Observations on the functional significance of regional cerebral blood flow in “resting” normal subjects

Regional Cerebral Blood Flow (rCBF) of 16 cortical regions was measured bilaterally in 22 healthy adults, with 4–8 repeated measurements per individual. All measurements were done during “rest”, i.e. with minimal external stimulation, by the Xe-133 inhalation method. The data are presented to serve as normal controls for research and clinical work, but more importantly because of their significance for neuropsychological theory. Some rCBF variance is shown to be meaningfully related to handedness, habituation processes, biological rhythms and possibly to regional lateral dominance. Further data and discussion relate to the possible role of frontal lobe structures during non-task-oriented cognition. Finally, data are interpreted as showing that regional functional coupling across the midline, in this situation, is inversely related to the characteristic level-of-processing associated with each area.     

Decreases in regional cerebral blood flow with normal aging

Positron emission tomographic (PET) images of regional cerebral blood flow (rCBF) from 30 normal, resting volunteers aged 30 to 85 years were analysed to identify areas where rCBF fell with age. Images were anatomically normalised, and a pixel-by-pixel linear regression was performed to remove differences in global CBF between subjects. Pixels at which rCBF then showed a significant (p less than 0.01) negative correlation with age were identified. They were displayed as a statistical parametric map (SPM) of correlations. We demonstrate an age-related decrease in adjusted rCBF in the cingulate, parahippocampal, superior temporal, medial frontal, and posterior parietal cortices bilaterally, and in the left insular and left posterior prefrontal cortices (omnibus significance, chi 2 = 2,291, p less than 0.0001, df = 1). Decreases in rCBF suggest a regionally specific loss of cerebral function with age. The affected areas were all limbic, or association, cortices. Therefore, these decreases may constitute the cerebral substrate of the cognitive changes that occur during normal aging.     

Abnormal resting regional cerebral blood flow patterns and their correlates in schizophrenia

Regional cerebral blood flow (CBF) was measured under resting conditions in 108 right-handed schizophrenic inpatients and a matched group of normal controls with the xenon 133 inhalation technique. Forty-six patients were free of all medication for two weeks. There were no significant differences in CBF to the two hemispheres. The patients showed a comparatively reduced anteroposterior (AP) gradient for CBF. Though there were no differences in frontal flow, the patients had higher flow to several postcentral brain regions, bilaterally. Cerebral blood flow in the patients correlated inversely with age and positively with carbon dioxide level. Women had higher flow than men. Duration of the illness was the only significant predictor of the reduced AP gradient in patients. Higher left temporal and right parietal flow were found to be the best discriminators between patients and controls. Mean hemispheric flow to both hemispheres and several brain regions correlated with the total score and the item, unusual thought content, of the Brief Psychiatric Rating Scale. There were no differences in regional CBF between medicated and unmedicated patients.     

Effect of worry on regional cerebral blood flow in nonanxious subjects

Several studies suggest that cognitive tasks attenuate activation of the limbic system by emotional stimuli. We investigated the possibility that worry would similarly inhibit the limbic system by examining its effects on regional cerebral blood flow (rCBF). Ten nonanxious volunteers underwent four scans within one session, using positron emission tomography (PET) with H(2)(15)O as tracer. The first two scans recorded emotionally neutral thinking induced after listening to tapes describing neutral statements. Preceding the third and fourth scans, subjects listened to the self-recorded tape describing their individual worries, were instructed to continue to worry, and were scanned 5 min later. Subjects rated themselves as more anxious during the worry scans but showed no significant heart interbeat or skin conductance changes. During worry, rCBF increases were found bilaterally in the medial fronto-orbital gyri and the right thalamus; rCBF decreases were found bilaterally in the hippocampi and amygdalae, in the right insula, the left and right inferior, middle and superior temporal gyri and the occipito-temporal gyri, the right inferior occipital gyrus and the left supramarginal gyrus. Activity of the left orbito-frontal gyrus was negatively correlated with activity of the amygdalae. The results support the hypothesis that worry-induced prefrontal activity suppresses affect-related subcortical regions.     

Effect of worry on regional cerebral blood flow in nonanxious subjects

Several studies suggest that cognitive tasks attenuate activation of the limbic system by emotional stimuli. We investigated the possibility that worry would similarly inhibit the limbic system by examining its effects on regional cerebral blood flow (rCBF). Ten nonanxious volunteers underwent four scans within one session, using positron emission tomography (PET) with H₂¹⁵O as tracer. The first two scans recorded emotionally neutral thinking induced after listening to tapes describing neutral statements. Preceding the third and fourth scans, subjects listened to the self-recorded tape describing their individual worries, were instructed to continue to worry, and were scanned 5 min later. Subjects rated themselves as more anxious during the worry scans but showed no significant heart interbeat or skin conductance changes. During worry, rCBF increases were found bilaterally in the medial fronto-orbital gyri and the right thalamus; rCBF decreases were found bilaterally in the hippocampi and amygdalae, in the right insula, the left and right inferior, middle and superior temporal gyri and the occipito-temporal gyri, the right inferior occipital gyrus and the left supramarginal gyrus. Activity of the left orbito-frontal gyrus was negatively correlated with activity of the amygdalae. The results support the hypothesis that worry-induced prefrontal activity suppresses affect-related subcortical regions.     

Vibration-induced regional cerebral blood flow responses in normal aging.

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 H2(15)O 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.     

Nicotine effects on regional cerebral blood flow in awake, resting tobacco smokers

The hypothesis for this research was that regional cerebral blood flow (rCBF) would increase following nasal nicotine administration to overnight abstinent tobacco smokers in relationship to the known brain distribution of nicotinic cholinergic receptors (nAChRs). Nine male and nine female healthy adult smokers were studied. They abstained overnight from tobacco products for 10 or more hours prior to study the next morning. Nicotine nasal spray was given in doses of 1-2.5 mg total with half in each nostril while the subject was awake and resting in a supine position. Oleoresin of pepper solution in a similar volume was used as an active placebo to control for the irritating effects of nicotine. Both substances were given single blind to the subjects. Positron emission tomography (PET) with H(2)(15)O was used to measure rCBF. The data from each subject volunteer were normalized to global activity to better assess regional brain changes. Both nasal nicotine and pepper spray produced similar increases in CBF in somesthetic area II, consistent with the irritant effects of both substances. The mean rCBF effects of nasal pepper were subtracted from those of nasal nicotine to determine the actions of nicotine alone. The latter produced increases in rCBF in the thalamus, pons, Brodman area 17 of the visual cortex, and cerebellum. Some brain areas that contain a large number of nAChRs, such as the thalamus, showed an increase in CBF. Other areas that have few nAChRs, such as the cerebellum, also showed an increase in relative CBF. The hippocampal/parahippocampal areas showed greater regional decreases (left) and lesser increases (right) in CBF that correlated with the increase in plasma arterial nicotine concentrations. The results obtained indicate complex primary and secondary effects of nicotine in which only some regional brain CBF changes correlate with the known distribution of nAChR. No gender differences were noted.     

A comparison of regional cerebral blood flow and middle cerebral artery blood flow velocities: simultaneous measurements in healthy subjects.

Blood flow velocities were measured in both middle cerebral arteries (MCAs) of 36 healthy subjects using transcranial Doppler ultrasound. Measurements were first made using a hand-held probe. Velocities were then studied bilaterally with fixed probes under resting conditions and during simultaneous regional CBF (rCBF) measurements. A significant (p < 0.05) positive correlation was found between MCA flow velocities and rCBF in the estimated perfusion territory of this artery. The correlation coefficient was highest when the measurements were performed simultaneously (p < 0.001) or when velocities recorded with a hand-held probe were adjusted to take into account the significant velocity increase induced by the CBF study situation. The increased velocities during CBF measurements cannot be fully explained by the moderate but significant PCO2 increase. Other possible mechanisms are increased blood flow due to mental activation or MCA vasoconstriction secondary to stimulation of the sympathetic nervous system. The effect of mental activation and PCO2 differences should therefore be considered when comparing the results of repeated velocity and CBF measurements.     

Self-rating depression scales correlated with regional cerebral blood flow in normal volunteers

In order to investigate possible influences of satisfaction with life on regional cerebral blood flow (rCBF), we studied the relationship between the self-rating depression scale and rCBF in normal middle-aged volunteers. A significant inverse correlation between SDS scores and the rCBF was observed. This result was independent of the influences of risk factors for stroke and age. Our findings suggest that satisfaction in daily life is important in maintaining active levels of brain metabolism.     

Resting regional cerebral blood flow and gambling task performance in cocaine-dependent subjects and healthy comparison subjects

OBJECTIVE: Orbitofrontal cortex regional cerebral blood flow (rCBF) is lower in cocaine-dependent subjects than in non-cocaine-dependent subjects. Performance on the Gambling Task, a test of decision making, is a putative correlate of orbitofrontal cortex activity and is reportedly impaired in drug-dependent subjects. The authors tested the hypothesis that lower Gambling Task scores would be associated with lower resting orbitofrontal cortex rCBF in cocaine-dependent subjects. METHOD: Fifteen healthy comparison subjects and 13 abstinent cocaine-dependent subjects underwent resting single photon emission computed tomography to measure rCBF, after which they completed the Gambling Task. RESULTS: Resting anterior cingulate and left dorsolateral prefrontal cortex rCBF significantly correlated with performance on the Gambling Task, but orbitofrontal cortex rCBF did not. Left dorsolateral prefrontal cortex rCBF was lower in the cocaine-dependent subjects than in the comparison subjects. CONCLUSIONS: Resting anterior cingulate and dorsolateral prefrontal cortex rCBF is significantly related to decision making, as assessed by the Gambling Task.     

Sex differences in brain-behavior relationships between verbal episodic memory and resting regional cerebral blood flow

Women have better verbal memory, and higher rates of resting regional cerebral blood flow (rCBF). This study examined whether there are also sex differences in the relationship between verbal episodic memory and resting rCBF. Twenty eight healthy right-handed volunteers (14 male, 14 female) underwent a neuropsychological evaluation and a Positron Emission Tomography (PET) (15)O-water study. Immediate and delayed recall was measured on the logical memory subtest of the Wechsler Memory Scale - Revised (WMS-R), and on the California Verbal Learning Test (CVLT). Resting rCBF (ml/100 g/min) was calculated for four frontal, four temporal, and four limbic regions of interest (ROIs). Women had better immediate recall on both WMS-R and CVLT tasks. Sex differences in rCBF were found for temporal lobe regions. Women had greater bilateral blood flow in a mid-temporal brain region. There were also sex differences in rCBF correlations with performance. Women produced positive correlations with rCBF laterality in the temporal pole. Greater relative CBF in the left temporal pole was associated with better WMS-R immediate and delayed recall in women only. These results suggest that trait differences in temporal pole brain-behavior relationships may relate to sex differences in verbal episodic memory.     

Effects of advancing age on regional cerebral blood flow. Studies in normal subjects and subjects with risk factors for atherothrombotic stroke.

Regional cerebral blood flow (rCBF) was measured by 133Xe inhalation in 46 normal volunteers, aged 21 to 63 years, and 14 neurologically asymptomatic subjects above age 40 with risk factors for atherothrombotic stroke, including hypertension, diabetes mellitus, and hyperlipidemia. In normal volunteers, there was diffuse and progresive reduction of gray matter flow and weight as well as increases of cerebrovascular resistance (CVR) with advancing age. Reduction of gray matter flow with advancing age appears to be attributed in part to neuronal atrophy and in part to cerebral arteriosclerosis. Regional increases of CVR and reduction of gray matter flow with advancing age were most evident in the middle cerebral arterial (MCA) distribution and were enhanced by the association of risk factors. Development of cerebral arteriosclerosis with age and/or risk factors appears to be most evident in MCA distribution.     

The dose-response relationship of acetazolamide on the cerebral blood flow in normal subjects

BACKGROUND: Acetazolamide (AA) is used to determine the cerebral vasoreactivity (CVR). To investigate whether the usually applied standard dose of 1 g intravenously will guarantee stable test conditions, the dose-response relationship of AA on cerebral blood flow (CBF) and cerebral blood flow velocity (CBFV) in normal subjects was determined. METHODS: In 59 healthy volunteers, rCBF was measured with a (133)Xenon inhalation device, and CBFV of the middle cerebral artery (MCA) by transcranial Doppler sonography. The first CBF measurement was taken at rest, the second 15 min after application of AA at a dosage of 5, 10, 13, 15 and 18 mg/kg of body weight, respectively. The CBFV (n = 52) of the middle cerebral artery on the side of the better temporal window was taken 25 min after application of AA 13 mg/kg. In order to determine the side effects of AA, statements of an additional 172 patients were included. RESULTS: A significant dosage dependence of AA on the CBF (fast flow and initial slope index) exists between 5 and 18 mg/kg intravenously. After AA 13 mg/kg, the fast flow increases from 70.8 +/- 10.8 to 110.1 +/- 13.5 ml/100 g/min, the initial slope index from 46.5 +/- 5.4 to 62.8 +/- 5.8, and the CBFV from 51.5 +/- 8.5 to 85.4 +/- 14.2 cm/s. The CVR of CBF and CBFV ascertained that way shows an age dependence equivalent to the situation at rest. Severity and frequency of side effects are dosage-dependent, significantly in part, but reversible without exception. CONCLUSION: For the determination of CVR of CBF with AA, a dosage related to body weight is required. The usually applied standard dose of 1 g intravenously is not sufficient for standardized test conditions. For evaluation of the results obtained, the apparent age dependence of CVR must be taken into account. Because of the severity of side effects occurring at a higher dose, an AA dosage of 13 mg/kg intravenously is recommended.     

Gender differences in regional cerebral blood flow

Gender differences have been noted in neurobehavioral studies. The 133xenon inhalation method for measuring regional cerebral blood flow (rCBF) can contribute to the understanding of the neural basis of gender differences in brain function. Few studies have examined gender differences in rCBF. In studies of normal subjects, women have higher rates of CBF than men, and this is related to age. Usually by the sixth decade men and women have similar flow rates. Fewer studies on rCBF in schizophrenia have examined sex differences. The pattern of higher flows for females maintains, but its correlates with gender differences in clinical as well as other parameters of brain function remain to be examined.     

Sex differences in regional cerebral blood flow

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

Hyperfrontality of regional cerebral blood flow distribution in normals during resting wakefulness: fact or artifact?

Earlier studies with two-dimensional measurement techniques consistently found higher frontal flow in normal subjects during resting wakefulness. However, this finding could not be confirmed by several laboratories with the more modern and technologically more sophisticated three-dimensional measurement techniques. This discrepancy can have strong implications for psychiatric research in which both types of techniques are frequently used. This article reviews the existing literature, discusses possible reasons for the discrepancy, and evaluates evidence from other sources on the activity of the frontal lobe during wakefulness.     

Regional cerebral blood flow in children--normal value and regional distribution of cerebral blood flow in childhood

The changes in CBF and rCBF through the entire age range include the rapid period in childhood was reported. Sixteen children between the ages of 1 and 15 and 14 adults were studied. These 30 subjects were either volunteers of out-patients without CT and EEG abnormalities. rCBF was measured by the 133Xe intravenous injection method using Varmet rCBF analyzer. Ther relationship between age and CBF, the correlation coefficient was calculated based on the regression equations and the regression curve with the highest correlation was chosen. For the analysis of rCBF, he mean rCBF values (ISI) of 3 channels corresponding to the frontal, temporal, parietal and occipital lobes were expressed as a percentage of the hemispheric CBF. The hemispheric blood flow (ISI and CBF gray) of children less than 5 years of age was approximately twice that found in adults. This value decreased rapidly with age and in the 10-15 years the blood flow was approximately 1.3-fold that of adults. Thereafter, there was a slow decrease and a negative correlation with age was found. The decrease showed the correlation on the following equations; y = 146.5 - 58.5 log x. (r = -0.903) for ISI and log y = 2.26 - 0.29 log x. (r = -0.881) for CBF gray, which was statistically significant. In contrast, the CBF white showed a slightly higher value in the 1-2 years old children, but thereafter the CBF did not show a notable decreases with age. Through the entire age range, a best fit for the Fw values was found with : y = 18.3 + 37.5/x. (r = 0.798), which was also statistically significant.