differing methodologies. Here they are presented by a single automatic objective method.
Kinetic Analysis of Transport and Opioid Receptor Binding of [3H](−)-Cyclofoxy in Rat Brain in vivo: Implications for Human Studies
Authors: Sawada Yasufumi , Kawai Ryosei , McManaway Mary , Otsuki Hideo , Rice Kenner C. , Patlak Clifford S. , Blasberg Ronald G.
Published: April 2011

[3H]Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-α-epoxy-6-β-fluoromorphinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model (Sawada et al., 1990 a) and a classical compartmental pharmacokinetic model (Wong et al., 1986 a) were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found tobe essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures ( Keq = 3–9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6–32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures ( KD = 2.1–5.2 n M), whereas the apparent receptor density ( Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum ( k4 = 0.08–0.16 min−1; koff = 0.16–0.23 min−1) and brain vascular permeability ( PS = 1.3–3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis (Patlak and Blasberg, 1985) of the data is inappropriate due to the high tissue-loss rate constant ( kb = 0.03–0.07 min−1) for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using [18F]CF and positron emission tomography.
Dopamine D2 Receptor Imaging with SPECT: Studies in Different Neuropsychiatric Disorders
Authors: Brücke T. , Podreka I. , Angelberger P. , Wenger S. , Topitz A. , Küfferle B. , Müller Ch. , Deecke L.
Published: April 2011

The purpose of the present study is to visualize and quantify dopamine D2 receptors in the living human brain using an 123I-labeled ligand and the single photon emission computerized tomography (SPECT) technique. S-(–)-Iodobenzamide [ S-(–)-IBZM] has been shown to be a highly selective ligand with high affinity for D2 receptors in experimental studies. Five millicuries (185 MBq) of 123I-labeled S-(–)-IBZM was administered intravenously to 12 control subjects, 22 parkinsonian patients under L-Dopa therapy, 12 parkinsonian patients without L-Dopa, 10 unmedicated patients with Huntington's disease, and 12 patients under different neuroleptics. Data collection with a rotating double-head scintillation camera started 1 h after injection and lasted for 50 min. In a semiquantitative approach, a ratio was calculated between mean counts per pixel in the striatum and a region in the lateral frontal cortex, which was 1.74 ± 0.10 in the control group. A marked reduction of this ratio was found in patients with Huntington's disease (1.38 ± 0.12; p = 0.0001), no significant changes in untreated parkinsonian patients (1.67 ± 0.14), but a reduction in L-Dopa-treated cases (1.59 ± 0.13; p = 0.0014). A curvilinear relationship was found between total daily dose of neuroleptics and the reduction of this ratio. Estimated receptor blockade under full neuroleptic treatment was 75–80%. S-(–)-IBZM binding was reduced with increasing age (p < 0.01). Specific binding was reduced markedly when the racemic mixture of IBZM was used, and no specific binding was seen with the R-(+)-isomer, demonstrating the stereoselectivity of IBZM binding. The results show that dopamine D2 receptors can be clearly visualized with high resolution using the SPECT technique and S-(–)-IBZM as a ligand. A semiquantitative approach can give estimates for receptor blockade or receptor density. This method is of clinical value for the diagnosis of degenerative neurological disorders such as Huntington's disease and for the monitoring of neuroleptic treatment.
Chronic Trigeminal Ganglionectomy or Topical Capsaicin Application to Pial Vessels Attenuates Postocclusive Cortical Hyperemia but Does Not Influence Postischemic Hypoperfusion
Authors: Macfarlane Robert , Tasdemiroglu Erol , Moskowitz Michael A. , Uemura Yoshihiko , Wei Enoch P. , Kontos Hermes A.
Published: April 2011

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p < 0.01). CBF returned to preischemic levels ∼45 min after reperfusion and was reduced to ∼65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p < 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p < 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 n M; 50 μl) to the middle or posterior temporal branch of the MCA 10–14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (Paco2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.
Regional Cerebral Metabolites, Blood Flow, Plasma Volume, and Mean Transit Time in Total Cerebral Ischemia in the Rat
Authors: Crumrine R. Christian , LaManna Joseph C.
Published: April 2011

Cerebral high-energy metabolites and metabolic end products were measured during and following total cerebral ischemia in the rat. During cerebral ischemia, lactate accumulation was greatest in the hippocampus, followed by the cerebral cortex and striatum. Following reperfusion, the rate of lactate clearance was slower in the hippocampus than in the other two regions. Regional CBF, cerebral plasma volume (CPV), and calculated mean transit time (MTT) were determined following refow of ischemic tissue. During hyperemia, CPV, used as an indicator of capillary volume, increased concomitantly with CBF while the MTT remained near the control value, suggesting that the linear flow rate through the vasculature was unchanged. During hypoperfusion, CPV returned to control values, but there was a signif-cant increase in MTT that would result from a decreased linear velocity. The finding of normal tissue energy charge, pHi, and concentration of other metabolites during hypoperfusion shows that hypoperfusion does not result in CBF-metabolic mismatch.
Autoradiographic Analysis on Second-Messenger Systems and Local Cerebral Blood Flow in Ischemic Gerbil Brain
Authors: Tanaka Kortaro , Gotoh Fumio , Gomi Shintaro , Takashima Shutaro , Mihara Ban
Published: April 2011

Alterations of the second-messenger systems, adenylate cyclase (AC) and protein kinase C (PKC), and local cerebral blood flow (1CBF) were evaluated during experimental cerebral ischemia in gerbils employing a quantitative autoradiographic method, which permitted these three parameters to be measured in the same brain. Ischemia was induced by occlusion of the right common carotid artery for 6 h. Animals attaining more than 5 in their ischemic scores were utilized for further experiments. At the end of ischemia, 1CBF was measured by the [14C]iodoantipyrine method. The AC and PKC activities were estimated by the autoradiographic technique developed in our laboratory using [3H]forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu), respectively. The 1CBF fell below 10 ml/100 g/min in most cerebral regions on the ligated side. The greatest reduction in FK binding was noted in the olfactory tubercle, caudate-putamen, and globus pallidus, followed by the hippocampus and cerebral cortices. The FK binding tended to be low at 1CBF < 20 ml/100 g/min in the cerebral cortices. However, the PDBu binding was relatively well preserved in each cerebral structure, and no significant correlation between 1CBF and PDBu binding was noted in the cerebral cortices. The AC system may thus be vulnerable to ischemic insult over extensive brain regions, while the PKC system may be relatively resistant to ischemia.
Macrophage and Astrocyte Populations in Relation to [3H]PK 11195 Binding in Rat Cerebral Cortex following a Local Ischaemic Lesion
Authors: Myers Ralph , Manjil Luisa G. , Cullen Beulah M. , Price Gary W. , Frackowiak Richard S. J. , Cremer Jill E.
Published: April 2011

PK 11195 is a selective and specific ligand for the peripheral-type benzodiazepine binding site. Its potential for in vivo visualisation of lesioned human brain using positron emission tomography (PET) is currently being assessed. The present study examines the relationship between the temporal development of a local ischaemic lesion with its associated cell populations and the binding of [3H]PK 11195 in rat brain. Unilateral cortical infarcts were induced using the photosensitive dye Rose Bengal. At time intervals from 1 to 7 days after lesioning, the localisation of [3H]PK 11195 binding was determined using in vivo and in vitro autoradiography. Sections adjacent to those used for autoradiography were processed for immunohistochemistry using glial fibrillary acidic protein for astrocytes and ED-1 for macrophages. The results show that the binding of [3H]PK 11195 correlates in both time and spatial localisation with the appearance of macrophages around the lesion. Reactive astrocytes, although present, occupy a separate region in the tissue surrounding the lesion and lie outside the region defined by the [3H]PK 11195 binding. We conclude that the [3H]PK 11195 signal associated with this ischaemic lesion originates primarily from binding to macrophages and that [C]PK 11195 could be used for imaging acute inflammatory response in human brain using PET.