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Biomedical subjects

M E Raichle

Publications and source records attributed to M E Raichle.

At least 91 records · Page 5Linked to original sources
PubMed1989

Left striato-pallidal hyperactivity in schizophrenia. Part II: Phenomenology and thought disorder.

Our previous paper summarized abundant evidence that schizophrenic patients show forms of sensory and motor hemineglect compatible with a left striato-pallidal hyperactivity model of schizophrenia. In this paper we discuss how the model may also account for some of the cognitive and phenomenological aspects of this disorder. Hemineglect can be associated with pallidal hyperactivity through its mediation of the anterior attention system of the frontal lobe. We postulate that this same attentional deficit can also affect higher functions such as the control of language and thought by internal motivations. Many symptoms of schizophrenia can be explained as a form of hemineglect of these higher functions.

Arousal↗
PubMed1989

Hyperactivity of the left striato-pallidal projection. Part I: Lower level theory.

We have observed increased relative blood flow to the left globus pallidus and evidence for subtle forms of right-sided hemineglect in neuroleptic-naive schizophrenic patients. These findings occur in animals following certain lesions such as unilateral destruction of midbrain dopaminergic neurons, and are presumed to be due to left striato-pallidal hyperactivity. A survey of the literature reveals many similarities between animals with unilateral dopaminergic denervation and schizophrenic patients. It has previously been suggested that available evidence does not preclude the possibility that schizophrenic patients have something like a dopaminergic deficiency. Other studies demonstrate that neuroleptics reverse asymmetries in indices of dopamine turnover. A model based upon dopaminergic hemideficiency is outlined, and can potentially explain other abnormalities in schizophrenic patients including eye movement abnormalities and the link between temporal lobe epilepsy and psychosis. A companion article describes how this model can account for some of the phenomenological symptoms of psychosis.

Arousal↗
PubMed1989

Non-steady-state measurement of in vivo receptor binding with positron emission tomography: "dose-response" analysis.

We previously developed a non-steady-state technique using positron emission tomography (PET) and the radioligand 18F-spiperone (18F-SP) for the measurement of in vivo radioligand-receptor binding in brain. The purpose of this investigation is to determine the sensitivity of this method to alterations in the apparent number of available specific binding sites. Nine studies were performed on the same baboon. The animal was pretreated with varying doses of unlabeled SP (15-600 micrograms) to compete for specific binding sites. The experimental procedure included measurement of regional cerebral blood flow, cerebral blood volume, and the protein binding of 18F-SP in arterial blood. At least 3.5 hr after pretreatment, no-carrier-added 18F-SP (containing less than 3 micrograms SP) was administered intravenously. Sequential PET scans and measurements of arterial-blood radioactivity due to radioligand and its labeled metabolites continued for 3 hr. A 3-compartment model representing the in vivo behavior of radioligand was used to analyze the data. As expected, we found that an index of binding called the combined forward rate constant (which equals the product of the apparent maximum number of available specific binding sites and the association rate constant of radioligand for receptor) declined with increasing dose of unlabeled SP. Other estimated variables including the dissociation rate constant did not change. This demonstrates that our non-steady-state method for estimating radioligand-receptor binding kinetics can detect a decrease in the apparent number of available specific binding sites. This is an important step in the validation of this in vivo receptor binding assay and its subsequent application.

Animals↗
PubMed1988

Effect of carbon dioxide in acute mountain sickness: a rediscovery.

The effect of adding CO2 to inhaled air in six subjects with acute mountain sickness was investigated during a medical expedition to 5400 m.3% CO2 in ambient air increased ventilation and resulted in a rise in PaO2 of between 24% and 40%. There was a 9-28% increase in PaCO2 and a reduction of the respiratory alkalosis normally seen at high altitude. Symptoms of acute mountain sickness were rapidly relieved. In three subjects cerebral blood flow increased by 17-39%, so that oxygen delivery to the brain would have been considerably improved. This study confirms earlier suggestions of the beneficial effect of CO2 inhalation at high altitude.

Administration, Inhalation↗
PubMed1988

Nonoxidative glucose consumption during focal physiologic neural activity.

Brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with positron emission tomography, and a resting-state molar ratio of oxygen to glucose consumption of 4.1:1 was obtained. Physiological neural activity, however, increased glucose uptake and blood flow much more (51 and 50 percent, respectively) than oxygen consumption (5 percent) and produced a molar ratio for the increases of 0.4:1. Transient increases in neural activity cause a tissue uptake of glucose in excess of that consumed by oxidative metabolism, acutely consume much less energy than previously believed, and regulate local blood flow for purposes other than oxidative metabolism.

Brain↗
PubMed1988

Localization of cognitive operations in the human brain.

The human brain localizes mental operations of the kind posited by cognitive theories. These local computations are integrated in the performance of cognitive tasks such as reading. To support this general hypothesis, new data from neural imaging studies of word reading are related to results of studies on normal subjects and patients with lesions. Further support comes from studies in mental imagery, timing, and memory.

Attention↗
PubMed1988

N-(3-[18F]fluoropropyl)-spiperone: the preferred 18F labeled spiperone analog for positron emission tomographic studies of the dopamine receptor.

The ligands currently used for PET studies of the dopamine receptor are fluorine-18-labeled spiperone (FSp) and carbon-11 or fluorine-18-labeled N-methyl-spiperone. All three of these ligands have drawbacks in either their chemical preparation or their biological behavior. We have previously prepared a series of N-fluoroalkyl-spiperone derivatives which are simple to prepare in high radiochemical yield. N-[18F]fluoropropyl-spiperone (3-F-Pr-Sp) and N-[18F]fluoroethyl-spiperone (2-F-Et-Sp) were the most promising ligands. In vitro competitive binding studies showed affinities for the dopamine receptor of 3-F-Pr-Sp greater than FSp greater than 2-F-Et-Sp. Brain extraction studies in a primate model showed that FSp, 2-F-Et-Sp, and 3-F-Pr-Sp were not completely extracted by the brain. High bone uptake and kidney clearance was observed with 3-F-Pr-Sp, while 2-F-Et-Sp cleared through the intestine in rats. This is in contrast to FSp where clearance is through the kidney. Studies to evaluate the extraction of metabolites in the brain were carried out by administering large doses (10 mCi) of FSp, 2-F-Et-Sp and 3-F-Pr-Sp to rats and reinjecting the metabolites in blood into other rats. These experiments showed that less than 0.02% of the metabolites from FSp and 3-F-Pr-Sp entered the brain, while 0.5% of the metabolites from 2-F-Et-Sp entered the brain. The majority of the activity present in the cerebellum after the administration of 2-F-Et-Sp is metabolites; therefore 2-F-Et-Sp is unsuitable for PET imaging studies. PET imaging studies in baboons and in one normal human volunteer with 3-F-Pr-Sp showed a high striatum-to-cerebellum ratio, showing that 3-F-Pr-Sp can replace ligands currently in use to study dopamine receptors.

Animals↗
PubMed1988

Enhanced detection of focal brain responses using intersubject averaging and change-distribution analysis of subtracted PET images.

Intersubject averaging and change-distribution analysis of subtracted positron emission tomographic (PET) images were developed and tested. The purpose of these techniques is to increase the sensitivity and objectivity of functional mapping of the human brain with PET. To permit image averaging, all primary tomographic images were converted to anatomically standardized three-dimensional images using stereotactic anatomical localization and interslice interpolation. Image noise, measured in control-minus-control subtractions, was strongly suppressed by averaging. Signal-to-noise ratio, measured in stimulus-minus-control subtractions (hand vibration minus eyes-closed rest), rose steadily with averaging, confirming the accuracy of our method of anatomical standardization. Distribution analysis of CBF change images (outlier detection by gamma-2 statistic) was assessed as an omnibus test for state-dependent changes in regional neuronal activity. Sensitivity in detecting the somatosensory response rose steadily with averaging, increasing from 50% in individual images to 100% when three or more images were averaged. Specificity was 100% at all averaging levels. Although described here as a technique for functional brain mapping with H2(15O) CBF images, image averaging, and change-distribution analysis are more generally applicable techniques, not limited to a single purpose or tracer.

Adolescent↗
PubMed1988

Regional correction of positron emission tomography data for the effects of cerebral atrophy.

Given the low spatial resolution of positron emission tomography (PET), regional measurements of neural tissue are often inaccurate because of the presence of non-neural elements and to mixtures of different tissue types within the volume of space influencing the measurements. These effects are significant in scans of brains both with and without atrophy, but are particularly significant when comparing measurements of brains with atrophy with those of normals, as is typically done in studies of aging and dementia. Previous attempts to correct for cerebral atrophy have been limited to global measurements. Using computer simulations, we illustrate the effects of atrophy and describe a method for correcting regional PET data to represent units of actual neural tissue volume.

Atrophy↗
PubMed1988

The effect of carotid artery disease on the cerebrovascular response to physiologic stimulation.

Eight of 16 patients with severe carotid artery disease, but no evidence of functional or structural brain damage, had abnormal regional cerebral blood flow (rCBF) responses to physiologic stimulation of sensorimotor cortex (unilateral reduction in six, abnormal diffuse increase in two). Thus, in patients with cerebrovascular disease the rCBF responses during physiologic tasks may not be reliable indicators of local neuronal activity.

Brain↗
PubMed1987

Radiolabeled hypoxic cell sensitizers: tracers for assessment of ischemia.

Hypoxic, non-functional, but viable, tissue may exist in heart and brain following an arterial occlusion. Identification of such tissue in vivo is crucial to the development of effective treatment strategies. It has been suggested that certain compounds capable of sensitizing hypoxic tumor cells to killing by x-rays (i.e., misonidazole) might serve as in vivo markers of hypoxic tissue in ischemic myocardium or brain if properly radiolabeled. To this end we have radiolabeled two fluorinated analogs of nitroimidazole based hypoxic cell sensitizers with the 110 minute half-lived positron-emitting fluorine-18. The ability of these tracers to quantitate the presence of hypoxic tissue has been studied in a gerbil stroke model. The in vivo uptake of one of these tracers [F-18]-fluoronormethyoxymisonidazole is dependent on the extent of tissue hypoxia, and thus, appears to have potential as a diagnostic indicator of non-functional but viable tissue when the tracer is used in conjunction with positron emission tomography.

Animals↗
PubMed1987

Positron emission tomographic measurement of cerebral blood flow and permeability-surface area product of water using [15O]water and [11C]butanol.

We have previously adapted Kety's tissue autoradiographic method for measuring regional CBF in laboratory animals to the measurement of CBF in humans with positron emission tomography (PET) and H2(15)O. Because this model assumes diffusion equilibrium between tissue and venous blood, the use of a diffusion-limited tracer, such as H2(15)O, may lead to an underestimation of CBF. We therefore validated the use of [11C]butanol as an alternative freely diffusible tracer for PET. We then used it in humans to determine the underestimation of CBF that occurs with H2(15)O, and thereby were able to calculate the extraction Ew and permeability-surface area product PSw of H2(15)O. Measurements of the permeability of rhesus monkey brain to [11C]butanol, obtained by means of an intracarotid injection, external detection technique, demonstrated that this tracer is freely diffusible up to a CBF of at least 170 ml/min-100 g. CBF measured in baboons with the PET autoradiographic method and [11C]butanol was then compared with CBF measured in the same animals with a standard residue detection method. An excellent correspondence was obtained between both of these measurements. Finally, paired PET measurements of CBF were made with both H2(15)O and [11C]butanol in 17 normal human subjects. Average global CBF was significantly greater when measured with [11C]butanol (53.1 ml/min-100 g) than with H2(15)O (44.4 ml/min-100 g). Average global Ew was 0.84 and global PSw was 104 ml/min-100 g. Regional measurements showed a linear relationship between local PSw and CBF, while Ew was relatively uniform throughout the brain. Simulations were used to determine the potential error associated with the use of an incorrect value for the brain-blood partition coefficient for [11C]butanol and to calculate the effect of tissue heterogeneity and errors in flow measurement on the calculation of PSw.

Adolescent↗
PubMed1987

Cerebral blood volume measured with inhaled C15O and positron emission tomography.

Local cerebral blood volume (CBV) has been measured previously with inhaled 11CO and positron emission tomography (PET). The model used assumes that equilibrium in tracer concentration has occurred between arterial and systemic venous blood before the PET measurement is made. To verify that this model may be used with the much shorter half-lived C15O, we have simultaneously measured arterial and venous blood radioactivity following C15O inhalation. Equilibrium occurred 95 +/- 39 s after inhalation (n = 7). If the PET measurement is commenced prior to arteriovenous equilibrium, significant errors occur in calculated CBV. These data indicate that C15O may be used as a tracer for CBV measurement provided that emission data collection commences at approximately 120 s after inhalation. Strict quality control measures must be maintained to minimize the contamination of administered C15O with 15O-labeled CO2.

Administration, Inhalation↗
PubMed1987

Tracer-kinetic models for measuring cerebral blood flow using externally detected radiotracers.

All tracer-kinetic models currently employed with positron-emission tomography (PET) are based on compartmental assumptions. Our first indication that a compartmental model might suffer from severe limitations in certain circumstances when used with PET occurred when we implemented the Kety tissue-autoradiography technique for measuring CBF and observed that the resulting CBF estimates, rather than remaining constant (to within predictable statistical uncertainty) as expected, fell with increasing scan duration T when T greater than 1 min. After ruling out other explanations, we concluded that a one-compartment model does not possess sufficient realism for adequately describing the movement of labeled water in brain. This article recounts our search for more realistic substitute models. We give our derivations and results for the residue-detection impulse responses for unit capillary-tissue systems of our two candidate distributed-parameter models. In a sequence of trials beginning with the simplest, we tested four progressively more detailed candidate models against data from appropriate residue-detection experiments. In these, we generated high-temporal-resolution counting-rate data reflecting the history of radiolabeled-water uptake and washout in the brains of rhesus monkeys. We describe our treatment of the data to yield model-independent empirical values of CBF and of other parameters. By substituting these into our trial-model functions, we were able to make direct comparisons of the model predictions with the experimental dynamic counting-rate histories, confirming that our reservations concerning the one-compartment model were well founded and obliging us to reject two others. We conclude that a two-barrier distributed-parameter model has the potential of serving as a substitute for the Kety model in PET measurements of CBF in patients, especially when scan durations for T greater than 1 min are desired.

Animals↗
PubMed1987

Regional asymmetries of cerebral blood flow, blood volume, and oxygen utilization and extraction in normal subjects.

Positron emission tomography (PET) and 15O-labeled radiotracers were used to measure regional CBF, cerebral blood volume (CBV), CMRO2, and oxygen extraction in 32 right-handed subjects at rest. Mean left hemispheric CBF (46.2 +/- 6.8 ml/100 g/min) and CMRO2 (2.60 +/- 0.59 ml/100 g/min) were significantly lower than right hemispheric values (47.4 +/- 7.2 and 2.66 +/- 0.61 ml/100 g/min, respectively; p less than 0.0001 for both), whereas left and right hemispheric CBV and oxygen extraction were not significantly different. We further investigated these asymmetries by comparing left- and right-sided values for specific cortical and subcortical regions. We found that left-sided CBF and CMRO2 were significantly lower than right-sided values for sensorimotor, occipital, and superior temporal regions, whereas only left-sided CBF values were lower for anterior cingulum. CBV was asymmetric for the anterior cingulate and mid-frontal regions, and oxygen extraction was asymmetric for the sensorimotor area. No asymmetries were observed in inferior parietal cortex, thalamus, putamen, or pallidum. Knowledge of these normal physiological asymmetries is essential for proper interpretation of PET studies of physiology and pathology. Furthermore, the ability to detect asymmetries with PET may lead to a better understanding of the lateralization of specific functions in the human brain.

Adult↗
PubMed1987

Brain blood volume, flow, and oxygen utilization measured with 15O radiotracers and positron emission tomography: revised metabolic computations.

We have revised our methods for calculating regional blood volume, flow, oxygen extraction, and oxygen utilization from positron emission tomography data obtained using 15O-labeled radiotracers. These revisions include radioactive decay explicitly within the model equations instead of requiring all measured activity to be corrected for decay prior to incorporation in the equations. The revised equations yield small but significant differences in the computed values.

Blood Volume↗