Metabolic control of resting hemispheric cerebral blood flow is oxidative,not glycolytic

Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO₂) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO₂, CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO₂ was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO₂: arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO₂ and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.     

Altered task-induced cerebral blood flow and oxygen metabolism underlies motor impairment in multiple sclerosis

The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural–vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO₂), and flow–metabolism coupling (ΔCBF/ΔCMRO₂), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO₂ increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow–metabolism coupling (ΔCBF/ΔCMRO₂) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO₂ in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO₂ responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural–vascular coupling.     

Impaired cerebral vascular and metabolic responses to parametric N-back tasks in subjective cognitive decline

Previous studies reported abnormally increased and/or decreased blood oxygen level-dependent (BOLD) activations during functional tasks in subjective cognitive decline (SCD). The neurophysiological basis underlying these functional aberrations remains debated. This study aims to investigate vascular and metabolic responses and their dependence on cognitive processing loads during functional tasks in SCD. Twenty-one SCD and 18 control subjects performed parametric N-back working-memory tasks during MRI scans. Task-evoked percentage changes (denoted as δ) in cerebral blood volume (δCBV), cerebral blood flow (δCBF), BOLD signal (δBOLD) and cerebral metabolic rate of oxygen (δCMRO₂) were evaluated. In the frontal lobe, trends of decreased δCBV, δCBF and δCMRO₂ and increased δBOLD were observed in SCD compared with control subjects under lower loads, and these trends increased to significant differences under the 3-back load. δCBF was significantly correlated with δCMRO₂ in controls, but not in SCD subjects. As N-back loads increased, the differences between SCD and control subjects in δCBF and δCMRO₂ tended to enlarge. In the parietal lobe, no significant between-group difference was observed. Our findings suggested that impaired vascular and metabolic responses to functional tasks occurred in the frontal lobe of SCD, which contributed to unusual BOLD hyperactivation and was modulated by cognitive processing loads.     

Interindividual variations of cerebral blood flow, oxygen delivery, and metabolism in relation to hemoglobin concentration measured by positron emission tomography in humans

Regional cerebral blood flow (CBF) and oxygen metabolism can be measured by positron emission tomography (PET) with ¹⁵O-labeled compounds. Hemoglobin (Hb) concentration of blood, a primary determinant of arterial oxygen content (C_aO₂), influences cerebral circulation. We investigated interindividual variations of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) in relation to Hb concentration in healthy human volunteers (n=17) and in patients with unilateral steno-occlusive disease (n=44). For the patients, data obtained only from the contralateral hemisphere (normal side) were analyzed. The CBF and OEF were inversely correlated with Hb concentration, but CMRO₂ was independent of Hb concentration. Oxygen delivery defined as a product of C_aO₂ and CBF (C_aO₂ CBF) increased with a rise of Hb concentration. The analysis with a simple oxygen model showed that oxygen diffusion parameter (L) was constant over the range of Hb concentration, indicating that a homeostatic mechanism controlling CBF is necessary to maintain CMRO₂. The current findings provide important knowledge to understand the control mechanism of cerebral circulation and to interpret the ¹⁵O PET data in clinical practice.     

Imaging neurovascular function and functional recovery after stroke in the rat striatum using forepaw stimulation

Negative functional magnetic resonance imaging (fMRI) response in the striatum has been observed in several studies during peripheral sensory stimulation, but its relationship between local field potential (LFP) remains to be elucidated. We performed cerebral blood volume (CBV) fMRI and LFP recordings in normal rats during graded noxious forepaw stimulation at nine stimulus pulse widths. Albeit high LFP–CBV correlation was found in the ipsilateral and contralateral sensory cortices (r=0.89 and 0.95, respectively), the striatal CBV responses were neither positively, nor negatively correlated with LFP (r=0.04), demonstrating that the negative striatal CBV response is not originated from net regional inhibition. To further identify whether this negative CBV response can serve as a marker for striatal functional recovery, two groups of rats (n=5 each) underwent 20- and 45-minute middle cerebral artery occlusion (MCAO) were studied. No CBV response was found in the ipsilateral striatum in both groups immediately after stroke. Improved striatal CBV response was observed on day 28 in the 20-minute MCAO group compared with the 45-minute MCAO group (P<0.05). This study shows that fMRI signals could differ significantly from LFP and that the observed negative CBV response has potential to serve as a marker for striatal functional integrity in rats.     

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO₂) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO₂ during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO₂ responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R² = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO₂ response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.     

Endogenous opioid-dopamine neurotransmission underlie negative CBV fMRI signals

Previous studies showed noxious unilateral forepaw electrical stimulation surprisingly evoked negative blood-oxygenation-level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) fMRI responses in the bilateral striatum whereas the local neuronal spike and c-Fos activities increased. These negative responses are associated with vasoconstriction and appeared to override the increased hemodynamic responses that typically accompanied with increased neural activity. The current study aimed to investigate the role of μ-opioid system in modulating vasoconstriction in the striatum associated with noxious stimulation on a 4.7-Tesla MRI scanner. Specifically, we investigated: i) how morphine (a μ-opioid receptor agonist) affects the vasoconstriction in the bilateral striatum associated with noxious electrical forepaw stimulation in rats, and ii) how naloxone (an opioid receptor antagonist) and eticlopride (a dopamine D(2)/D(3) receptor antagonist) modulates the morphine effects onwards. Injection of morphine enhanced the negative striatal CBV responses to noxious stimulation. Sequential injection of naloxone in the same animals abolished the stimulus-evoked vasoconstriction. In a separate group of animals, injection of eticlopride following morphine also reduced the vasoconstriction. Our findings suggested that noxious stimulation endogenously activated opioid and dopamine receptors in the striatum and thus leading to vasoconstriction.     

Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease

In moyamoya disease (MMD), surgical revascularization may be complicated with postoperative hyperperfusion. We analyzed cerebral perfusion and metabolism using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) before and after bypass surgery on 42 sides of 34 adult patients with MMD. In seven cases (16.7%) with symptomatic hyperperfusion, diagnosed by qualitative ¹²³I-iodoamphetamine (IMP) SPECT, a subsequent PET study during postoperative subacute stages revealed significantly increased cerebral blood flow (CBF) from 34.1±8.2 to 74.3±12.8 mL/100 g per minute (P<0.01), a persistent increase in cerebral blood volume (CBV) from 5.77±1.67 to 7.01±1.44 mL/100 g and a significant decrease in oxygen extraction fraction (OEF) from 0.61±0.09 to 0.40±0.08 (P<0.01). Mean absolute CBF values during symptomatic hyperperfusion were more than the normal control +2 standard deviations, the predefined criteria of PET. Interestingly, two patients with markedly increased cerebral metabolic rate of oxygen (CMRO₂) at hyperperfusion were complicated with postoperative seizure. Among preoperative PET parameters, increased OEF was the only significant risk factor for symptomatic hyperperfusion (P<0.05). This study revealed that symptomatic hyperperfusion in MMD is characterized by temporary increases in CBF >100% over preoperative values caused by prolonged recovery of increased CBV.     

Measurement of CMRO2 and its relationship with CBF in hypoxia with an extended calibrated BOLD method

Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO₂) are physiological parameters that not only reflect brain health and disease but also jointly contribute to blood oxygen level-dependent (BOLD) signals. Nevertheless, unsolved issues remain concerning the CBF–CMRO₂ relationship in the working brain under various oxygen conditions. In particular, the CMRO₂ responses to functional tasks in hypoxia are less studied. We extended the calibrated BOLD model to incorporate CMRO₂ measurements in hypoxia. The extended model, which was cross-validated with a multicompartment BOLD model, considers the influences of the reduced arterial saturation level and increased baseline cerebral blood volume (CBV) and deoxyhemoglobin concentration on the changes of BOLD signals in hypoxia. By implementing a pulse sequence to simultaneously acquire the CBV-, CBF- and BOLD-weighted signals, we investigated the effects of mild hypoxia on the CBF and CMRO₂ responses to graded visual stimuli. Compared with normoxia, mild hypoxia caused significant alterations in both the amplitude and the trend of the CMRO₂ responses but did not impact the corresponding CBF responses. Our observations suggested that the flow-metabolism coupling strategies in the brain during mild hypoxia were different from those during normoxia.     

Paradoxical reduction of cerebral blood flow after acetazolamide loading: a hemodynamic and metabolic study with 15O PET

Paradoxical reduction of cerebral blood flow (CBF) after administration of the vasodilator acetazolamide is the most severe stage of cerebrovascular reactivity failure and is often associated with an increased oxygen extraction fraction (OEF). In this study, we aimed to reveal the mechanism underlying this phenomenon by focusing on the ratio of CBF to cerebral blood volume (CBV) as a marker of regional cerebral perfusion pressure (CPP). In 37 patients with unilateral internal carotid or middle cerebral arterial (MCA) steno-occlusive disease and 8 normal controls, the baseline CBF (CBF_b), CBV, OEF, cerebral oxygen metabolic rate (CMRO₂), and CBF after acetazolamide loading in the anterior and posterior MCA territories were measured by ¹⁵O positron emission tomography. Paradoxical CBF reduction was found in 28 of 74 regions (18 of 37 patients) in the ipsilateral hemisphere. High CBF_b (>47.6 mL/100 mL/min, n = 7) was associated with normal CBF_b/CBV, increased CBV, decreased OEF, and normal CMRO₂. Low CBF_b (<31.8 mL/100 mL/min, n = 9) was associated with decreased CBF_b/CBV, increased CBV, increased OEF, and decreased CMRO₂. These findings demonstrated that paradoxical CBF reduction is not always associated with reduction of CPP, but partly includes high-CBF_b regions with normal CPP, which has not been described in previous studies.     

Physiological origin for the BOLD poststimulus undershoot in human brain: vascular compliance versus oxygen metabolism

The poststimulus blood oxygenation level-dependent (BOLD) undershoot has been attributed to two main plausible origins: delayed vascular compliance based on delayed cerebral blood volume (CBV) recovery and a sustained increased oxygen metabolism after stimulus cessation. To investigate these contributions, multimodal functional magnetic resonance imaging was employed to monitor responses of BOLD, cerebral blood flow (CBF), total CBV, and arterial CBV (CBV_a) in human visual cortex after brief breath hold and visual stimulation. In visual experiments, after stimulus cessation, CBV_a was restored to baseline in 7.9±3.4 seconds, and CBF and CBV in 14.8±5.0 seconds and 16.1±5.8 seconds, respectively, all significantly faster than BOLD signal recovery after undershoot (28.1±5.5 seconds). During the BOLD undershoot, postarterial CBV (CBV_pa, capillaries and venules) was slightly elevated (2.4±1.8%), and cerebral metabolic rate of oxygen (CMRO₂) was above baseline (10.6±7.4%). Following breath hold, however, CBF, CBV, CBV_a and BOLD signals all returned to baseline in ∼20 seconds. No significant BOLD undershoot, and residual CBV_pa dilation were observed, and CMRO₂ did not substantially differ from baseline. These data suggest that both delayed CBV_pa recovery and enduring increased oxidative metabolism impact the BOLD undershoot. Using a biophysical model, their relative contributions were estimated to be 19.7±15.9% and 78.7±18.6%, respectively.     

Cerebral blood flow and metabolism in patients with silent brain infarction: occult misery perfusion in the cerebral cortex

OBJECTIVES—Silentbrain infarction (SBI) is of growing interest as a possible risk factorfor symptomatic stroke. Although morphological characteristics of SBIhave been well defined, their characteristic patterns of cerebral bloodflow (CBF) and metabolism are in dispute. The purpose of this study wasto elucidate CBF and metabolism in patients with SBI in relation tosymptomatic stroke.
METHODS—The patientsunderwent PET and were separated into three groups; control group (Cgroup), with no lesions on CT (n=9, mean age 57), SBI group, with noneurological signs or history of stroke, but with ischaemic lesions onCT (n=9, mean age 63), and brain infarction group (BI group), withneurological deficits and compatible CT lesions in the area supplied byperforating arteries (n=19, mean age 56). Regional CBF, oxygenextraction fraction (OEF), cerebral metabolic rate for oxygen(CMRO₂), and cerebral blood volume (CBV) were measured by PET.
RESULTS—Mean valuesfor CBF to the cerebral cortex and deep grey matter were lower in theSBI group (31.6 (SD 5.8) and 34.3 (SD 6.9) ml/100 g/min, respectively)and in the BI group (30.8 (SD 5.2), 33.9 (SD 5.9), respectively) thanin the C group (36.0 (SD 6.6) and 43.5 (SD 9.5), respectively).Although mean CMRO₂ of deep grey matter (2.36 (SD 0.52)ml/100 g/min) was significantly decreased in the SBI group comparedwith the C group (2.76 (SD 0.480), p<0.01), CMRO₂ of thecortical area was as well preserved in the SBI patients (2.36 (SD0.39)) as in the controls (2.48 (SD 0.32)) with a compensatory increaseof mean OEF (0.45 (SD 0.06) and 0.41 (SD 0.05), respectively).
CONCLUSIONS—Patientswith SBI showed decreased CBF and CMRO₂ in deep greymatter. On the other hand, decreased CBF with milder increased OEF,resulting in preserved CMRO₂ in the cerebral cortexindicates the presence of occult misery perfusion, suggesting thatpatients with SBI have reduced cerebral perfusional reserves.

     

Early Derangements in Oxygen and Glucose Metabolism Following Head Injury: The Ischemic Penumbra and Pathophysiological Heterogeneity

Introduction  Conclusive evidence of cerebral ischemia following head injury has been elusive. We aimed to use ¹⁵O and ¹⁸Fluorodeoxyglucose positron emission tomography (PET) to investigate pathophysiological derangements following head injury. Results   Eight patients underwent PET within 24 h of injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO₂), oxygen extraction fraction (OEF), and cerebral glucose metabolism (CMRglc). Physiological regions of interest (ROI) were generated for each subject using a range of OEF values from very low (<10), low (10–30), normal range (30–50), high (50–70), and critically high (≥70%). We applied these ROIs to each subject to generate data that would examine the balance between blood flow and metabolism across the injured brain independent of structural injury. Discussion   Compared to the normal range, brain regions with higher OEF demonstrate a progressive CBF reduction (P < 0.01), CMRO₂ increase (P < 0.05), and no change in CMRglc, while regions with lower OEF are associated with reductions in CBF, CMRO₂, and CMRglc (P < 0.01). Although all subjects demonstrate a decrease in CBF with increases in OEF > 70%, CMRO₂ and CMRglc were generally unchanged. One subject demonstrated a reduction in CBF and small fall in CMRO₂ within the high OEF region (>70%), combined with a progressive increase in CMRglc. Conclusions  The low CBF and maintained CMRO₂ in the high OEF ROIs is consistent with classical cerebral ischemia and the presence of an ‘ischemic penumbra’ following early head injury, while the metabolic heterogeneity that we observed suggests significant pathophysiological complexity. Other mechanisms of energy failure are clearly important and further study is required to delineate the processes involved.     

Differential responses in CBF and CBV to cocaine as measured by fMRI: Implications for pharmacological MRI signals derived oxygen metabolism assessment

Introduction

Cognitive performance-induced brain oxygen metabolism has been successfully measured by functional magnetic resonance imaging (fMRI) in human studies. The measurement of the cerebral metabolic rate of oxygen consumption (CMRO₂) is typically achieved by assuming a fixed coupling of cerebral blood flow (CBF) and cerebral blood volume (CBV) and by performing a separate experiment to assess the vascular response to a hypercapnic challenge. Psychoactive drugs may have directly effect on the cerebral vasculature, potentially confounding the interpretation of pharmacological MRI (phMRI) data. In this study, we tested the assumptions of the standard CMRO₂ calculation following the administration of cocaine, in order to test the validity of this measurement in phMRI studies. The initial transient state and later steady state CBF and CBV responses to a hypercapnic challenge were measured.

Methods

CBF and CBV responses were directly measured by fMRI using continuous arterial spin-labeling (ASL) and contrast-enhanced fMRI, respectively. The coupling between changes in CBF and CBV during a hypercapnic challenge was examined under normal conditions and following the administration of cocaine.

Results

A decoupling of changes in CBF and CBV was observed during the transient state immediately following the administration of cocaine, and an altered coupling of CBF and CBV was found during the steady state after cocaine injection.

Discussion

These data suggest caution in interpreting CMRO₂ measurements from phMRI studies and may also lead to an improved understanding of the complex neuronal and vascular mechanisms of drug action.     

Effects of the α2‐adrenergic receptor agonist dexmedetomidine on neural,vascular and BOLD fMRI responses in the somatosensory cortex

This article describes the effects of dexmedetomidine (DEX) – the active ingredient of medetomidine, which is the latest popular sedative for functional magnetic resonance imaging (fMRI) in rodents – on multiple unit activity, local field potential (LFP), cerebral blood flow (CBF), pial vessel diameter [indicative of cerebral blood volume (CBV)], and blood oxygenation level‐dependent (BOLD) fMRI. These measurements were obtained from the rat somatosensory cortex during 10 s of forepaw stimulation. We found that the continuous intravascular systemic infusion of DEX (50 μg/kg/h, doses typically used in fMRI studies) caused epileptic activities, and that supplemental isoflurane (ISO) administration of ~0.3% helped to suppress the development of epileptic activities and maintained robust neuronal and hemodynamic responses for up to 3 h. Supplemental administration of N₂O in addition to DEX nearly abolished hemodynamic responses even if neuronal activity remained. Under DEX + ISO anesthesia, spike firing rate and the delta power of LFP increased, whereas beta and gamma power decreased, as compared with ISO‐only anesthesia. DEX administration caused pial arteries and veins to constrict nearly equally, resulting in decreases in baseline CBF and CBV. Evoked LFP and CBF responses to forepaw stimulation were largest at a frequency of 8–10 Hz, and a non‐linear relationship was observed. Similarly, BOLD fMRI responses measured at 9.4 T were largest at a frequency of 10 Hz. Both pial arteries and veins dilated rapidly (artery, 32.2%; vein, 5.8%), and venous diameter returned to baseline slower than arterial diameter. These results will be useful for designing, conducting and interpreting fMRI experiments under DEX sedation.     

Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals

After its discovery in 1990, blood oxygenation level-dependent (BOLD) contrast in functional magnetic resonance imaging (fMRI) has been widely used to map brain activation in humans and animals. Since fMRI relies on signal changes induced by neural activity, its signal source can be complex and is also dependent on imaging parameters and techniques. In this review, we identify and describe the origins of BOLD fMRI signals, including the topics of (1) effects of spin density, volume fraction, inflow, perfusion, and susceptibility as potential contributors to BOLD fMRI, (2) intravascular and extravascular contributions to conventional gradient-echo and spin-echo BOLD fMRI, (3) spatial specificity of hemodynamic-based fMRI related to vascular architecture and intrinsic hemodynamic responses, (4) BOLD signal contributions from functional changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of O(2) utilization (CMRO(2)), (5) dynamic responses of BOLD, CBF, CMRO(2), and arterial and venous CBV, (6) potential sources of initial BOLD dips, poststimulus BOLD undershoots, and prolonged negative BOLD fMRI signals, (7) dependence of stimulus-evoked BOLD signals on baseline physiology, and (8) basis of resting-state BOLD fluctuations. These discussions are highly relevant to interpreting BOLD fMRI signals as physiological means.     

Smoking normalizes cerebral blood flow and oxygen consumption after 12-hour abstention

Acute nicotine administration stimulates [¹⁴C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO₂) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO₂. At the end of the abstention period, global grey-matter CBF and CMRO₂ were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO₂ had increased by 11%. Regional analysis showed that CMRO₂ had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO₂ had increased by 11-12%. Thus, we find substantial and global impairment of CBF/CMRO₂ in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO₂ during acute abstention may mediate the cognitive changes described in chronic smokers.     

Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion

The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level-dependent (BOLD) MRI was performed in 11 patients (65±7 years) and 14 controls (66±4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) were evaluated. The CBF was 34±5 and 36±11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44±20 and 53±10% per 10 mm Hg ▵EtCO₂ in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3±0.8 versus 2.2±0.4% per 10 mm Hg ▵EtCO₂, P<0.01). The OEF was 41±8% and 38±6%, and the CMRO₂ was 116±39 and 111±40 μmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2±0.6 versus 1.6±0.5% per 10 mmHg ▵EtCO₂, P<0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients.     

Global cerebral oxidative metabolism during hypercapnia and hypocapnia in humans: implications for BOLD fMRI

The effect of carbon dioxide (CO₂) on cerebral metabolism is of tremendous interest to functional imaging. In particular, mild-to-moderate hypercapnia is routinely used in calibrated blood oxygen-level dependent (BOLD)-functional magnetic resonance imaging (fMRI)-based quantification of cerebral oxidative metabolism changes (ΔCMRO₂), and relies on the assumption of a stable CMRO₂ during CO₂ challenges. However, this assumption has been challenged by certain animal studies, necessitating its verification in humans and under conditions customary to fMRI. We report, for the first time, on global ΔCMRO₂ measurements made noninvasively in humans during graded hypercapnia and hypocapnia. We used computerized end-tidal CO₂ modulation to minimize undesired concurrent changes in oxygen pressure, and our findings suggest that no significant change in global CMRO₂ is expected at the levels of end-tidal CO₂ changes customary to calibrated BOLD.     

Increases in oxygen consumption without cerebral blood volume change during visual stimulation under hypotension condition.

The magnitude of the blood oxygenation level-dependent (BOLD) signal depends on cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2). Thus, it is difficult to separate CMRO2 changes from CBF and CBV changes. To detect the BOLD signal changes induced only by CMRO2 responses without significant evoked CBF and CBV changes, BOLD and CBV functional magnetic resonance imaging (fMRI) responses to visual stimulation were measured under normal and hypotension conditions in isoflurane-anesthetized cats at 4.7 T. When the mean arterial blood pressure (MABP) decreased from 89+/-10 to 50+/-1 mm Hg (mean+/-standard deviation, n=5) by infusion of vasodilator sodium nitroprusside, baseline CBV in the visual cortex increased by 28.4%+/-8.3%. The neural activity-evoked CBV increase in the visual cortex was 10.8%+/-3.9% at normal MABP, but was negligible at hypotension. Positive BOLD changes of +1.8%+/-0.5% (gradient echo time=25 ms) at normal MABP condition became prolonged negative changes of -1.2%+/-0.3% at hypotension. The negative BOLD response at hypotension starts approximately 1 sec earlier than positive BOLD response, but similar to CBV change at normal MABP condition. Our finding shows that the negative BOLD signals in an absence of CBV changes are indicative of an increase in CMRO2. The vasodilator-induced hypotension model simplifies the physiological source of the BOLD fMRI signals, providing an insight into spatial and temporal CMRO2 changes.