Cerebral activation, hostility, and cardiovascular control during mental stress.

OBJECTIVE: Hostility has been established as a risk factor for the development of coronary artery disease. Putatively pathogenic hemodynamic and neuroendocrine responses to psychological stressors are associated with hostility, but the cerebral effects of hostility and their relationship to these responses are unknown. This pilot study examined cardiovascular and cerebral blood flow responses to stress in subjects with high and low levels of trait hostility. METHODS: Regional cerebral blood flow was measured by single-photon emission computed tomography (SPECT) during a control condition and in response to mental arithmetic stress. RESULTS: The stressor was associated with reduced blood flow to the prefrontal cortex, and this reduction was greater in the high hostility subjects. CONCLUSION: These preliminary findings support the hypothesis that mental arithmetic stress is associated with reduced blood flow to prefrontal cortex, and that trait hostility is associated with a stronger effect.

Hippocampal pathology in schizophrenia: magnetic resonance imaging and spectroscopy studies.

The hippocampus is a site of previously reported structural and functional abnormalities in schizophrenia. We used magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) to measure gray matter volumes, the neuronal marker N-acetylaspartate (NAA), and the combination of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA), designated Glx. Measurements were obtained of the medial temporal lobe, centered on the hippocampus, in 10 male patients with schizophrenia (3 neuroleptic-medicated and 7 medication-free), and 10 matched normal volunteers. MRI volumetric measurements and MRS data obtained with short echo time (TE=20 ms) one-dimensional STEAM chemical shift imaging (CSI) on a GE 1.5 Tesla Signa system were analyzed. A laterality index ¿(L-R)/(L+R) was generated from the ratio of Glx to choline-containing compounds (Cho) to test asymmetry changes. Reliability of the MRS measures was assessed with five test-retest studies of healthy volunteers and showed coefficients of variation (CV) in the range of 36-44% for the MRS ratios and standard deviations (S.D.) of 0.15-0.17 for the laterality indices. The Glx/Cho laterality index showed a relative right-sided excess in this region in the patients (-0.23+/-0.20) compared to the controls (+0.06+/-0.20), which was not confounded by tissue composition or placement variability of the MRS voxels. Hippocampal volume deficit and asymmetry were not significant, and other MRS measures showed no differences between patients and controls. The preliminary finding of a lateralized abnormality in Glx is consistent with postmortem findings of asymmetric neurochemical temporal lobe abnormalities in schizophrenia.

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.

The effect of heterogeneity of lung structure on particle deposition in the rat lung.

Differences in particle deposition patterns between human and rat lungs may be attributed primarily to their differences in breathing patterns and airway morphology. Heterogeneity of lung structure is expected to impact acinar particle deposition in the rat. Two different morphometric models of the rat lung were used to compute particle deposition in the acinar airways: the multiple-path lung (MPL) model (Anjilvel and Asgharian, 1995, Fundam. Appl. Toxicol. 28, 41-50) with a fixed airway geometry, and the stochastic lung (SL) model (Koblinger and Hofmann, 1988, Anat. Rec. 221, 533-539) with a randomly selected branching structure. In the MPL model, identical acini with a symmetric subtree (Yeh et aL, 1979, Anat. Rec. 195, 483-492) were attached to each terminal bronchiole, while the respiratory airways in the SL model are represented by an asymmetric stochastic subtree derived from morphometric data on the Sprague-Dawley rat (Koblinger et al., 1995, J. Aerosol. Med. 8, 7-19). In addition to the original MPL and SL models, a hybrid lung model was also used, based on the MPL bronchial tree and the SL acinar structure. Total and regional deposition was calculated for a wide range of particle sizes under quiet and heavy breathing conditions. While mean total bronchial and acinar deposition fractions were similar for the three models, the SL and hybrid models predicted a substantial variation in particle deposition among different acini. The variances of acinar deposition in the MPL model were consistently much smaller than those for the SL and the hybrid lung model. The similarity of acinar deposition variations in the two latter models and their independence on the breathing pattern suggests that the heterogeneity of the acinar airway structure is primarily responsible for the heterogeneity of acinar particle deposition.

PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756.

NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.

Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil.

OBJECTIVE: Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]iomazenil. METHOD: They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences). RESULTS: The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution volume than comparison subjects in the frontal, anterior cingulate, and cerebellar cortices. Statistical parametric mapping revealed two large excursions in which the distribution volume in alcoholic patients was significantly lower than in comparison subjects: the anterior cingulate, extending into the right middle frontal gyrus, and the left occipital cortex. CONCLUSIONS: Benzodiazepine receptor distribution volume is significantly lower in several cortical regions and the cerebellum in alcoholic subjects than in healthy comparison subjects. These results are consistent with previous reports and might indicate either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism.

A multiple-path model of fiber deposition in the rat lung.

An asymmetric multiple-path model of particle deposition in the lung airways developed previously (S. Anjilvel and B. Asgharian, 1995, Fundam. Appl. Toxicol. 28, 41-50), was extended to calculate deposition of fibers in the rat lung by replacing the deposition efficiency expressions for particles with those of fibers. The effects of various parameters such as breathing parameters or fiber dimensions on deposition were studied. Fiber deposition fraction for one single breath was calculated per acini, lobe, and region of interest in the lung. The results were compared with one other model prediction and with data available in the literature. Good agreement between the model predictions and other studies was found.

Inertial and interceptional deposition of fibers in a bifurcating airway.

A computer model of a three-dimensional bifurcating airway was constructed in which the parent and daughter airways had different lengths but equal diameters. A diameter of 0.6 cm was chosen for the airways based on the third generation of Weibel's symmetric lung model. Different bifurcation angles of 60 degrees, 90 degrees, and 120 degrees were studied. Airflow fields in the airway were obtained by a finite-element method (FIDAP, Fluid Dynamics International, Evanston, IL) for Reynolds numbers of 500 and 1000, assuming uniform parent inlet velocities. The equations of motion for fiber transport in the airways were obtained, and deposition by the combined mechanisms of impaction and interception was incorporated. A computer code was developed that utilized the flow field data and calculated fiber transport in the airways using the equations of motion for fibers. Deposition efficiency was obtained by simulating a large number of fibers of various sizes. Fiber entering the daughter airways tended to orient themselves parallel to the flow. A site of enhanced deposition (or hot spot) was observed at the carina. The dominant parameter for the deposition was the fiber Stokes number. Flow Reynolds number and airway bifurcation angle were also found to affect the deposition.

A multiple-path model of particle deposition in the rat lung.

A multiple-path model of particle deposition in the entire rat lower respiratory tract was developed. Deposition in every branch of an asymmetric lung model was calculated using published analytic formulas for efficiencies of deposition by sedimentation, diffusion, and impaction. The conducting airway tree of the model included the entire set of airway measurements for the Long-Evans rat collected by Raabe et al. (1976). A model acinus defined by Yeh et al. (1979) was attached to each terminal bronchiole. Deposition was calculated for each acinus. Substantial variations in acinar deposition were predicted. These depended on inhaled particle size and tidal volume. The standard deviation in acinar dose was on the order of 0.2 times the average dose. Dose to some pulmonary acini was nearly twice the average acinar dose, suggesting that the geometry of the conducting airway tree of the rat lung may cause a fraction of pulmonary sites to sustain damage from inhaled particles at levels of exposure which cause no effect in the majority of the lung. The results represent a first step toward a complete model of inhaled particle deposition which assesses the effect of heterogeneity of lung structure on deposition at the level of individual airways.

Inhomogeneity of ventilatory unit volume and its effects on reactive gas uptake.

This study addressed the question of whether variations in the volume of alveoli and alveolar ducts forming single units of ventilation can significantly influence the distribution and uptake of inspired reactive gases. Quantitative serial section analyses of vascular perfusion-fixed rat lungs were used to determine the anatomic dead space proximal to specific ventilatory units as well as the gas volume of these ventilatory units. Three reconstructions, each consisting of ventilatory units distal to a specific bronchus, were carried out. The number of ventilatory units for each reconstruction varied from 26 to 71. The average ventilatory unit volume for the three reconstructions [0.53 +/- .03 (SE) mm3] was not significantly different from measurements based on random sampling. The distribution of ventilatory unit volume was diverse, with 15% of the population having a volume less than 0.3 mm3 and 9% of the population having a volume greater than 1.0 mm3. For a gas of relatively low reactivity (e.g., oxygen) the predicted oxygen uptake per unit surface area did not vary significantly between ventilatory units. The predicted oxygen uptake was approximately 92% of the uptake in the absence of gradients in oxygen concentration between ventilatory units. For a highly reactive gas (e.g., ozone), the predicted uptake per unit surface area in the proximal portions of larger ventilatory units was significantly greater than the average uptake. These results suggest that focal areas of injury likely result from exposure to inhaled reactive gases.

Approximation of surfaces in quantitative 3-D reconstructions.

In serial section reconstructions a series of planar profiles are taken representing curves on the surface of the structure to be reconstructed. For a number of quantitative serial section methods, approximation of a surface is done by the formation of tiles between points of adjacent profiles. As generally proposed, finding this approximation has been difficult due to the inordinately large number of possible solutions resulting from different combinations of tiles between points. Current algorithms have either applied heuristic criteria to force the formation of only one solution or have searched all acceptable combinations for one that minimizes some cost function. The algorithm presented has been developed to choose the tiling which minimizes the estimated error when the tile approximation of the surface is used in subsequent quantitative algorithm such as the calculation of surface area.