bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Thalamus and White Matter in Cognitive Outcome after Head Injury
Authors: Terayama Yasuo , Meyer John Stirling , Kawamura Jun , Weathers Susan
Published: April 2011

Local CBF (LCBF) and local partition coefficients (LΛ) were measured by xenon-enhanced computed tomography among 15 patients with remote cerebral trauma resulting from severe head injury. Results were compared with similar measures among age-matched normal volunteers (N = 20). The patients were divided into two groups according to different outcomes based on serial cognitive testing: Group I (N = 10) improved but Group D (N = 5) deteriorated throughout a mean interval of 10 years of follow-up. Initial LCBF measurements were performed at mean intervals of 6.8 years after injury. Cortical LCBF values were decreased in frontal (p < 0.01) and temporal (p < 0.05) regions among both groups, but only in Group D were flow values decreased in putamen and thalamus (p < 0.05). LΛ values were reduced in frontotemporal cortex among both groups but in the thalamus only among Group D (p < 0.05). Mean white matter flow values were normal in Group I but were reduced in Group D (p < 0.05). Mean partition coefficients for white matter were reduced in both groups (p < 0.01) but were lower in Group D (p < 0.05). Reduced perfusion of frontotemporal gray matter is consonant with neuropathological reports following severe brain trauma of neuronal atrophy, gliosis, and infarction affecting these regions. Group comparisons between patients who cognitively improved versus those that deteriorated demonstrate an association between reductions of CBF in putamen, thalamus and subcortical white matter and impaired cognition after severe head injury.
Choline Acetyltransferase Activity Associated with Cerebral Cortical Microvessels Does Not Originate in Basal Forebrain Neurons
Authors: Galea Elena , Fernández-Shaw Clara , Triguero Domingo , Estrada Carmen
Published: April 2011

Cerebral cortical microvessels are innervated by cholinergic fibers that are probably involved in the regulation of local cerebral blood flow and blood-brain barrier permeability. The possibility exists that the cholinergic terminals associated with the cortical microvasculature belong to neurons from the nucleus basalis magnocellularis (NBM), where 70% of the cortical cholinergic projections originate. To test this hypothesis, ibotenic acid (25 nmol) was injected unilaterally in the NBM in rats, and 14 days later, choline acetyltransferase (ChAT) activity was measured in the frontoparietal cortex and in a blood vessel fraction isolated from this region. Lesions of the NBM resulted in a 50% decrease of cortical ChAT as compared with control or sham-operated hemispheres; however, no changes were observed in the ChAT activity associated with cortical microvessels. These results indicate that, in rat cerebral cortex, the perivascular cholinergic terminals do not originate in the basal forebrain.
Flow Estimation Using Ultrasound Imaging (Color M-Mode) and Computer Postprocessing
Authors: Juul Roar , Slørdahl Stig A. , Torp Hans , Angelsen Bjørn A. J. , Brubakk Alf O.
Published: April 2011

We have developed a method to calculate flow noninvasively in blood vessels using color Motion-mode (M-mode) and computer postprocessing. The velocity of each point in the cross-sectional area of the vessel was found from the color M-mode recording by correcting for angle both distances and velocities and by assuming a symmetrical circular velocity field. Volume flow was then found by integrating the velocity field at 5-ms intervals through the cardiac cycle. In a cardiovascular hydromechanical model, a correlation of 0.99 and p value of <0.001 were found between estimated and measured flow in the model (n = 8). In 20 healthy individuals, we made 31 investigations in the common carotid (CCA), internal carotid (ICA), and external carotid (ECA) artery, comparing flow in the CCA with the added flow in the ICA and ECA. The values (CCA versus ICA + ECA) correlated with r = 0.91 and p < 0.01. Repeated investigations (n = 8) in one individual gave flow estimates of 495 ± 50 ml/min in the CCA, 304 ± 45 ml/min in the ICA, and 165 ± 37 ml/min in the ECA (means ± SD). This article shows that this system can make accurate estimation of blood flow to the brain noninvasively.
The Microglial Reaction in the Rat Dorsal Hippocampus following Transient Forebrain Ischemia
Authors: Morioka Takato , Kalehua Audrey N. , Streit Wolfgang J.
Published: April 2011

We have examined the distribution and time course of the microglial reaction in the rat dorsal hippocampus after 25-min transient forebrain ischemia (four-vessel occlusion model). Microglial cells were visualized in brain sections using lectin staining with the Griffonia simplicifolia B4-isolectin following intervals of reperfusion ranging from 20 min to 4 weeks. Increased staining of microglial cells was detected in the dentate hilus and area CA1 as early as 20 min after reperfusion. These same regions demonstrated more intense microglial staining after 24 h. The strongest microglial reaction was observed 4–6 days after reperfusion when reactive microglia were abundant throughout all laminae of CA1 and the dentate hilus. Following longer reperfusion intervals, the microglial reaction became less intense; however, it remained above normal levels until the end of the fourth week. At all time points examined, microglial reactivity in the CA3 pyramidal and dentate granule cell layers was considerably lower than that observed in CA1 and dentate hilus. Our results are consistent with the known serial pathological changes associated with cerebral ischemia, but, in addition, show that the examination of the microglial reaction provides an extremely sensitive indicator of subtle and morphologically nonapparent neuronal damage during the early stages of injury.
Assessment of Accuracy of PET Utilizing a 3-D Phantom to Simulate the Activity Distribution of [18F]Fluorodeoxyglucose Uptake in the Human Brain
Authors: Hoffman Edward J. , Cutler P. Duffy , Guerrero Thomas M. , Digby Ward M. , Mazziotta John C.
Published: April 2011

A three-dimensional brain phantom has been developed to simulate the activity distributions found in human brain studies currently employed in positron emission tomography (PET). The phantom has a single contiguous chamber and utilizes thin layers of lucite to provide apparent relative concentrations of 5, 1, and 0 for gray matter, white matter, and CSF structures, respectively. The phantom and an ideal image set were created from the same set of data. Thus, the user has a basis for comparing measured images with an ideal set that allows a quantitative evaluation of errors in PET studies with an activity distribution similar to that found in patients. The phantom was employed in a study of the effect of deadtime and scatter on accuracy in quantitation on a current PET system. Deadtime correction factors were found to be significant (1.1–2.5) at count rates found in clinical studies. Deadtime correction techniques were found to be accurate to within 5%. Scatter in emission and attenuation correction data consistently caused 5–15% errors in quantitation, whereas correction for scatter in both types of data reduced errors in accuracy to <5%.
The Precision of Positron Emission Tomography: Theory and Measurement
Authors: Alpert Nathaniel M. , Barker W. Craig , Gelman Andrew , Weise Stephen , Senda Michio , Correia John A.
Published: April 2011

The limits of quantitation with positron emission tomography (PET) are examined with respect to the noise propagation resulting from radioactive decay and other sources of random error. Theoretical methods for evaluating the statistical error have been devised but seldom applied to experimental data obtained on human subjects. This paper extends the analysis in several ways: (1) A Monte Carlo method is described for tracking the propagation of statistical error through the analysis of in vivo measurements; (2) Experimental data, obtained in phantoms, validating the Monte Carlo method and other methods are presented; (3) A difference in activation paradigm, performed on regional CBF (rCBF) data from five human subjects, was analyzed on 1.6-cm diameter regions of interest to determine the mean fractional statistical error in PET tissue concentration and in rCBF before and after stereotactic transformation; and (4) A linear statistical model and calculations of the various statistical errors were used to estimate the magnitude of the subject-specific fluctuations under various conditions. In this specific example, the root mean squared (RMS) noise in flow measurements was about three times higher than the RMS noise in the concentration measurements. In addition, the total random error was almost equally partitioned between statistical error and random fluctuations due to all other sources.
MRI-PET Correlation in Three Dimensions Using a Volume-of-Interest (VOI) Atlas
Authors: Evans A. C. , Marrett S. , Torrescorzo J. , Ku S. , Collins L.
Published: April 2011

Quantitative interpretation of functional images (PET or SPECT) is hampered by poor spatial resolution, low counting statistics, and, for many tracers, low contrast between different brain structures of interest. Furthermore, normal tracer distributions can be severely disrupted by such gross pathologies as stroke, tumor, and dementia. Hence, the complementary anatomical information provided by CT or MRI is essential for accurate and reproducible regional analysis of functional data. We have developed methods for the simultaneous three-dimensional display and analysis of image volumes from MRI and PET. A general algorithm for defining the affine transformation between two equivalent point ensembles has been adapted for the purpose of registering MRI and PET image volumes by means of a simple fiducial arrangement. In addition, we have extended previous MRI-based computerized atlas methodology to three dimensions. The native atlas planes were spaced at 2 mm intervals, sufficient axial sampling to permit the generation of oblique planar sections through the atlas space. This will allow for an infinite number of angulations and axial offsets in two-dimensional region-of-interest (ROI) templates, all derived from the same master three-dimensional volume-of-interest (VOI) atlas and therefore maintaining topographical consistency throughout. These ROI templates may be selected to match the image orientation for conventional two-dimensional segmentation and data extraction.
A Regional Covariance Approach to the Analysis of Functional Patterns in Positron Emission Tomographic Data
Authors: Moeller J. R. , Strother S. C.
Published: April 2011

This article provides a complete description of the subprofile scaling model (SSM) approach to the analysis of positron emission tomography (PET) data. The goals and assumptions underlying the development of SSM are outlined, and its strengths and weaknesses are discussed. It is demonstrated that all obtainable information about regional ratios can, in theory, be derived from the SSM regional covariance patterns. A general constraint on the ability to effectively remove global variation while identifying region-specific information about PET data sets is outlined and discussed within the SSM framework. Finally, an extension of the SSM technique to the generation of disease-specific covariance patterns is demonstrated for paraneoplastic cerebellar degeneration, the acquired immune deficiency syndrome dementia complex, and Parkinson's disease, and the importance of multidimensional descriptions of disease, such as may be obtained from PET data using SSM, is emphasized.
The Effect of α-Adrenergic Receptor Blockers Prazosin and Yohimbine on Cerebral Metabolism and Biogenic Amine Content of Traumatized Brain
Authors: Inoue Masaru , McHugh Michael , Pappius Hanna M.
Published: April 2011

Widespread decrease in local cerebral glucose utilization (LCGU) previously shown to occur 3 days after a focal freezing lesion was interpreted as reflecting a depression of functional activity in the affected areas. In parallel experiments, cortical norepinephrine (NE) content of traumatized brain was found to be decreased. The effects of prazosin (PZ), an α1-adrenergic receptor blocker, and yohimbine (YOH), an α2-blocker, on glucose use and biogenic amine content of lesioned rat brain were studied to determine if the changes in the noradrenergic system associated with injury are of functional importance, to identify the receptors that may be involved in mediating the action of NE in injured brain, and to look for evidence of interaction between the noradrenergic and the serotonergic systems in traumatized brain. PZ (1 mg/kg) given 30 min before the lesion ameliorated the subsequent metabolic cortical depression seen in untreated animals. PZ given for 3 days starting before the lesion (3 mg/kg/day) was also effective in normalizing LCGU in areas where it was depressed by lesioning, despite the fact that this regimen induced significant global decrease in LCGU in normal animals. Once cortical metabolic depression had developed 3 days after the lesion, it could not be modified by PZ. YOH was less effective than PZ and was so only when given for 3 days (22.5 mg/kg/day in three divided doses). PZ (3 mg/kg/day in three divided doses) slightly but significantly decreased the accumulation of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid in the traumatized hemisphere. These results provide evidence that blockage of α1adrenergic receptors prevents the development of cortical dysfunction associated with brain trauma. This implies that the noradrenergic system plays a role in the functional consequences of injury and that this effect is, at least in part, mediated by α1-adrenergic receptors. Furthermore, α1-adrenergic receptor blockage appears to modulate cortical turnover of 5-HT, previously also implicated in functional consequences of brain injury. The data are compatible with inhibitory effects of NE in the cortex and suggest a potential of α1-adrenergic blockage in development of novel therapeutic approaches to brain injury.
The Effect of Stable Xenon on ICP
Authors: Marion Donald W. , Crosby Kelly
Published: April 2011

Recent studies have suggested that under certain conditions, inhalation of stable xenon can cause an increase in CBF or intracranial pressure (ICP). We reviewed the ICP changes that occurred during 48 stable xenon/CT CBF studies in 23 comatose head-injured patients to determine if the concentration (32%) and duration of inhalation (4.5 min) of stable xenon we used caused an increase in ICP. In the group as a whole, there was no significant difference between the mean ICP at the start of xenon inhalation and the mean ICP immediately after completion of the studies. An increase in ICP also was not found in subgroups with low, normal, or high global CBF, or groups with or without intracranial hypertension. Changes in ICP that occurred during individual studies usually were related to corresponding changes in the arterial pco2 (p < 0.0001, Pearson's correlation test). Our data suggest that 32% stable xenon administered for 4.5 min does not cause a significant increase in ICP during xenon/CT CBF studies.
Effects of Topical Adenosine Analogs and Forskolin on Rat Pial Arterioles in vivo
Authors: Ibayashi Setsuro , Ngai Al C. , Meno Joseph R. , Winn H. Richard
Published: April 2011

We utilized the closed window technique to study the in vivo responses of rat pial arterioles to superfused adenosine agonists. Adenosine and its analogs dilated pial arterioles and exhibited the following order of potency: 5′ N-ethylcarboxamide adenosine (NECA) > 2-chloroadenosine (2-CADO) > adenosine = R-N6-phenylisopropyladenosine ( R-PIA) = S-PIA > N6-cyclohexyladenosine (CHA). This potency profile suggests that cerebral vasodilation is mediated through the A2 receptor. Forskolin (10−9 M) potentiated the vasodilation caused by 10−6 M NECA, thus implicating adenylate cyclase activation during NECA-induced vasodilation and providing further support for involvement of the A2 receptor.
Relative Hypoperfusion in Rat Cerebral Cortex during Recurrent Seizures
Authors: Kreisman Norman R. , Magee Jeffery C. , Brizzee Barbara L.
Published: April 2011

Focal cortical CBF and oxygenation were measured in rats during repetitive seizures to determine whether CBF is maintained above a critical level for adequate delivery of O2. Cerebral oxygenation was determined by measuring relative changes in the oxidation/reduction level of cytochrome aa3 and CBF was measured by the washout of H2. During early seizures, cortical CBF increased to 350% of control and cortical oxygenation also rose markedly. During later seizures, both the increases in CBF and in cortical oxygenation were attenuated progressively. This was accompanied also by attenuation of the associated increases in MABP. Cortical oxygenation decreased during a seizure if the increase in CBF failed to exceed 150–200% of control, defining the critical CBF value. Ventilating the rats on 97% O2 resulted in restoration of the seizure-associated increases in cortical oxygenation in 50% of the cases. The elevation of inspired O2 was effective only if CBF increased once again above 150–200% of control, confirming that the critical CBF lies within this range of values. We conclude that CBF must rise >200% of control levels to provide sufficient O2 to meet the enhanced metabolic requirements of repetitive seizures.
Eicosanoid Production in the Caudate Nucleus and Dorsal Hippocampus after Forebrain Ischemia: A Microdialysis Study
Authors: Patel Piyush M. , Drummond John C. , Mitchell Murray D. , Yaksh Tony L. , Cole Daniel J.
Published: April 2011

Thromboxane (Tx)B2 and 6-keto-prostaglandin (6-keto-PG) F1α formation in the hippocampus and caudate nucleus were evaluated by microdialysis during and following forebrain ischemia. Spontaneously hypertensive rats were subjected to bilateral carotid artery occlusion with simultaneous hypotension for 8, 14, or 20 min. Dialysate was collected during the ischemic interval and during the reperfusion period. TxB2 and 6-keto-PGF1α levels were measured by radioimmunoassay. In both structures, TxB2 production increased significantly during the reperfusion period in all three ischemic groups. By contrast, increased 6-keto-PGF1α elaboration was observed after only the longest ischemic duration. While TxB2 levels gradually decreased during the 3-h reperfusion period in all groups, the levels in the group subjected to 8 min of ischemia returned to control values most rapidly. A relationship between the duration of ischemia and TxB2 production was therefore evident. 6-Keto-PGF1α levels increased in only the group subjected to 20 min of ischemia and, by contrast to the pattern of TxB2 change, 6-keto-PGF1α levels remained elevated throughout the reperfusion period. During reperfusion, the ratio of TxB2 to 6-keto-PGF1α increased substantially versus the preischemic period in both structures. The data demonstrate that eicosanoid elaboration following cerebral ischemia can be evaluated by the microdialysis technique. In addition, they indicate that the thresholds (duration of ischemia) for the postischemic production and the temporal profiles of TxB2 and 6-keto-PGF1α in the caudate and hippocampus differ. They also demonstrate that there is regional heterogeneity in the patterns of eicosanoid elaboration after forebrain ischemia.
Calcium Channels and Nifedipine Inhibition of Serotonin-Induced [3H]Thymidine Incorporation in Cultured Cerebral Smooth Muscle Cells
Authors: Kent Thomas A. , Jazayeri Allahyar , Simard J. Marc
Published: April 2011

Cultures of smooth muscle cells were prepared from the basilar artery of adult guinea pigs. Passaged cultures (10–30 passages) that expressed serotonin receptors were studied using [3H]thymidine incorporation. When tested in quiescent medium, serotonin potently stimulated [3H]thymidine incorporation (EC50 of 31 n M) by as much as 400% at 24 h. The number of cells was not significantly increased at 24 or 48 h. At concentrations of 10−8–10−5 M 5-HT, [3H]thymidine uptake was reduced 40–50% by the dihydropyridine Ca2+ channel blocker, nifedipine (1 μ M). To demonstrate a possible mechanism for the sensitivity to nifedipine, Ca2+ currents were measured using the whole cell patch clamp technique. The cells expressed dihydropyridine-sensitive L-type Ca2+ channels, but not other subtypes of Ca2+ channels, as indicated by the kinetic and voltage-dependent characteristics of the current and by the stimulatory effect of Bay K 8644. The magnitude of the Ca2+ currents was related exponentially to the membrane surface area, measured as cell capacitance. These data support the association of dihydropyridine-sensitive Ca2+ channels with mitogenesis in vascular smooth muscle, and suggest an alternate mechanism of action for the beneficial effect of dihydropyridines in prophylaxis of cerebral vasospasm.
Postischemic Blockade of AMPA but Not NMDA Receptors Mitigates Neuronal Damage in the Rat Brain following Transient Severe Cerebral Ischemia
Authors: Nellgård B. , Wieloch T.
Published: April 2011

Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg−1 followed by an intravenous infusion of 75 μg min−1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine(MK-801) given 1 mg kg−1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist dl-( E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg−1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44–69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor–mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor–coupled processes or to changes of AMPA receptor characteristics.
Hyperglycemia Suppresses c-Fos mRNA Expression following Transient Cerebral Ischemia in Gerbils
Authors: Combs David J. , Dempsey Robert J. , Donaldson David , Kindy Mark S.
Published: April 2011

The c- fos proto-oncogene is activated by transient cerebral ischemia. This activation may signify a specific genetic response to ischemia affecting tolerance to ischemia and ultimate cell survival. Hyperglycemia, which enhances brain injury from transient ischemia, was studied for its effects on this gene system in gerbils by measuring c- fos mRNA 2 h after 20 min of bilateral carotid artery occlusion. Brain c- fos mRNA was increased by ischemia (11.7 ± 5.0, p ≤ 0.05, fold increase) compared to nonischemic controls (1.0 ± 1.3). Pretreatment with 1 g/kg of glucose partially reduced postischemic c- fos mRNA (6.3 ± 1.6, p ≤ 0.05) while 4 g/kg of glucose completely suppressed postischemic c- fos expression (0.7 ± 0.3, p ≤ 0.05). These data indicate that hyperglycemia suppresses normal postischemic gene expression and suggest the possibility that such suppression is a predictor or even a contributor to hyperglycemia-enhanced ischemic brain damage.
The Effect of Glutamate Receptor Blockade on Anoxic Depolarization and Cortical Spreading Depression
Authors: Lauritzen Martin , Hansen Anker Jon
Published: April 2011

We examined the effect of blockade of N-methyl-d-aspartate (NMDA) and non-NMDA subtype glutamate receptors on anoxic depolarization (AD) and cortical spreading depression (CSD). [K+]e and the direct current (DC) potential were measured with microelectrodes in the cerebral cortex of barbiturate-anesthetized rats. NMDA blockade was achieved by injection of (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine maleate [MK-801; 3 and 10 mg/kg] or amino-7-phosphonoheptanoate (APH; 4.5 and 10 mg/kg). Non-NMDA receptor blockade was achieved by injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( F)quinoxaline (NBQX; 10 and 20 mg/kg). MK-801 and APH blocked CSD, while NBQX did not. In control rats, the latency from circulatory arrest to AD was 2.1 ± 0.1 min, while the amplitude of the DC shift was 21 ± 1 mV, and [K+]e increased to 50 ± 6 m M. All variables remained unchanged in animals treated with MK-801, APH, or NBQX. Finally, MK-801 (14 mg/kg) and NBQX (40 mg/kg) were given in combination to examine the effect of total glutamate receptor blockade on AD. This combination slightly accelerated the onset of AD, probably owing to circulatory failure. In conclusion, AD was unaffected by glutamate receptor blockade. In contrast, NMDA receptors play a crucial role for CSD.
Effects of Endothelium-Derived Nitric Oxide on Cerebral Circulation during Normoxia and Hypoxia in the Rat
Authors: Koźniewska E. , Osȩka M. , Styś T.
Published: April 2011

The aim of this study was to determine the effects of endogenous nitric oxide (NO) on cerebral blood flow (CBF) and cerebrovascular resistance (CVR) under conditions of normoxia and hypoxia. Experiments were performed on anesthetized, mechanically ventilated Wistar rats. CBF was measured using the intracarotid 133Xe injection technique. NO formation was inhibited by NG-monomethyl-l-arginine (l-NMMA). Administration of l-NMMA (100 mg kg−1 i.v.) during normoxia resulted in an increase in mean arterial blood pressure from 113 ± 4 to 145 ± 4 mm Hg ( p < 0.001), a decrease in CBF of 21% (from 91 ± 4 to 75 ± 5 ml 100 g−1 min−1, p < 0.001), and an increase in CVR of 53% (from 1.3 ± 0.1 to 2.0 ± 0.2 mm Hg ml−1 100 g min, p < 0.001). These effects were reversed by i.v. administration of 300 mg kg−1 of l-arginine but not d-arginine. Moreover, the administration of l-NMMA abolished the enhancement of CBF and the diminution in CVR observed during intracarotid infusion of acetylcholine (ACh). The increase in CBF and decrease in CVR during hypoxia in the group of rats that received l-NMMA were similar to that in the control group, although CBF and CVR levels attained during hypoxia in both groups were different. The results show that NO is involved in the maintenance of basal CBF and CVR, and is responsible for the ACh-elicited increase in CBF and the decrease in CVR in rats. They also suggest that NO modulates hypoxic changes of CBF and CVR, but is probably not the main factor responsible for the increase in CBF during hypoxia.
Regional Distribution and Kinetics of Three Sites on the GABAA Receptor: Lack of Effect of Portacaval Shunting
Authors: Mans Anke M. , Kukulka Kelli M. , McAvoy Keith J. , Rokosz Norman C.
Published: April 2011

The regional distribution of binding sites on the GABAA receptor and their kinetic parameters were measured by quantitative autoradiography in brains from normal rats and rats with a portacaval shunt, a model of portal systemic encephalopathy in which GABA neurotransmission may be altered. The ligands used were [3H]flunitrazepam (a benzodiazepine-site agonist), [3H]-Ro 15-1788 (a benzodiazepine-site antagonist), [3H]muscimol (a GABA-site agonist), and [35S] t-butylbicyclo-phosphorothionate (35S-TBPS, a convulsant that binds to a site near the chloride channel). Some brains were analyzed by computerized image analysis and three-dimensional reconstruction. The regional distribution of binding of the benzodiazepines was very similar, but the patterns obtained with [3H]muscimol and [35S]TBPS were different in many areas, suggesting a heterogeneous distribution of several subtypes of the GABAA receptor. The kinetic parameters were determined in brain regions for [3H]flunitrazepam, [3H]Ro15-1788, and [3H]muscimol. For each ligand, the Kd showed a significant heterogeneity among brain regions (at least threefold), contrary to conclusions drawn from earlier studies. In portacaval shunted rats, binding of all four ligands was essentially unchanged from that in control rats, indicating that, if there was an abnormality in GABA neurotransmission during portal systemic shunting, it was not reflected by altered binding to the main sites on the GABAA receptor.
Acute Improvement in Histological Outcome by MK-801 following Focal Cerebral Ischemia and Reperfusion in the Cat Independent of Blood Flow Changes
Authors: Dezsi Laszlo , Greenberg Joel H. , Hamar Janos , Sladky John , Karp Andrea , Reivich Martin
Published: April 2011

The present study reports on the acute effects of MK-801 on the histopathological outcome and blood flow changes during focal cerebral ischemia and reperfusion. In addition, acute changes in the EEG and blood pressure are also reported. In 16 halothane-anesthetized cats, the left middle cerebral artery (MCA) was occluded for 2 h followed by 4 h of reperfusion. Thirty minutes after the onset of ischemia, eight animals were treated with 1 mg/kg of MK-801, while eight animals received saline. Blood flow from the peripheral MCA territory was measured with H2 clearance. There was a comparable reduction in blood flow (down to 20% of control) in the ischemic gyri of the two groups followed by a partial recovery after recirculation. There was a similar decrease in the EEG amplitude over the ischemic central MCA territory in the treated and the untreated group. Treatment with MK-801 induced a burst suppression in the EEG and a transient drop (11.4 ± 6.5 mm Hg) in the mean arterial pressure. The volume of early ischemic damage decreased by one-third in the MK-801-treated group compared to the untreated one, both in the total hemisphere (from 29 ± 10 to 20 ± 5%) and in the hemispheric cortex (range 36 ± 8 to 24 ± 13%). A major fraction of this improvement was localized to the middle and posterior parietal (mainly perifocal) regions of the MCA territory. These results show that in our model, MK-801 improves histopathological outcome despite the lack of apparent effect on the cortical blood flow, and an adverse effect on the systemic blood pressure. This is the first report that describes data on a reproducible model of reperfusion after temporary occlusion of the MCA in a cat, extending the findings of the Glasgow group, who observed similar neuroprotection in models of permanent MCA occlusion.
Alteration of Voltage-Dependent Calcium Channels in Canine Brain during Global Ischemia and Reperfusion
Authors: Hoehner Paul J. , Blanck Thomas J. J. , Roy Rita , Rosenthal Robert E. , Fiskum Gary
Published: April 2011

Elevated intracellular calcium (iCa2+) plays an important role in the pathophysiology of ischemic brain damage. The mechanisms by which iCa2+ increases are uncertain. Recent evidence implicates the voltage-dependent calcium channel (VDCC) as a likely site for the alteration in Ca2+ homeostasis during ischemia. The purpose of this study was to determine whether VDCCs are altered by global ischemia and reperfusion in a canine cardiac arrest, resuscitation model. We employed the radioligand, [3H]PN200-110, to quantitate the equilibrium binding characteristics of the VDCCs in the cerebral cortex. Twenty-five adult beagles were separated into four experimental groups: (a) nonischemic controls, (b) those undergoing 10-min ventricular fibrillation and apnea, (c) those undergoing 10-min ventricular fibrillation and apnea followed by spontaneous circulation and controlled respiration for 2 and (d) 24 h. Brain cortex samples were taken prior to killing of the animal, frozen immediately in liquid nitrogen, and crude synaptosomal membranes isolated by differential centrifugation/filtration. After 10 min of ischemia the maximal binding (Bmax) of [3H]PN200-110 increased to >250% of control values (control Bmax 11.16 ± 0.98; ischemic 28.35 ± 2.78 fmol/mg protein; p < 0.05). Bmax returned to near control values after 2 h of reperfusion but remained significantly greater than the control at 24 h. Although the affinity constant (Kd) (control = 0.12 ± 0.03 n M) appeared to increase with ischemia and normalize with reperfusion, the changes were not statistically significant. We conclude that the binding of [3H]PN200-110 to L-type VDCCs is increased after 10 min of global ischemia/anoxia produced by ventricular fibrillation and apnea in the dog. This change is only partially reversible after 24 h of reperfusion. This study supports the hypothesis that ischemia increases the number of VDCCs in the cell membrane which may allow increased entry of Ca2+ into the cell during ischemia and early reperfusion.
Effects of Hyperglycemia on the Time Course of Changes in Energy Metabolism and pH during Global Cerebral Ischemia and Reperfusion in Rats: Correlation of 1H and 31P NMR Spectroscopy with Fatty Acid and Excitatory Amino Acid Levels
Authors: Widmer Hans , Abiko Hisashi , Faden Alan I. , James Thomas L. , Weinstein Philip R.
Published: April 2011

The effects of hyperglycemia on the time course of changes in cerebral energy metabolite concentrations and intracellular pH were measured by nuclear magnetic resonance (NMR) spectroscopy in rats subjected to temporary complete brain ischemia. Interleaved 31P and 1H NMR spectra were obtained every 5 min before, during, and for 2 h after a 30-min bilateral carotid occlusion preceded by permanent occlusion of the basilar artery. The findings were compared with free fatty acid and excitatory amino acid levels as well as with cations and water content in funnel-frozen brain specimens. One hour before occlusion, nine rats received 50% glucose (12 ml/kg i.p.) and five received 7% saline (12 ml/kg i.p.). Before ischemia, there were no differences in cerebral metabolite levels or pH between hyperglycemic rats and controls. During the carotid occlusion, the lactate/ N-acetylaspartate (Lac/NAA) peak ratio was higher (0.73–1.48 vs. 0.56–0.82; p < 0.05) and pH was lower (<6.0 vs. 6.45 ± 0.05; p < 0.05) in the hyperglycemic rats than in the controls. Phosphocreatine and adenosine triphosphate were totally depleted in both groups. Within 5–15 min after the onset of reperfusion, the Lac/NAA peak ratio increased further in all rats; however, only in extremely hyperglycemic rats (serum glucose > 960 mg/dl) did the lactic acidosis progress rather than recover later during reperfusion. Total free fatty acid and excitatory amino acid levels, but not cation concentration or water content, in brain correlated with serum glucose levels during and after ischemia and with NMR findings after 2 h of reperfusion. Although profound hyperglycemia (serum glucose of 970–1,650 mg/dl) appears to be associated with progression of anaerobic glycolysis and failure of cerebral energy metabolism to recover after temporary complete brain ischemia and with postischemic excitotoxic and lipolytic reactions thought to participate in delayed cellular injury, severe hyperglycemia (490–720 mg/dl) was associated with recovery of energy metabolism.
The Effect of Hyperglycemia on Intracellular Calcium in Stroke
Authors: Araki Nobuo , Greenberg Joel H. , Sladky John T. , Uematsu Daisuke , Karp Andrea , Reivich Martin
Published: April 2011

The effect of hyperglycemia on cytosolic free calcium ([Ca2+]i) during temporary focal cerebral ischemia was investigated in cats using a fluorometric technique. The middle cerebral artery (MCA) was occluded for a period of 1 h, after which the clip was removed. In seven animals, plasma glucose was raised to 500–700 mg/dl by infusion of a 50% glucose solution starting 30 min after MCA occlusion, while eight animals were kept normoglycemic during and following occlusion. MCA occlusion induced a significant, but identical, elevation of the [Ca2+]i signal ratio (400/506 nm) in both the normoglycemic group (from 1.40 to 1.97 ± 0.34, p < 0.01) and in the hyperglycemic group (from 1.40 to 2.00 ± 0.53, p < 0.01) at the end of the occlusion. Between 10 and 30 min after reopening, the [Ca2+]i signal ratio decreased to control levels in the normoglycemic group (1.40 ± 0.11 and 1.36 ± 0.08 at 10 and 30 min after reopening, respectively), but remained elevated in the hyperglycemic group (1.69 ± 0.18 and 1.65 ± 0.21 at 10 and 30 min after reopening, respectively). There was a statistically significant difference between the two groups ( p < 0.01). These data suggest that hyperglycemia may be harmful to calcium recovery during the early recirculation period following focal cerebral ischemia.
Direct Evidence for Increased Continuous Histamine Release in the Striatum of Conscious Freely Moving Rats Produced by Middle Cerebral Artery Occlusion
Authors: Adachi Naoto , Itoh Yoshinori , Oishi Ryozo , Saeki Kiyomi
Published: April 2011

Extracellular histamine in the striatum of conscious freely moving rats collected by intracerebral microdialysis 1 day after implantation of a U-shaped dialysis probe was measured by HPLC coupled with postcolumn o-phthalaldehyde derivatization fluorometry. The basal fractional histamine outputs were almost constant from 1 to 7 h after the start of perfusion (5.9–8.4 pg/30 min). Depolarization by perfusion with a high K+ (100 m M)-containing medium produced a significant (124%) increase and neuronal blockade by perfusion with a tetrodotoxin (1 μM)-containing medium resulted in a 68% reduction in the histamine output. The histamine output was markedly reduced by intraperitoneal injection of α-fluoromethylhistidine (100 mg/kg), an irreversible inhibitor of histidine decarboxylase, or ( R)-α-methylhistamine (5 mg/kg), a potent and specific H3-receptor agonist. After middle cerebral artery (MCA) occlusion, the histamine output gradually increased, and reached four times the control value 8 h later. When rats were pretreated with metoprine (10 mg/kg), a histamine N-methyltransferase inhibitor, there was no significant difference in the histamine output between the MCA-occluded and the sham-operated groups during the first 3.5 h after the operation, but the histamine output gradually increased thereafter in the MCA-occluded group. In rats treated with α-fluoromethylhistidine, MCA occlusion failed to cause an increase in the histamine output. These results demonstrate that MCA occlusion induces a long-lasting increase in neuronal histamine release in the rat striatum.
Influence of Ischemia on Blood—Brain and Blood—CSF Calcium Transport
Authors: Ohta Sukejuro , Gidö Gunilla , Siesjö Bo K.
Published: April 2011

The objective was to explore whether the increased incorporation of 45Ca into selectively vulnerable neurons, observed after transient ischemia, can be explained by enhanced blood-tissue and/or enhanced blood–CSF transfer. Anesthetized rats were subjected to 15 min of forebrain ischemia, with recirculation for 20 or 60 min, or 24 h. The transfer constants ( Kin) and unidirectional fluxes ( Jin) for calcium in tissue and CSF were determined following i.v. injection of 45Ca, integration of the curve for plasma-specific activity over 10 min, and sampling of cisternal CSF, and tissue (cortex, caudoputamen, hippocampus, and cerebellum). Predictably, values for Kin and Jin in control animals were much larger in CSF than in tissues, and hippocampus had higher values than the other areas, probably because of its closeness to the lateral ventricle. Ischemia failed to alter the Kin and Jin values, demonstrating that the low permeability of blood–brain and blood–CSF barriers to calcium is upheld both in the immediate recirculation period, and after 24 h of recirculation. The results support the contention that the increased 45Ca incorporation during recovery is due to increased calcium cycling across functionally altered cell membranes.
Cerebral Blood Flow Response to Increases in Arterial CO2 Tension during Alfentanil Anesthesia in the Rabbit
Authors: Ludbrook G. L. , Helps S. C. , Gorman D. F.
Published: April 2011

The stability of cerebral function and blood flow (CBF), and the CBF response to changes in arterial carbon dioxide tension (CBF reactivity) during alfentanil anesthesia were examined in rabbits. This model was first shown to provide stable anesthesia, cortical function, and CBF for 4 h. CBF increased significantly to 159% [of baseline] in the left hemisphere and to 167% in the right within 5 min of an exposure to 5% CO2 ( p = 0.009 on the left and p = 0.003 on the right), but then decreased to 123% on the left and to 137% on the right (not significantly different from baseline, p = 0.11 on the left and p = 0.07 on the right) while PaCO2 was still rising. Steady state reactivity levels (0.8 ml 100 g−1/min−1/mm Hg−1 CO2 on the left and 0.65 ml 100 g−1/min−1/mm Hg−1 CO2 on the right) were consistent with previous work and were reached at 20 min. These results suggest that mechanisms other than perivascular hydrogen ion concentration mediate the CBF response to changes in arterial CO2 tension during alfentanil anesthesia.
Potential Language and Attentional Networks Revealed through Factor Analysis of rCBF Data Measured with SPECT
Authors: McLaughlin Thomas , Steinberg Bruce , Christensen Birger , Law Ian , Parving Agnete , Friberg Lars
Published: April 2011

We used changes in regional cerebral blood flow (rCBF) to disclose regions involved in central auditory and language processing in the normal brain. rCBF was quantified with a fast-rotating, single-photon emission computerized tomograph (SPECT) and inhalation of 133Xe. rCBF data were obtained simultaneously from parallel, transverse slices of the brain. The lower slice was positioned to include both Broca's and Wernicke's areas. The upper slice included regions generally regarded by neurobehaviorists as less related to primary auditory or linguistic functions. We presented three types of auditory stimuli to ten healthy, young volunteers: (a) diotically presented Danish speech, (b) dichotic word stimulation, and (c) white noise. Wilcoxon's signed ranks sum test revealed increased rCBF in language-related areas of cortex, viz., Wernicke's area and its right-sided homologous area as well as in Broca's area (left hemisphere), when subjects listened to narrative speech, compared to white noise (baseline). No significant rCBF differences were detected with this test during dichotic stimulation vs. white noise. A more sophisticated statistical method (factor analysis) disclosed patterns of functionally intercorrelated regions. The factor analysis reduced the highly intercorrelated rCBF measures from 28 regions of interest to a set of three independent factors. These factors accounted for 77% of the total variation in rCBF values. These three factors appeared to represent statistical analogues of independent brain networks involved in (I) auditory/linguistic, (II) attentional, and (III) visual imaging activity.
Vibration-Induced Regional Cerebral Blood Flow Responses in Normal Aging
Authors: Tempel Lee W. , Perlmutter Joel S.
Published: April 2011

Task-induced changes in regional CBF (rCBF) can be measured with positron emission tomography (PET) and provide a powerful tool to map brain function. Many studies using these techniques have investigated responses in healthy young subjects. Since many pathological conditions occur more commonly in older subjects, it is necessary to compare blood flow responses in these patients with appropriately age-matched controls. Furthermore, the effects of normal aging on such blood flow responses remain unknown. For both reasons, we designed this study to determine whether vibration-induced CBF responses change with advancing age in normals. CBF was measured with PET and bolus-administered H215O in 26 subjects from 20 to 72 years old (mean = 39; SD = 19). Regional responses were identified by subtraction-image analysis. Left and right hand vibration produced consistent responses in contralateral primary sensorimotor area (PSA) and supplementary motor area (SMA). Response magnitudes were compared to age by linear regression. There were no substantial relationships between age and responses to vibration for PSA or SMA (PSA r = −0.28, p = 0.054; SMA r = −0.33, p = 0.13). Power analysis demonstrates a high degree of confidence (99.7% for PSA and 87% for SMA) for detecting at least a moderate correlation ( r = 0.6) between response magnitude and age. We conclude that the rCBF responses to vibrotactile hand stimulation do not change with normal aging.
Anoxia-Induced Changes in Extracellular K+ and pH in Mammalian Central White Matter
Authors: Ransom Bruce R. , Walz Wolfgang , Davis Peter K. , Carlini Walter G.
Published: April 2011

In gray matter (GM), anoxia induces prominent extracellular ionic changes that are important in understanding the pathophysiology of this insult. White matter (WM) is also injured by anoxia but the accompanying changes in extracellular ions have not been studied. To provide such information, the time course and magnitude of anoxia-induced changes in extracellular K+ concentration ([K+]o) and extracellular pH (pHo) were measured in the isolated rat optic nerve, a representative central WM tract, using ion-selective microelectrodes. Anoxia produced less extreme changes in [K+]o and pHo in WM than are known to occur in GM; in WM during anoxia, the average maximum [K+]o was 14 ± 2.9 m M (bath [K+]o = 3 m M) and the average maximum acid shift was 0.31 ± 0.07 pH unit. The extracellular space volume rapidly decreased by ∼20% during anoxia. Excitability of the rat optic nerve, monitored as the amplitude of the supramaximal compound action potential, was lost in close temporal association with the increase in [K+]o Increasing the bath glucose concentration from 10 to 20 m M resulted in a much larger acid shift during anoxia (0.58 ± 0.08 pH unit) and a smaller average increase in [K+]o (9.2 ± 2.6 m M). The increased extracellular glucose concentration presumably provided more substrate for anaerobic metabolism, resulting in more extracellular lactate accumulation (although not directly measured) and a greater acid shift. Enhanced anaerobic metabolism during anoxia would provide energy for operation of ion pumps, including the sodium pump, that would result in smaller changes in [K+]o. These effects were probably responsible for the observation that the optic nerve showed significantly less damage after 60 min of anoxia in the presence of 20 m M glucose compared to 10 m M glucose. Under normoxic conditions, increasing bath K+ concentration to 30 m M (i.e., well beyond the level shown to occur with anoxia) for 60 min caused abrupt loss of excitability during the period of application but minimal change in the amplitude of the compound action potential following the period of exposure. The anoxia-induced increase in [K+]o, therefore, was not itself directly responsible for irreversible loss of optic nerve function. These observations indicate that major qualitative differences exist between mammalian GM and WM with regard to anoxia-induced extracellular ionic changes.