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Oligemia is blood flow reduction without acute tissue damage that occurs in shock, migraine, and stroke penumbra. We developed a mouse model of oligemia by lowering mean arterial pressure to 30-40 mm Hg, resulting in a 50% reduction in cerebral blood flow as measured by laser Doppler, and reperfusing the blood after 30 min. Control experiments included anesthesia-only and surgery without blood withdrawal. Using immunohistochemistry, we localized the transcription factors Nrf2, which regulates expression of antioxidant and detoxification protein, and c-Fos, a marker of neuronal activation. Nrf2 was found only in oligemia mice and was localized in neurons of the cingulate cortex and cerebellar Purkinje cells. By contrast, c-Fos was found widely expressed in both groups and was localized in neurons in regions associated with response to stress, immunomodulation, and fluid homeostasis, including the periaqueductal gray and periventricular nucleus. These data indicate that c-Fos expression occurs as a result of surgical stress, but Nrf-2 upregulation is specific to oligemia. The CLONTECH Atlas 1.2 Mouse Array was used to assess genes that were up or down-regulated in oligemia versus surgery controls. Of 1176 genes, 29 differed between oligemia and surgery groups. Upregulation of oxidative stress induced (OSI) protein, heat shock protein (HSP) 84 and transthyretin (TTR) precursor in the oligemia group was confirmed with RT-PCR. The expression of HSP 84, transthyretin precursor, and OSI genes adds further evidence that oligemia induces an oxidative stress response in the brain.

Background and Purpose: Headache is the most common neurologic symptom following minor closed head injury. There is often a lack of objective evidence supporting an organic basis of cerebral pathology in these cases. This pilot study considers the possibility of alterations in cerebral blood flow, indicating evidence of an organic disorder in posttraumatic headache., Methods: Regional cerebral blood flow studies of 35 patients with chronic posttraumatic headache (PTH) (International Headache Society criteria), identified retrospectively from our cerebral blood flow data base, were compared with those of 49 nonheadache controls and 92 migraineurs (Ad Hoc Committee criteria). Regional cerebral blood flow (initial slope index method) was measured using the xenon Xe 133 inhalation technique., Results: Compared to migraineurs and controls, and after adjusting for differences (analysis of covariance) in baseline variables such as blood pressure, hematocrit, and PCO2, patients with PTH had: (1) significantly lower mean initial slope indices (P < 0.001, P = 0.002, respectively); (2) regional interhemispheric flow differences (rIFD), with higher distribution of regional asymmetrical probe pairs (rIFD > or = 7%: P[PTH versus control] = 0.006, P[PTH versus migraine] = 0.016: rIFD > or = 10%; P[PTH versus control] = 0.011, P[PTH versus migraine] = 0.003); and (3) more hemispheric asymmetries (P[PTH versus control] = 0.023, P[PTH versus migraine] = 0.57). Lower mean initial slope indices and hemispheric asymmetry (mean interhemispheric flow difference > or = 3.2%) predicted PTH over control (P = 0.023 and 0.002, respectively). Lower mean initial slope indices predicted PTH over migraine (P = 0.002)., Conclusions: Patients with PTH have reduced regional cerebral blood flow, and regional and hemispheric asymmetries. These cerebral hemodynamic alterations support an organic basis to chronic posttraumatic headache.

We wished to determine in asymptomatic hypertensive patients with > or = 70% stenosis of an internal carotid artery the change in regional cerebral blood flow (rCBF) produced by ramipril and enalapril and to evaluate the influence of age on drug-induced changes in rCBF. In a prospective, randomized, single-blind, placebo-controlled investigation, using the 133Xenon inhalation technique, we assessed baseline rCBF in 15 patients (9 men and 6 women aged 60-79 years) after a 24-h antihypertensive drug-free period. All patients then received a single 5-mg oral dose of ramipril, enalapril, or placebo. rCBF was reassessed 2 h postdose. There was no significant change in the median rCBF in any of the three treatment groups. Neither did we observe any lateralization of BF to any specific cerebral region in any of the three groups. There were no observed or patient-reported adverse events (AE). Single 5-mg oral doses of either ramipril or enalapril did not decrease CBF significantly in asymptomatic hypertensive patients with > or = 70% stenosis of an internal carotid artery and are probably safe starting doses in such patients. In addition, this effect was not modified by age.

Study Objective: To determine the short-term effects of antihypertensive therapy on cerebral blood flow (CBF)., Design: Prospective, observational study., Setting: A university-affiliated teaching hospital., Patients: Twenty-four patients (age range 53-85 yrs) with chronic hypertension, nine of whom had carotid artery occlusive disease (CAOD)., Interventions: The CBF (xenon-133 inhalation technique) and blood pressure were measured before and at 60 minutes after administration of antihypertensive therapy., Measurements and Main Results: Age was inversely related to the change in CBF in patients with CAOD (p < 0.01). In all patients, the change in CBF after taking antihypertensive drugs was significantly inversely associated with baseline CBF (p < 0.01). Changes in regional CBF, measured by asymmetry scores, were significantly greater in patients with CAOD than in those without CAOD (p < 0.05)., Conclusions: Elderly patients with occlusive extracranial cerebrovascular disease are at risk of drug-induced changes in both mean and regional CBF, and may benefit from a CBF assessment before being prescribed antihypertensive therapy.

Background and Purpose: Transient neurological symptoms of brain stem or occipital lobe origin may be caused by transient ischemic attack in the vertebrobasilar territory (VB-TIA) or late-onset (or late-life) migraine accompaniment (LOMA). It is often clinically difficult to distinguish between VB-TIA and LOMA., Methods: Cerebral blood flow of 23 patients with VB-TIA, 24 with LOMA, and 28 age-matched control subjects was measured using the 133Xe inhalation regional cerebral blood flow (rCBF) technique., Results: After adjusting for differences in baseline variables such as blood pressure, hematocrit, and PCO2, patients with VB-TIA had (1) lower mean rCBF than control subjects (P < .003) as measured by the initial slope index method; (2) more frequent anterior rCBF asymmetries than control subjects and patients with LOMA (P < .03 for both comparisons); and (3) higher mean interhemispheric rCBF differences compared with patients with LOMA (P = .08) and control subjects (P < .02)., Conclusions: Regional CBF patterns in patients with VB-TIA and LOMA differ, with lower rCBF and more asymmetry of the anterior blood flows in patients with VB-TIA, probably reflecting the effects of stroke risk factors on the cerebral circulation. Patients with LOMA have rCBF patterns more closely resembling those of age-matched healthy subjects. rCBF measurements may assist in the clinical diagnosis of VB-TIA and late-onset migrainous events.

We have noninvasively produced low-resolution, quantitative nuclear magnetic resonance images of cerebral blood flow in 2-ml voxels in eight cats. Typical signal-to-noise of 4 to 1 was obtained in cerebral voxels in 16.5-s epochs. Mean flow during normocapnia (paCO2 = 39 +/- 4 mm Hg) and hypercapnia (paCO2 = 62 +/- 4 mm Hg) was 53 +/- 20 ml/100 g-min and 140 +/- 36 ml/100 g-min, respectively. Fast flows in normocapnia were 94 +/- 13 and 182 +/- 39 ml/100 g-min in hypercapnia. These results suggest that an atraumatic quantitative imaging assessment of cerebral perfusion may be possible in humans using these techniques.

Patients with carotid artery occlusive disease (CAOD) may be at increased risk of iatrogenic cerebral hypoperfusion. Using the 133xenon-inhalation technique, we evaluated the effects of enalapril on regional cerebral blood flow (CBF) in 14 patients with chronic hypertension, 7 with CAOD and 7 without CAOD (no CAOD). Regional CBF and blood pressure were measured before and 60 minutes after a single dose of enalapril. Changes in mean arterial pressure after enalapril were not significantly different between the two groups: CAOD -4.67 +/- 8.7 mm Hg, no CAOD -6.18 +/- 8.2 mm Hg. Changes in mean CBF after enalapril were also not statistically different: CAOD -1.0 +/- 3.9, no CAOD 1.0 +/- 2.8. In the CAOD group only, however, changes in CBF were significantly related to increasing age (r = -0.9253, p less than 0.01), such that in patients 65 years or older CBF tended to decrease, whereas in younger patients it increased. Elderly patients with CAOD may be at increased risk of iatrogenic cerebral hypoperfusion, and it may be appropriate to evaluate prospectively the effects of antihypertensive medications on CBF.

Dynamic cerebral blood flow (CBF) studies using acetazolamide or hypercapnia as a vasodilatory challenge have attempted to evaluate intracranial hemodynamics. We report two patients with asymptomatic internal carotid artery occlusion in whom the vasodilatory stimulus was a single oral dose of antihypertensive medication (prazosin hydrochloride or enalapril maleate). In both patients, changes in regional CBF occurred that were larger than those seen in nine normal controls. One patient experienced an improvement in regional CBF with a reduction in probe pair asymmetry. In the other patient, who had bilateral carotid artery disease, a decrease in regional CBF in all 16 probes (mean decrease 12 percent) and an accentuation of the predose asymmetry were observed. Both patients remained asymptomatic throughout the study. Assessing these effects on cerebral circulation may help identify patients at risk for iatrogenic focal cerebral ischemia and provide information regarding the functional status of the cerebral vasculature.

Background and Purpose: This study sought to determine the degree of agreement between asymmetries of neuropsychological functioning and nine methods of quantifying asymmetries of regional cerebral blood flow., Methods: The regional cerebral blood flow methods combined three markers of cerebral blood flow asymmetry (percent hemispheric difference, maximum percent probe-pair asymmetry, and number of probe-pair asymmetries) with three indexes of regional cerebral blood flow (fast compartment flow, initial slope index, and initial slope). Eleven patients with left hemispheric ischemic strokes and 13 with right hemispheric ischemic strokes were studied with the xenon-133 inhalation technique and neuropsychological tests., Results: Blind clinical judgments of neuropsychological asymmetry significantly correlated with all nine methods of cerebral blood flow asymmetry determination; correlations ranged from -0.42 to -0.77. Clinical judgment of asymmetry of neuropsychological functioning accurately predicted the hemisphere of lower flow in 71-92% of cases, depending on the method of cerebral blood flow asymmetry determination. Agreement between cerebral blood flow and neurobehavioral signs of asymmetry was greater for initial slope and initial slope index than for the fast flow index. The initial slope and initial slope index showed equally good agreement. The use of the number of asymmetrical probe pairs to detect cerebral blood flow asymmetries agreed less well with neurobehavioral asymmetry than did the other two markers studied., Conclusions: Both the initial slope index and the initial slope measures of cerebral blood flow are useful in predicting neuropsychological asymmetries, especially when the magnitude of the asymmetry is taken into account.

Techniques for the quantitative imaging assessment of cerebral blood flow are presented in a cat using 19F NMR imaging of trifluoromethane. The input function of the indicator was acquired noninvasively, while its uptake and clearance were followed in 2-cc volume voxels from images acquired at 67 s intervals. A single compartment model yielded normal cerebral blood flow estimates.

We studied trifluoromethane as a potential gaseous indicator in nuclear magnetic resonance measurements of cerebral blood flow. We considered the effects of trifluoromethane on cerebral blood flow in 17 cats and on the electroencephalogram and electrocardiogram in nine cats and compared these with the effects of the more toxic compound chlorodifluoromethane in five cats. Inhaled at 60%, trifluoromethane had no effect on cerebral blood flow, the cerebral metabolic rate for oxygen, or oxyhemoglobin content. At 70%, trifluoromethane sensitized the cats' hearts to epinephrine, but to a much lesser degree than 40% chlorodifluoromethane, and produced only moderate changes in cerebral electrical activity as measured by the electroencephalogram. We found trifluoromethane to be suitable for use in animals, but its toxicity needs to be studied further before it can be used in humans for the measurement of cerebral blood flow.

We employed fluorocarbon-23 (trifluoromethane) as a nuclear magnetic resonance gaseous indicator of cerebral blood flow in seven cats. Pulsed inhalation of this indicator and switching between two coils allowed the acquisition of both an arterial input and a cerebral response function, making possible multicompartmental curve fits to cerebral uptake and clearance data. The brain:blood partition coefficient for trifluoromethane was 0.9 for both gray and white matter. Fast-compartment blood flows were normal and showed appropriate CO2 reactivity. Slow-compartment blood flows did not demonstrate CO2 reactivity, probably because cranial as well as white-matter blood flows were lumped together in the slow compartment. Although cerebral blood flow was stable during administration of 60% trifluoromethane, the compound did prove to be a mild cardiac sensitizer to epinephrine in five cats.

Although asymmetric EEG abnormalities have been reported during the headache-free period in migraineurs, asymmetries of regional cerebral blood flow (rCBF) have not been studied. Headache-free rCBF values measured by 133Xe inhalation were lower in migraineurs than in controls. Interhemispheric CBF and regional (anterior versus posterior) CBF did not differ between the groups. When a novel scoring system was used to obtain a mean asymmetry index (MAI), the MAI of the classic/complicated group was significantly higher than that of the controls but not significantly different from that of the common migraine group. These data suggest that in the headache-free interval rCBF asymmetries, variable in location, exist in classic/complicated migraineurs. These rCBF changes may be related to the cause or the effect of the focal neurologic dysfunction that occurs during an attack in these patients.

We developed techniques to assess the utility of a nuclear magnetic resonance (NMR) indicator for cerebral blood flow studies in cats, using Freon-22 for the first candidate. A PIN-diode-switched NMR experiment allowed the acquisition of an arterial as well as a cerebral fluorine-19 signal proportional to concentration vs. time in a 1.89 T magnet. Mean +/- SD blood:brain partition coefficients for Freon-22 were estimated at 0.93 +/- 0.08 for gray matter and 0.77 +/- 0.12 for white matter. Using maximum-likelihood curve fitting, estimates of mean +/- SD resting cerebral blood flow were 50 +/- 19 ml/100 g-min for gray matter and 5.0 +/- 2.0 ml/100 g-min for white matter. Hypercapnia produced the expected increases in gray and white matter blood flow. The physiologic effects of Freon-22, including an increase in cerebral blood flow itself with administration of 40% by volume, may limit its use as an indicator. Nevertheless, the NMR techniques described demonstrate the feasibility of fluorine-19-labeled compounds as cerebral blood flow indicators and the promise for their use in humans.

The effect of intravenous infusion of 10 per cent glycerol on regional cerebral blood flow (using hydrogen bolus and Xenon-133 (133Xe) clearance methods) and metabolism was investigated in 57 patients with recent cerebral infarction. Hemispheric blood flow (HBF) increased, together with increase in regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV), in foci of brain ischemia. Hemispheric oxygen consumption (HMIO2) decreased together with hemispheric respiratory quotient. Systemic blood levels of glucose, lactate, pyruvate, and triglycerides also increased after glycerol while free fatty acids (FFA) and inorganic phosphate (Pi) decreased. Hemispheric glucose consumption was unaltered after glycerol so that hemispheric glucose to oxygen ratio tended to rise. Pyruvate and lactate production by brain was unchanged. Glycerol moved across the blood brain barrier into brain and cerebrospinal fluid (CSF). Release of FFA and Pi from infarcted brain was reversed by glycerol. Total phosphate balance was maintained actoss brain both before and after glycerol infusion. Triglycerides increased in CSF after glycerol, originating either from cerebral blood or as a result of lipogenesis in cerebral tissue. The EEG Recording and neurological status of the patients improved despite decreased brain oxygen consumption. Results of this study suggest that after intravenous infusion of 10 per cent glycerol in patients with recent cerebral infarction, glycerol rapidly enters the CSF and brain compartments and favorably affects the stroke process in two ways: first, by redistribution of cerebral blood flow with increase in rCBF and rCBV in ischemic brain secondary to reduction in focal cerebral edema; and second glycerol may become an alternative source of energy either by being directly metabolized by the brain, or indirectly, by enhancing lipogenesis, or by both processes. Involvement of glycerol in lipogenesis with esterification to accumulated FFA might lead to improved coupling of oxidative phosphorylation, a hypothesis that fits the finding of improved neuronal function despite further decrease in cerebral hemispheric oxygen consumption.

We studied cerebral blood flow (CBF) with the 133xenon inhalation technique in 92 migraine patients (49 classic/complicated, 43 common), aged 19 to 85 years, in the headache-free period. We compared results to 49 control subjects, aged 22 to 80 years. CBF declined with age in both groups, but at a slower rate in migraine patients, a difference most pronounced in classic migraine. CBF was lower in migraine patients than in controls under 48 years of age. In addition, regional asymmetry of blood flow was found more frequently in young migraine patients than in controls. These results suggest that differences exist in cerebrovascular resistance tone in migraine patients, which may contribute to the threshold for a migraine attack and result in differing age-related changes in blood flow.

Adenosine 3',5'-cycle monophosphate (cyclic AMP) (0.5 mg/kg) was infused into the carotid artery of baboons anesthesized with sodium pentobarbital, causing a biphasic increase in cerebral blood flow (CBF) and reduction in cerebrovascular resistance (CVR) associated in each phase with stimulation of cerebral metabolism evidenced by increased cerebral oxygen consumption (COMRO2) and cerebral glucose consumption (CMRG1). Intracarotid dibutyryl cyclic AMP (0.5 mg/kg) caused a monophasic increase in CBF and reduction of CVR but failed to alter cerebral metabolism. This may be due to its rapid removal from the circulation with ineffective passage across the blood-brain barrier since intracisternal infusion of dibutyryl cyclic AMP caused sustained increase in CBF, CMRO2 and CMRG1 and reduction in CVR. Intracarotid AMP (0.4 mg/kg) and adenosine (0.3 mg/kg) caused an immediate and more marked increase in CBF and decrease in CVR unassociated with cerebral metabolic change making it unlikely that the observed effects of cyclic AMP can be attributed to its breakdown products. Cyclic AMP or its dibutyryl derivative may alter cerebral metabolism secondary to neuronal activation but increase in glucose/oxygen utilization ratio after intracarotid cyclic AMP and intracisternal dibutytyl cyclic AMP also suggests an influence on enzymatic regulation of glucose metabolism.

Regional cerebral blood flow (rCBF) asymmetries were studied in controls and patients with common and classic/complicated migraine using 133Xe inhalation with 8 homologously situated external collimators over each cerebral hemisphere. Migraine patients as a group more frequently had posterior rCBF asymmetries than controls (p less than 0.03). Although there were no differences in the number of anterior rCBF asymmetries, migraine patients had 2 or more asymmetric probe pairs more often than controls (p less than 0.02). The posterior rCBF asymmetries, consistent with the site of activation of many migraine attacks, may be related to more labile control of the cerebral circulation.

The metabolic effects of graded whole body hypothermia on complete global cerebral ischemia and recirculation was investigated in the cat. Hypothermia was induced to one of three levels prior to ischemia; T = 26.8 degrees +/- 0.5 degrees C (n = 4), T = 32.1 degrees +/- 0.2 degrees C (n = 5), and T = 34.6 degrees +/- 0.3 degrees C (n = 6), and maintained constant throughout 16 min of ischemia and 1.5-2 h of recirculation. Intracellular cerebral pH and relative concentrations of high-energy phosphate metabolites were continuously monitored, using in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. Except for the first 4 min of ischemia, no significant differences were detected in the response of adenylate intensities and intracellular pH to ischemia and recirculation between the hypothermic groups. The three hypothermic groups were then pooled into one group, and the data compared to previously published data from a normothermic group, T = 38.4 degrees +/- 0.6 degrees C (n = 14), and a hyperthermic group, T = 40.6 degrees +/- 0.2 degrees C (n = 9), subjected to the identical ischemic and NMR measurement protocols. The hypothermic animals exhibited a statistically significant reduction of cerebral intracellular acidosis, both during ischemia and recirculation, as well as a more rapid return of adenylate intensities during recirculation, compared to the normothermic or hyperthermic groups. The data thus suggest that mild hypothermia has an ameliorative affect on brain energy metabolism and intracellular pH under conditions of complete global cerebral ischemia and recirculation.

Cerebral hemispheric blood flow (HBF) and metabolism were measured before and after withdrawal of 20 to 30 ml of cerebrospinal fluid (CSF) over a 10-minute interval in eight patients with recent cerebral infarction and in four patients with Alzheimer's disease (AD). Immediately after CSF removal HBF decreased significantly in the AD group (-14%) but showed no significant change in the stroke group (-5%). There was rapid reduction in cerebral venous O2 content and some increase in cerebral venous PCO2 appearing within 60 seconds of CSF withdrawal, interpreted as a rapid reduction of cerebral blood flow (CBF) as judged by cerebral A-VO2 differences. The reduction in CBF was confirmed by the hydrogen clearance method. Reduction of CBF in response to lowering CSF pressure is presumably of neurogenic origin since it was rapid and occurred without changes in PaCO2 or MABP. Furthermore, measurement of HBF demonstrated that cerebral metabolism constant after CSF removal. It is postulated that in AD, reduction of HBF following CSF withdrawal is mediated by a disordered neurogenic veno-arterial vasoconstriction reflex which is stimulated by rapid reduction in CSF pressure (CSFP). In patients with stroke, when cerebral perfusion pressure is increased by lowering CSFP, CBF is maintained constant most likely by a physiological cerebral veno-arterial vasoconstrictive reflex. Apparently, this vasocontrictive reflex becomes excessive in Alzheimer's disease, possibly due to cerebral neurogenic imbalance.

Regional cerebral blood flow was measured by the 133Xe inhalation technique in patients with unilateral carotid occlusion, unilateral carotid occlusion and contralateral carotid stenosis, bilateral carotid occlusion, or normal arteriograms. After adjusting for age, sex, and history of stroke, hemispheric blood flow asymmetry was shown to be a predictor of unilateral carotid occlusion with a sensitivity of 80.6% and a specificity of 80.5%. Asymmetry of regional cerebral blood flow is useful in the assessment of patients with extracranial cerebrovascular disease.

The effect of intracarotid injection of serotonin (5-HT) on internal carotid artery flow and oxygen availability (O(2)a) of the cerebral cortex was studied in 10 baboons. Vasoconstriction occurred in the vascular bed of the territory supplied by the injected artery. After one middle cerebral artery was occluded the vasoconstrictor effect of 5-HT was more pronounced, particularly in the non-ischaemic hemisphere. The capacity of the cerebral vessels to provide collateral blood flow was reduced in both ischaemic and non-ischaemic areas of brain. As a result of focal cerebral ischaemia, 5-HT may accumulate in the brain and contribute to the progression of infarction.