Olaf B. Paulson

Regional Cerebral Blood Flow in Man Determined by the Initial Slope of the Clearance of Intra-arterially Injected l33Xe

The regional cerebral blood flow can be calculated from the initial slope of the logarithmically displayed clearance curve following intra-arterial injection of 133Xe (rCBFinitial). The relationship between this parameter and the values resulting from stochastic (height over area) and compartmental analyses is extensively discussed. Experimental results demonstrate the theoretically expected close relationship between rCBFinitial and flow of gray substance (rCBFinitial 20% to 30% lower than Fg). It is shown how the cerebral clearance curve (normally biexponential) with low flow values becomes gradually monoexponential. Thus only flow of gray substance changes, whereas flow of white substance is independent of CBF∞. CBF10 was shown to overestimate CBF∞ with about 15% independent of the flow level. Correlation between CBFinitial and CBF10 was linear (r=0.98) at CBF10 values above 20 ml/100 gm/min. The CBFinitial normal value is found to be 64±9 ml/100 gm/min, and the interchannel coefficient of variation is 8.2%. A correction for remaining radioactivity from previous measurements is described. Using this, no significant difference was found between repeated resting state measurements. The CBFinitial-Paco2 relationship was found to be best described as exponential. In a group of patients with various intracranial diseases, 1 mm Hg change in Paco2 resulted in 4% change of CBFinitial quite independent of the CBFinitial level.

Determination of relative CMRO2 from CBF and BOLD changes: Significant increase of oxygen consumption rate during visual stimulation

The blood oxygenation level‐dependent (BOLD) effect in functional magnetic resonance imaging depends on at least partial uncoupling between cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) changes. By measuring CBF and BOLD simultaneously, the relative change in CMRO2 can be estimated during neural activity using a reference condition obtained with known CMRO2 change. In this work, nine subjects were studied at a magnetic field of 1.5 T; each subject underwent inhalation of a 5% carbon dioxide gas mixture as a reference and two visual stimulation studies. Relative CBF and BOLD signal changes were measured simultaneously using the flow‐sensitive alternating inversion recovery (FAIR) technique. During hypercapnia established by an end‐tidal CO2 increase of 1.46 kPa, CBF in the visual cortex increased by 47.3 ± 17.3% (mean ± SD; n = 9), and ΔR*2 was −0.478 ± 0.147 sec−1, which corresponds to BOLD signal change of 2.4 ± 0.7% with a gradient echo time of 50 msec. During black/white visual stimulation reversing at 8 Hz, regional CBF increase in the visual cortex was 43.6 ± 9.4% (n = 18), and ΔR*2 was −0.114 ± 0.086 sec−1, corresponding to a BOLD signal change of 0.6 ± 0.4%. Assuming that CMRO2 does not change during hypercapnia and that hemodynamic responses during hypercapnia and neural stimulation are similar, relative CMRO2 change was determined using BOLD biophysical models. The average CMRO2 change in the visual cortex ranged from 15.6 ± 8.1% (n = 18) with significant cerebral blood volume (CBV) contribution to 29.6 ± 18.8% without significant CBV contribution. A weak positive correlation between CBF and CMRO2 changes was observed, suggesting the CMRO2 increase is proportional to the CBF increase. Magn Reson Med 41:1152–1161, 1999.

Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation.

This study validates transcranial Doppler sonography (TCD) for determination of the lower limit of cerebral blood flow (CBF) autoregulation and establishes a relation between global CBF and mean flow velocity (Vmean) in the middle cerebral artery. Methods Relative changes in CBF and in Vmean were compared in 12 normal volunteers (2 women and 10 men; median age, 30 years [range, 21 to 61 years]). Catheters was placed in the left radial artery and in the bulb of the right internal jugular vein, respectively. Baseline CBF was measured by single-photon emission computed tomography scanning; concomitantly, blood samples were drawn for calculation of the cerebral arteriovenous oxygen difference. Then changes in mean arterial pressure (MAP) were induced, and relative changes in global CBF were calculated according to Ficks principle assuming a constant cerebral oxygen metabolism. MAP was increased 30 mm Hg by norepinephrine infusion and was decreased by lower body negative pressure. Vmean was measured in the right middle cerebral artery by a 2-MHz probe, and blood samples were drawn at intervals of 5 mm Hg. Results MAP values between 122 (range, 110 to 140) and 48 (range, 34 to 75) mm Hg were measured. The lower limit of autoregulation (the blood pressure under which autoregulation is off) as determined by Vmean did not differ significantly from that determined by relative changes in global CBF: 91 (range, 41 to 108) and 79 (range, 53 to 113) mm Hg, respectively. A significant correlation between Vmean and relative changes in global CBF was demonstrated below the lower limit of autoregulation (R2=.73, P<.001; CBF=−6.3+1.0· Vmean). Above the lower lim1it both values were stable. Conclusions TCD is valid for determination of the lower limit of CBF autoregulation, and changes in CBF may be reliably evaluated by TCD during changes in cerebral perfusion pressure in normal subjects.

Effect of acetazolamide on cerebral blood flow and cerebral metabolic rate for oxygen.

The aim of this study was to evaluate the effect of acetazolamide on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). CBF, arterial and jugular venous partial O2 pressure, partial CO2 pressure, pH, and O2 saturation percentage were measured in six patients before and 3 and 20 minutes after intravenous administration of 1 g of acetazolamide. CBF was measured by the intracarotid 133xenon injection technique. In addition, changes in CBF were estimated from the arteriovenous oxygen content difference. CBF increased in all patients after acetazolamide, by approximately 55 and 70% after 3 and 20 min, respectively. The CBF changes were of the same order whether calculated from the 133Xe clearance or from the arteriovenous oxygen differences (A-V)O2. CMRO2, calculated from (A-V)O2 differences and CBF, remained constant. Except for an increase in the venous oxygen saturation, the blood gases remained constant. Acetazolamide, in a dose sufficient to inhibit the erythrocyte carbonic anhydrase (EC 4.2.1.1), thus induced a rapid and marked increase in CBF, leaving CMRO2 unchanged. This effect of acetazolamide on CBF is probably explained by a decrease in brain pH rather than by brain tissue hypoxia due to inhibition of oxygen unloading in the brain capillaries.

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.

Brain activation during dichotic presentations of consonant-vowel and musical instrument stimuli : A 15O-PET study

Dichotic listening means that two different stimuli are presented at the same time, one in each ear. This technique is frequently used in experimental and clinical studies as a measure of hemispheric specialization. The primary aim of the present study was to record regional changes in the distribution of cerebral blood flow (CBF) with the 15O-PET technique to dichotically presented consonant-vowel (CV) and musical instrument stimuli, in order to test the basic assumption of differential hemispheric involvement when stimuli presented to one ear dominate over stimuli presented in the other ear. All stimuli were 380 ms in duration with a 1000 ms interstimulus interval, and were presented in blocks of either CV-syllable or musical instrument pairs. Twelve normal healthy subjects had to press a button whenever they detected a CV-syllable or a musical instrument target in a stream of CV- and musical instrument distractor stimuli. The targets appeared equally often in the right and left ear channel. The CV-syllable and musical instrument targets activated bilateral areas in the superior temporal gyri. However, there were significant interactions with regard to asymmetry of the magnitude of peak activation in the significant activation clusters. The CV-syllables resulted in greater neural activation in the left temporal lobe while the musical instruments resulted in greater neural activation in the right temporal lobe. Within-subjects correlations between magnitude of dichotic listening and CBF asymmetry were, however, non-significant. The changes in neural activation were closely mimicked by the performance data which showed a right ear superiority in response accuracy for the CV-syllables, and a left ear superiority for the musical instruments. In addition to the temporal lobe activations, there were activation tendencies in the left inferior frontal lobe, right dorsolateral prefrontal cortex, left occipital lobe, and cerebellum.

Motion or activity: their role in intra- and inter-subject variation in fMRI.

Functional MRI (fMRI) carries the potential for non-invasive measurements of brain activity. Typically, what are referred to as activation images are actually thresholded statistical parametric maps. These maps possess large inter-session variability. This is especially problematic when applying fMRI to pre-surgical planning because of a higher requirement for intra-subject precision. The purpose of this study was to investigate the impact of residual movement artefacts on intra-subject and inter-subject variability in the observed fMRI activation. Ten subjects were examined using three different word-generation tasks. Two of the subjects were examined 10 times on 10 different days using the same paradigms. We systematically investigated one approach of correcting for residual movement effects: the inclusion of regressors describing movement-related effects in the design matrix of a General Linear Model (GLM). The data were analysed with and without modeling the residual movement artefacts and the impact on inter-session variance was assessed using F-contrasts. Inclusion of motion parameters in the analysis significantly reduced both the intra-subject as well as the inter-subject-variance.

Restoration of autoregulation of cerebral blood flow by hypocapnia

DURING RECENT YEARS, a state of cerebral vasomotor paralysis has been demonstrated in foca2Zy diseased brain tissue in patients with apoplexy and intracranial tumors. 14 In these vasoparalytic areas there is a loss of autoregulation normally the cerebral blood flow is independent of the arterial blood pressure within wide limits and a loss of the normal response to changed arterial carbon dioxide tension (PaCOz) vasodilation during increased PaCOz and vasoconstriction during decreased PaCOz. Moreover, in some patients with apoplexy or intracranial tumors it has been observed that the vasomotor function also may be affected in nonfocal parts of the diseased hemisphere. Here, an impaired autoregulation but a preserved reaction to changes ofthe PaCOz was observed. 2-6 This nonfocal loss of autoregulation has been called global, as it was expected that a loss of autoregulation would also be present in the contralateral “nondiseased” hemisphere. It was also predicted that the global loss of autoregulation might be restored by hypocapnia.6 A restoration of autoregulation by hypocapnia might be of essential importance for the possible beneficial effect of the therapeutic use of hyperventilation in patients with intracranial diseases, as will be further commented on in the Discussion. In the present study the autoregulation has been examined in the nondiseased hemisphere of patients with apoplexy or intracranial tumors at different levels of PaCOz to test the abovementioned predictions. patients were studied under general anesthesia induced by 300 mg. of thiopental sodium and 30 mg. of d-tubocurarine chloride and maintained with oxygen and nitrous oxide (1:2). Relaxation was maintained with repeated doses of 5 to 10 mg. d-tubocurarine chloride. Regional c e r e b r a l blood P o w ( r C B F ) measurements were performed in the nondiseased hemisphere (contralateral to the focal lesion) in all patients. After stabilization of PaCOz at about the patient’s own level as recorded during spontaneous respiration before anesthesia, 2 flow measurements were carried out at intervals of fifteen minutes. The first was made during normotension and the second during hypertension induced by infusion of angiotensin (Hypertensin@). Thereafter the patient was hyperventilated, and following stabilization of the PaCOz at about 25 mm. Hg (after forty-five to sixty minutes ) , 2 more measurements were taken during normotension and hypertension. The 133Xe intracarotid injection method was used for the rCBF measurements and the flow was determined in 35 regions of the nondiseased hemisphere. This method has been described in detail p r e v i ~ u s l y ~ ~ ~ ~ * and shall be only briefly summarized here. A small polyethylene catheter was placed into the internal carotid artery by means of the Seldinger technique. Then, 2 to 3 mc. of 133Xe dissolved in 3 ml. of isotonic saline were injected rapidly (one to two seconds) through the catheter into the internal carotid artery. The clear-

Validation of in vitro probabilistic tractography

Diffusion weighted imaging (DWI) and tractography allow the non-invasive study of anatomical brain connectivity. However, a gold standard for validating tractography of complex connections is lacking. Using the porcine brain as a highly gyrated brain model, we quantitatively and qualitatively assessed the anatomical validity and reproducibility of in vitro multi-fiber probabilistic tractography against two invasive tracers: the histochemically detectable biotinylated dextran amine and manganese enhanced magnetic resonance imaging. Post mortem DWI was used to ensure that most of the sources known to degrade the anatomical accuracy of in vivo DWI did not influence the tracking results. We demonstrate that probabilistic tractography reliably detected specific pathways. Moreover, the applied model allowed identification of the limitations that are likely to appear in many of the current tractography methods. Nevertheless, we conclude that DWI tractography can be a precise tool in studying anatomical brain connectivity.

Rate Dependence of Regional Cerebral Activation During Performance of a Repetitive Motor Task: A PET Study

Using repeated positron emission tomography (PET) measures of regional cerebral counts, we investigated the regional cortical activations induced in eight normal subjects performing eight different frequencies of fingertapping (0.5–4 Hz) with the right index finger. The task was auditorially cued and the performance recorded during the scanning procedure. Performance evaluation showed increased error rates, during fingertapping, of high and low frequencies, and the best tapping performance was measured in the midrange of frequencies. Significantly activated areas (p < 0.05) of normalized cerebral counts were located in the left sensorimotor cortex (M1S1), right motor cortex, left thalamus, right insula, supplementary motor area (SMA), and bilaterally in the primary auditory cortex and the cerebellum. Statistical evaluation showed a significant (p < 0.01) and positive dependence of cerebral activation upon movement rate in the contralateral M1S1. There was no significant rate dependence of cerebral activation in other activated motor areas. The SMA and the right cerebellar hemisphere showed a more uniform activation throughout the tapping frequency range. Furthermore, we found a stimulus rate dependence of cerebral activation in the primary auditory cortex. We believe that the present data provide useful information for the preparation and interpretation of future motor activation studies of normal human subjects and may serve as reference points for studies of pathological conditions.