Peter Lund Madsen

Persistent Resetting of the Cerebral Oxygen/Glucose Uptake Ratio by Brain Activation: Evidence Obtained with the Kety—Schmidt Technique:

Global cerebral blood flow (CBF), global cerebral metabolic rates for oxygen (CMRO2), and for glucose (CMRglc), and lactate efflux were measured during rest and during cerebral activation induced by the Wisconsin card sorting test. Measurements were performed in healthy volunteers using the Kety–Schmidt technique. Global CMRO2 was unchanged during cerebral activation, whereas global CBF and global CMRglc both increased by 12%, reducing the molar ratio of oxygen to glucose consumption from 6.0 during baseline conditions to 5.4 during activation. Data obtained in the period following cerebral activation showed that the activation-induced resetting of the relation between CMRglc and CMRO2 persisted virtually unaltered for ≥40 min after the mental activation task was terminated. The activation-induced increase in cerebral lactate efflux measured over the same time period accounted for only a small fraction of the activation-induced excess glucose uptake. These data confirm earlier reports that brain activation can induce resetting of the cerebral oxygen/glucose consumption ratio, and indicate that the resetting persists for a long period after cerebral activation has been terminated and physiologic stress indicators returned to baseline values. Activation-induced resetting of the cerebral oxygen/glucose uptake ratio is not necessarily accounted for by increased lactate production from nonoxidative glucose metabolism.

Cerebral Oxygen/Glucose Ratio is Low during Sensory Stimulation and Rises above Normal during Recovery: Excess Glucose Consumption during Stimulation is Not Accounted for by Lactate Efflux from or Accumulation in Brain Tissue

Functional activation stimulates CMRglc more than CMRO2 and raises lactate levels in brain. This has been interpreted as evidence that brain work is supported mainly by energy derived from anaerobic glycolysis. To determine if lactate production accounts for the “excess” glucose consumption, cerebral arteriovenous differences were measured in conscious rats before, during, and 15 minutes after sensory stimulation; the brains were rapidly frozen in situ immediately after completion of blood sampling and assayed for metabolite levels. The molar O2/glucose uptake ratio fell from 6.1 ± 1.1 (mean ± SD) before stimulation to 5.0 ± 1.1 during activation (P < 0.01); lactate efflux from brain to blood was detectable at rest but not during stimulation. By 15 minutes after activation, O2 and lactate arteriovenous differences normalized, whereas that for glucose fell, causing the O2/glucose ratio to rise above preactivation levels to 7.7 ± 2.6 (P < 0.01). Brain glucose levels remained stable through all stages of activity. Brain lactate levels nearly doubled during stimulation but normalized within 15 minutes of recovery. Brain glycogen content fell during activation and declined further during recovery. These results indicate that brain glucose metabolism is not in a steady state during and shortly after activation. Furthermore, efflux from and increased content of lactate in the brain tissue accounted for less than 54% of the “excess” glucose used during stimulation, indicating that a shift to anaerobic glycolysis does not fully explain the disproportionately greater increases in CMRglc above that of CMRO2 in functionally activated brain. These results also suggest that the apparent dissociation between glucose utilization and O2 consumption during functional activation reflects only a temporal displacement; during activation, glycolysis increases more than oxidative metabolism, leading to accumulation of products in intermediary metabolic pools that are subsequently consumed and oxidized during recovery.

Human regional cerebral blood flow during rapid-eye-movement sleep.

Owing to the coupling between CBF and neuronal activity, regional CBF is a reflection of neural activity in different brain regions. In this study we measured regional CBF during polysomnographically well-defined rapid-eye-movement (REM) sleep by the use of single photon emission computerized tomography and the new tracer 99mTc-dl-hexamethylpropyleneamine. Eleven healthy volunteers aged between 22 and 27 years were studied. CBF was measured on separate nights during REM sleep and during EEG-verified wakefulness. On awakening from REM sleep, all subjects reported visual dreams. During REM sleep CBF increased by 4% (p < 0.01) in the associative visual area, while it decreased by 9% (p < 0.01) in the inferior frontal cortex. The CBF increase in the associative visual area suggests that activation of cerebral structures processing complex visual material is correlated to visual dream experiences. On the other hand, the reduced involvement of the inferior frontal cortex observed during REM sleep might explain the poor temporal organization and bizarreness often experienced in dreams.

Average Blood Flow and Oxygen Uptake in the Human Brain During Resting Wakefulness: a Critical Appraisal of the Kety-Schmidt Technique

The Kety–Schmidt technique can be regarded as the reference method for measurement of global average cerebral blood flow (average CBF) and global average cerebral metabolic rate of oxygen (average CMRO2). However, in the practical application of the method, diffusion equilibrium for inert gas tracer between the brain and its venous blood is not reached. As a consequence, normal values for CBF and CMRO2 of 54 ml 100 g−1 min−1 and 3.5 ml 100 g−1 min−1 obtained with the Kety–Schmidt technique are an overestimation of the true values. Using the Kety–Schmidt technique we have performed 57 measurements of CBF and CMRO2 during EEG-verified wakeful rest in young normal adults. In order to estimate the equilibrium values for CBF and CMRO2, a simple computer-based simulation model was employed to quantitate the systematic overestimation caused by incomplete tracer equilibrium. When correcting the measured data, we find that the true average values for CBF and CMRO2 in the healthy young adult are ∼46 ml 100 g−1 min−1 and ∼3.0 ml 100 g−1 min−1. Previous studies have suggested that some of the variation in CMRO2 values could be ascribed to differences in cerebral venous anatomy. However in the present study, no correlation between CMRO2 and cerebral venous anatomy as imaged by magnetic resonance angiography could be established. Our data show that the interindividual variation of CMRO2 is 11% (coefficient of variation).

Regional cerebral blood flow during light sleep--a H(2)(15)O-PET study.

This is the first report on the distribution of regional cerebral blood flow (rCBF) changes during stage‐1 sleep or somnolence. Two hypotheses were tested: (A) that rCBF differed between the awake relaxed state and stage‐1 sleep, (B) that hypnagogic hallucinations frequently experienced at sleep onset would be accompanied by measurable changes in rCBF using positron emission tomography (PET). Eight subjects were PET‐scanned with 15O‐labeled water injection in three conditions: awake, stage‐1 sleep with reportable experiences and stage‐1 sleep without reportable experiences. Electroencephalography (EEG) was performed continuously during the experiment. Sleep interviews were performed after each scan. The EEG was scored blindly to determine sleep stage. The sleep interviews revealed a substantial increase in how unrealistic and how leaping the thoughts were during stage‐1 sleep. During sleep there was a relative flow increase in the occipital lobes and a relative flow decrease in the bilateral cerebellum, the bilateral posterior parietal cortex, the right premotor cortex and the left thalamus. Hypnagogic experiences seemed not to be associated with any relative flow changes. The topography of the occipital activation during stage‐1 sleep supports a hypothesis of this state being a state of imagery. The rCBF decreases in premotor cortex, thalamus and cerebellum could be indicative of a general decline in preparedness for goal directed action during stage‐1 sleep. Stage‐1 sleep seems more similar to other forms of altered awareness, for example, relaxation meditation than to deeper sleep stages. We are of the opinion that stage‐1 sleep represents the dreaming state of wakefulness, while rapid eye movement (REM) sleep reflects the dreaming state of the unaware, sleeping brain.

Activation-Induced Resetting of Cerebral Oxygen and Glucose Uptake in the Rat

In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial—venous differences. During baseline conditions, rats were kept in a closed box designed to minimize interference. During baseline conditions CBF was 1.08 ± 0.25 mL·g−1·minute−1, and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL·g−1·minute−1. During activation cerebral glucose uptake increased disproportionately to cerebral oxygen uptake, and the cerebral oxygen to glucose uptake ratio was 4.2. The accumulated excess glucose uptake during 6 minutes of activation amounted to 2.4 μmol/g. Activation was terminated by closure of the sheltering box. In the postactivation period, the cerebral oxygen to glucose uptake ratio rose to a maximum of 6.4. This response is exactly opposite to the excess cerebral glucose uptake observed during activation.

Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2)

We measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) during light sleep (stage 2) in 8 young healthy volunteers using the Kety-Schmidt technique with 133Xe as the inert gas. Measurements were performed during wakefulness and light sleep as verified by standard polysomnography. Unlike our previous study in man showing a highly significant 25% decrease in CMRO2 during deep sleep (stage 3-4) we found a modest but statistically significant decrease of 5% in CMRO2 during stage 2 sleep. Deep and light sleep are both characterized by an almost complete lack of mental activity. They differ in respect of arousal threshold as a stronger stimulus is required to awaken a subject from deep sleep as compared to light sleep. Our results suggest that during non-rapid eye movement sleep cerebral metabolism and thereby cerebral synaptic activity is correlated to cerebral readiness rather than to mental activity.

Calculation of the FDG Lumped Constant by Simultaneous Measurements of Global Glucose and FDG Metabolism in Humans

The lumped constant defined as the conversion factor between the net uptake of fluoro-2-deoxy-D-glucose (FDG) and glucose was calculated from global CMRglc and from positron emission tomography (PET) using FDG as tracer (CMRFDG). Fifteen healthy, normal volunteers (mean age 24 ± 4 years) were studied. Global CBF and CMRglc were measured with the Kety-Schmidt technique using 133Xe as tracer, and values were corrected for errors from incomplete diffusion equilibrium for inert gas tracer between brain tissue and cerebral venous blood. Measurements of CMRFDG were obtained with PET using the dynamic and single-scan methods and the K1–k3 model. Measurements with the Kety-Schmidt technique and PET-FDG were performed simultaneously. Global CBF was 47.1 ± 8.0 mL · 100 g−1 · min−1, and CMRglc was 22.8 ± 4.1 μmol · 100 g−1 · min−1. No difference in CMRFDG was found with the two methods (17.8 ± 1.6 and 18.2 ± 1.3 μmol · 100 g−1 · min−1, dynamic and single scan methods, respectively). Accordingly, the lumped constant ranged from 0.80 ± 0.16 to 0.82 ± 0.15, with a mean value of 0.81 ± 0.15. The mean ratio between phosphorylation of FDG and glucose (k3*/k3) was 0.39 ± 0.25. The discrepancy between the lumped constant determined in this study and previously obtained values can be explained partly by methodologic problems, and we conclude that most of the discrepancy results from previous overestimation of global CBF. Key Words: Positron emission tomography—18F-Fluro-deoxy-D-glucose—Lumped constant—Brain glucose metabolism.

The 18F-fluorodeoxyglucose Lumped Constant Determined in Human Brain From Extraction Fractions of 18F-fluorodeoxyglucose and Glucose

Quantification of regional cerebral glucose metabolism (CMRglc) using positron emission tomography and 18F-fluorodeoxyglucose (PET-FDG) requires knowledge of the correction factor between FDG and glucose net clearance, the FDG lumped constant (LC). Because diverging values for LC have been obtained, the authors reevaluated LC by measuring the ratio of the cerebral net extraction fractions of FDG (E*) and glucose (E) from arteriovenous cerebral measurements. Thirty subjects were studied (mean age = 25 ± 4 years): 12 during a programed infusion of FDG and 18 after a bolus injection of FDG. In the infusion study, LC was calculated as the ratio E*/E. In the bolus study, E* was calculated from the slope of a Patlak–Gjedde plot. Lumped constant was significantly smaller in the infusion study as compared with the bolus study (0.48 ± 0.16 vs. 0.81 ± 0.27, P < 0.001). In 4 subjects studied during continuous FDG infusion for 2.5 hours, LC decreased to 0.36 ± 0.11. These results suggest that the “steady-state” method underestimates LC because E* continues to decline because of significant labeled product. Further, the authors provide evidence for resetting of LC toward a greater value. The subsequent resetting of CMRglc provides a physiologically more meaningful estimate and allows for comparison of CMRglc values between different methodologies.

Evaluation of a 7.5 French pulmonary catheter for continuous monitoring of cerebral venous oxygen saturation.

We studied a 7.5 French Opticat fiberoptic catheter/Oximetrix computer system as a tool for continuous monitoring of oxygen saturation of jugular venous blood. Eight healthy volunteers had a catheter placed with the tip in the bulb of the right internal jugular vein. During baseline condition, hyperventilation, and rebreathing, jugular venous oxygen saturations ranging from 35 to 85% were obtained. Simultaneous with drawing a blood sample, the value obtained with the fiberoptic catheter was recorded. The oxygen saturation of the blood sample was analyzed in vitro using a bench oximeter. A total of 150 paired values was obtained. In 15 of these cases, the computer indicated that the intensity of the reflected light was insufficient. A difference of > 12% oxygen saturation between the paired values was obtained for all of these pairs. The regression coefficient for the remaining 135 data pairs was 0.95, the mean difference was -0.54%, and the limits of agreement were -9.5 to 8.4%. We conclude that the 7.5 French Opticat catheter is useful if values obtained during improper light intensity are excluded.