bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Oxygen Metabolism after Aneurysmal Subarachnoid Hemorrhage
Authors: Carpenter David A. , Grubb Robert L. , Tempel Lee W. , Powers William J.
Published: April 2011

Previous studies of cerebral oxygen metabolism and extraction in patients with subarachnoid hemorrhage (SAH) have yielded conflicting results. We used positron emission tomography (PET) to measure the regional cerebral metabolic rate for oxygen (rCMRO2), oxygen extraction fraction (rOEF), and cerebral blood flow (rCBF) 16 times in 11 patients with aneurysmal SAH. All studies were performed preoperatively; no patient had hydrocephalus or intracerebral hematoma on brain CT. Eight patients with no arteriographic vasospasm who were studied on days 1–4 post-SAH had a significant 25% reduction in global CMRO2 compared to age-matched controls, and no significant change in global OEF, suggesting a primary reduction in CMRO2 caused by SAH. Four patients studied seven times during arteriographic vasospasm had significantly increased rOEF with unchanged CMRO2 in arterial territories affected by arteriographic vasospasm compared to territories without vasospasm, indicative of cerebral ischemia without infarction. No brain regions studied with PET were infarcted on follow-up CT. We conclude that the initial aneurysm rupture produces a primary reduction in CMRO2, and that subsequent vasospasm causes ischemia.
A Method to Quantitatively Measure Transcapillary Transport of Iodinated Compounds in Canine Brain Tumors with Computed Tomography
Authors: Groothuis Dennis R. , Lapin Gregory D. , Vriesendorp Francine J. , Mikhael Michael A. , Patlak Clifford S.
Published: April 2011

We present a quantitative method for determining a blood-to-tissue influx constant ( K1), a tissue-to-blood efflux constant ( k2), and tissue plasma vascular space ( Vp) that uses a computed tomographic (CT) scanner to make tissue and plasma measurements of the concentration of an iodinated compound. Meglumine iothalamate was infused intravenously over time periods of 0.5–5 min, up to 49 CT scans were obtained at one brain level, and arterial plasma was sampled over a 30- to 40-min period. K1, k2, and Vp were calculated for each voxel of the 320 × 320 matrix, using a two-compartment pharmacokinetic model and nonlinear least-squares regression. The method was used in dogs with avian sarcoma virus–induced brain tumors. As many as four studies on different days were done in the same animal. In tumor-free cortex, K1 of meglumine iothalamate was 2.4 ± 1.7 μl g−1 min−1 (mean ± SD) and Vp was 3.4 ± 0.5 ml 100 g−1. Mean whole-brain tumor K1 values ranged from 3.3 to 97.9 μl g−1 min−1; k2 ranged from 0.032 to 0.27 min−1; and Vp ranged from 1.1 to 11.4 ml 100 g−1. These values were reproducible in serial experiments in single animals. Independent verification of K1 values was obtained with quantitative autoradiographic measurements of α-aminoisobutyric acid, which has similar physicochemical properties to meglumine iothalamate. The CT methodology is capable of demonstrating regional variation of trans-capillary transport in brain tumors and may be of value in the study of human brain tumors.
A New Method for Producing Temporary Complete Cerebral Ischemia in Rats
Authors: Shirane Reizo , Shimizu Hiroaki , Kameyama Motonobu , Weinstein Philip R.
Published: April 2011

A new model of temporary complete cerebral ischemia was developed and tested in 64 rats. With use of microsurgical techniques, both pterygopalatine and external carotid arteries were occluded and the basilar artery was coagulated to reduce potential collateral CBF during ischemia. After this preliminary five-vessel occlusion, temporary global ischemia was induced by occluding the common carotid arteries (CCAs) with microclips. To validate the method, CBF was measured autoradiographically in 24 anatomical regions at death after 5 min of ischemia or after 15 min of ischemia followed by 5 min of reperfusion. Mean arterial blood pressure and arterial blood gases remained stable under controlled endotracheal ventilation and anesthesia (halothane, 70% N2O, and 30% O2) throughout the CBF experiments, except for a 10–15% increase in mean arterial blood pressure for 1–5 min after bilateral CCA occlusion. After the initial five-vessel occlusion, the EEG did not change, and local CBF levels were comparable to those in anesthetized nonsurgical controls. When the CCAs were occluded, the EEG flattened rapidly; after 5 min of ischemia, autoradiography showed no detectable blood flow in the forebrain and cerebellum. The local CBF levels measured after 15 min of temporary global ischemia and 5 min of reperfusion demonstrated relatively homogeneous postischemic hyperperfusion; only two of eight rats had several 1- to 3-mm areas of no-reflow. Survival studies showed increasing motor impairment after 10, 15, 30, and 60 min of temporary CCA occlusion. Ischemic neuronal damage was observed histologically in the hippocampus and basal ganglia 24 h after 10 min of temporary ischemia. This model consistently produces reversible complete cerebral ischemia in the rat without the use of intracranial hypertension, systemic hypotension, hypoxia, or a neck tourniquet.
Safety of Hypercapnic Challenge: Cardiovascular and Neurologic Considerations
Authors: Gitelman Darren R. , Prohovnik Isak , Tatemichi Thomas K.
Published: April 2011

The hemodynamic, cerebrovascular, and neurologic effects of hypercapnia with 4% and 6% CO2 were retrospectively reviewed in 217 patients referred for regional CBF (rCBF) procedures. Inhalation of CO2 significantly increased rCBF, blood pressure, and pulse from baseline. The findings suggest a higher incidence of side effects with 6% CO2 concentration and an equivalent vasoreactivity to 4%. We recommend the use of 4% CO2 for hypercapnic stimulation, and present safety guidelines for its use.
Direct Measurement of the λ of the Lumped Constant of the Deoxyglucose Method in Rat Brain: Determination of λ and Lumped Constant from Tissue Glucose Concentration or Equilibrium Brain/Plasma Distribution Ratio for Methylglucose
Authors: Dienel Gerald A. , Cruz Nancy F. , Mori Kentaro , Holden James E. , Sokoloff Louis
Published: April 2011

Steady-state distribution spaces of 2-[14C]deoxyglucose ([14C]DG), glucose, and 3- O-[14C]methylglucose at various concentrations of glucose in brain and plasma ranging from hypoglycemic to hyperglycemic levels have been determined by direct chemical analyses in the brains of conscious rats. The hexose concentrations were measured chemically in freeze-blown brain extracted with ethanol to avoid the degradation of acid-labile products of [14C]DG back to free [14C]DG that has been found to occur with the more commonly used perchloric acid extraction of brain. Corrections were also made for nonphosphorylatable, labeled products of [14C]DG found in the nonacidic fractions of the brain extracts, which were previously included with the assayed [14C]DG, and for the contribution of the hexose contents in the blood in the brain, which was found to be particularly critical for the determination of the glucose distribution space, especially in hypoglycemic states. From the measured contents of the hexoses in brain and plasma, the relationships of the tissue concentrations and distribution spaces of each of the hexoses and of the Λ (i.e., ratio of tissue distribution space of DG to that of glucose) of the DG method to the tissue glucose concentration were derived. The Λ was then quantitatively related to the measured equilibrium ratio for [14C]methylglucose over the full range of brain and plasma glucose levels. By combining these new data with the values for the lumped constant, the factor that converts rate of DG phosphorylation to glucose phosphorylation, previously determined in rats over the same range of plasma glucose levels, the phosphorylation coefficient was calculated and the lumped constant graphed as a function of the measured distribution space in brain for [14C]methylglucose.
Absolute Quantitation in Neurological PET: Do We Need it?
Authors: Strother S. C. , Liow J-S. , Moeller J. R. , Sidtis J. J. , Dhawan V. J. , Rottenberg D. A.
Published: April 2011

This article addresses the question posed in the title by examining the effects of parameters traditionally associated with improved absolute quantitation, on the analysis of 12 acquired immune deficiency syndrome dementia complex (ADC) patients compared to a normal control group. Results are discussed within the framework of the subprofile scaling model (SSM) for analyzing patterns of regional covariation. It is demonstrated that the ability to extract measures of group discrimination and disease progression are unaffected by (1) limited improvements in image resolution, (2) the use of transmission scan smoothing, (3) the application of a scatter deconvolution correction, and (4) converting region-of-interest measurements of counts per voxel to measurements of regional CMRglc. This “robustness” of the SSM approach is partly due to the extraction of disease-related subject weights, independent of any subject's global scaling effects. It is argued that other analysis techniques that initially reduce intersubject variation (e.g., using regional ratios or normalizing by global metabolic rates before applying traditional multivariate procedures) lack analytic features that may be important to identify multidimensional, disease-related image patterns. Based on the ADC patient data, it is concluded that measures of group discrimination and disease progression will not necessarily benefit from the optimization of parameters traditionally associated with improved absolute quantitation.
Metabolic Maturation of the Brain: A Study of Local Cerebral Glucose Utilization in the Developing Cat
Authors: Chugani Harry T. , Hovda David A. , Villablanca Jaime R. , Phelps Michael E. , Xu Wei-Fang
Published: April 2011

Previously, using positron emission tomography (PET), we showed that local cerebral metabolic rates for glucose (lCMRglc) in children undergo dynamic maturational trends before reaching adult values. In order to develop an animal model that can be used to explore the biological significance of the different segments of the lCMRglc maturational curve, we measured lCMRglc in kittens at various stages of postnatal development and in adult cats using quantitative [14C]2-deoxyglucose autoradiography. In the kitten, very low lCMRglc levels (0.14 to 0.53 μmol min−1 g−1) were seen during the first 15 days of life, with phylogenetically older brain regions being generally more metabolically mature than newer structures. After 15 days of age, many brain regions (particularly telencephalic structures) underwent sharp increases of lCMRglc to reach, or exceed, adult rates by 60 days. This developmental period (15 to 60 days) corresponds to the time of rapid synaptic proliferation known to occur in the cat. At 90 and 120 days, a slight decline in lCMRglc was observed, but this was followed by a second, larger peak occurring at about 180 days, when sexual maturation occurs in the cat. Only after 180 days did lCMRglc decrease to reach final adult values (0.21 to 2.04 μmol min−1 g−1). In general, there was good correlation between the metabolic maturation of various neuroanatomical regions and the emergence of behaviors mediated by the specific region. At least in the kitten visual cortex, which has been extensively studied with respect to developmental plasticity, the “critical period” corresponded to that portion of the lCMRglc maturational curve surrounding the 60-day metabolic peak. These normal maturational lCMRglc data will serve as baseline values with which to compare anatomical and metabolic plasticity changes induced by age-related lesions in the cat.
Physiological ROI Definition by Image Subtraction
Authors: Fox Peter T.
Published: April 2011

Quantitative analysis of functional images requires a strategy for reducing to tractable size the overwhelming amount of numeric data contained therein. Region-of-interest (ROI) selection is the most widely used means of image-data reduction, but it has many limitations. Spatial bias, introduced by selection of regions as being “of interest,” is probably the greatest limitation of ROI analyses. Change-distribution analysis is a new data-analysis strategy that eliminates this a priori selection bias in a way that can increase the sensitivity, specificity, and localization precision. All image pixels are surveyed for changes from the control condition. Only areas of change are sampled and contribute to statistical analysis. Change-distribution analysis has been validated for within-subject pairs of images, but it is potentially applicable in a wide variety of imaging protocols.
Cerebrocerebellar Relationship during Behavioral Activation: A PET Study
Authors: Barker W. W. , Yoshii F. , Loewenstein D. A. , Chang J. Y. , Apicella A. , Pascal Shlomo , Boothe T. E. , Ginsberg M. D. , Duara R.
Published: April 2011

The effect of behavioral activation on cerebral and cerebellar glucose metabolism was studied in normal subjects when performing either a verbal memory task or a tactile somatosensory task. Each subject was also studied in a resting state control condition, either 1 h earlier or later than the activation task. Compared to the resting state, both tasks produced asymmetrical metabolic activation, which was opposite in direction within the cerebral and cerebellar hemispheres. In both tasks, the difference of activation of CMRglc in the right and left hemispheres in the cerebellum was negatively correlated with that in the sensory-motor region. This apparently coupled metabolic activation of one cerebellum and areas within the opposite cerebral hemisphere represents the inverse of the crossed cerebellar diaschisis phenomenon commonly observed when a vascular lesion affects one cerebral hemisphere and hypometabolism occurs in the opposite cerebellum. Because these correlations were selective and concordant with known anatomical connections, and were found in two different tasks, they suggest strong functional connections between these specific brain regions.
Sex Differences in Postischemic Neuronal Necrosis in Gerbils
Authors: Hall Edward D. , Pazara Kay E. , Linseman Kelley L.
Published: April 2011

Twenty-four hour postischemic neuronal necrosis was compared in male vs. female Mongolian gerbils subjected to a 3-h period of severe incomplete hemispheric ischemia produced by unilateral carotid occlusion. The incidence of stroke-prone males was 42.9% versus 26.7% for the females. Among the stroke-prone animals, the males displayed significantly greater neuronal necrosis at 24 h after ischemia compared to the females in the cerebral cortex and CA, region of the hippocampus. In the CA, region of the stroke-prone males, only 2.0% of the normal neuronal population remained by 24 h compared to 36.8% in the stroke-prone females (p < 0.02). In the cerebral cortex, the males had only 19.9% of normal versus 58.2% in the females (p < 0.05). In a second series of mechanistic experiments, no differences in cortical blood flow (CBF) were disclosed between preselected male and female stroke-prone animals before, during, or for 2 h after ischemia. As with the CBF, the extent of cortical extracellular hypocalcia during ischemia did not differ significantly. However, the degree of postischemic recovery of cortical extracellular calcium was significantly better in the females from 30 min to 2 h after reperfusion. In the same experiments, hemispheric vitamin E levels were measured at the 2 h time point as an index of postischemic brain lipid peroxidation. No difference in baseline vitamin E levels was observed between male and female sham-operated gerbils. In the males subjected to 3 h of ischemia plus 2 h of reperfusion, the hemispheric vitamin E decreased by 43.5% compared to the sham-operated males. In contrast, the females displayed only a 4.2% decline (p < 0.05 versus males). Previous studies showing the protective efficacy of antioxidants in this model have suggested an important role of oxygen radical-induced lipid peroxidation. Thus, it is proposed that the lesser ischemic vulnerability of females may be based upon an antioxidant effect of endogenous estrogen. Indeed, estrogen was found to be a more potent inhibitor of iron-catalyzed lipid peroxidation in brain tissue than vitamin E.
Diminished Glucose Transport in Alzheimer's Disease: Dynamic PET Studies
Authors: Jagust William J. , Seab J. Philip , Huesman Ronald H. , Valk Peter E. , Mathis Chester A. , Reed Bruce R. , Coxson Pamela G. , Budinger Thomas F.
Published: April 2011

Dynamic positron emission tomography with [18F]fluorodeoxyglucose was used in six patients with Alzheimer's disease (AD) and seven healthy age-matched control subjects to estimate the kinetic parameters K1*, k2*, and k3* that describe glucose transport and phosphorylation. A high-resolution tomograph was used to acquire brain uptake data in one tomographic plane, and a radial artery catheter connected to a plastic scintillator was used to acquire arterial input data. A nonlinear iterative least-squares fitting procedure that included terms for the vascular fraction and time delay to the peripheral sampling site was used to fit a three-compartment model to the brain data. Regions studied included frontal, temporal, occipital, and the entire cortex and subcortical white matter. The values obtained for the individual rate constants and regional CMRglc (rCMRglc; calculated using regional values of the rate constants) were higher than those reported previously. A significant (p < 0.05) decrease was found in K1* in frontal and temporal cortex in the AD patients compared with the controls, with values of 0.157 and 0.161 ml/g/min in frontal and temporal cortex, respectively, of controls and 0.127 and 0.126 ml/ g/min in frontal and temporal cortex of the AD patients. rCMRglc was also significantly (p < 0.02) lower in the AD patients than controls in all cortical brain regions. Lower values of k3* were found in all brain regions in the AD patients, although these were not statistically significant. These findings provide evidence of an in vivo abnormality of forward glucose transport in AD. This transport defect, however, is probably not the cause of the diminution in glucose metabolism that has been widely found in AD patients, since a diminution of this magnitude should not lower intracerebral glucose content enough to alter rCMRglc.
The Influence of a Cryogenic Brain Injury on the Cerebrovascular Response to Isoflurane in the Rabbit
Authors: Ramani R. , Todd Michael M. , Warner David S.
Published: April 2011

To determine if an acute neurologic injury alters the cerebrovascular response to isoflurane, rabbits were anesthetized with morphine/N2O, mechanically ventilated, surgically instrumented, and assigned to one of three groups. Group 1 animals (n = 8) served as controls and received no injury. In Groups 2 (n = 9) and 3 (n = 8), a 30-s cryogenic injury was produced in the left parietal region using liquid N2 poured into a funnel affixed to the surface of the skull. Regional CBF was measured using microspheres. In Groups 2 and 3, flow was determined before and then 30 and 90 min after injury or at equivalent times in Group 1. After the 90-min data were collected, 1% [≈0.5 minimal alveolar concentration (MAC)] and then 2% (≈1.0 MAC) isoflurane was administered to uninjured rabbits in Groups 1 and to lesioned rabbits in Group 3. A mean arterial pressure of ≥80 mm Hg was maintained during isoflurane administration by an infusion of angiotensin II. In uninjured rabbits (Group 1), 2% isoflurane produced bilaterally symmetrical increases in hemispheric CBF, from 76 ± 21 (mean ± SD) to 150 ± 48 ml 100 g−1 min−1. CBF in the hindbrain increased from 91 ±25 to 248 ± 102 ml 100g−1 min−1. By contrast, in the lesioned rabbits of Group 3, 2% isoflurane resulted in CBF in the lesioned hemisphere changing from 56 to only 77 ml 100 g−1 min−1 (NS), while in the contralateral hemisphere, CBF rose from 68 to 97 ml 100 g−1 min−1 (also NS). These results indicate that a cryogenic injury attenuates the normal CBF response to a volatile anesthetic, both in the damaged hemisphere as well as in apparently uninjured regions distant from the injury focus. In a separate group of animals, a similar cryogenic injury abolished the CBF response to changing PaCO2 in the injured hemisphere, but not in either the contralateral hemisphere or the cerebellum. It is possible that the CBF effects of isoflurane may be mediated via some intermediary neurogenic and/or biochemical process.
Quantitative Immunocytochemistry (Image Analysis) of Glucose Transporters in the Normal and Postischemic Rodent Hippocampus
Authors: Gerhart David Z. , Djuricic Bogdan , Drewes Lester R.
Published: April 2011

The bilateral carotid occlusion model and a polyclonal antibody to the carboxyl terminus of the rat brain/human hepatoma glucose transporter were used to examine quantitatively changes in the transporter in gerbil hippocampal microvessels following 6–7.5 min of ischemia. The optical densities of immunocytochemically stained microvessels in the stratum lacunosum-moleculare (SLM) below the CA, subfield were determined using image analysis of frozen sections from gerbils killed 2 h, 3 days, 6 days, 4 weeks, and 7 weeks after the ischemic episode. Microvessels were sparsely distributed in the stratum oriens, stratum pyramidale, and stratum radiatum. In contrast, the SLM was relatively well vascularized, and this distribution of microvessels persisted following ischemia. The SLM was identifiable based solely on microvessel distribution both in control gerbils and in gerbils that exhibited complete destruction of CA1 pyramidal cells. The abundance of the glucose transporter in SLM microvessels remained constant, suggesting that down-regulation of this protein cannot account for reported declines in brain glucose utilization and cell death following ischemia. Conversely, the presence and metabolic activity of CA, pyramidal cells do not appear to be determinants of glucose transporter abundance in hippocampal microvessels. The brain/hepatoma glucose transporter was abundant in brain microvessels and the epithelial cells of the choroid plexus of gerbil and rat. Staining of hippocampal neuropil was less intense, poorly localized, and, at the light microscope level, not clearly associated with a particular cell type.
NADH Fluorescence and Regional Energy Metabolites during Focal Ischemia and Reperfusion of Rat Brain
Authors: Welsh Frank A. , Marcy Val Robert , Sims Reneé E.
Published: April 2011

Transient focal ischemia was produced in rat brain using simultaneous, reversible occlusion of the middle cerebral artery (MCA) and both carotid arteries. NADH tissue fluorescence and regional levels of ATP and lactate were measured after occlusion for 1 or 2.5 h and after reperfusion for 1 or 24 h following a 2.5-h insult. Occlusion for 1 or 2.5 h caused a marked but microheterogenous increase in NADH fluorescence, which was restricted to the MCA territory of the ipsilateral cortex. In this ischemic core, tissue levels of ATP were nearly depleted, while lactate accumulated to 10–13 mmol/kg. Metabolic alterations were less pronounced in regions adjacent to the ischemic core; however, one border region experienced a progressive increase in lactate between 1 and 2.5 h. NADH fluorescence and metabolite levels were not significantly altered in subcortical structures. In animals reperfused after a 2.5-h insult, NADH fluorescence diminished in the ischemic core to abnormally low levels, ATP was restored only to 37–50% of control, and lactate remained elevated. By 24 h, histologic infarction was evident in the regions with metabolic impairment. These results indicate that focal depletion of energy metabolites for 2.5 h caused irreversible impairment of energy metabolism and focal infarction even though lactate accumulation was moderate.
Cerebral Lactate Uptake during Cardiopulmonary Resuscitation in Humans
Authors: Rivers Emanuel P. , Paradis Norman A. , Martin Gerard B. , Goetting Mark E. , Rosenberg Jack A. , Smithline Howard A. , Appleton Timothy J. , Nowak Richard M.
Published: April 2011

Animal studies have shown cerebral lactate uptake under conditions of anoxia and ischemia. Cerebral lactate uptake in humans during cardiopulmonary resuscitation (CPR) has not been previously reported in the literature. Forty-five patients receiving CPR underwent simultaneous sampling through jugular venous bulb, right atrial, and central aortic catheterization. The mean net cerebral lactate uptake (central aortic minus jugular venous bulb) was 0.76 ± 1.86 and 0.80 ± 2.03 m M on initial measurement and 10 min later, respectively. Both measurements were statistically significant (p = 0.01) compared to normal controls who have net cerebral output of lactate of −0.18 ± 0.1 m M. Seventy-one percent of all patients had a cerebral uptake on initial sampling and this gradient persisted upon sampling 10 min later in 68% of the remaining 40 patients who did not have a return of spontaneous circulation. Among multiple variables measured, patients who exhibited a cerebral lactate uptake were 13.2 years younger (p = 0.004), received an additional 7.6 min of CPR (p = 0.05), and had a mean arterial lactate concentration of 4.8 m M higher (p = 0.005) than the nonuptake group. The pathophysiologic explanation of cerebral lactate uptake during CPR is multifactorial and includes utilization and/or diffusion.
Estimation of Local Cerebral Glucose Utilization by Positron Emission Tomography: Comparison of [18F]2-Fluoro-2-Deoxy-D-Glucose and [18F]2-Fluoro-2-Deoxy-D-Mannose in Patients with Focal Brain Lesions
Authors: Wienhard K. , Pawlik G. , Nebeling B. , Rudolf J. , Fink G. , Hamacher K. , Stöcklin G. , Heiss W.-D.
Published: April 2011

A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K*1 was almost unchanged, whereas k*2, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k*3 was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.
Individual Integration of Positron Emission Tomography and High-Resolution Magnetic Resonance Imaging
Authors: Steinmetz Helmuth , Huang Yanxiong , Seitz Rüdiger J. , Knorr Uwe , Schlaug Gottfried , Herzog Hans , Hackländer Thomas , Freund Hans-Joachim
Published: April 2011

We have developed, validated, and employed a technique of retrospective spatial alignment and integrated display of positron emission tomographic (PET) and high-resolution magnetic resonance (MR) brain images. The method was designed to improve the anatomical evaluation of functional images obtained from single subjects. In the first computational step, alignment of PET and MR data sets is achieved by iteratively matching in three orthogonal views the outermost scalp contours derived from front-to-back projections of each data set. This procedure avoids true three-dimensional modeling, runs without user interaction, and tolerates missing parts of the head circumference in the image volume, as usually the case with PET. Thereafter, high-resolution MR sections corresponding to the PET slices are reconstructed from the spatially transformed MR data. In a phantom study of this method, PET/MR alignment of the phantom's surface was accurate with average residual misfits of 2.17 to 2.32 mm as determined in three orthogonal planes. In-plane alignment of the phantom's insertion holes was accurate with an average residual misfit of 2.30 mm. In vivo application in six subjects allowed the individual anatomical localization of regional CBF (rCBF) responses obtained during unilateral manual exploration. In each subject, the maxima of the rCBF activations in the hand area were precisely allocated to gray matter in the anterior or posterior wall of the central sulcus. The configuration of the rCBF responses closely followed the gyral structures. The technique provided a better topographical understanding of rCBF changes in subtraction images of PET activation studies. It opens the perspective for studies of structural–functional relationships in individual subjects.
Effects of Temperature on Evoked Electrical Activity and Anoxic Injury in CNS White Matter
Authors: Stys Peter K. , Waxman Stephen G. , Ransom Bruce R.
Published: April 2011

Temperature is known to influence the extent of anoxic/ischemic injury in gray matter of the brain. We tested the hypothesis that small changes in temperature during anoxic exposure could affect the degree of functional injury seen in white matter, using the isolated rat optic nerve, a typical CNS white matter tract (Foster et al., 1982). Functional recovery after anoxia was monitored by quantitative assessment of the compound action potential (CAP) area. Small changes in ambient temperature, within a range of 32 to 42°C, mildly affected the CAP of the optic nerve under normoxic conditions. Reducing the temperature to <37°C caused a reversible increase in the CAP area and in the latencies of all three CAP peaks; increasing the temperature to >37°C had opposite effects. Functional recovery of white matter following 60 min of anoxia was strongly influenced by temperature during the period of anoxia. The average recovery of the CAP, relative to control, after 60 min of anoxia administered at 37°C was 35.4 ± 7%; when the temperature was lowered by 2.5°C (i.e., to 34.5°C) for the period of anoxic exposure, the extent of functional recovery improved to 64.6 ± 15% ( p < 0.00001). Lowering the temperature to 32°C during anoxic exposure for 60 min resulted in even greater functional recovery (100.5 ± 14% of the control CAP area). Conversely, if temperature was increased to >37°C during anoxia, the functional outcome worsened, e.g., CAP recovery at 42°C was 8.5 ± 7% ( p < 0.00001). Hypothermia (i.e., 32°C) for 30 min immediately following anoxia at 37°C did not improve the functional outcome. Many processes within the brain are temperature sensitive, including O2 consumption, and it is not clear which of these is most relevant to the observed effects of temperature on recovery of white matter from anoxic injury. Unlike the situation in gray matter, the temperature dependency of anoxic injury cannot be related to reduced release of excitotoxins like glutamate, because neurotransmitters play no role in the pathophysiology of anoxic damage in white matter (Ransom et al., 1990 a). It is more likely that temperature affects the rate of ion transport by the Na+–Ca2+ exchanger, the transporter responsible for intracellular Ca2+ loading during anoxia in white matter, and/or the rate of some destructive intracellular enzymatic mechanism(s) activated by pathological increases in intracellular Ca2+.
Hippocampal CA3 Lesion Prevents Postconcussive Metabolic Dysfunction in CA1
Authors: Yoshino Atsuo , Hovda David A. , Katayama Yoichi , Kawamata Tatsuro , Becker Donald P.
Published: April 2011

Immediately following fluid-percussion (F-P) brain injury, the hippocampus exhibits a marked increase in its local CMRglc (LCMRglc; μmol/100 g/min) as determined using [14C]2-deoxy-d-glucose autoradiography. This injury-induced increase in metabolism is followed in 6 h by a subsequent decrease in LCMRglc. These two postinjury metabolic states may be the result of ionic disruptions following trauma via stimulation of glutamategated ion channels. To determine if endogenous glutamate innervation to the CA1 region of the hippocampus can provide an anatomical basis for this proposed mechanism, it was removed by kainic-acid–induced destruction of CA3, and the effect on CA1 metabolism following concussive injury was studied. Five days before a lateral F-P injury (3.5–4.5 atm), kainic acid (0.5 μg) or vehicle was stereotaxically injected into the left ventricle of 65 rats. Histological inspection indicated that kainic acid produced severe cell loss primarily in the CA3 region of the hippocampus ipsilateral to the injection. The metabolic results indicated that immediately following injury, animals with an intact hippocampus exhibited an increase in LCMRglc to 84.6 ± 5 within the CA1 region, representing a 81.5% increase over controls. However, in the CA3-lesioned animals, CA1 showed no evidence of an injury-induced hypermetabolism, with LCMRglc remaining at control levels (51.4 ± 3.9). At 6 h postinjury, the intact hippocampus exhibited a reduction of LCMRglc to rates of 40.7 ± 4.7 within the CA1 region, representing a 17.9% reduction compared with controls. In contrast, CA3-lesioned animals exhibited less of an injury-induced decrease in LCMRglc within the CA1 region, exhibiting a mean rate of 43.4 ± 4.5, representing only a 12.5% reduction compared with controls. These results indicate that the removal of the CA3 projection to CA1 protects the CA1 cells from the metabolic dysfunction typically seen following injury. This supports our previous work indicating the important role glutamate plays in the ionic flux and subsequent metabolic changes that follow traumatic brain injury.
Exercise and the Brain: Angiogenesis in the Adult Rat Cerebellum after Vigorous Physical Activity and Motor Skill Learning
Authors: Isaacs Krystyna R. , Anderson Brenda J. , Alcantara Adriana A. , Black James E. , Greenough William T.
Published: April 2011

This study compared the morphology of cerebellar cortex in adult female rats exposed for 1 month to repetitive exercise, motor learning, or an inactive condition. In the exercise conditions, rats that were run on a treadmill or housed with access to a running wheel had a shorter diffusion distance from blood vessels in the molecular layer of the paramedian lobule when compared to rats housed individually or rats that participated in a motor skill learning task. Rats taught complex motor skills substantially increased the volume of the molecular layer per Purkinje neuron and increased blood vessel number sufficiently to maintain the diffusion distance. These results dissociate angiogenesis associated with increased neuropil volume (as seen in the motor learning group) from angiogenesis associated with increased metabolic demands (as seen in the exercise groups). While the volume fraction of mitochondria did not differ among groups, the mitochondrial volume fraction per Purkinje cell was significantly increased in the motor skill rats. This appears to parallel the previously reported increase in synapses and associated neuropil volume change.
In vivo Muscarinic Cholingeric Receptor Imaging in Human Brain with [11C]Scopolamine and Positron Emission Tomography
Authors: Frey K. A. , Koeppe R. A. , Mulholland G. K. , Jewett D. , Hichwa R. , Ehrenkaufer R. L. E. , Carey J. E. , Wieland D. M. , Kuhl D. E. , Agranoff B. W.
Published: April 2011

Cerebral muscarinic cholinergic receptors were imaged and regionally quantified in vivo in humans with the use of [11C]scopolamine and positron emission tomography. Previous studies in experimental animals have suggested the utility of radiolabeled scopolamine for in vivo measurements, on the bases of its maintained pharmacologic specificity following systemic administration and the exclusion of labeled metabolites from the brain. The present studies describe the cerebral distribution kinetics of [11C]scopolamine in normal subjects following intravenous injection. Scopolamine is initially delivered to brain in a perfusion-directed pattern. After 30 to 60 min, activity is lost preferentially from cerebral structures with low muscarinic receptor density including the cerebellum and thalamus. Activity continues to accumulate throughout a 2 h postinjection period in receptor-rich areas including cerebral cortex and the basal ganglia. The late regional concentration of [11C]scopolamine does not, however, accurately parallel known differences in muscarinic receptor numbers in these receptor-rich areas. Tracer kinetic analysis of the data, performed on the basis of a three-compartment model, provides receptor binding estimates in good agreement with prior in vitro measurements. Kinetic analysis confirms significant contributions of ligand delivery and extraction to the late distribution of [11C]scopolamine, reconciling the discrepancy between receptor levels and tracer concentration. Finally, a novel dual-isotope method for rapid chromatographic processing of arterial blood samples in radiotracer studies is presented. The combination of rapid chromatography and compartmental analysis of tracer distribution should have broad utility in future in vivo studies with short-lived radioligands.
Progressive Derangement of Periinfarct Viable Tissue in Ischemic Stroke
Authors: Heiss W.-D. , Huber M. , Fink G. R. , Herholz K. , Pietrzyk U. , Wagner R. , Wienhard K.
Published: April 2011

Sixteen patients were studied by multitracer positron emission tomography (PET) within 6–48 (mean of 23) h of onset of a hemispheric ischemic stroke and again 13–25 (mean of 15.6) days later. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) were measured each time by standard methods, and the sets of brain slices obtained at the two studies were matched using a three-dimensional alignment procedure. On matched brain slices, regions of interest (ROIs) for infarct and peri-infarct tissue, contralateral mirror regions, and major brain structures were outlined. In the core of infarction, blood flow and metabolism were significantly lower than in the corresponding contralateral regions at the first study, and did not change during the observation period. In the peri-infarct tissue, CMRO2 was moderately decreased at the first measurement; over time, the CMRO2 deteriorated progressively while flow did not change. When peri-infarct regions were selected on the basis of increased OEF (25 ± 29.8% above corresponding contralateral regions) on the early scans, the CBF was significantly decreased (23 ± 6.6%) while the CMRO2 showed only a slight difference from the mirror region. Within the observation period, the CBF improved but the CMRO2, OEF, and CMRglc deteriorated. Only in a few regions with increased OEF and slightly impaired CMRO2 was metabolism preserved close to normal values. These data from repeat PET studies in reproducibly defined tissue compartments furnish evidence of viable tissue in the border zone of ischemia up to 48 h after stroke. While this viable peri-infarct tissue exhibits some potential for effective treatment of ischemic stroke, therapeutic routines available today cannot prevent subsequent metabolic derangement and progression to necrosis. Multitracer PET studies identifying viable tissue could be of value in the development of effective treatment of ischemic stroke.
Administration of Excitatory Amino Acid Antagonists via Microdialysis Attenuates the Increase in Glucose Utilization Seen following Concussive Brain Injury
Authors: Kawamata Tatsuro , Katayama Yoichi , Hovda David A. , Yoshino Atsuo , Becker Donald P.
Published: April 2011

Immediately following concussive brain injury, cells exhibit an increase of energy demand represented by the activation of glucose utilization. We have proposed that this trauma-induced hypermetabolism reflects the effort of cells to restore normal ionic balance disrupted by massive ionic fluxes through transmitter-gated ion channels. In the present study, changes in local CMRglc following fluid-percussion concussive injury were determined using [14C]2-deoxy-d-glucose autoradiography, and the effects of in situ administration (via microdialysis) of excitatory amino acid (EAA) antagonists [kynurenic acid (KYN), 2-amino-5-phosphonovaleric acid (APV; 100 μ M, 1 m M, and 10 m M), and 6-cyano-7-nitroquinoxaline-2,3-dine (CNQX; 300 μ M, 1 m M, and 10 m M] on glucose utilization were investigated. Animals that did not receive dialysis showed a remarkable increase (up to 181% of normal control) in cortical glucose utilization following injury. In contrast, this high demand for glucose was reduced in areas infiltrated with KYN, APV, and CNQX. These results indicate that EAA-activated ion channels are involved in the posttraumatic increase in glucose utilization, reflecting the energy demand of cells required to drive pumping mechanisms against an ionic perturbation seen immediately following the concussive injury. The effects of KYN, APV, and CNQX suggest that although all subtypes of the glutamate receptor appear to be involved in this phenomenon, N-methyl-d-aspartate-activated channels may play a major role.
Hyperglycemic versus Normoglycemic Stroke: Topography of Brain Metabolites, Intracellular pH, and Infarct Size
Authors: Wagner Kenneth R. , Kleinholz Marla , de Courten-Myers Gabrielle M. , Myers Ronald E.
Published: April 2011

Hyperglycemia aggravates brain pathologic outcome following middle cerebral artery (MCA) occlusion in cats. We presently determined if hyperglycemia during occlusion leads to high lactic acid accumulations in the ischemic MCA territory. We measured brain metabolite concentrations in 14 MCA territory sites at 0.5 and 4 h following occlusion in hyper- (20 m M) and normoglycemic (5 m M) cats and correlated these results with previous brain pathologic findings. Hyper- versus normoglycemia during MCA occlusion resulted in significantly higher lactate concentrations in the ischemic territory and more numerous loci with lactates >17 μmol/g. At 0.5 h of occlusion, ATP levels were lower in normoglycemic cats, while at 4 h, ATP was similarly reduced (40%) in both glycemia groups. At 4 h, PCr was more reduced in hyperglycemics secondary to a greater brain tissue acidosis. Carbohydrate substrates at 0.5 h were more markedly depleted in normoglycemics, likely limiting lactate accumulation (34.3% versus only 5.0% of sites in hyperglycemics with glucose <0.5 μmol/g). Although lactate was markedly elevated at both 0.5 and 4 h in hyperglycemic ischemic territories, clip release at 4 versus 0.5 h yields a significantly poorer brain pathologic outcome. Correspondingly, intracellular pH, calculated from the creatine kinase equilibrium, was more markedly depressed at 4 than at 0.5 h of occlusion, demonstrating a time-dependent dissociation between tissue lactate and hydrogen ion accumulations. The present findings show that following MCA occlusion (a) hyperglycemia increases the magnitude and topographic extent of marked tissue lactic acidosis, (b) infarct size following 0.5 h of clip release correlates more closely with tissue acidosis than with lactate concentrations, (c) ischemic tissue ATP concentrations correlate poorly with infarct size, (d) normoglycemia limits lactate accumulation during focal ischemia because tissue glucose is depleted, and (e) early during ischemia, tissue buffering or antiport mechanisms may prevent marked increases in intracellular hydrogen ion activity.
Immunocytochemical Study of an Early Microglial Activation in Ischemia
Authors: Gehrmann Jochen , Bonnekoh Petra , Miyazawa Takahito , Hossmann Konstantin-Alexander , Kreutzberg Georg W.
Published: April 2011

Transient arrest of the cerebral blood circulation results in neuronal cell death in selectively vulnerable regions of the rat brain. To elucidate further the involvement of glial cells in this pathology, we have studied the temporal and spatial distribution pattern of activated microglial cells in several regions of the ischemic rat brain. Transient global ischemia was produced in rats by 30 min of a four-vessel occlusion. Survival times were 1, 3, and 7 days after the ischemic injury. The microglial reaction was studied immunocytochemically using several monoclonal antibodies, e.g., against CR3 complement receptor and major histocompatibility complex (MHC) antigens. Two recently produced monoclonal antibodies against rat microglial cells, designated MUC 101 and 102, were also used to identify microglial cells. Following ischemia, the microglial reaction was correlated with the development of neuronal damage. The earliest presence of activated microglial cells was observed in the dorsolateral striatum, the CA1 area, and the dentate hilus of the dorsal hippocampus. However, the microglial reaction was not confined to areas showing selective neuronal damage, but also occurred in regions that are rather resistant to ischemia, such as the CA3 area. Particularly in the frontoparietal cortex, the appearance of MHC class II–positive microglial cells provided an early indication of the subsequent distribution pattern of neuronal damage. The microglial reaction would thus seem to be an early, sensitive, and reliable marker for the occurrence of neuronal damage in ischemia.
Effects of Angiotensin and Atrial Natriuretic Peptide on the Cerebral Circulation
Authors: Tamaki Kinya , Saku Yoshisuke , Ogata Jun
Published: April 2011

The purpose of the present study was to determine effects of angiotensin (ANG) II on the cerebral circulation. We measured the pial artery pressure (PAP) and CBF in anesthetized rabbits. ANG II (5 μg/min) was infused into each carotid artery, and systemic arterial pressure was maintained constant. During infusion of ANG II, there was a significant increase in CBF and fall of PAP, with no change in the large artery resistance (LAR) and a significant decrease in the small vessel resistance (SVR). To investigate whether prostaglandin modulated the ANG II-induced increase in CBF, indomethacin was administered (10 mg/kg i.v.) in another group of animals. Indomethacin itself reduced PAP and increased LAR significantly without changing CBF or SVR. Indomethacin did not attenuate the effects of ANG II on the cerebral circulation. The CMRO2 was assessed during ANG II intracarotid infusion in another group of rabbits. CMRO2 did not change during infusion of ANG II. We also investigated effects of α-atrial natriuretic peptide (ANP) on the cerebral circulation. Infusion of ANP (1 μg/min) decreased LAR by 28% (p < 0.05) without altering SVR. Administration of ANG II after ANP tended to reduce LAR (p > 0.05), with a significant decrease in SVR. The results of the present study suggest that high doses of ANG II can produce cerebral vasodilatation, particularly of small vessels. Blood-borne ANP dilated the large arteries of the cerebral circulation selectively and neither interfered with nor reversed the ANG II-induced increase in CBF.
Glycolysis, Oxidative Metabolism, and Brain Potassium Ion Clearance
Authors: Raffin Cesar N. , Rosenthal Myron , Busto Raul , Sick Thomas J.
Published: April 2011

Studies were directed toward defining relationships between brain ion transport, glycolysis, and oxidative phosphorylation. This was done by examining the relative sensitivity to hypoxemia and to iodoacetate (IAA)-induced inhibition of glycolysis in rats anesthetized with pentobarbital. Both insults had minimal effects on K+o baseline. In response to neuronal activation, IAA increased the time required for K+o clearance from maximal values to half-recovery of baseline. Hypoxemia slowed the later phase of K+o clearance, when K+o was approaching “resting” levels. Hypoxemia produced greater declines in high-energy intermediates than did IAA, which indicated that the IAA effect was not due to a greater overall insult to metabolism and suggested a direct link between ATP produced by glycolysis and ion transport activity. These data demonstrate that K+o clearance requires energy from glycolysis and oxidative phosphorylation for different phases of the recovery process and that inhibition specific to glycolysis or oxidative phosphorylation may be temporally resolved within a single stimulus.