bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional Kinetic Constants and Cerebral Metabolic Rate for Glucose in Normal Human Volunteers Determined by Dynamic Positron Emission Tomography of [18F]-2-Fluoro-2-Deoxy-D-Glucose
Authors: Heiss W.-D. , Pawlik G. , Herholz K. , Wagner R. , Göldner H. , Wienhard K.
Published: April 2011

Using dynamic [18F]fluorodeoxyglucose (FDG) positron emission tomography with a high-resolution, seven-slice positron camera, the kinetic constants of the original three-compartment model of Sokoloff and co-workers (1977) were determined in 43 distinct topographic brain regions of seven healthy male volunteers aged 28–38 years. Regional averages of the cerebral metabolic rate for glucose (CMRglu) were calculated both from individually fitted rate constants (CMRglukinetic) and from activity maps recorded 30–40 min after FDG injection, employing a four-parameter operational equation with standard rate constants from the literature (CMRgluautoradiographic). Metabolic rates and kinetic constants varied significantly among regions and subjects, but not between hemispheres. k1 ranged between 0.0485 ± 0.00778 min−1 in the oval center and 0.0990 ± 0.01347 min−1 in the primary visual cortex. k2 ranged from 0.1198 ± 0.01533 min−1 in the temporal white matter to 0.1472 ± 0.01817 min−1 in the cerebellar dentate nucleus. k3 was lowest (0.0386 ± 0.01482 min−1) in temporal white matter and highest (0.0823 ± 0.02552 min−1) in the caudate nucleus. Maximum likelihood cluster analysis revealed four homogeneous groups of brain regions according to their respective kinetic constants: (1) white matter and mixed brainstem structures; (2) cerebellar gray matter and hippocampal formations; (3) basal ganglia and frontolateral and primary visual cortex; and (4) other cerebral cortex and thalamus. Across the entire brain, k1 and k2 were positively correlated (r = 0.79); k1 and k3 showed some correlation (r = 0.59); but no significant linear association was found between k2 and k3. A strong correlation with CMRglu could be demonstrated for k1 (r = 0.88) and k3 (r = 0.90), but k2 was loosely correlated (r = 0.56). CMRglu kinetic ranged from 17.0 ± 2.45 μmol/100 g/min in the occipital white matter to 41.1 ± 5.62 μmol/100 g/min in the frontolateral cortex. In most regions the mean values of CMRglu kinetic did not differ significantly from CMRglu autoradiographic. With few exceptions, however, within-region variance was significantly less for CMRglu kinetic than for CMRglu autoradiographic, suggesting greater individual reliability of results obtained by the kinetic approach.
Measurement of Cerebral Blood Flow Using Bolus Inhalation of C15O2 and Positron Emission Tomography: Description of the Method and its Comparison with the C15O2 Continuous Inhalation Method
Authors: Kanno Iwao , Lammertsma Adriaan A. , Heather Jon D. , Gibbs Jeremy M. , Rhodes Christopher G. , Clark John C. , Jones Terry
Published: April 2011

This article describes a rapid method for the regional measurement of cerebral blood flow using a single breath of C15O2 and positron emission tomography. The technique is based on the bolus distribution principle and utilises a reference table for the calculation of flow. Seven subjects were studied using both this method and the C15O2 continuous inhalation steady-state technique. The single-breath method gave flow values 20% higher than those obtained using the steady-state method. A simulation study was performed in an attempt to define the reasons for the difference between the two techniques. Estimations were made of identified sources of error in the measurement of regional cerebral blood flow using the single-breath technique and compared with results from a similar study previously described for the steady-state technique. However, further comparative studies will be necessary to satisfactorily explain the difference between both techniques.
Evaluation of [18F]-4-Fluoroantipyrine as a New Blood Flow Tracer for Multiradionuclide Autoradiography
Authors: Sako Kazuhiro , Diksic Mirko , Kato Amami , Yamamoto Y. Lucas , Feindel William
Published: April 2011

This article reports the evaluation of [18F]-4-fluoroantipyrine (FAP) as a quantitative blood flow tracer by comparing blood flow measured with [18F]FAP to that determined simultaneously with [14C]-4-iodoantipyrine (IAP), a standard blood flow tracer, by means of double-tracer autoradiography. The single-pass extraction value ( m), which indicates diffusibility of a tracer, was determined according to the procedure described by Crone. The diffusibility of FAP was essentially the same as that of IAP. The brain–blood partition coefficient for FAP was found to be similar to that for IAP, 0.89 ± 0.01. Values of local cerebral blood flow obtained with FAP agree with those determined with IAP. From these results, we concluded that FAP is indeed as good a blood flow tracer as IAP. Since 18F is a positron-emitting radionuclide, it might be a useful tracer for blood flow measurement by positron emission tomography.
Total Cerebral Ischemia: Effect of Alterations in Arterial PCO2 on Cerebral Microcirculation
Authors: Koch Kathryn A. , Jackson David L. , Schmiedl Mark , Rosenblatt Judah I.
Published: April 2011

Radiolabeled 15-μm microspheres were used to examine alterations in regional CBF and cerebrovascular resistance in response to changes in arterial PCO2. Flow measurements were obtained before and 1–3 and 24 h after 12 min of total cerebral ischemia. Striking sensitivity of blood flow in all areas of the central nervous system was shown to changes in arterial PCO2 between 24 and 50 mm Hg during the control nonischemic period. Following 12 min of total cerebral ischemia, cerebrovascular resistance increased, producing a decrease in regional blood flow when the important controlling variables for CBF were held constant. One to 3 h after total cerebral ischemia, the effect of variations in arterial PCO2 on cerebral blood flow was almost completely abolished. Within 24 h after total cerebral ischemia, the sensitivity of CBF to changes in PCO2 was almost completely restored, whereas the secondary severe neurologic deficit remained. Therapeutic interventions following global cerebral ischemia, designed to ameliorate the “no-reflow” phenomenon and minimize residual ischemic neurologic damage, must take into account this marked early postischemic reduction in sensitivity to normally potent cerebrovasodilatory influences.
Correlation between Cerebral Blood Flow and ATP Content following Tourniquet-Induced Ischemia in Cat Brain
Authors: Marcy Val Robert , Welsh Frank A.
Published: April 2011

Cerebral ischemia was produced in anesthetized cats using a neck tourniquet, which diminished cortical blood flow to <2 ml/100 g/min and depleted levels of ATP throughout the brain. Following a 30-min insult, cortical flow measured with H2 electrodes returned nearly to control, but subsequently decreased to 14–47% of control values. Despite this secondary hypoperfusion, ATP levels adjacent to the H2 electrode were restored to 75% of normal during the 2-h recirculation period. Therefore, this degree of hypoperfusion did not cause a secondary failure of energy metabolism. Following a 60-min insult, impaired reperfusion prevented the regeneration of brain ATP. However, preischemic bilateral craniectomies significantly improved recovery of blood flow and ATP levels following 60 min of ischemia. Therefore, in the present model, insufficient reflow is a primary factor limiting recovery of energy metabolism. Further, surgical decompression prevented the occurrence of “no reflow” caused by 60 min of ischemia.
The Modular Organization of the Pial Arterial System in Phylogeny
Authors: McHedlishvili George , Kuridze Nina
Published: April 2011

We have investigated the pial arterial microcircles formed by the consecutive ramifications and anastomoses of minute pial vessels on the surface of the cerebral neocortex in various vertebrate species, representatives of various levels of phylogenic development. We found that the pial arterial microcircles became gradually more complex in the following order: hen < rabbit < cat < dog < monkey. The gradual development of microcircles involves various features in these species: (a) They become formed predominantly of smaller pial arterial branches whose vasomotor activity is much higher as compared with that of the larger ones; (b) each circle occupies a smaller area, and hence the number of circles per surface of neocortex increases; (c) the density of arterial branches feeding the circles increases despite the smaller size of the latter; (d) the number of offshooting precortical and radial arteries penetrating the cortex increases; (e) the areas of neocortex fed by individual radial arteries get gradually smaller. Thus, the development of the pial arterial bed contributes more and more toward precise spatial regulation of an adequate blood supply to increasingly smaller areas of neocortical tissue as we rise toward higher levels in phylogeny.
Significance of the Cerebrovascular Effects of Immobilization Stress in the Rabbit
Authors: Lacombe Pierre , Seylaz Jacques
Published: April 2011

The question of the significance of the cerebrovascular effects of stressful situations in animals is still controversial. In the present article, an experimental model of immobilization stress in the rabbit is described, and its specificity in relation to arterial blood pressure and PaCO2 is investigated. CBF was measured with the multiregional tissue sampling technique using [14C]-ethanol as tracer. After dissipation of althesin anesthesia, the stress reaction was elicited by tactile abdominal stimuli. The response was evidenced by an instantaneous acute hypertension (+ 33.8% during the CBF measurement period). Within the first minute of the reaction, the CBF was significantly increased in all nine structures studied by 39% (caudate nucleus) to 82% (parietotemporal cortex). The study of the influence of arterial blood pressure and the PaCO2 on CBF showed that cerebrovascular autoregulation and CO2 sensitivity were differently affected in the various structures during the stress reaction. However, the stress response of the brain circulation could not be entirely ascribed to one or both of these two systemic factors, thus suggesting the contribution of a local intrinsic activation. The model presented here could be useful for long-term studies of cerebrovascular repercussions of repeated acute hypertensions of a stressful nature.
Delayed Postischemic Hypoperfusion: Evidence against Involvement of the Noradrenergic Locus Ceruleus System
Authors: Blomqvist Photjanee , Lindvall Olle , Wieloch Tadeusz
Published: April 2011

This study explores the possibility that the delayed hypoperfusion observed after an ischemic insult might be due to vasoconstriction induced by the release of noradrenaline from nerves originating in the locus ceruleus. Bilateral 6-hydroxydopamine lesions of the ascending bundles from the locus ceruleus were carried out in the caudal mesencephalon of rats. Local CBF was measured with an autoradiographic technique 60 min following the start of recirculation after incomplete forebrain ischemia. No significant differences in CBF between nonoperated, sham-operated, and noradrenaline-depleted animals were observed in any structure of the forebrain. It is concluded that the noradrenergic locus ceruleus system does not contribute to the development of delayed postischemic hypoperfusion.
Mitochondrial Response to Transient Forebrain Ischemia and Recirculation in the Rat
Authors: Hillered Lars , Siesjö Bo K. , Arfors Karl-E.
Published: April 2011

Recovery of brain mitochondrial function was studied following forebrain ischemia induced in rats by common carotid artery occlusion in combination with hypotension caused by bleeding. A reversible insult was induced by 15-min ischemia in fasted animals (hypoglycemic ischemia), and an irreversible one by 30-min ischemia in fed animals (normoglycemic ischemia), the latter procedure causing exaggerated lactic acidosis as well. Mitochondrial function recovered during a 30-min recirculation period after 15-min hypoglycemic ischemia, although a small amount of Ca2+ accumulated during recirculation. Thirty-minute normoglycemic ischemia induced irreversible mitochondrial damage that was not associated with Ca2+ accumulation during recirculation. Ischemia of 15 and 30 min caused a loss of mitochondrial Mg2+ ∼25%) that persisted during recirculation but did not influence recovery. Based on our earlier data obtained on isolated brain mitochondria in vitro, it is suggested that the lack of full recovery following 30 min of normoglycemic ischemia was due to the profound lactic acidosis during this insult.
Effect of Topical Adenosine Deaminase Treatment on the Functional Hyperemic and Hypoxic Responses of Cerebrocortical Microcirculation
Authors: Dóra Eörs , Koller Ákos , Kovách Arisztid G. B.
Published: April 2011

The purpose of this study was to investigate the possible importance of adenosine in cerebrocortical vasodilatation accompanying brain activation (epileptic seizures and direct electrical stimulation) and hypoxia (arterial hypoxia and cyanide poisoning of the brain cortex). In chloralose-anesthetized cats a circumscribed area of the brain cortex was treated with adenosine deaminase (Type III; Sigma), which potently deaminates adenosine to the nonvasoactive inosine. Cerebrocortical vascular volume and fluorescence of reduced nicotinamide adenine dinucleotide were measured in vivo by surface fluororeflectometry. The responses of small pial and intracortical vessels to brain activation and hypoxia were studied in brain cortices superfused with artificial (mock) CSF and 5 U/ml adenosine deaminase. It was found that superficially applied adenosine deaminase readily diffuses onto the brain cortex. Prolonged pretreatment of the brain cortices with 0.025 U/ml adenosine deaminase eliminated almost completely the vasodilative effect of 10−7 mol/ml adenosine. The inhibitory effect of the enzyme on adenosine-induced cortical vasodilatation was specific, because 5 U/ml adenosine deaminase did not attenuate the vasodilative potency of 10−8 mol/ml 2-chloroadenosine. Adenosine deaminase (5 U/ml) pretreatment of the brain cortices did not diminish the cerebrocortical vascular volume, which increased with arterial hypoxia, topical cyanide poisoning, and direct electrical stimulation. However, it slightly decreased the vasodilative effect of epileptic seizures. On the basis of these results, it seems very unlikely that adenosine is a critical factor in the control of cerebrovascular tone during arterial hypoxia and brain activation.
Blood—Brain Barrier to Ammonia in Humans
Authors: Lockwood Alan H. , Bolomey Leonard , Napoleon Franz
Published: April 2011

We have developed a method to evaluate the diffusion of ammonia across the blood–brain barrier (BBB) in normal humans, based on measures of CBF and the regional cerebral metabolic rate for ammonia, obtained by positron emission tomography. The extraction fraction for ammonia passing through the cerebral capillary bed was a reciprocal function of CBF. The product of the BBB surface area and ammonia permeability, calculated from the Renkin-Crone model, was 0.32 ± 0.19 cm3 g−1 min−1 (±SD) in gray matter and 0.24 ± 0.16 cm3 g−1 min−1 in white matter. From literature values of the expected capillary surface area ratio, a gray-to-white matter ammonia permeability ratio of 0.37:1.0 was calculated. We speculate that astrocytes may mediate this unexpected difference in permeability, and that the permeability of the BBB to ammonia may be important in the pathogenesis of hyperammonemic brain dysfunction.
Long-Lasting Reduction of Cortical Blood Flow of the Rat Brain after Spreading Depression with Preserved Autoregulation and Impaired CO2 Response
Authors: Lauritzen Martin
Published: April 2011

The purpose of the present study was to examine the cerebral perfusion after spreading depression with special emphasis on its relation to the perfusion changes in migraine. The cerebrovascular reactivity to changes of arterial Pco2 tension in the range of 24–70 mm Hg and to changes of MABP in the range of 55–150 mm Hg was studied in the rat brain after one episode of cortical spreading depression. Regional CBF (rCBF) was measured in the frontal, parietal, and occipital cortex, the basal ganglia, and the cerebellum of both hemispheres after the intravenous bolus injection of [14C]iodoantipyrine. rCBF decreased in the cortical regions to 69–73% of control values for 1 h after spreading depression in every single rat, but remained unchanged in the basal ganglia and cerebellum. CBF changed with alterations of arterial carbon dioxide tension in all brain regions. In control regions, CBF changed by 2.8–3.9% per mm Hg Paco2 change, whereas in the spreading depression cortex, CBF changed by only 1.3–1.5%. The difference between control and spreading depression cortex was significant at p < 0.001, indicating a reduced CO2 sensitivity of the cortical regions invaded by spreading depression. rCBF remained unchanged in all brain regions in the MABP range of 80–150 mm Hg, reflecting the intact autoregulatory function of the two sides, and at a MABP of <80 mm Hg, rCBF decreased in parallel in symmetrical regions. It is concluded that the hypoperfusion after spreading depression is due to a vasoconstrictor stimulus overriding the vasodilatory effect of acid pH. The reduced CO2 response is probably the effect and not the cause of this vasoconstriction. The coexistence of rCBF reduction with perserved autoregulation and impaired CO2 response in an otherwise normally perfused brain has previously been found in patients during migraine attacks. This study therefore corroborates the notion that the perfusion changes of migraine may be pathophysiologically related to spreading depression and that spreading depression may serve as an experimental model of migraine.
Comparison of the Effects of Ischaemia on Early Components of the Somatosensory Evoked Potential in Brainstem, Thalamus, and Cerebral Cortex
Authors: Branston Neil M. , Ladds Amanda , Symon Lindsay , Wang Alexander D.
Published: April 2011

In 14 ventilated, normocapnic baboons anaesthetised with α-chloralose, local CBF (hydrogen clearance) and the amplitude and latency of local components of the somatosensory evoked potential (SEP, median nerve stimulation) were measured bilaterally in ventrobasal thalamus (VPL), medial lemniscus (ML), and cerebral cortex before and during progressive ischaemia, produced by occlusion of the right middle cerebral artery and subsequent controlled reductions in mean systemic blood pressure (MSBP). The first significant reduction from control of the left cortical SEP amplitude occurred in the range of 30–40 mm Hg MSBP, but those of the VPL and ML responses only below 30 mm Hg; in the range of 20–30 mm Hg, the average SEP amplitudes in cortex, VPL, and ML were 8.6, 72.6, and 90.7% of control, respectively. In terms of local CBF, the cortical SEP threshold was in the range of 15–20 ml/100 g/min (as in previous work), that of VPL in the range of 10–15 ml/100 g/min, but the ML response was only markedly reduced below 10 ml/100 g/min. Thus, the differential ischaemic sensitivity of the SEP between the three regions was clearly demonstrated. These results indicate that as one descends the neuraxis, there is an increasing resistance of electrophysiological function to systemic hypotension, together with a decreasing threshold for local ischaemia.
Cerebral Blood Flow and Metabolism in Normal Human Aging, Pathological Aging, and Senile Dementia
Authors: Dastur Darab K.
Published: April 2011

A review and a reappraisal are presented of earlier data on cerebral circulatory and metabolic studies in normal active elderly men (Group I) of mean age 71 years, compared with normal young subjects of mean age 21 years, conducted at the National Institutes of Health, Bethesda, MD, U.S.A., during 1956–1958. There was no significant difference in the mean CBF and cerebral metabolic rate for oxygen (CMRO2) values between the two populations; i.e., these important parameters did not fall with chronological aging per se. There was significant depression in the mean cerebral metabolic rate for glucose (CMRG) value (by ∼23%) in the aged compared with the young. Newer methods using positron emission tomography and appropriate isotopes have confirmed these findings in normal aging in human subjects and experimental animals. As expected, MABP and cerebral vascular resistance (CVR) were significantly elevated in the normal aged. MABP was even more elevated in elderly hypertensive subjects, and the CVR more elevated in the subjects with arteriosclerosis (Group II), who also showed a small but significant fall in CBF and in internal jugular venous Po2. The CBF showed a more pronounced fall in senile aged patients with chronic brain syndrome (Group III), in whom the CMRO2 also showed a marked drop (by ∼22%); the CMRG fell still further (∼40% of that in the young). Of the few aged subjects followed up after a lapse of 11 years by a repeat estimation of the same physiological and psychological parameters and of the EEG, most showed clear worsening, together with a fall in overall physical and intellectual performance, probably related to a rise in CVR and an increase in atherosclerosis with aging. Over this period, the number of surviving subjects fell strikingly from Group I to II to III. Our own limited observations and a brief review of the literature on “degenerative” and “vasogenic” dementias suggest that senile dementia, i.e., abnormal cerebral aging, results from the operation of both these factors or from one alone.
A Noninvasive Positron Computed Tomography Technique Using Oxygen-15-Labeled Water for the Evaluation of Neurobehavioral Task Batteries
Authors: Mazziotta John C. , Huang Sung-Cheng , Phelps Michael E. , Carson Richard E. , MacDonald Norman S. , Mahoney Kirk
Published: April 2011

A technique is described that provides information about relative cerebral responses to differing neurobehavioral tasks in normal subjects studied with positron computed tomography and oxygen-15-labeled water. Simulation studies demonstrate that this technique is sensitive to changes in true local CBF within a physiological range and tends to underestimate relative flow changes at high flow values (>30 ml min−1 100 g−1) and to overestimate these changes for flow values of <25 ml min−1 100 g−1. Image acquisition times of 60 s following the arrival of oxygen-15-labeled water in the brain were the most accurate for identifying such relative changes between radioisotope administrations and were not limited by statistical noise from total image counts. Studies in normal volunteers indicate that the technique is highly reproducible, demonstrating a coefficient of variation for small (<2 cm2) regions of 2.98 between studies in the same state. Visual stimulation studies in normal volunteers demonstrated relative radioisotope concentration changes between control and stimulated states that are in good agreement with similar results obtained using the same stimulation paradigm but with the use of fluorodeoxyglucose to determine cerebral glucose metabolism.
Multiparametric Imaging of Blood Flow and Metabolism after Middle Cerebral Artery Occlusion in Cats
Authors: Hossmann K.-A. , Mies G. , Paschen W. , Csiba L. , Bodsch W. , Rapin J. R. , Le Poncin-Lafitte M. , Takahashi K.
Published: April 2011

In anesthetized adult cats, acute stroke was produced by transorbital occlusion of the left middle cerebral artery. A battery of imaging techniques was used for simultaneous evaluation of regional blood flow, glucose utilization, protein synthesis, pH, and the regional tissue content of glucose, ATP, and potassium. The electrophysiological impact of stroke was monitored by EEG frequency analysis and recording of somatosensory evoked potentials. Two hours after vascular occlusion, a close correlation existed between the degree of electrophysiological changes and biochemical alterations, in particular with the extent of tissue acidosis, ATP depletion, decrease of tissue potassium content, and suppression of protein synthesis. However, there was only a poor correlation with blood flow and glucose utilization. Both of these exhibited a greatly inhomogeneous pattern with regions of reduced, normal, or increased rates. In areas remote from the infarct, the content of biochemical substrates was normal but blood flow was reduced globally by ∼50% and glucose utilization by ∼20%. An anatomically defined regional pattern of cerebral or cerebellar diaschisis was not observed. It is concluded that during the acute phase of stroke, imaging of blood flow and glucose utilization does not provide an accurate estimate of the actual functional or metabolic disturbance. For the clinical evaluation of the development or treatment of stroke, in consequence, alternative noninvasive techniques such as imaging of protein synthesis and/or pH may be more relevant.
Rapid Amino Acid Uptake in Rat Pituitary Neural Lobe during Functional Stimulation by Chronic Dehydration
Authors: Gross Paul M. , Blasberg Ronald G. , Fenstermacher Joseph D. , Patlak Clifford S.
Published: April 2011

We studied the transfer of a small neutral amino acid, α-aminoisobutyric acid, from arterial blood into the pituitary neural lobe in normal rats and in rats deprived of water for 5 days. A threefold increase in the neural lobe uptake of the amino acid was found in the chronically dehydrated rats. Possible causes for this effect include enlargement of the capillary and pituicyte membrane surface areas available for solute flux and increased permeability of these membranes. Such functional and structural alterations may be associated with an increase in protein turnover in the neural lobe during dehydration.
Performance Comparison of Parameter Estimation Techniques for the Quantitation of Local Cerebral Blood Flow by Dynamic Positron Computed Tomography
Authors: Koeppe Robert A. , Holden James E. , Ip W. Raymond
Published: April 2011

Local CBF (LCBF) can be quantitated from positron computed tomographic (PCT) data and physiologically based mathematical models by several general methods. Those using a dynamic sequence of PCT scans allow the simultaneous estimation of both LCBF and p, the indicator's tissue–blood partition coefficient. This article presents a comparison of three rapid estimation techniques for use with inert diffusible radioindicators and serial PCT, each of which is based on the original Kety model. One method, developed in our laboratory, involves minimizing the mean squared discrepancy between measured data and model predictions, whereas the other two methods, recently reported in the literature, are weighted integration techniques that involve multiplying the measured data by time-dependent weighting functions. Simulation studies of noise propagation and other sources of error were performed under a variety of simulated conditions. Functional images of LCBF and p were calculated using each method for both phantom and human subject data. Errors can differ by as much as a factor of 2–3 between methods, with each having its own unique advantages and disadvantages.
Double-Tracer Study of the Fine Regional Blood—Brain Glucose Transfer in the Rat by Computer-Assisted Autoradiography
Authors: Gjedde Albert , Diemer Nils Henrik
Published: April 2011

Glucose is transported from blood to brain tissue by facilitated diffusion of limited capacity. The regional variation of the glucose transport capacity is not known in detail because methods used previously have been too gross to detect fine regional differences. Therefore, it is not known to what extent the glucose transport capacity varies in proportion to regional blood flow and metabolic rate. To resolve this question, we used double-tracer, dual-label autoradiography to measure blood–brain glucose clearance and blood flow simultaneously in hypo-, normal, and hyperglycemic rats. From the values of glucose clearance and blood flow at various plasma glucose levels, we calculated the affinity constant and maximal transport capacity of the glucose transport system. The transport capacity ( Tmax) varied in approximate proportion to the blood flow and, by inference, the metabolic rate. In contrast, the affinity constant ( K t) did not vary systematically between the regions (mean value 7.1 m M). The variation of Tmax from 270 to 890 μmol hg−1 min11 reflected a parallel variation of total regional capillary length and surface. We conclude from the study that the cerebral capillary is a fixed unit, i.e., that the number of glucose transporters per unit of capillary surface area is the same in all regions. Regional differences are the result of different capillary densities in the regions of the brain.
Tomographic Mapping of Brain Intracellular pH and Extracellular Water Space in Stroke Patients
Authors: Syrota A. , Samson Y. , Boullais C. , Wajnberg P. , Loc'h C. , Crouzel C. , Mazière B. , Soussaline F. , Baron J. C.
Published: April 2011

Functional images of regional intracellular pH (pHi) and of fractional volume of extracellular water (FVECW) were obtained in 10 patients with recent hemispheric infarction (between 10 and 19 days after onset of symptoms) using positron emission tomography (PET). The volume of extracellular water relative to that of total water was evaluated in each pixel of the PET scan 7–8 h after injection of 76Br. The pHi image was calculated from the data obtained after injection of [11C]5,5-dimethyl-2,4-oxazolidinedione and from the FVECW image. Regional CBF, oxygen extraction, and oxygen metabolism were also measured in the same patients. In normal hemisphere, mean ± SD values for FVECW and pHi were 0.12 ± 0.01 and 6.86 ± 0.11, respectively. FVECW was increased in the infarcted area in most patients. pHi was increased in the infarct in seven patients and unchanged in three. The increase in pHi was not correlated with changes in FVECW, CBF, or CMRO2, but there was a significant correlation with the decrease in oxygen extraction fraction in the same region. Thus, the decreased H+ content in the infarcted area was correlated with the occurrence of perfusion in excess of metabolic demand. An alkaline shift in pHi enhances the glycolysis rate and could explain why the glucose metabolism is less affected than the oxygen metabolism in recent cerebral infarction. The pHi measured in the infarct could represent mainly the pHi of phagocytic cells that use aerobic glycolysis to synthesize hydrogen peroxide.
Kinetics of Saturable Transport across the Blood—Brain Barrier
Authors: Cunningham Vincent J.
Published: April 2011

This article is concerned with the extension of the Renkin-Crone model to a case of saturable transport across the blood–brain barrier, i.e., when the apparent permeability-surface area product is concentration dependent. A well-mixed tissue compartment is assumed, together with a simple symmetric saturable transport system. A computation scheme, or algorithm, is described that allows the calculation of arteriovenous differences and net influx rates for parent substance and tracer in terms of arterial and tissue concentrations of each, the transport maximum Tmax, the half-saturation constant Kt, and plasma flow rate. The scheme was devised initially for the analysis of experiments in which the parent substance was not in a steady state and in which tracer backflux from tissue to capillary was significant.
Adrenergic-Induced Enhancement of Brain Barrier System Permeability to Small Nonelectrolytes: Choroid Plexus versus Cerebral Capillaries
Authors: Murphy Vincent A. , Johanson Conrad E.
Published: April 2011

Acute hypertension induced by adrenergic agents opens up the blood–CSF barrier (choroid plexus) to nonelectrolyte and protein tracers. Sprague-Dawley adult rats anesthetized with ketamine were given an intravenous bolus of either epinephrine (10 μg/kg), phenylephrine (100 μg/kg), isoproterenol (10 μg/kg), or d,l-amphetamine (2 mg/kg). Tracers were injected simultaneously with test agents, and the animals killed 10 min later. Epinephrine raised MABP by 57 mm Hg, to a peak pressure of 160 mm Hg; and it increased the volume of distribution ( Vd) of urea, mannitol, and 125I-bovine serum albumin in CSF by 1.5-, 2.7-, and 30-fold, respectively. There was enhanced uptake by lateral and fourth ventricle choroid plexuses, cerebral cortex, cerebellum, medulla, and thalamus. Phenylephrine also elevated MABP to 160 mm Hg, but it increased permeation of tracers into CSF (and several brain regions) to a lesser extent than epinephrine, attributable to protective vasoconstriction associated with α-agonist activity. Ratio analysis of Vd data provides evidence that augmented permeation of nonelectrolyte tracers in acute hypertension occurs predominantly by diffusion rather than vesicular transport. It is postulated that elevated MABP distends the central cores of choroid plexus villi and cerebral capillaries, with resultant stretching and opening of tight junctions in both barrier systems; with less hindrance to diffusion, urea and mannitol are cleared at rates closer to free diffusion. Neither isoproterenol (decreased MABP by 40 mm Hg) nor amphetamine (did not alter MABP) significantly opened the choroid plexus or blood–brain barrier to tracers.
Brain Tissue Acidosis and Changes of Energy Metabolism in Mild Incomplete Ischemia—Topographical Study
Authors: Kim Soo-Ho , Handa Hajime , Ishikawa Masatsune , Hirai Osamu , Yoshida Shinzo , Imadaka Kiyoharu
Published: April 2011

Regional changes of brain tissue pH and its correlation to energy metabolism were studied in various degrees of incomplete ischemia for 5 and 60 min in the unilateral common carotid occlusion of normally fed mongolian gerbils. The degree of ischemia was evaluated by the severity of neurological deficits following 60 min of occlusion, and animals were divided into three groups: symptomatic, borderline, and asymptomatic. Changes of NADH and ATP distribution corresponded well to the degree of ischemia. On the other hand, acidosis developed more clearly and extended in wider areas than the changes of NADH and ATP distribution. These changes were already seen at 5 min of occlusion. From the results of this experiment, it was suspected that acidosis in mild incomplete ischemia was due to stimulated anaerobic glycolysis that might supplement NADH oxidation and ATP yields. Further, acidosis without energy failure was considered not to be detrimental to neuronal cells.
Blocking Effect of Diltiazem on Thiopentone-Induced Vasoconstriction in Isolated Canine Internal Carotid Arteries
Authors: Tsuji T. , Chiba S.
Published: April 2011

Stainless-steel cannulas were inserted into isolated internal carotid arteries of the dog to observe vasoconstrictor responses to thiopentone. Thiopentone at a relatively large dose (100–3,000 μg) induced vasoconstrictor responses in a dose-dependent manner. A dose of 1 mg thiopentone usually produced a definite increase in perfusion pressure of <50 mm Hg. These effects were not influenced by treatment with phentolamine in doses that significantly suppressed noradrenaline-induced vasoconstrictor responses. Diltiazem inhibited the constriction in response to thiopentone as well as that to potassium chloride in a noncompetitive antagonistic manner. It is suggested that the constriction induced by thiopentone may be due in part to activation of the calcium-inward channel in the wall of the internal carotid artery.
Effects of Enkephalins, Morphine, and Naloxone on Pial Arteries during Perivascular Microapplication
Authors: Wahl Michael
Published: April 2011

The effects of the opiate receptor agonists, enkephalins and morphine, and the antagonist, naloxone, on cerebrovascular resistance vessels was investigated in situ by employing perivascular microapplication. Feline pial arteries with a resting diameter of 66–294 μm were tested. Vascular diameter was measured using television image splitting. Concentration-response curves revealed no change of diameter when Leu-enkephalin, d-Ala2-Leu-enkephalinamide, d-Ala2-Met-enkephalinamide, and morphine were applied in concentrations of 10−11–10−5 M. Considering the concentrations of enkephalins that have been found in natural cerebrospinal fluid or that can be expected in the vicinity of enkephalinergic synapses, the data obtained with the lower concentrations indicate that enkephalins are probably not important for the regulation of pial arterial resistance. At 10−4 M only the dilatation (4.3%) elicited by d-Ala2-Leu-enkephalinamide was statistically significant (p < 0.01). All four agonists at 10−3 M induced significant dilatations varying between 5.4 and 13.6%. Naloxone exerted no vascular effect per se at 10−5 and 10−4 M but a dilatation of 15.3% at 10−3 M. The latter can be explained by a partial agonist action. During simultaneous administration, naloxone (10−4 M) reduced the dilatations induced by 10−4 and 10−3 M d-Ala2-Leu-enkephalinamide dose dependently. This indicates that μ-and δ-opioid receptors, probably located at the vascular smooth muscle cell, were involved in the mediation of the dilatation induced by the highest concentrations of the compounds.
Standardized Mean Regional Method for Calculating Global Positron Emission Tomographic Measurements
Authors: Perlmutter Joel S. , Herscovitch Peter , Powers William J. , Fox Peter T. , Raichle Marcus E.
Published: April 2011

A new “mean regional” method for calculating global hemispheric values of blood flow, blood volume, and metabolism with positron emission tomography is presented. It is based on a standardized set of regions defined according to coordinates in a stereotactic atlas of the brain. Region locations in each individual scan were determined by a localization technique that is independent of the appearance of the physiological images. Measurements obtained with this mean regional method minimize contributions from nonbrain structures such as ventricles or venous sinuses and provide the necessary basis for comparisons among different subjects and laboratories.
Cerebral Intracellular Changes during Supercarbia: An in vivo 31P Nuclear Magnetic Resonance Study in Rats
Authors: Litt Lawrence , González-Méndez Ricardo , Severinghaus John W. , Hamilton William K. , Shuleshko Julia , Murphy-Boesch Joseph , James Thomas L.
Published: April 2011

31P nuclear magnetic resonance (NMR) spectroscopy was used noninvasively to measure in vivo changes in intracellular pH and intracellular phosphate metabolites in the brains of rats during supercarbia (Paco2 ⩾ 400 mm Hg). Five intubated rats were mechanically ventilated with inspired gas mixtures containing 70% CO2 and 30% O2. Supercarbia in the rat was observed to cause a greater reduction in cerebral intracellular pH (pHi) and increase in Pco2 than observed in other experiments with rats after 15 min of global ischemia. Complete neurologic and metabolic recovery was observed in these animals, despite an average decrease in pH; of 0.63 ± 0.02 pH unit during supercarbia episodes that raised Paco2 to 490 ± 80 mm Hg. No change was observed in cerebral intracellular ATP and only a 25% decrease was detected in phosphocreatine. The concentration of free cerebral intracellular ADP, which can be calculated if one assumes that the creatine kinase reaction is in equilibrium, decreased to approximately one-third of its control value. The calculated threefold decrease in the concentration of free ADP and twofold increase in the cytosolic phosphorylation potential suggest that there is increased intracellular oxygenation during supercarbia. Because a more than fourfold increase in intracellular hydrogen ion concentration was tolerated without apparent clinical injury, we conclude that so long as adequate tissue oxygenation and perfusion are maintained, a severe decrease in intracellular pH need not induce or indicate brain injury.
Cerebral Blood Flow with the Continuous Infusion of Oxygen-15-Labeled Water
Authors: Jones S. C. , Greenberg J. H. , Dann R. , Robinson G. D. , Kushner M. , Alavi A. , Reivich M.
Published: April 2011

This work describes the determination of CBF in eight normal human subjects with positron emission tomographic (PET) imaging using the continuous intravenous infusion of H215O. A whole-brain CBF model is described that permits the comparison of the CBF values determined using PET with those obtained using other methods. This model includes a correction for whole-brain recovery coefficient, a correction for the underestimation of flow due to the nonlinearity of the CBF model when considering tissue that includes both gray and white matter, the use of in vitro-determined brain–blood partition coefficients for gray and white matter, and a variation of the equilibrium model that permits the arterial concentration to vary. CBF values using this method compare well with values determined previously. Regional determinations using a brain overlay atlas are presented. Radiation dosimetry for the continuous infusion of H215O is also included.
Role of a Hydrostatic Pressure Gradient in the Formation of Early Ischemic Brain Edema
Authors: Hatashita Shizuo , Hoff Julian T.
Published: April 2011

We studied whether a hydrostatic pressure gradient between arterial blood and brain tissue plays a role in the formation of early ischemic cerebral edema after middle cerebral artery (MCA) occlusion in cats. Tissue pressure, regional CBF, and water content were measured from the cortex in the core and the peripheral zone of brain normally perfused by the MCA. Intraluminal arterial pressure was altered at intervals by inflation of an aortic balloon to vary the blood–tissue pressure gradient in the ischemic zone. Brain water content in the ischemic core, where flow fell to 5.5 ml/100 g/min, increased within 1 h of occlusion. After occlusion tissue pressure rose from 7.95 ± 0.72 mm Hg at 1 h to 13.16 ± 1.13 mm Hg at 3 h. When intraluminal pressure was increased, water content increased further, but only at 1 h after occlusion. In the periphery where flow was 18.9 ml/100 g/min during normotension. neither water content nor tissue pressure rose within 3 h of occlusion. Increased intraluminal pressure was accompanied by increased water content only at 3 h. This study indicates that a hydrostatic pressure gradient is an important element in the development of ischemic brain edema, exerting its major effect during the initial phase of the edema process.
Infarct Rim: Effect of Hyperglycemia on Direct Current Potential and [14C]2-Deoxyglucose Phosphorylation
Authors: Nedergaard Maiken , Astrup Jens
Published: April 2011

Focal ischemia was produced by occlusion of the right middle cerebral artery (MCA) in normo- and hyperglycemic rats. In the cortical infarct rim, regional [14C]2-deoxyglucose ([14C]2-DG) phosphorylation was correlated to spontaneous transient changes in extracellular potassium recorded as direct current (DC) potential deflections. In normoglycemic rats the DC potential showed transient but recurrent deflections in the first hours following MCA occlusion. The 2-DG phosphorylation was elevated by 200% in the same area. In contrast, hyperglycemic rats had no, or a single, deflection of the DC potential in the rim, and the 2-DG phosphorylation remained normal. The same pattern was obtained by application of 3 M KCl to the exposed cortex. In normoglycemia potassium application resulted in recurrent deflections of the DC potential, and 2-DG phosphorylation increased in most parts of the hemisphere. Hyperglycemic animals had a nearly stable DC potential, and 2-DG phosphorylation increased only in the tissue area situated directly below the site of potassium application. The results indicate that metabolism in the cortical infarct rim is stimulated by spontaneous and recurrent changes in extracellular potassium—a phenomenon that may be related to spreading depression—and that the metabolism remained normal in the same area in hyperglycemic animals owing to an inhibition of transient increases of extracellular potassium.
Distribution of Cytochrome Oxidase in Rat Brain: Studies with Diaminobenzidine Histochemistry in vitro and [14C]Cyanide Tissue Labeling in vivo
Authors: Darriet Danielle , Der Terry , Collins Robert C.
Published: April 2011

Studies in experimental animals and postmortem studies in humans have indicated that the level of the mitochondrial enzyme cytochrome oxidase within brain anatomical pathways is regulated by the long-term functional use of those pathways. To study this relationship, we have measured cytochrome oxidase spectropho-tometrically in punch biopsies from different brain regions of rat. We compared these assays against results from the diaminobenzidine histochemical technique. We found a high degree of correlation ( r = 0.90) between the density of diaminobenzidine reaction product and enzyme activity. This validates the usefulness of the diaminobenzidine technique for anatomical localization and measurement of this enzyme. To study the feasibility of using radioactive cyanide as an in vivo ligand of cytochrome oxidase, we performed quantitative autoradiographic analysis of rat brains of animals given an intravenous bolus injection of [14C]cyanide. Analysis of the arterial blood curve indicated a complex redistribution of cyanide between red blood cells, plasma, and tissues. Brain labeling reached peak levels at 1 min and then fell despite rising concentrations of free plasma cyanide. Analysis of autoradiographic images revealed good anatomical resolution. The density of labeling in individual structures over time failed to show a strong correlation with cytochrome oxidase activity or diaminobenzidine reaction product.
Tomographic Mapping of Kinetic Rate Constants in the Fluorodeoxyglucose Model Using Dynamic Positron Emission Tomography
Authors: Sasaki Hiroshi , Kanno Iwao , Murakami Matsutaro , Shishido Fumio , Uemura Kazuo
Published: April 2011

A quick computing algorithm to calculate the rate constants ( k*1, k*2, k*3) in the [18F]2-fluoro-2-deoxy-d-glucose (FDG) model was developed. The algorithm solved for the rate constants pixel by pixel using a conventional least-squares method and two tables consisting of a set of various rate constants, to shorten the computing time. Five planes of rate constant images were obtained. A combined study using the dynamic FDG method and the 15O-labeled gas continuous inhalation method was performed on seven healthy male volunteers aged 26–35 years. Results indicated an apparent discrepancy between CMRglu and CMRO2 in the cerebellum, where the low glucose utilization was correlated with a low FDG phosphorylation rate ( k*3) despite a sufficient FDG transportation rate ( k*1) from plasma to tissue.
Effects of Traumatic Brain Injury on Cerebral High-Energy Phosphates and pH: A 31P Magnetic Resonance Spectroscopy Study
Authors: Vink Robert , McIntosh Tracy K. , Weiner Michael W. , Faden Alan I.
Published: April 2011

Traumatic injuries to the CNS produce tissue damage both through mechanical disruption and through more delayed autodestructive processes. Delayed events include various biochemical changes whose nature and time course remain to be fully elucidated. Magnetic resonance spectroscopy (MRS) techniques permit repeated, noninvasive measurement of biochemical changes in the same animal. Using phosphorus MRS, we have examined certain biochemical responses of rats over an 8-h period following lateralized brain injury (1.5–2.5 atmospheres) using a standardized fluid-percussion model recently developed in our laboratory. Following injury, the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) showed a biphasic decline: The first decline reached its nadir (4.8 ± 0.4 to 2.8 ± 0.7) by 40 min post-trauma with recovery by 100 min, followed by a second decline by 2 h that persisted for the remaining 6-h observation period (mean 2.5 ± 0.5). The first, but not the second, decrease in PCr/Pi was associated with tissue acidosis (pH 7.10 ± 0.03 to 6.86 ± 0.11). No changes in ATP occurred at any time during the injury observation period. Such changes may be indicative of altered mitochondrial energy production following brain injury, which may account for the reduced capacity of the cell to recover from traumatic injury.