bluuebunny/crossref_metadata_2025 huggingface dataset:
Nimodipine Does Not Affect Cerebral Lactate Levels following Complete Ischemia in Dogs
Authors: Michenfelder John D. , Milde James H.
Published: April 2011

Nimodipine is known to improve postischemic cerebral blood flow (CBF) and neurologic outcome in experimental animals. Whether or not the two observations are related is unknown. This study searched for a possible improved rate of brain metabolic recovery in animals treated with nimodipine postischemia. Complete cerebral ischemia was produced for 11 min in 16 dogs, followed by reperfusion for 70 min. Prior to ischemia, glucose was administered (0.75 g · kg−1) in 12 dogs. Half of the glucose-treated dogs were given i.v. nimodipine, beginning 5 min postischemia (10 μg · kg−1 bolus followed by 1 μg · kg−1 · min−1). The other half were given only saline postischemia. The remaining four dogs were given no glucose and received saline only postischemia. In all dogs, serial brain biopsies were taken at 2, 20, 40, and 70 min postischemia. In 5 dogs, the integrity of the blood–brain barrier (BBB) was tested by injection of Evans blue dye and postmortem examination of the brains. Brain biopsies were assayed for concentrations of phosphocreatine, ATP, ADP, AMP, glucose, lactate, and pyruvate. In all dogs, there was rapid restoration of a normal brain energy state following reperfusion. Brain lactate had returned to near normal in all dogs by 70 min postischemia, and the rate of lactate depletion was not different between groups. The integrity of the BBB was only minimally affected. A portion of the brain lactate was converted to pyruvate rather than crossing the BBB. If lactate is a valid marker of the washout of metabolic products postischemia, there is no apparent benefit resulting from a nimodipine-induced increase in CBF during the initial 70 min following ischemia.
Peering through the Windows of the Brain
Authors: Gross Paul M. , Weindl Adolf , Knigge Karl M.
Published: April 2011

These seven specialized circumventricular structures of the mammalian brain represent windows with individualized structural characteristics permitting intimate contact between blood and cerebrospinal fluid, neurones and specialized ependyma-glia. These “Seven Windows of the Brain”, like the seven lucky deities of Japan, may each have a specific patron of body -brain function which they serve.1
Increases in Cerebral Cortical Perfusate Adenosine and Inosine Concentrations during Hypoxia and Ischemia
Authors: Phillis John W. , Walter Gary A. , O'Regan Michael H. , Stair Robert E.
Published: April 2011

The cerebral cortical cup technique was used to monitor changes in adenosine and inosine levels in the rat cerebral cortex during periods of hypoxia, anoxia, or hemorrhagic hypotension. Basal levels of adenosine and inosine in cortical perfusates stabilized within 10 min at concentrations of 30–50 and 75–130 n M, respectively. Comparable levels were observed in normal CSF collected from the cisterna magna. Reductions in the oxygen content of the inspired air (14, 12, 8, and 5% oxygen) resulted in increases in the adenosine and inosine levels in the cortical perfusates, the magnitude of the increase being progressively more pronounced with greater reductions in the oxygen content. Cerebral anoxia/ischemia, induced by 100% nitrogen inhalation, caused a rapid increase in the adenosine and inosine contents of the cortical perfusates. Hemorrhagic hypotension (46.1 ± 1.7 mm Hg) of 5 min duration did not result in an elevated adenosine or inosine release. The results suggest that interstitial fluid adenosine levels are likely to be in the low n M range in the normoxic animal and are capable of rapid increases during hypoxic or anoxic episodes. The findings support the adenosine hypothesis of CBF regulation.
Regional Cerebral and Neural Lobe Blood Flow during Insulin-Induced Hypoglycemia in Unanesthetized Rats
Authors: Bryan Robert M. , Hollinger Bryan R. , Keefer Kerry A. , Page Robert B.
Published: April 2011

The effects of hypoglycemia on regional cerebral blood flow (rCBF) were studied in awake restrained rats. The rats were divided into three groups consisting of (1) a normoglycemic control group that received only saline, (2) a hypoglycemic group A, which was given insulin 30 min before flow was measured, and (3) a hypoglycemic group B, which was given insulin 90 and 30 min before flow was measured. Regional CBF was measured using 14C-iodoantipyrine. Mean plasma glucose was 8.76 μmol/ml in the control group, 2.63 μmol/ml in hypoglycemic group A, and 1.51 μmol/ml in hypoglycemic group B. Plasma epinephrine and norepinephrine concentrations increased to approximately 375% and 160%, respectively, of control values in hypoglycemic groups A and B. In the hypoglycemic group A, rCBF significantly increased in three brain regions. In the hypoglycemic group B, rCBF increased significantly in all brain regions measured, with the exception of the neural lobe, in which it decreased. The increase in rCBF ranged from 38% in the hypothalamus to 138% in the thalamus. Neural lobe blood flow significantly decreased by 31%. The neural lobe was the only brain region studied that is not protected by a blood-brain barrier. It may be sensitive to changes in the concentration of vasoactive agents in blood, such as epinephrine and norepinephrine.
Reversibility of Hemodynamic Hypofrontality in Schizophrenia
Authors: Geraud G. , Arné-Bès M. C. , Güell A. , Bes A.
Published: April 2011

Regional cerebral blood flow (CBF) was studied in 51 young schizophrenics. A significant decrease of CBF was seen in frontal and prefrontal regions (hypofrontal pattern) in chronic patients whose disease had evolved for more than 2 years and who were in remission. This hypofrontal pattern was reversible, as it disappeared during exacerbation of the disease. In 10 patients who had not been treated with neuroleptics for several weeks, we found a dopaminergic hypersensitivity in the frontal lobes, as a weak dose of piribedil restored near-normal frontality. This may reflect either the role of neuroleptic washout or a primitive dopaminergic depletion, as proposed by some authors in the chronic form of schizophrenia.
Behavioral Activation and the Variability of Cerebral Glucose Metabolic Measurements
Authors: Duara Ranjan , Gross-Glenn Karen , Barker Warren W. , Chang Jen Yueh , Apicella Anthony , Loewenstein David , Boothe Thomas
Published: April 2011

Variability in cerebral glucose metabolism was examined between and within subjects when paired studies were performed in the resting state or in a behaviorally activated state. Both normal and demented subjects were studied twice each, from 1 to 6 weeks apart, under near-identical conditions, using positron emission tomography (PET) and [18F]fluorodeoxyglucose. Resting state studies were repeated in nine normal and four demented subjects. A picture-viewing test, used for activation during PET, was used repeatedly in seven normal and five demented subjects. Within-subject variability, as assessed by the percent difference in metabolic rates in paired studies, was reduced by 60–70% for activation state compared to resting state studies in normals. It is concluded that PET studies of brain metabolism, which are designed to study the active brain, should indeed be performed in functionally activated states, as in addition to demonstrating metabolism during a defined functional state, activation studies show reduced variability of cerebral metabolic measures.
Histopathological and Hemodynamic Consequences of Complete versus Incomplete Ischemia in the Rat
Authors: Dietrich W. Dalton , Busto Raul , Yoshida Shinichi , Ginsberg Myron D.
Published: April 2011

The primary objective of this study was to compare the histopathological consequences of complete versus incomplete ischemia under experimental conditions that limit lactate accumulation. Fasted rats underwent 1 h of either complete or incomplete ischemia by a procedure combining bilateral common carotid artery occlusion, halothane-induced systemic hypotension, and CSF pressure elevation. Histopathological outcome was evaluated 4 h later and was graded on a 4-point scale. Incomplete ischemia resulted in ischemic neuronal damage within selectively vulnerable brain regions. In contrast, complete ischemia, in addition to diffuse neuronal damage, resulted in focal sites of parenchymal necrosis with vascular stasis. Perfusion defects were detected by carbon black infusion within cortical and subcortical regions following only 25 min of complete, but not incomplete, ischemia. Ultrastructural abnormalities at the same duration of complete ischemia included a high frequency of endothelial microvilli and compressed lumina with severe perivascular astrocytic swelling. When recirculation was instituted for 1 h following 1 h of complete ischemia, regions of nonperfusion were detected autoradiographically. Thus, when the degree of lactic acidosis is controlled, prolonged periods of complete ischemia result in a more severe pathological outcome compared to incomplete ischemia. Focally impaired postischemic cerebral perfusion appears to be an important factor in infarct formation under the present experimental conditions.
Histaminergic Vasodilation of Intracerebral Arterioles in the Rat
Authors: Dacey Ralph G. , Bassett John E.
Published: April 2011

Histamine from various sources is found in significant amounts around cerebral vessels and may play a significant role in controlling CBF. The effect of histamine on the intracerebral microcirculation has not been examined. We have used an in vitro technique for the isolation and cannulation of intracerebral arterioles from the rat to study the effect of histamine on the spontaneous tone developed by these vessels. Extraluminally administered histamine caused dose-dependent vasodilation of isolated intracerebral arterioles with a maximal dilation of 139 ± 2.4% of control diameter. The dilation was blocked by the H2 receptor antagonist cimetidine, but was only incompletely attenuated by the H1 receptor blocker chlorpheniramine. Histamine effects a dilation of the spontaneous tone of intracerebral resistance vessels, which is mediated by H2 receptors.
In vivo Studies on Intracellular pH, Focal Flow, and Vessel Diameter in the Cat Cerebral Cortex: Effects of Altered CO2 and Electrical Stimulation
Authors: Yaksh T. L. , Anderson R. E.
Published: April 2011

The time course of changes in cortical tissue pH (pHi) and blood flow during cortical seizures in halothane-anesthetized cats was examined. The clearance of the molecular form of umbelliferone (Um) was used to estimate focal cortical blood flow (CBFu), whereas the ratio of the molecular to the ionic form of the molecule was used to concurrently calculate the local pHi. Resting pHi and flow in normocarbic animals was 7.116 ± 0.008 and 46 ± 8 ml/100 g/min, respectively. Respiratory induced alterations of Paco2 over a range of 20–60 torr revealed a correlated change in pHi from 7.39 ± 0.05 to 7.01 ± 0.03 and a monotonic increase in the rate of Um clearance (slope 0.89 ± 0.13 ml/100 g/min/torr). Focal electrical stimulation of the cortex resulted in a rapid vasodilation (50% dilation = 1–3 s) of pial arterioles and venules and an increase in Um clearance. pHi showed no significant change until around 10 s. The maximum fall in pHi occurred by 30–60 s (6.85 ± 0.054). Longer intervals of stimulation (10 min) resulted in no further decline in pHi, but upon cessation of stimulation, pHi remained acidotic for poststimulation periods up to 10 min, with a mild but statistically significant acidosis being observed at 20 min. The absolute decline in pH observed following stimulation appeared to be closely regulated, as comparable levels following stimulation were observed during hypocarbia and hypercarbia. These observations thus suggest that pHi regulation during intense cortical activation may be considered in three phases: (1) following the onset of activity, an initial acute regulation of pHi at control levels; (2) an intracellular acidosis of around 6.8, which is closely regulated and which can be readily reversed upon termination of stimulation; and (3) during continued stimulation, a change in state where in spite of no further change in pHi, the ability of the cortex to return to control pHi appears to be significantly impaired.
Pressure Distribution in the Pial Arterial System of Rats Based on Morphometric Data and Mathematical Models
Authors: Hudetz Antal G. , Conger Karl A. , Halsey James H. , Pal Miklos , Dohan Orsolya , Kovach Arisztid G. B.
Published: April 2011

The objective of the present work was a theoretical evaluation of pial arterial pressures in normotensive rats and spontaneously hypertensive rats based on the geometry and topography of the pial arterial system as well as on various topological models of the vascular trees. Pial branches of the middle cerebral artery in the diameter range of 30–320 μm were selectively visualized by corrosion compound, and the diameter and length of vascular segments were measured. The vessels were classified into branching orders by the methods of Horsfield and Strahler. The steady-state pressure distribution in the pial arterial system was calculated assuming that the flow at the bifurcations was partitioned in proportion to a given power of the diameters of the daughter branches (diameter exponent). The maximum number of vascular segments along the longest branch varied between 16 and 33. The mean branching ratio was 4.14 ± 0.23 (SD). The mean diameter of vessels classified into Strahler orders 1–5 were: 50 ± 12, 71 ± 19, 106 ± 22, 168 ± 22, and 191 ± 7 μm, respectively. The calculated pressure drop in the pial trees of normotensive rats was approximately twice as large in proximal orders 3 and 4 than in distal orders 1 and 2. The mean pressure in arteries of order 1 ranged from 54.4 to 58.4 mm Hg in the normotensive rat (input pressure: 83 mm Hg), and from 77.2 to 89.0 mm Hg in the spontaneously hypertensive rat (input pressure: 110 mm Hg). The coefficient of variation of terminal pressures in vessels of order I increased linearly with the mean pressure drop in the system. The coefficient of variation in terminal pressure had a minimum as a function of the diameter exponent in case of each pial tree. At its minimum, it was higher in all spontaneously hypertensive rats (10.1–22.9%) than in any normotensive rats (6.0–8.5%). The corresponding diameter exponents were in most cases lower in the spontaneously hypertensive rat (1.3–2.5) than in the normotensive rat (2.5–3.0). Topologically consistent models of the pial arterial network predicted significantly less variation in intravascular pressures than was obtained by direct calculations. More idealized models suggested the dependence of coefficient of variation in terminal pressure on the total number of vascular segments contained by the tree. All models predicted the existence of the minimum of coefficient of variation in terminal pressure in function of the diameter exponent. From these, we conclude that (a) a hemodynamic configuration of the pial arterial system resulting in the smallest variation in cerebral perfusion pressure may exist, and (b) the pial vascular structure of spontaneously hypertensive rat allows less homogeneous terminal pressure distribution than does that of normotensive rats.
Lidoflazine Does Not Improve Neurologic Outcome When Administered after Complete Cerebral Ischemia in Primates
Authors: Fleischer Jerry E. , Lanier William L. , Milde James H. , Michenfelder John D.
Published: April 2011

In order to investigate the effects of the calcium entry blocker lidoflazine on neurologic outcome in primates following an episode of global brain ischemia. 12 pigtail monkeys ( Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia, followed by 48 h of intensive care treatment and daily neurologic evaluations for 96 h. The monkeys were randomly assigned to receive, in a blind fashion, either lidoflazine 1.0 mg/kg (n = 6) or inactive lidoflazine solvent (n = 6) at 5 min, 8 h, and 16 h postischemia. One monkey in the lidoflazine group did not meet preestablished protocol criteria and was excluded from data analysis. The remaining monkeys were well matched for age, sex, and other physiologic variables. Neurologic outcome was not significantly different between the lidoflazine- and placebo-treated groups (p > 0.5). No monkey in either group achieved a normal neurologic exam by 96 h postischemia. Three lidoflazine-treated monkeys and two placebo-treated monkeys died prior to the 96-h neurologic evaluation. These deaths were judged to be neurologic in origin. The authors conclude that lidoflazine does not improve neurologic outcome in primates when administered after 17 min of complete cerebral ischemia.
Head Injury Induces Increased Prostaglandin Synthesis in Rat Brain
Authors: Shohami E. , Shapira Y. , Sidi A. , Cotev S.
Published: April 2011

Head injury was induced in the left hemisphere of rats, The rats were killed at various time intervals after trauma (immediately, 15 min, 1 and 18 h, and 4 and 10 days), and the rates of synthesis and release of prostaglandin PGE2, 6-keto-PGF1α, and thromboxane TXB2 from cortical slices of both hemispheres were studied. The rate of synthesis of PGE2 after 18 h was six and four times higher than control in the contused and contralateral hemispheres, respectively. By 10 days posttrauma, both hemispheres had normal rate of PGE2 release. TXB2 and 6-keto-PGF1α synthetases were affected already 15 min after the injury, and a similarly elevated rate of synthesis was found in both hemispheres. The maximal effect was detected after 1 or 18 h with return to normal after 4 or 10 days for TXB2, and 6-keto-PGF1α, respectively. Tissue specific gravity was determined for both hemispheres using linear gradient columns. The results of these determinations indicate that development of edema occurs in the contused hemisphere as early as 15 min post trauma; it reaches its maximal level at 18 h and returns to normal at 10 days. Arterial pressure was monitored, and a transient increase was found at 10 min post trauma. We suggest that the production of edema after brain injury may be related to the increased rate of PGE2 and PGI2 synthesis, which occurs at similar time intervals after injury.
Acute Cerebral Ischaemia: Concurrent Changes in Cerebral Blood Flow, Energy Metabolites, pH, and Lactate Measured with Hydrogen Clearance and 31P and 1H Nuclear Magnetic Resonance Spectroscopy. II. Changes during Ischaemia
Authors: Crockard H. Alan , Gadian David G. , Frackowiak Richard S. J. , Proctor Edward , Allen Kathryn , Williams Stephen R. , Russell Ralph W. Ross
Published: April 2011

CBF has been measured with the hydrogen clearance technique in the two cerebral hemispheres of the gerbil under halothane anaesthesia. This has been correlated with changes in local pH, tissue lactate, and phosphorus energy metabolites measured in the same animals with 1H and 31P nuclear magnetic resonance spectroscopy. We demonstrate a threshold flow value for the metabolic changes associated with energy failure at a level similar to the values previously reported for electrical failure and tissue water accumulation, but higher than that associated with breakdown of extracellular potassium homeostasis.
Human Cerebral Glucose Metabolism Determined by Positron Emission Tomography: A Revisit
Authors: Brooks Rodney A. , Hatazawa Jun , Di Chiro Giovanni , Larson Stephen M. , Fishbein Donn S.
Published: April 2011

The cerebral glucose utilization rate was studied for 27 normal volunteers with 18F-deoxyglucose positron emission tomography (PET). The scanner has a spatial resolution of 6–7 mm and contains corrections for scatter, attenuation, and random coincidences. The lumped constant (tracer-to-glucose dynamic uptake ratio) was determined by comparing the average global uptake of tracer in representative slices with average glucose utilization rates measured by the Kety-Schmidt method as reported in the literature. The resulting value of 0.50 is in excellent agreement with a recent direct determination done by arterial and jugular bulb blood sampling. Gray and white matter values of glucose utilization in various areas of the brain were determined by placing small regions of interest over various cortical, basal, and white matter structures. These values are within 20% of published autoradiographic data on the macaque monkey. The average ratio of gray to white glucose utilization was 2.9, compared with a range of 3–5 for the monkey study and 1.6–2.2 reported in previous PET studies. The effect of instrumental errors on the results is analyzed and discussed.
Regional Asymmetries of Cerebral Blood Flow, Blood Volume, and Oxygen Utilization and Extraction in Normal Subjects
Authors: Perlmutter Joel S. , Powers William J. , Herscovitch Peter , Fox Peter T. , Raichle Marcus E.
Published: April 2011

Positron emission tomography (PET) and 15O-labeled radiotracers were used to measure regional CBF, cerebral blood volume (CBV), CMRO2, and oxygen extraction in 32 right-handed subjects at rest. Mean left hemispheric CBF (46.2 ± 6.8 ml/100 g/min) and CMRO2 (2.60 ± 0.59 ml/100 g/min) were significantly lower than right hemispheric values (47.4 ± 7.2 and 2.66 ± 0.61 ml/100 g/min, respectively; p < 0.0001 for both), whereas left and right hemispheric CBV and oxygen extraction were not significantly different. We further investigated these asymmetries by comparing left- and right-sided values for specific cortical and subcortical regions. We found that left-sided CBF and CMRO2 were significantly lower than right-sided values for sensorimotor, occipital, and superior temporal regions, whereas only left-sided CBF values were lower for anterior cingulum. CBV was asymmetric for the anterior cingulate and midfrontal regions, and oxygen extraction was asymmetric for the sensorimotor area. No asymmetries were observed in inferior parietal cortex, thalamus, putamen, or pallidum. Knowledge of these normal physiological asymmetries is essential for proper interpretation of PET studies of physiology and pathology. Furthermore, the ability to detect asymmetries with PET may lead to a better understanding of the lateralization of specific functions in the human brain.
Effects of Calcium Entry Blocker Emopamil on Postischemic Energy Metabolism of the Isolated Perfused Rat Brain
Authors: Bielenberg Gerhard Wilhelm , Haubruck Heinz , Krieglstein Josef
Published: April 2011

The effects of emopamil on postischemic energy metabolism and electroencephalographic (EEG) recovery were investigated in the isolated rat brain perfused at either constant pressure or, alternatively, at constant flow rate. Flow rate and perfusion pressure were monitored continuously. The brains were perfused with a fluorocarbon emulsion for 30 min, and after 30 min of ischemia, perfusion was reinstituted for 5, 30, or 60 min. Global cerebral perfusion rate was increased by emopamil throughout the perfusion period and, accordingly, in brains perfused at a constant flow rate, perfusion pressure was reduced by the drug. At constant pressure perfusion, after 5 min after ischemia, cortical levels of creatine-phosphate, adenosine triphosphate (ATR), glucose, glucose-6-phosphate, and fructose-6-phosphate were higher in emopamil-treated brains than in controls, although the levels of adenosine diphosphate (ADP) and adenosine monophosphate (AMP) were reduced. When brains were perfused at constant flow rate, however, emopamil exhibited no effect on brain energy metabolism in the early reperfusion period. Postischemic restoration of high-energy phosphates proved to depend on the flow rate used. After 30 min of postischemic reperfusion, cortical levels of lactate were lower in emopamil-treated brains compared to controls at both constant pressure and constant volume perfusion. Postischemic lactate levels were independent of flow rate and were also reduced when emopamil was only present during reperfusion. The postischemic restoration of cortical EEG activity was improved by the calcium entry blocker. The results suggest that the restoration of high-energy phosphates during the early postischemic recovery can be mainly attributed to the vascular effect of emopamil, whereas the lower lactate levels are caused by a direct action of the calcium entry blocker on brain parenchyma.
Serotonergic Neuron Stimulation Modulates Thalamocortical Glucose Use in the Conscious Rat
Authors: Cudennec Annie , Duverger Danielle , MacKenzie Eric T. , Scatton Bernard , Serrano André
Published: April 2011

We have studied the effects, in the conscious rat, of electrical stimulation of the dorsal or median raphe nuclei on integrated functional activity, as assessed by the quantitative 2-deoxyglucose autoradiographic technique, Stimulation of serotonergic neurons elicits metabolic changes in cortical and thalamic regions that are not limited to those structures known to receive the densest serotonergic innervation. The thalamic nuclei that are activated by raphe stimulation include those that subserve the processing of somesthetic, accessory visual, and limbic information, Raphe stimulation increased cortical glucose use in a laminar and columnar pattern, but only in a highly circumscribed region that corresponds to the somatotopic representation of the rat's face and head. These findings indicate that ascending serotonergic neurons play an important modulatory role in the regulation of thalamocortical glucose use, observations that may be of value in the understanding of the etiology and expression of classic migraine.
Scopolamine Reduces Frontal Cortex Perfusion
Authors: Honer William G. , Prohovnik Isak , Smith Gwenn , Lucas Louis R.
Published: April 2011

While the cognitive deficits of Alzheimer's disease are considered related to a cholinergic deficit, no attempt has yet been made to test the hypothesis that the characteristic regional cerebral blood flow (rCBF) pattern of Alzheimer's disease may also relate to such a deficit. We therefore measured rCBF using the [133Xe] inhalation technique in 15 young normal subjects before and after induction of reversible cholinergic blockade with scopolamine at doses of 6.1 and 7.3 μg/kg i.v. Significant cognitive impairment was observed at both doses, while rCBF changes occurred only at the higher dose. Global CBF was significantly reduced 25 min after scopolamine. The pattern of regional change in CBF was not similar to Alzheimer's disease. Rather than a focal parietotemporal deficit as seen in Alzheimer's disease, we observed a predominantly frontal reduction in flow of about 20%. These results suggest that the frontal but not the parietotemporal deficits seen in several dementing conditions may be related to cholinergic dysfunction.
Direct Comparison of Single-Scan Autoradiographic with Multiple-Scan Least-Squares Fitting Approaches to PET CMRO2 Estimation
Authors: Holden J. E. , Eriksson L. , Roland P. E. , Stone-Elander S. , Widen L. , Kesselberg M.
Published: April 2011

The time course of local cerebral radioactivity concentration after bolus inhalation of oxygen gas labeled with O-15 was measured in a rapid dynamic sequence of positron tomographic images. Four normal subjects were studied at rest. In each study, 15 multiple-slice image sets were acquired over a 3-min period in a Scanditronix model 384 tomograph. The radioactivity concentration in arterial blood was measured at 1-s intervals by means of a pump-fed flow-through detector. Pump effluent was directed to discrete samples that were separated into plasma and cell fractions to estimate the accumulation of labeled, recirculating water arising from systemic metabolism. Stereotactically matched scans of local cerebral blood flow and volume were acquired in the same imaging session, and the derived values were used as fixed parameters in the model fits of the time courses of pixel radioactivity in the oxygen study. Rapid nonlinear least-squares parameter optimization was used to estimate simultaneously the local CMRO2 and the brain/blood relative distribution volume for water in each image pixel. The same scan data were combined into effective single frames of various starting times and durations for analysis using the single-scan (“autoradiographic”) approach to CMRO2 estimation, which requires a presumed value for relative distribution volume. Oxygen use values derived using this approach were observed to be strongly dependent on the relative distribution volume value chosen, particularly for long study durations. However, for each gray matter region of interest studied, a uniform value for the relative distribution volume existed such that the estimated CMRO2 values were independent of the starting time and duration of the single scan used, and were furthermore the same as that yielded by the multiple-scan least-squares fitting of the total time course in the same region. We conclude that the properties of the single-scan and multiple-scan approaches are very similar at the same total study duration, provided that the value selected for the water relative distribution volume brings the measured and computed tissue time courses into correspondence.
Comparison between the Photoelectric Method and H2 Clearance Method for Measuring Cerebrocortical Blood Flow in Cats
Authors: Tomita Minora , Gotoh Fumio , Tanahashi Norio , Kobari Masahiro , Terayama Yasuo , Mihara Ban , Ohta Kouichi , Gerdsen Ingo
Published: April 2011

The photoelectric method using carbon black as a nondiffusible tracer of blood was compared with the hydrogen clearance (H2) method in nine anesthetized cats. A photoelectric apparatus and H2 electrode were applied to a small region of the cerebral cortex (left ectosylvian gyrus) for simultaneous measurement of the regional CBF. The values of CBF(H2) and CBF(photoelectric) were 50.7 ± 19.2 and 52.1 ± 14.5 ml − 100 g−1 · min−1, respectively. CBF(H2) and CBF(photoelectric) were found to correlate well ( r = 0.588, p < 0.01) when changes in CBF were induced by CO2 inhalation, exsanguination, hyperventilation, and occlusion of the middle cerebral artery. The correlation between CBF(H2) and CBF(photoelectric) was much better in the case of intraindividual comparisons ( r = 0.957, p < 0.01). In addition to its merits in common with the H2 clearance method, such as handiness, low cost, and strict regionality, the photoelectric method displayed the following advantages: time-to-time measurements of CBF (<20 s), immediate display of the microcirculatory flow pattern, and simultaneous monitoring of cerebral blood volume. However, measurements from deep structures of the brain are better performed by the H2 method despite the disadvantage of the use of a potentially explosive gas.
Effects of Deoxycoformycin on Adenosine, Inosine, Hypoxanthine, Xanthine, and Uric Acid Release from the Hypoxemic Rat Cerebral Cortex
Authors: Phillis John W. , O'Regan Michael H. , Walter Gary A.
Published: April 2011

The effects of the adenosine deaminase inhibitor, deoxycoformycin, on purine release from the rat cerebral cortex were studied with the cortical cup technique. Deoxycoformycin (5 and 500 μg/kg i.v.) enhanced the hypoxia/ischemia-evoked release of adenosine from the cerebral cortex, indicating a marked rise in the adenosine content of interstitial fluid in the cerebral cortex. Inosine and hypoxanthine release were attenuated at the higher dose of deoxycoformycin, acid release into the cortical perfusates was enhanced at the higher dose level. These results demonstrate that low doses of deoxycoformycin can be used to elevate interstitial levels of adenosine in the brain during hypoxia, and to depress the formation of some of its metabolites. The elevation of hypoxia/ischemia-evoked adenosine levels can account for the previously reported potentiation of hypoxia-evoked increases in rat cerebral blood flow after deoxycoformycin administration. The potential therapeutic utility of these findings is discussed.
Reduction of Cerebrospinal Fluid Pressure by Hypocapnia: Changes in Cerebral Blood Volume, Cerebrospinal Fluid Volume and Brain Tissue Water and Electrolytes. II. Effects of Anesthetics
Authors: Artru Alan A.
Published: April 2011

Part I of these studies (Artru, 1987) examined how cerebral blood volume (CBV), CSF volume, and brain tissue water and electrolytes determined CSF pressure during 4 h of hypocapnia in sedated dogs. The three groups reported were: hypocapnia (PaCO2 20 mm Hg) with no intracranial mass (group 1), intracranial mass (epidural balloon, CSF pressure 35 cm H2O) but no hypocapnia (group 2), and intracranial mass with hypocapnia used to lower CSF pressure (group 3). It was found that in dogs with an intracranial mass (group 3) the CSF pressure-lowering effect of hypocapnia was sustained for 4 h due to improved reabsorption of CSF, decrease of CSF volume to offset reexpansion of CBV and no increase in the sum of CSF volume and CBV. The present Part II studies (groups 4–8) examine the effects of anesthetics on CSF pressure during conditions like those used for group 3, namely, intracranial mass present and hypocapnia used to lower CSF pressure. When halothane or enflurane were used for anesthesia, the CSF pressure-lowering effect of hypocapnia was not sustained. CSF pressure increased from 17.3 ± 4.7 and 19.0 ± 4.1 cm H2O, respectively (mean ± SD), at 10 min to 50.3 ± 12.8 and 43.2 ± 12.8 cm H2O, respectively at 4 h. Increase of CSF pressure was associated with increased resistance to reabsorption of CSF (Ra) and increase in the sum of CSF volume and CBV. With halothane the intracranial volume increase was comprised chiefly of cerebral blood and with enflurane the intracranial volume increase was comprised chiefly of CSE When isoflurane, fentanyl, or thiopental were used for anesthesia, the CSF pressure-lowering effect of hypocapnia was sustained. Ra did not increase and the sum of CBV and CSF volume remained reduced.
Role of Prostaglandins in Blood-Induced Vasoconstriction of Canine Cerebral Arteries
Authors: Lang Sally A. , Maron Michael B.
Published: April 2011

We tested the hypothesis that the vasoconstriction produced by the application of blood to the adventitial surfaces of the vessels of an isolated perfused canine circle of Willis preparation was mediated by products of prostaglandin metabolism. In this preparation (perfused at constant flow and outflow pressure), topical application of blood produced an average 16.6 ± 1.8 (SE) mm Hg increase in inflow pressure. This response could be prevented with four structurally dissimilar cyclooxygenase inhibitors (aspirin, indomethacin, ibuprofen, and meclofenamate), suggesting that the blood-induced increase in vascular resistance was mediated by prostaglandins. Imidazole, an inhibitor of thromboxane synthetase, had no effect on the blood response. Further support for the involvement of prostaglandins in this response was provided by additional experiments in which either arachidonic acid, prostaglandin E2 (PGE2), or PGF2α were administered. All three treatments produced vasoconstriction. These results suggest that the vessels of this preparation are capable of synthesizing vasoconstrictor prostaglandins and indicate that they are reactive to known vasoactive prostaglandins.
Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat
Authors: Ozyurt E. , Graham D. I. , Woodruff G. N. , McCulloch J.
Published: April 2011

The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery and the animals were killed 6 h later. The amount of early ischemic damage was assessed in coronal sections at 16 predetermined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.), 30 min before occlusion of the middle cerebral artery significantly reduced the volume of ischemic damage (from 32.7 ± 4.0% of the cerebral hemisphere in vehicle-treated cats to 16.2 ± 4.5% in MK-801-treated cats). NMDA receptor antagonists that penetrate the blood-brain barrier, such as MK-801, merit further study as protective agents against ischemic brain damage.
Extraction of [99mTc]—d,l-HM-PAO across the Blood—Brain Barrier
Authors: Andersen Allan R. , Friberg Hans , Knudsen Karen B. M. , Barry David I. , Paulson Olaf B. , Schmidt Jes F. , Lassen Niels A. , Neirinckx Rudi D.
Published: April 2011

The initial extraction ( E) across the blood–brain barrier (BBB) of [99mTc]– d,l-HM-PAO after intracarotid injection was measured in 14 Wistar rats and 6 patients using the double indicator, single injection method with Na-24 as the cotracer. In both series, cerebral blood flow (CBF) was measured using the initial slope of the xenon-133 washout curve after intracarotid bolus injection. In rats, bolus size (20 or 120 μl), bolus type (saline or 10% albumin), or CBF were changed. First-pass extraction was dependent on CBF ( p < 0.001): With a small bolus of saline and at resting CBF (0.75 ml/g/min), E was 0.81, decreasing to 0.56 at a high CBF (1.5 ml/g/min). The calculated permeability surface area product ( PS) increased linearly from 1.2 to 1.5 ml/g/min when CBF increased from 0.8 to 1.5 ml/g/min (p < 0.01). E was found to increase when the bolus volume of saline was increased from 20 to 120 μl, while using a 120 μl bolus containing 10% albumin resulted in a decrease in E. This suggests that HM-PAO binding to albumin is not totally and rapidly reversible during a single passage through brain capillaries and that binding to blood elements may reduce the apparent extraction across brain capillaries. In patients using a bolus of 1 ml saline, E decreased linearly with increasing CBF ( r = −0.81, p < 0.001). For a CBF of 0.59 ml/g/min and an average apparent E of 0.72, an apparent PS product of 0.76 ml/g/min was calculated. Analysis of the apparent E vs. time profiles indicated a backdiffusion of the tracer during the experimental period. This could lead to a small underestimation of the actual extraction values.
Quantitative Measurements of Cerebral Blood Flow Using SPECT and [99mTc]-d,l-HM-PAO Compared to Xenon-133
Authors: Andersen Allan R. , Friberg Hans H. , Schmidt Jes F. , Hasselbalch Steen G.
Published: April 2011

The uptake and retention in a 2 cm thick brain section was recorded serially by SPECT after i.v. injection of [99mTc]– d,l-HM-PAO (HM-PAO). In 16 patients, the fraction of the administered dose retained by the brain was 5.2 ± 1%, showing a peak after 40–50s, then decreasing by 10% within the first 10 min and then by only 0.4% per hour. The image contrast was measured in each patient as the regional hemispheric asymmetry difference in percent of the highest value of the two regions. It deceased from 31% at 30–40 s to 25% at 10 min. At 24 h, a value of 19% was reached. Using the images obtained at 10 min after injection, a region to region comparison of the original and corrected HM-PAO images to the xenon-133 regional cerebral blood flow (rCBF) images was performed. Forty-four patients with stroke, epilepsy, dementia, basal ganglia disease, and tumors and control subjects were included in this comparison. The algorithm proposed by Lassen et al. was used to correct the original images for back diffusion of tracer (brain to blood); a good correlation very close to the line of identity between the corrected HM-PAO and xenon-133 data was obtained when using a conversion/clearance ratio of 1.5 and when the noninvolved hemisphere was used as a reference region ( r = 0.86, p < 0.0001). Serial arterial and cerebral venous blood sampling was performed over 10 min following i.v. injection of HM-PAO in six patients. An overall brain retention fraction of 0.37 ± 0.03 (mean ± SEM) was calculated from the data. An average CBF of 0.62 ± 0.12 ml/g/min was determined on the basis of the Fick principle; this compared to a value of 0.59 ± 0.09 ml/g/min (mean ± SEM) measured by the xenon-133 inhalation method. The two sets of CBF values correlated linearly with a correlation coefficient of 0.97 ( p < 0.01). Inserting the average CBF value for the hemisphere as measured by the Fick principle into the algorithm described by Lassen et al. yields absolute rCBF values (ml/g/min) directly from the corrected HM-PAO images. We conclude that the xenon-133 inhalation method and [99mTc]– d,l-HM-PAO may supplement each other for SPECT studies of rCBF: xenon-133 inhalation for easy, repeatable, and quantitative measurements and [99mTc]– d,l-HM-PAO for high resolution static imaging in relative or absolute flow units.
SPECT Measurements with 99mTc-HM-PAO in Focal Epilepsy
Authors: Ryding Erik , Rosén Ingmar , Elmqvist Dan , Ingvar David H.
Published: April 2011

The ability of SPECT measurements with [99mTc]–HM-PAO (Ceretec) to find the location of the epileptic focus was studied in patients under consideration for neurosurgical treatment for therapy-resistant focal epilepsy. The location of low [99mTc]–HM-PAO uptake regions found at interictal measurements, and of high [99mTc]–HM-PAO uptake regions found at ictal measurements, was compared to the findings of extensive ictal and interictal EEG examinations, and to the results of CT and MRT. While EEG revealed focal epileptic activity in all of the 14 patients, SPECT showed regional abnormalities in 13 (93%). CT and MRT showed abnormal findings in 30%.
CBF Tomograms with [99mTc-HM-PAO in Patients with Dementia (Alzheimer Type and HIV) and Parkinson's Disease—Initial Results
Authors: Costa D. C. , Ell P. J. , Burns A. , Philpot M. , Levy R.
Published: April 2011

We present preliminary data on the utility of functional brain imaging with [99mTc]– d,l-HM-PAO and single photon emission computed tomography (SPECT) in the study of patients with dementia of the Alzheimer type (DAT), HIV-related dementia syndrome, and the “on–off” syndrome of Parkinson's disease. In comparison with a group of age-matched controls, the DAT patients revealed distinctive bilateral temporal and posterior parietal deficits, which correlate with detailed psychometric evaluation. Patients with amnesia as the main symptom (group A) showed bilateral mesial temporal lobe perfusion deficits ( p < 0.02), More severely affected patients (group B) with significant apraxia, aphasia, or agnosia exhibited patterns compatible with bilateral reduced perfusion in the posterior parietal cortex, as well as reduced perfusion to both temporal lobes, different from the patients of the control group ( p < 0.05). SPECT studies of HIV patients with no evidence of intracraneal space occupying pathology showed marked perfusion deficits. Patients with Parkinson's disease and the “on–off” syndrome studied during an “on” phase (under levodopa therapy) and on another occasion after withdrawal of levodopa (“off”) demonstrated a significant change in the uptake of [99mTc]– d,l-HM-PAO in the caudate nucleus (lower on “off”) and thalamus (higher on “off”). These findings justify the present interest in the functional evaluation of the brain of patients with dementia. [99mTc]– d,l-HM-PAO and regional cerebral blood flow (rCBF)/SPECT appear useful and highlight individual disorders of flow in a variety of neuropsychiatric conditions.
The Use of [99mTc]-HM-PAO in the Diagnosis of Primary Degenerative Dementia
Authors: Testa H. J. , Snowden J. S. , Neary D. , Shields R. A. , Burjan A. W. I. , Prescott M. C. , Northen B. , Goulding P.
Published: April 2011

The clinical value of single photon emission computed tomography (SPECT) in the differential diagnosis of dementia due to cerebral atrophy was evaluated by comparing the pattern of distribution [99mTc]–HM-PAO in three dementing conditions. Imaging was carried out in 26 patients with suspected Alzheimer's disease, 14 with dementia of the frontal-lobe type, and 13 with progressive supranuclear palsy. Images were evaluated and reported without knowledge of clinical diagnosis with respect to regions of reduced uptake of tracer. Reduced uptake in the posterior cerebral hemispheres was characteristic of Alzheimer's disease, while selective anterior hemisphere abnormalities characterized both dementia of the frontal-lobe type and progressive supranuclear palsy. The latter conditions could be distinguished on the basis of the appearance of integrity of the rim of the frontal cortex. The technique has an important role in the differentiation of degenerative dementias.
In vivo Fluorometric Measurement of Changes in Cytosolic Free Calcium from the Cat Cortex during Anoxia
Authors: Uematsu Daisuke , Greenberg Joel H. , Reivich Martin , Kobayashi Sei , Karp Andrea
Published: April 2011

A new approach to assess the mean changes in intracellular free calcium [Ca2+]i directly from the cortex in situ is described along with the [Ca2+]i changes during nitrogen anoxia. Following incision of the dura and part of the pia-arachnoid membrane, quin2 acetoxymethyl ester, 100 μ M in artificial CSF, was superfused for 60 min onto the cat cortex. A small cortical area was irradiated with ultraviolet rays (350/30 nm) and the changes in the fluorescence and reflectance were recorded microfluorometrically at 506 and 366 nm, respectively. The net change in the quin2-Ca2+ fluorescence was calculated after correction for the hemodynamic artifact and subtraction of the basal NADH change. The quin2-Ca2+ fluorescence began to increase significantly (48.0 ± 13.4 units; p < 0.05) 20 s prior to the isoelectric electrocorticogram (ECoG) and remained elevated during nitrogen anoxia. It decreased steeply 7.3 ±1.7 s prior to the recovery of the ECoG activity after the animal was reoxygenated. Thus, the changes in the intracellular free calcium preceded those of the ECoG during a reversible anoxic insult, suggesting that the increase in the [Ca2+]i might be related to the electrical failure during anoxia.
Pathogenesis of Substantia Nigra Lesions following Hyperglycemic Ischemia: Changes in Energy Metabolites, Cerebral Blood Flow, and Morphology of Pars Reticulata in a Rat Model of Ischemia
Authors: Inamura Kenji , Smith Maj-Lis , Olsson Yngve , Siesjö Bo K.
Published: April 2011

A spectacular spongiotic lesion, symmetrical in distribution and restricted to the pars reticulata of the substantia nigra (SNPR) has recently been described in hyperglycemic rats surviving 1–18 h after a brief period of transient ischemia. The purpose of this study was to clarify the pathogenesis of the lesion. In order to study whether the lesion was due to changes occurring during ischemia, local cerebral blood flow (1-CBF) and energy metabolites were measured in the substantia nigra (SN) and in other brain areas. Furthermore, brains were examined by light and electron microscopy immediately after ischemia and in the early recirculation period. Autoradiographic CBF measurements showed ischemia flow levels in the SN of 30–40% of control, similar in normo- and hyperglycemic rats. Thus, although ischemic, this structure had a considerable amount of residual flow. There was also a corresponding partial preservation of the adenylate energy charge. However, lactate levels were high, and in hyperglycemic subjects they rose to values previously described during status epilepticus (about 25 μmol/g). In hyperglycemic animals, neuronal alterations were consistently present in SNPR by the end of the 10min period of ischemia. They included clumping of nuclear chromatin and subplasmalemmal clearing of the perikaryon. Some mitochondrial swelling was present in neuronal perikarya and in dendrites. The normal alignment of microtubules in the dendrites was disturbed, but there was no or only slight swelling of the dendrites. Aggregation of synaptic vesicles was a conspicuous finding in axonal terminals, which were also slightly swollen. Otherwise, the axons appeared largely spared. Microvessels looked quite intact. Similar cellular changes were observed in the early recovery period. Dendrites, however, started to swell, and their expansion finally caused the spongiotic appearance of the pars reticulata. The appearance of the dendritic lesions is strongly suggestive of transmitter-mediated (“excitotoxic”) damage. However, it seems likely that the marked acidosis is injurious as well. We tentatively conclude that both mechanisms interact to give the final lesion. The results, and those previously obtained in epileptic seizures, suggest that mitochondria of SN neurons and neuronal processes are particularly prone to damage.