bluuebunny/crossref_metadata_2025 huggingface dataset:
Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. Generalizations
Authors: Patlak Clifford S. , Blasberg Ronald G.
Published: April 2011

The method of graphical analysis for the evaluation of sequential data (e.g., tissue and blood concentrations over time) in which the test substance is irreversibly trapped in the system has been expanded. A simpler derivation of the original analysis is presented. General equations are derived that can be used to analyze tissue uptake data when the blood–plasma concentration of the test substance cannot be easily measured. In addition, general equations are derived for situations when trapping of the test substance is incomplete and for a combination of these two conditions. These derivations are independent of the actual configuration of the compartmental system being analyzed and show what information can be obtained for the period when the reversible compartments are in effective steady state with the blood. This approach is also shown to result in equations with at least one less nonlinear term than those derived from direct compartmental analysis. Specific applications of these equations are illustrated for a compartmental system with one reversible region (with or without reversible binding) and one irreversible region.
Regional Quantitative Determination of Lactate in Brain Sections. A Bioluminescent Approach
Authors: Paschen W.
Published: April 2011

Regional lactate distribution in brain was assessed quantitatively in coronal sections using a bioluminescent technique. This bioluminescence can be induced by covering freeze-dried and heat-inactivated brain sections with a frozen solution containing enzymes and coenzymes both for lactate-dependent NADH formation and NADH-dependent bioluminescence, which was recorded photographically. Quantification and density coding of bioluminescent images were carried out by utilizing the regression coefficients of the correlation between the optical density of bioluminescent pictures and the lactate content measured in tissue samples. Regional quantitative lactate images were obtained from brain tissue taken from brain tumors or after experimental cerebral ischemia.
Subarachnoid Hemorrhage in the Rat: Cerebral Blood Flow and Glucose Metabolism during the Late Phase of Cerebral Vasospasm
Authors: Delgado Tia J. , Arbab Mohamed A.-R. , Diemer Nils H. , Svendgaard Niels-Aage
Published: April 2011

A double-isotope technique for the simultaneous measurement of CBF and CMRglu was applied to a subarachnoid hemorrhage (SAH) model in the rat. Cisternal injection of 0.07 ml blood caused a rather uniform 20% reduction in CBF together with an increase in glucose utilization of 30% during the late phase of vasospasm. In one-third of the SAH animals, there were focal areas where the flow was lowered to 30% of the control values and the glucose uptake increased to ∼250% of control. We suggest that blood in the subarachnoid space via a neural mechanism induces the global flow and metabolic changes, and that the foci are caused by vasospasm superimposed on the global flow and metabolic changes. In the double-isotope autoradiographic technique, [14C]iodoantipyrine and [3H]deoxyglucose were used for CBF and CMRglu measurements, respectively, in the same animal. In half of the sections, the [l4C]iodoantipyrine was extracted using 2,2-dimethoxypropane before the section was placed on a 3H- and 14C-sensitive film. The other sections were placed on x-ray film with an emulsion insensitive to 3H. The validity of the double-isotope method was tested by comparing the data with those obtained in animals receiving a single isotope. The CBF and metabolic values obtained in the two groups were similar.
Effect of Selective Lesions in the Hypothalamic—Pituitary Region on the Development of Cerebral Vasospasm following an Experimental Subarachnoid Hemorrhage in the Rat
Authors: Svendgaard N. Aa. , Delgado T. J. , Brun A.
Published: April 2011

Intracisternal injection of blood in the rat induced an angiographically demonstrable biphasic cerebral vasospasm with a maximal acute spasm at 10 min and a maximal late spasm at 2 days after the subarachnoid hemorrhage. Systemic administration of 6-hydroxydopamine, which destroys catecholamine fibers in the circumventricular areas characterized by the absence of a blood–brain barrier, prevented the development of both the acute and the late spasm. Isolation or removal of one of the circumventricular organs, the pituitary, from the brain via a stalk transection or a hypophysectomy did not affect the degree of vasospasm. Lesion of the median eminence, another region without a blood–brain barrier, prevented the development of both types of spasm. The median eminence receives projections from the A1 and A2 nuclei in the medulla oblongata. It is suggested that the projections of these nuclei to the internal layer of the median eminence underlie the development of spasm.
Cerebral Acidosis in Focal Ischemia: I. A Method for the Simultaneous Measurement of Local Cerebral pH with Cerebral Glucose Utilization or Cerebral Blood Flow in the Rat
Authors: Hakim Antoine M. , Arrieta Marie
Published: April 2011

We developed a technique for the simultaneous autoradiographic determination of local cerebral pH (LCpH) using [14C]dimethyloxazolidinedione ([14C)DMO) with either local cerebral glucose utilization (LCGU) using [14C]deoxyglucose ([14C]DG) or local CBF (LCBF) using [14C]iodoantipyrine ([14C]IAP). The method evolved from the observation that [14C]DMO is “unstable,” which is shown here to be due to sublimation of the compound. Thus, the technique consists of administering to rats [14C]DMO followed by either [14C]DG or [14C]IAP. The first autoradiographic film that results contains both labeled compounds. The brain sections are then exposed in a fume hood until the complete disappearance of [14C]DMO, which usually required 10 days. The second film thus contains only the non-DMO isotope administered. Blood levels of the two isotopes are calculated from the total concentrations of isotope and the rate of decline of [14C]DMO in blood. This information is then used to determine cerebral pH and the other cerebral function of interest. Using this double-label technique in normal rats, LCpH, LCGU, and LCBF can be determined with the same accuracy as with single-label techniques. In rats with middle cerebral artery occlusion, this technique yielded LCpH and LCBF values 4 h after occlusion that were not statistically different from those obtained by separate determinations. Thus, interactions between LCpH and either LCBF or LCGU can be studied by this technique in normal and pathological conditions.
Carotenoid Compound Crocetin Improves Cerebral Oxygenation in Hemorrhaged Rats
Authors: Seyde Walter C. , McKernan Daniel J. , Laudeman Thomas , Gainer John L. , Longnecker David E.
Published: April 2011

The carotenoid compound crocetin has been shown to increase oxygen diffusivity in vitro. In the present study the effect of crocetin on tissue oxygenation was examined in the cerebral cortex of rats subjected to hemorrhage. Twelve male Sprague–Dawley rats were anesthetized with pentobarbital and ventilation was controlled (PaCO2 = 33 mm Hg). A craniotomy was performed and the animals were hemorrhaged (20% of estimated total blood volume). Six of 12 animals then received a bolus of crocetin (2 U in 0.1 ml saline); the remaining animals received saline (0.1 ml i. v.) only. Values for mean arterial pressure. PO2, PCO2, pH, and hematocrit did not differ in rats that received either saline or crocetin. Tissue oxygen tension (PtO2) was measured at ∼170 locations in the parietal cerebral cortex of each rat by a platinum–oxygen microelectrode technique. Results were compared by PtO2 frequency histograms. Crocetin as compared with saline treatment resulted in a right shift of the PtO2 frequency distribution and a significant decrease in the frequency of occurrence of low PtO2 values. The average of individual median PtO2 values was significantly greater in crocetin-treated animals as compared with those receiving saline (7.6 ± 1.7 vs. 3.2 ± 1.2 mm Hg, respectively). The results suggest that the carotenoid compound crocetin improves tissue oxygenation in the cerebral cortex of hemorrhaged rats.
Regression Model for Predicting Dissociations of Regional Cerebral Glucose Metabolism in Individuals at Risk for Huntington's Disease
Authors: Clark C. M. , Hayden M. R. , Stoessl A. J. , Martin W. R. W.
Published: April 2011

This article describes and partially validates a method for predicting whether an observed regional metabolic value is consistent with the observed value of another region, A regression equation was generated from a set of normal metabolic values, and then this equation was applied to patients with symptomatic Huntington's disease and patients at risk for this disorder. The results of the regression method were consistent with observations of the absolute rate for the normal subjects and Huntington's patients. For the at-risk patients, 6 of 18 were found to have reduced caudate metabolism relative to observed thalamic values. Since the initial scan, one of these identified at-risk individuals has developed symptomatic Huntington's disease. The method may be appropriate for other disorders where there are potential subgroups (e.g., schizophrenia) within a diagnostic category.
Quantification of Neuroreceptors in the Living Human Brain. I. Irreversible Binding of Ligands
Authors: Wong Dean F. , Gjedde Albert , Wagner Henry N.
Published: April 2011

A first step in the quantification of receptor density in the living human brain is the measurement of the binding of a labeled ligand to the receptor in question. In the present study, we determined the rate of binding of 11C-labeled N-methylspiperone (NMSP) to the D2 dopamine receptor in 11 normal volunteers, using a three-compartment model to relate the time integral of the measured plasma concentration to the distribution of the tracer in the caudate nucleus. The plasma concentrations of NMSP were separated from the contaminating metabolites by the ratio of radioactivities in cerebellum and blood plasma. Plasma concentrations calculated in this way agreed with plasma concentrations determined by HPLC. The rate of binding of labeled NMSP to its receptors ( k3) was defined as the product of the bimolecular association rate ( kon) and the quantity of available receptors ( B'max) and calculated as the ratio between the steady-state rate of accumulation and the volume of distribution of labeled NMSP in the caudate nucleus. The average value of k3 in the 11 normal volunteers was 0.065 min−1. The fractional clearance of labeled NMSP from the caudate nucleus ( k2) was 0.070 min−1 and thus close to the value of k3. We also examined several indexes of binding based on ratios between different regions in brain. The indexes required that binding be negligible compared to the efflux of labeled NMSP (i.e., k2 ≫ k3) and therefore yielded incorrectly low values of k3. Thus, the only accurate approach used measured plasma concentrations to estimate transfer constants at steady state and yielded the absolute rate of binding k3. The approach is applicable to other irreversibly bound ligands.
Photochemically Induced Cortical Infarction in the Rat. 2. Acute and Subacute Alterations in Local Glucose Utilization
Authors: Dietrich W. Dalton , Ginsberg Myron D. , Busto Raul , Watson Brant D.
Published: April 2011

Local CMRglu (LCMRglu) values were measured by [14C]2-deoxyglucose autoradiography in the rat at 4 h and 5 days following photochemically induced cortical infarction, and these data were compared with neuropathological findings in adjacent serial sections. At both time periods, LCMRglu was markedly reduced within the lesion center, and irregular regions of moderate-to-marked glucose hypermetabolism were noted within the marginal zone of the developing infarct. At 4 h, the hypermetabolic zones were shown by pathological examination to be characterized by normal-sized, moderately hyperchromatic neurons scattered among occasional dark, shrunken neurons within preserved neuropil. In contrast, the hypermetabolic zones at 5 days coincided with foci of intense macrophage infiltration, with dissolution of the neuropil. Significant decreases in glucose utilization were also demonstrated at 4 h within brain structures remote from the site of focal injury. These structures included the lateral and auditory cortices ipsilaterally, the striatum and thalamus ipsilaterally, and the hippocampus bilaterally. In addition to these remote metabolic effects, depressed metabolism occurred within the homologous cortical region contralateral to the site of infarction. By 5 days, glucose utilization was severely depressed in all ipsilateral cortical regions but not within any contralateral cortical region. Analysis of these data suggests that more than one mechanism is responsible for the metabolic alterations occurring within brain regions remote from the site of irreversible damage. Results are discussed in light of the hemodynamic alterations occurring in this stroke model, which are presented in the accompanying report.
Glucose Transport across the Blood—Brain Barrier in Normal Human Subjects and Patients with Cerebral Tumours Studied Using [11C]3-O-Methyl-D-Glucose and Positron Emission Tomography
Authors: Brooks D. J. , Beaney R. P. , Lammertsma A. A. , Herold S. , Turton D. R. , Luthra S. K. , Frackowiak R. S. J. , Thomas D. G. T. , Marshall J. , Jones T.
Published: April 2011

The kinetics of the regional cerebral uptake of [11C]3- O-methyl-d-glucose ([11C]MeG), a competitive inhibitor of d-glucose transport, have been studied in normal human subjects and patients with cerebral tumours using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and blood flow enabled corrections for the contribution of intravascular tracer signal in PET scans to be carried out and regional unidirectional cerebral [11C]MeG extractions to be determined. A three-compartment model containing an arterial plasma and two cerebral compartments was required to produce satisfactory fits to experimental regional cerebral [11C]MeG uptake data. Under fasting, resting conditions, normal controls had mean unidirectional whole-brain, cortical, and white matter [11C]MeG extractions of 14, 13, and 17%, respectively. Mean values of k1 and k2, first-order rate constants describing forward and back transport, respectively, of tracer into the first cerebral compartment, were similar for [11C]MeG and [18F]2-fluoro-2-deoxy-d-glucose (18FDG), a second competitive inhibitor of d-glucose transport, k3, a rate constant describing FDG phosphorylation, was 20 times higher for cortical FDG uptake than the k3 fitted for [11C]MeG cortical uptake. Glioma [11C]MeG extractions ranged from normal levels of 12% to raised levels of 30%. Transport of [11C]MeG in and out of contralateral cortical tissue was significantly depressed in patients with gliomas. It is concluded that under fasting, resting conditions, regional cerebral glucose extraction remains relatively uniform throughout normal brain tissue. Gliomas, however, may have raised levels of glucose extraction. The nature of the second cerebral compartment required to describe [11C]MeG uptake is unclear, but it could represent either a useless phosphorylation–dephosphorylation cycle or nonspecific tracer uptake by a cerebral sub-compartment.
Selective Gene Expression in Focal Cerebral Ischemia
Authors: Jacewicz Michael , Kiessling Marika , Pulsinelli William A.
Published: April 2011

Regional patterns of protein synthesis were examined in rat cortex made ischemic by the occlusion of the right common carotid and middle cerebral arteries. At 2 h of ischemia, proteins were pulse labeled with intracortical injections of a mixture of [3H]leucine, [3H]isoleucine, and [3H]proline. Newly synthesized proteins were analyzed by two-dimensional gel fluorography, and the results correlated with local CBF, measured with [14C]iodoantipyrine as tracer. Small blood flow reductions (CBF = 50–80 ml 100 g−1 min−1) were accompanied by a modest inhibition in synthesis of many proteins and a marked increase in one protein (Mr 27,000). With further reduction in blood flow (CBF = 40 ml 100 g−1 min−1), synthesis became limited to a small group of proteins (Mr 27,000, 34,000, 73,000, 79,000, and actin) including two new polypeptides (Mr 55,000 and 70,000). Severe ischemia (CBF = 15–25 ml 100 g−1 min−1) caused the isoelectric modification of several proteins (Mr 44,000, 55,000, and 70,000) and induced synthesis of another protein (Mr 40,000). Two polypeptides (Mr 27,000 and 70,000) dominated residual protein synthesis in severe ischemia. The changes in protein synthesis induced by different grades of ischemia most likely comprise a variation of the so-called “heat shock” or “stress” response found in all eukaryotic cells subjected to adverse conditions. Since heat shock genes are known to confer partial protection against anoxia and a variety of other noxious insults, their induction may be a factor in limiting the extent of ischemic tissue damage.
Simultaneous Determination of Local Cerebral Glucose Utilization and Blood Flow by Carbon-14 Double-Label Autoradiography: Method of Procedure and Validation Studies in the Rat
Authors: Ginsberg Myron D. , Smith David W. , Wachtel Mitchell S. , Gonzalez-Carvajal Mayra , Busto Raul
Published: April 2011

Validation studies were undertaken to establish a computer-assisted double-label autoradiographic strategy employing [14C]2-deoxyglucose ([14C]2DG) and [14C]iodoantipyrine ([14C]IAP) to measure local CMRglu (LCMRglu) and CBF (LCBF). An organic solvent was used to extract the majority of IAP between first and second film exposures. In contrast to previously published data, all solvents tested produced partial losses of 2DG from tissue, and all allowed 2–6% of IAP to persist even after 5-day washes. Technical-grade chloroform permitted equal retention of unmetabolized and metabolized 2DG. A linear model was established, which was insensitive to the changes in tissue self-absorption that were shown to occur with chloroform extraction. Propagated error in computing tissue [14C]2DG and [14C]IAP was reduced by maximizing IAP extraction (by longer solvent wash times) and by administering 2.5 times as much IAP as 2DG. Fractional 2DG retention was measured in single-label 2DG sections placed on the films, and fractional IAP retention was evaluated by an optimization procedure. With this strategy, double-label values for LCMRglu and LCBF in anesthetized rats agreed with values obtained in matched single-label series to within 5%. The coefficients of variation for the double- and single-label LCMRglu data were virtually identical, whereas the coefficient of variation for double-label LCBF was 1.8 times that of single-label LCBF. The double-label strategy permitted pixel-by-pixel measurement and video display of the LCMRglu/LCBF ratio; the mean value among structures was 0.472 μmol/ml. With proper attention to methodological detail, this double-label strategy shows great promise for routine laboratory application.
Pial Vascular Behavior during Bilateral and Contralateral Cervical Sympathetic Stimulation
Authors: Auer Ludwig M. , Ishiyama Norio
Published: April 2011

The present study in cats investigates the effect of cervical sympathetic stimulation on changes of diameter of pial arteries and veins, CBF, and intracranial pressure (ICP) using the cranial window and hydrogen clearance techniques. During 20 min of bilateral stimulation, pial arteries maximally constricted by 12%, veins by 13–15%. While the constriction of the large arteries remained stable during the whole 20-min period of bilateral stimulation, small arteries escaped after some 2 min. A similar though weaker trend was noted for the veins. CBF was reduced at 2 min by 31%, and was not different from resting at 18 min. Contralateral stimulation for 20 min induced early constriction only in small arteries, while all other vessels remained more or less unreactive. This phenomenon is explained by interhemispheric arterial collaterals that bring sympathetic fibers mainly to small arteries contralaterally. ICP was lowered initially by 47 ± 12% during bilateral and by 23 ± 5% during contralateral stimulation. ICP escaped after 2 and 5 min during bilateral and contralateral stimulation, respectively, and even started to rise after some 10 min. From these data, it is concluded that the sympathoadrenergic system exerts a short-lasting protective effect upon cerebral vascular volume. Small arteries escape from constriction as a consequence of primarily myogenic counteraction of pial and intraparenchymal vessels, and probably additional metabolic dilatation of intraparenchymal vessels.
Effect of Phenytoin on Human Cerebral Glucose Metabolism
Authors: Theodore William H. , Bairamian Dikran , Newmark Michael E. , DiChiro Giovanni , Porter Roger J. , Larson Steven , Fishbein Donn
Published: April 2011

We used serial positron emission tomography scans with [18F]2-deoxyglucose to study the effect of phenytoin on human cerebral glucose metabolism in 10 patients with seizure disorders. Local CMRglu for each patient was measured in 10 regions of interest. EEGs were performed during each procedure to match scans for state of consciousness and exclude data from scans with ictal activity. Serial scans without a drug change were performed in six control patients. Metabolic rates were significantly lower in two cortical regions while patients were taking phenytoin. No significant changes on repeat scan were seen in the control population. Measured across all regions of interest, metabolic rates were 13% higher when patients were off phenytoin (p < 0.02).
Brain Luxury Perfusion during Cardiopulmonary Bypass in Humans. A Study of the Cerebral Blood Flow Response to Changes in CO2, O2, and Blood Pressure
Authors: Henriksen Leif
Published: April 2011

CBF and related parameters were studied in 68 patients before, during, and following cardiopulmonary bypass. CBF was measured using the intraarterial 133Xe injection method. The extracorporeal circuit was nonpulsatile with a bubble oxygenator administering 3–5% CO2 in the main group of hypercapnic patients (n = 59) and no CO2 in a second group of hypocapnic patients. In the hypercapnic patients, marked changes in CBF occurred during bypass. Evidence was found of a brain luxury perfusion that could not be related to the effect of CO2 per se. Mean CBF was 29 ml/100 g/min just before bypass, 49 ml/100 g/min at steady-state hypothermia (27°C), reached a maximum of 73 ml/100 g/min during the rewarming phase (32°C), fell to 56 ml/100 g/min at steady-state nor-mothermic bypass (37°C), and was 48 ml/100 g/min shortly after bypass was stopped. Addition of CO2 evoked systemic vasodilation with low blood pressure and a rebound hyperemia. The hypocapnic group responded more physiologically to the induced changes in hematocrit (Htc) and temperature, CBF being 25, 23, 25, 34, and 35 ml/100 g/min, respectively, during the five corresponding periods. Carbon dioxide was an important regulator of CBF during all phases of cardiac surgery, the responsiveness of CBF being ∼4% for each 1-mm Hg change of Paco2. The level of MABP was important for the CO2 response. At low blood pressure states, the CBF responsiveness to changes in Paco2 was almost abolished. An optimal level of Paco2 during hypothermic bypass of ∼25 mm Hg (at actual temperature) is recommended. A normal autoregulatory response of CBF to changes in blood pressure was found during and following bypass. The lower limit of autoregulation was at pressure levels of ∼50–60 mm Hg. CBF autoregulation was almost abolished at Paco2 levels of >50 mm Hg. The degree of hemodilution neither affected the CO2 response nor impaired CBF autoregulation, although, as would be expected, it influenced CBF: In 33 women CBF was 55 ml/100 g/min at an Htc of 24%, as compared with 42 ml/100 g/min in 35 men (Htc = 28%). High Pao2 was a vasoconstrictor, the autoregulatory plateau being narrowed. The lower limit of autoregulation was shifted to a higher pressure when Pao2 was low.
Effect of Transient Cerebral Ischemia on Metabolic Activation of a Somatosensory Circuit
Authors: Dietrich W. Dalton , Ginsberg Myron D. , Busto Raul
Published: April 2011

The effects of transient ischemia on the metabolic responsiveness of a well-defined brain circuit were investigated with [14C]2-deoxyglucose autoradiography. Rats underwent 30 min of severe forebrain ischemia followed by postischemic recirculation periods of 1, 2, 3, 5, and 10 days. At these times, unilateral whisker stimulation was carried out, resulting in the metabolic activation of the whisker barrel circuit. An altered pattern of glucose utilization within both stimulated and nonstimulated circuit relay stations was observed at 1, 2, and 3 days following ischemia. At 1 day, stimulus-evoked increases in metabolic activity were severely depressed within both the ventrobasal thalamus and layer IV of the cortical barrel field region. Baseline metabolic rate within nonstimulated relay areas was also severely depressed at this time. At postischemic days 2 and 3, moderate levels of increased glucose utilization were apparent overlying cortical layer IV and the superficial half of layer VI, while layers I, II, III, and V appeared less responsive to metabolic activation. By day 5, whisker stimulation resulted in normal levels of increased glucose utilization within the activated ventrobasal thalamus and layer IV of the cortical barrel field region. Glucose utilization within nonactivated relay stations, depressed at earlier time periods, had also returned to control levels by day 5. At both 5 and 10 days, an altered laminar pattern of elevated glucose utilization was apparent within the activated barrel field region, with local CMRglu being depressed in layer V compared with control values. These results demonstrate that periods of transient ischemia produce both reversible and longer-lasting effects on the ability of the CNS to respond to peripheral activation. Functional restitution occurs slowly over a period of days following ischemia and appears to be related to the postischemic baseline level of metabolic rate. Finally, the abnormal laminar pattern of cortical activation apparent at postischemic day 10 may suggest dysfunction of intracortical circuits, a result that might be expected to alter the processing of sensory information.
Evaluation of Artificial Plasma for Maintaining the Isolated Canine Brain
Authors: Kintner D. B. , Kao J. L. , Woodson R. D. , Gilboe D. D.
Published: April 2011

The use of canine erythrocytes suspended in artificial plasma to maintain the isolated brain was investigated in 18 preparations. Two plasmas were studied: One (AP1) contained electrolytes, amino acids, and albumin; the other (AP2) was similar to CSF and contained a mixture of 37 organic nutrients plus electrolytes and albumin. The CMRO2, CMRglu, and cerebral vascular resistance (CVR) were measured during 2 h of perfusion, and tissue high-energy phosphates were measured at the end of perfusion. The AP1 and AP2 groups were compared with control preparations perfused with canine red blood cells suspended in buffy coat-poor canine plasma. Both CMRO2 and ATP decreased to 60% of the control value; CVR increased to 187% of the control value in both groups following 2 h of perfusion. After 2 h of perfusion, the calculated value of intracellular pH (pHi)—based on creatine kinase equilibrium—remained normal (6.96) for the control brains, but decreased to 6.49 and 6.63, respectively, for the AP1- and AP2-perfused brains. Thus, there appears to be an eventual disruption of normal oxidative metabolism resulting in energy failure, possibly caused by the absence of an essential nutrient from the artificial plasma. For studies of intermediary metabolism in isolated normothermic brain, diluted whole blood appears to be the perfusate of choice.
Error Analysis of a Quantitative Cerebral Blood Flow Measurement Using H215O Autoradiography and Positron Emission Tomography, with Respect to the Dispersion of the Input Function
Authors: Iida Hidehiro , Kanno Iwao , Miura Shuichi , Murakami Matsutaro , Takahashi Kazuhiro , Uemura Kazuo
Published: April 2011

The effect of the inaccuracy of the input function on CBF measured by the H152O autoradiographic method was investigated. In H152O autoradiography the measured input function usually includes a larger dispersion than the true input function, as well as the absolute time axis having been already lost. The time constant of the external dispersion that occurred in our continuous sampling system was evaluated as 10–12 s when the dispersion function was approximated by a monoexponential function. The internal dispersion occurring in arterial lines in a human body was evaluated as 4–6 s. Such dispersion, indispensable in a patient study, was found to produce large errors in calculating CBF, e.g., 5(10) s of the dispersion caused + 15(33) and + 10(20)% systematic overestimations for the 40- and 60-s accumulation time, respectively. An analytical correction employing an inverse Laplace transform was applied to clinical CBF studies, and the results were compared with those from the C15O2 steady-state inhalation method. Correction by 10 s in time constant, corresponding to the external dispersion, reduced the overestimation significantly from 70–100% to ∼20%. Further correction by 5 s, corresponding to the internal dispersion, resulted in a negligible difference (less than a few percent) from the steady-state method.
Cerebral Energy Metabolism Measured in vivo by 31P-NMR in Middle Cerebral Artery Occlusion in the Cat—Relation to Severity of Stroke
Authors: Komatsumoto S. , Nioka S. , Greenberg J. H. , Yoshizaki K. , Subramanian V. H. , Chance B. , Reivich M.
Published: April 2011

The energy metabolism of the brain has been measured in a middle cerebral artery (MCA) occlusion model in the cat utilizing 31P-nuclear magnetic resonance (NMR). 31P-NMR spectra were serially obtained during 2 h of ischemia and a subsequent 4-h recovery period. The ratio of creatine phosphate (PCr) to inorganic phosphate (Pi) (PCr/Pi) showed a precipitous decrease in parallel with changes in electroencephalographic (EEG) amplitude in severe strokes during ischemia as well as during recirculation. Animals with mild strokes, as determined by EEG criteria, exhibited a much smaller decrease in PCr/Pi during ischemia. In the severe strokes, there was a splitting and significant shift of the Pi peak immediately after occlusion. In addition, the shifted Pi peak rapidly increased and remained elevated throughout the study. In the mild strokes, Pi also increased, but not as markedly. Intracellular pH determination by chemical shift of the Pi peak revealed a decrease from 7.1 to 6.2–6.3 during ischemia and the subsequent recovery period in the animals with severe strokes, whereas the pH in the animals with mild strokes did not show a significant change. A gradual decrease in adenosine triphosphate (ATP) to 57–79% of the control was exhibited in severely stroked animals during both the ischemia and the recovery period, whereas there was no change in ATP in the mild stroked animals. These results suggest that the dynamic process of pathophysiological changes in an MCA occlusion model in the cat leads to significant differences in cerebral metabolism between animals with mild and severe strokes.
Effect of the Muscarinic Agonist Carbachol on Pial Arteries in vivo after Endothelial Damage by Air Embolism
Authors: Haller C. , Sercombe R. , Verrecchia C. , Fritsch H. , Seylaz J. , Kuschinsky W.
Published: April 2011

Reactions of pial arteries to the muscarinic agonist carbachol were tested in vivo in chloralose anesthetized cats before and after endothelial damage. Moderate endothelial damage was induced by arterial air embolism and verified by electron microscopy for the vessels tested. The experiments had three phases: First, the normal reactivity of pial arteries to carbachol (10−7 to 10−5 M) was tested using the microapplication technique, then, after air embolism, the reactivity was reinvestigated at the same vessel. Finally, pial arteries were taken out for scanning electron microscopy. The results show carbachol (10−6 and 10−5 M) induced significant dilatations under control conditions, also after repetition at the same vessel. After air embolism, the reactions to carbachol were abolished. Morphologic data revealed that whereas control pial arteries showed intact endothelium, the embolized vessels revealed various degrees of endothelial alterations. All showed flattening of endothelial nuclei, to a greater or lesser degree, and in many cases, the endothelium had a wrinkled appearance; several arteries showed severe degradation of the intercellular junctions. It is concluded that (a) carbachol-induced muscarinic vasodilatation of pial arteries in vivo can be abolished after a morphologically verified endothelial lesion—thus confirming in vitro studies in larger arteries and (b) disturbed vascular function does not require rubbing of the endothelium, but occurs already with moderate endothelial damage.
Calcitonin Gene-Related Peptide and Cerebral Blood Vessels: Distribution and Vasomotor Effects
Authors: Edvinsson L. , Ekman R. , Jansen I. , McCulloch J. , Uddman R.
Published: April 2011

The innervation of cerebral blood vessels by nerve fibers containing calcitonin gene-related peptide (CGRP) and the vasomotor effects of this peptide are described for a number of different mammalian species. CGRP-immunoreactive nerve fibers were present in the adventitia of cerebral arteries in all species examined (guinea pig, cat, rabbit, rat, and mouse). Numerous perikarya containing CGRP immunoreactivity are demonstrable in the trigeminal ganglion of all species. In the cerebral perivascular nerve fibers and in trigeminal perikarya, CGRP is often colocalized with substance P and neurokinin A. Marked interspecies differences exist both in the density of CGRP-immunoreactive nerve fibers and in the cerebrovascular levels measured with radioimmunoassay. The highest concentrations were observed in cerebral vessels from guinea pigs, the lowest concentration in rabbit vessels, and intermediate levels in the feline and human cerebral vasculature. CGRP is a potent dilator of cerebral arteries in all species examined (human pial, feline middle cerebral, rabbit, guinea pig and rat basilar arteries). The concentration of CGRP eliciting half-maximal responses ranged from 0.4 n M (human pial artery) to 3 n M (rat and rabbit basilar arteries). Pretreatment of cerebral arteries with low concentrations of either substance P (0.1 n M) or neurokinin A (3 n M) attenuated slightly the CGRP-induced relaxations of guinea pig basilar arteries. Calcitonin was found to be a very weak dilator of cerebral arteries from human and guinea pig. Thus, cardiovascular nerve fibers containing CGRP appear to be present in all mammalian species (although to varying degrees) and CGRP is invariably a potent dilator of the cerebral arteries for all species.
Small Differences in Intraischemic Brain Temperature Critically Determine the Extent of Ischemic Neuronal Injury
Authors: Busto Raul , Dietrich W. Dalton , Globus Mordecai Y.-T. , Valdés Isabel , Scheinberg Peritz , Ginsberg Myron D.
Published: April 2011

We have tested whether small intraischemic variations in brain temperature influence the outcome of transient ischemia. To measure brain temperature, a thermocouple probe was placed stereotaxically into the left dorsolateral striatum of rats prior to 20 min of four-vessel occlusion. Rectal temperature was maintained at 36–37°C by a heating lamp, and striatal temperature prior to ischemia was 36°C in all animals. Six animal subgroups were investigated, including rats whose intraischemic striatal brain temperature was not regulated, or was maintained at 33, 34, 36, or 39°C. Postischemic brain temperature was regulated at 36°C, except for one group in which brain temperature was lowered from 36°C to 33°C during the first hour of recirculation. Energy metabolites were measured at the end of the ischemic insult, and histopathological evaluation was carried out at 3 days after ischemia. Intraischemic variations in brain temperature had no significant influence on energy metabolite levels measured at the conclusion of ischemia: Severe depletion of brain ATP, phosphocreatine, glucose, and glycogen and elevation of lactate were observed to a similar degree in all experimental groups. The histopathological consequences of ischemia, however, were markedly influenced by variations in intraischemic brain temperature. In the hippocampus, CA1 neurons were consistently damaged at 36°C, but not at 34°C. Within the dorsolateral striatum, ischemic cell change was present in 100% of the hemispheres at 36°C, but in only 50% at 34°C. Ischemic neurons within the central zone of striatum were not observed in any rats at 34°C, but in all rats at 36°C. In rats whose striatal temperature was not controlled, brain temperature fell from 36 to 30–31°C during the ischemic insult. In this group, no ischemic cell change was seen within striatal areas and was only inconsistently documented within the CA1 hippocampal region. These results demonstrate that (a) rectal temperature unreliably reflects brain temperature during ischemia; (b) despite severe depletion of brain energy metabolites during ischemia at all temperatures, small increments of intraischemic brain temperature markedly accentuate histopathological changes following 3-day survival; and (c) brain temperature must be controlled above 33°C in order to ensure a consistent histopathological outcome. Lowering of the brain temperature by only a few degrees during ischemia confers a marked protective effect.
The Effect of Hypoxia on Traumatic Head Injury in Rats: Alterations in Neurologic Function, Brain Edema, and Cerebral Blood Flow
Authors: Ishige Naoki , Pitts Lawrence H. , Berry Isabelle , Carlson Sara G. , Nishimura Merry C. , Moseley Michael E. , Weinstein Philip R.
Published: April 2011

We evaluated the effects of early posttraumatic hypoxia on neurologic function, magnetic resonance images (MRI), brain tissue specific gravities, and cerebral blood flow (CBF) in head-injured rats. By itself, an hypoxic insult (PaO2 40 mm Hg for 30 min) had little effect on any measure of cerebral function. After temporal fluid-percussion impact injury, however, hypoxia significantly increased morbidity. Of rats subjected to impact (4.9 ± 0.3 atm) plus hypoxia, 71% had motor weakness contralateral to the impact side 24 h after injury, while only 29% of rats subjected to impact alone had demonstrable weakness (p < 0.05). Lesions observed on MR images 24 h after injury were restricted to the impact site in rats with impact injury alone, but extensive areas with longer T1 relaxation times were observed throughout the ipsilateral cortex in rats with impact injury and hypoxic insult. Brain tissue specific gravity measurements indicated that much more widespread and severe edema developed in rats with impact injury and hypoxia. [14C]Iodoantipyrine autoradiography performed 24 h after injury showed that there was extensive hypoperfusion of the entire ipsilateral cortex in rats with impact injury and hypoxia. These results show that large areas of impact-injured brain are extremely vulnerable to secondary insults that can irreparably damage neural tissue, and provide experimental evidence for the observed adverse effects of hypoxia on outcome after human head injury.
The Effect of Anxiety on Cortical Cerebral Blood Flow and Metabolism
Authors: Gur Ruben C. , Gur Raquel E. , Resnick Susan M. , Skolnick Brett E. , Alavi Abass , Reivich Martin
Published: April 2011

The relation between anxiety and cortical activity was compared in two samples of normal volunteers. One group was studied with the noninvasive xenon-133 inhalation technique for measuring cerebral blood flow (CBF) and the other with positron emission tomography (PET) using 18Flurodeoxyglucose (18FDG) for measuring cerebral metabolic rates (CMR) for glucose. The inhalation technique produced less anxiety than the PET procedure, and for low anxiety subjects, there was a linear increase in CBF with anxiety. For higher anxiety subjects, however, there was a linear decrease in CBF with increased anxiety. The PET group manifested a linear decrease in CMR with increased anxiety. The results indicate that anxiety can have systematic effects on cortical activity, and this should be taken into consideration when comparing data from different procedures. They also suggest a physiologic explanation of a fundamental behavioral law that stipulates a curvilinear, inverted-U relationship between anxiety and performance.
Nerve Fibers Containing Neuropeptide Y in the Cerebrovascular Bed: Immunocytochemistry, Radioimmunoassay, and Vasomotor Effects
Authors: Edvinsson L. , Copeland J. R. , Emson P. C. , McCulloch J. , Uddman R.
Published: April 2011

Perivascular nerve fibers containing neuropeptide Y (NPY)-like immunoreactivity were identified around cerebral blood vessels of human, cat, guinea pig, rat, and mouse. The major cerebral arteries were invested by dense plexuses; veins, small arteries, and arterioles were accompanied by few fibers. Removal of the superior cervical ganglion resulted in a reduction of NPY-like material in pial vessels and dura mater. Pretreatment with 6-hydroxydopamine or reserpine reduced the number of visible NPY fibers and the concentration of NPY in rat cerebral vessels. Sequential immuno-staining with antibodies toward dopamine-β-hydroxylase (DBH) (an enzyme involved in the synthesis of noradrenaline) and NPY revealed an identical localization of DBH and NPY in nerve cell bodies in the superior cervical ganglion and in perivascular fibers of pial blood vessels, suggesting their coexistence. Administration of NPY in vitro resulted in concentration-dependent contractions that were not modified by a sympathectomy. The contractions induced by noradrenaline, 5-hydroxytryptamine, and prostaglandin F2α and the dilator responses to calcitonin gene-related peptide were not modified by NPY in rat cerebral arteries. However, the constrictor response to NPY was reduced by 70% in the presence of the calcium entry blocker nifedipine, and abolished following incubation in a calcium-free buffer. These data suggest an interaction of NPY at a postsynaptic site, which for induction of contraction may open calcium channels in the sarcolemma of cerebral arteries.
The Effect of Diazepam Sedation on Cerebral Glucose Metabolism in Alzheimer's Disease as Measured Using Positron Emission Tomography
Authors: Foster Norman L. , VanDerSpek Abraham F. L. , Aldrich Michael S. , Berent Stanley , Hichwa Richard H. , Sackellares J. Chris , Gilman Sid , Agranoff Bernard W.
Published: April 2011

The effect of sedation induced by intravenous diazepam on cerebral glucose metabolic activity was examined with [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in five patients with probable Alzheimer's disease. Each subject was studied on 2 separate days: on one occasion at rest with eyes patched and ears open, and on the second when sedated with intravenous diazepam titrated to maintain stage II sleep by clinical and EEG criteria. Similar patterns of glucose uptake were observed in both the presence and the absence of sedation, but overall glucose utilization was depressed an average of 20% and was closely correlated with the amount of diazepam administered prior to the injection of FDG. The predominant temporoparietal hypometabolism and relative sparing of frontal metabolism observed in this disease are therefore not explained by differences in anxiety or activity level in this patient group. Utilization of diazepam sedation for PET study appears to be safe and may permit the study of patients otherwise unable to cooperate with FDG-PET procedures.
Regional Correction of Positron Emission Tomography Data for the Effects of Cerebral Atrophy
Authors: Videen Tom O. , Perlmutter Joel S. , Mintun Mark A. , Raichle Marcus E.
Published: April 2011

Given the low spatial resolution of positron emission tomography (PET), regional measurements of neural tissue are often inaccurate because of the presence of non-neural elements and to mixtures of different tissue types within the volume of space influencing the measurements. These effects are significant in scans of brains both with and without atrophy, but are particularly significant when comparing measurements of brains with atrophy with those of normals, as is typically done in studies of aging and dementia. Previous attempts to correct for cerebral atrophy have been limited to global measurements. Using computer simulations, we illustrate the effects of atrophy and describe a method for correcting regional PET data to represent units of actual neural tissue volume.
Focal Cerebral Ischaemia in the Cat: Treatment with the Glutamate Antagonist MK-801 after Induction of Ischaemia
Authors: Park C. K. , Nehls D. G. , Graham D. I. , Teasdale G. M. , McCulloch J.
Published: April 2011

The effects of the glutamate N-methyl-D-aspartate receptor antagonist MK-801 in reducing ischaemic brain damage have been examined in anaesthetised cats, with drug treatment being initiated 2 h after the induction of cerebral ischaemia. Focal cerebral ischaemia was produced by permanent occlusion of one middle cerebral artery, and the animals were killed 6 h later. The amount of early irreversible ischaemic damage was assessed at 16 predetermined stereotactic planes. Treatment with MK-801 (5 mg/kg, i.v.) 2 h after middle cerebral artery occlusion reduced significantly the volume of ischaemic damage (from 1,625 ± 384 mm3 of the cerebral hemisphere in vehicle-treated cats to 792 ± 385 mm3 in MK-801-treated cats). The demonstration of reduced ischaemic brain damage with MK-801, when the agent is administered after the induction of ischaemia, extends the therapeutic potential of such agents in the treatment of focal cerebral ischaemia in humans.
Experimental Cerebral Ischemia: Barbiturate Resistant Increase in Regional Glucose Utilization
Authors: Nedergaard Maiken , Diemer Nils Henrik
Published: April 2011

During the first hours after experimental occlusion of the middle cerebral artery (MCA) cerebral glucose utilization increases in the tissue adjacent to ischemic focus, To test whether the increased glucose utilization was a consequence of increased neuronal activity, the effect of preocclusion pentobarbital administration was investigated, Rats in barbiturate-induced coma showed a metabolic response to MCA occlusion similar to those seen with light halothane anesthesia. This indicates that the enhanced glucose utilization adjacent to the ischemic core is not a result of increased neuronal activity.
Sex Differences in Regional Cerebral Blood Flow
Authors: Rodriguez Guido , Warkentin Siegbert , Risberg Jarl , Rosadini Guido
Published: April 2011

Regional cerebral blood flow was measured by the 133-xenon inhalation method during resting in 38 healthy men and 38 healthy women matched pairwise for age in the range 18–72 years. The results showed 11% higher global flow level in the women in all ages. A similar and significant regression of flow by age was seen for both sexes. The regional flow distribution also showed some sex-related differences. Frontal regions showed an asymmetry in the men with higher values on the right side. The female flows were more symmetric. As a hypothesis, it is suggested that the higher flow level in women may be a systemic phenomenon. In fact, other authors have found a higher cardiac index in females. The sex differences in regional flow pattern might be due to differences in the functional organization of the cortex and/or to differences in the mental processes of the “resting” state.