Striatal and cortical BOLD,blood flow,blood volume,oxygen consumption,and glucose consumption changes in noxious forepaw electrical stimulation

Recent reports showed noxious forepaw stimulation in rats evoked an unexpected sustained decrease in cerebral blood volume (CBV) in the bilateral striatum, whereas increases in spike activity and Fos-immunoreactive cells were observed. This study aimed to further evaluate the hemodynamic and metabolic needs in this model and the sources of negative functional magnetic resonance imaging (fMRI) signals by measuring blood oxygenation-level-dependent (BOLD), cerebral-blood-flow (CBF), CBV, and oxygen-consumption (i.e., cerebral metabolic rate of oxygen (CMRO₂)) changes using an 11.7-T MRI scanner, and glucose-consumption (i.e., cerebral metabolic rate of glucose (CMRglc)) changes using micro-positron emission tomography. In the contralateral somatosensory cortex, BOLD, CBF, CBV, CMRO₂ (n=7, P<0.05), and CMRglc (n=5, P<0.05) increased. In contrast, in the bilateral striatum, BOLD, CBF, and CBV decreased (P<0.05), CMRO₂ decreased slightly, although not significantly from baseline, and CMRglc was not statistically significant from baseline (P>0.05). These multimodal functional imaging findings corroborate the unexpected negative hemodynamic changes in the striatum during noxious forepaw stimulation, and support the hypothesis that striatal hemodynamic response is dominated by neurotransmitter-mediated vasoconstriction, overriding the stimulus-evoked fMRI signal increases commonly accompany elevated neuronal activity. Multimodal functional imaging approach offers a means to probe the unique attributes of the striatum, providing novel insights into the neurovascular coupling in the striatum. These findings may have strong implications in fMRI studies of pain.     

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.     

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.     

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.     

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.     

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.     

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.     

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.

     

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG

During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O₂ (CMRO₂) during wakefulness and sleep, leveraging the ‘OxFlow’ method, which provides venous O₂ saturation (SvO₂) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45–60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO₂ = 118 ± 12 µmol O₂/min/100 g, SvO₂ = 67.0 ± 3.7% HbO₂, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO₂ decreased 21% (range: 14%–32%; average nadir = 98 ± 16 µmol O₂/min/100 g), while EEG slow-wave activity, expressed in terms of δ-power, increased commensurately. Following sleep onset, CMRO₂ was found to correlate negatively with relative δ-power (r = −0.6 to −0.8, P < 0.005), and positively with heart rate (r = 0.5 to 0.8, P < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.     

Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study

Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF^max), and the resulting maximum cerebral metabolic rate of oxygen (CMRO₂^max) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF^max was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO₂^max (3.40±1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63±1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5±18.7 mm Hg) and conservative (163.0±10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2±11.9 versus 35.8±9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF^max (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO₂^max (3.16±1.66 versus 3.68±1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH.     

Method for rapid MRI quantification of global cerebral metabolic rate of oxygen

A recently reported quantitative magnetic resonance imaging (MRI) method denoted OxFlow has been shown to be able to quantify whole-brain cerebral metabolic rate of oxygen (CMRO₂) by simultaneously measuring oxygen saturation (S_vO₂) in the superior sagittal sinus and cerebral blood flow (CBF) in the arteries feeding the brain in 30 seconds, which is adequate for measurement at baseline but not necessarily in response to neuronal activation. Here, we present an accelerated version of the method (referred to as F-OxFlow) that quantifies CMRO₂ in 8 seconds scan time under full retention of the parent method''s capabilities and compared it with its predecessor at baseline in 10 healthy subjects. Results indicate excellent agreement between both sequences, with mean bias of 2.2% (P=0.18, two-tailed t-test), 3.4% (P=0.08, two-tailed t-test), and 2.0% (P=0.56, two-tailed t-test) for S_vO₂, CBF, and CMRO₂, respectively. F-OxFlow''s potential to monitor dynamic changes in S_vO₂, CBF, and CMRO₂ is illustrated in a paradigm of volitional apnea applied to five of the study subjects. The sequence captured an average increase in S_vO₂, CBF, and CMRO₂ of 10.1±2.5%, 43.2±9.2%, and 7.1±2.2%, respectively, in good agreement with literature values. The method may therefore be suited for monitoring alterations in CBF and S_vO₂ in response to neurovascular stimuli.     

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.     

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.     

SCALE-PWI: A pulse sequence for absolute quantitative cerebral perfusion imaging

The Bookend technique is a magnetic resonance imaging (MRI) dynamic susceptibility contrast method that provides reliable quantitative measurement of cerebral blood flow (CBF) and cerebral blood volume (CBV). The quantification is patient specific, is derived from a steady-state measurement of CBV, and is obtained from T₁ changes in the white matter and the blood pool after contrast agent injection. In the current implementation, the Bookend technique consists of three scanning steps requiring a cumulative scan time of 3 minutes 47 seconds, a well-trained technologist, and extra time for offline image reconstruction. We present an automation and acceleration of the multiscan Bookend protocol through a self-calibrating pulse sequence, namely Self-Calibrated Epi Perfusion-Weighted Imaging (SCALE-PWI). The SCALE-PWI is a single-shot echo-planar imaging pulse sequence with three modules and a total scan time of under 2 minutes. It provides the possibility of performing online, quantitative perfusion image reconstruction, which reduces the latency to obtain quantitative maps. A validation study in healthy volunteers (N=19) showed excellent agreement between SCALE-PWI and the conventional Bookend protocol (P>0.05 with Student''s t-test, r=0.95/slope=0.98 for quantitative CBF, and r=0.91/slope=0.94 for quantitative CBV). A single MRI pulse sequence for absolute quantification of cerebral perfusion has been developed.     

Baseline CBF,and BOLD,CBF, and CMRO2 fMRI of visual and vibrotactile stimulations in baboons

Neurovascular coupling associated with visual and vibrotactile stimulations in baboons anesthetized sequentially with isoflurane and ketamine was evaluated using multimodal functional magnetic resonance imaging (fMRI) on a clinical 3-Tesla scanner. Basal cerebral blood flow (CBF), and combined blood-oxygenation-level-dependent (BOLD) and CBF fMRI of visual and somatosensory stimulations were measured using pseudo-continuous arterial spin labeling. Changes in stimulus-evoked cerebral metabolic rate of oxygen (CMRO₂) were estimated using calibrated fMRI. Arterial transit time for vessel, gray matter (GM), and white matter (WM) were 250, 570, and 823 ms, respectively. Gray matter and WM CBF, respectively, were 107.8±7.9 and 47.8±3.8 mL per 100 g per minute under isoflurane, and 108.8±10.3 and 48.7±4.2 mL per 100 g per minute under ketamine (mean±s.e.m., N=8 sessions, five baboons). The GM/WM CBF ratio was not statistically different between the two anesthetics, averaging 2.3±0.1. Hypercapnia evoked global BOLD and CBF increases. Blood-oxygenation-level-dependent, CBF, and CMRO₂ signal changes by visual and vibrotactile stimulations were 0.19% to 0.22%, 18% to 23%, and 4.9% to 6.7%, respectively. The CBF/CMRO₂ ratio was 2.9 to 4.7. Basal CBF and fMRI responses were not statistically different between the two anesthetics. This study establishes a multimodal fMRI protocol to probe clinically relevant functional, physiological and metabolic information in large nonhuman primates.     

Cerebral oxygen metabolism in neonates with congenital heart disease quantified by MRI and optics

Neonatal congenital heart disease (CHD) is associated with altered cerebral hemodynamics and increased risk of brain injury. Two novel noninvasive techniques, magnetic resonance imaging (MRI) and diffuse optical and correlation spectroscopies (diffuse optical spectroscopy (DOS), diffuse correlation spectroscopy (DCS)), were employed to quantify cerebral blood flow (CBF) and oxygen metabolism (CMRO₂) of 32 anesthetized CHD neonates at rest and during hypercapnia. Cerebral venous oxygen saturation (S_vO₂) and CBF were measured simultaneously with MRI in the superior sagittal sinus, yielding global oxygen extraction fraction (OEF) and global CMRO₂ in physiologic units. In addition, microvascular tissue oxygenation (StO₂) and indices of microvascular CBF (BFI) and CMRO₂ (CMRO_2i) in the frontal cortex were determined by DOS/DCS. Median resting-state MRI-measured OEF, CBF, and CMRO₂ were 0.38, 9.7 mL/minute per 100 g and 0.52 mL O₂/minute per 100 g, respectively. These CBF and CMRO₂ values are lower than literature reports for healthy term neonates (which are sparse and quantified using different methods) and resemble values reported for premature infants. Comparison of MRI measurements of global S_vO₂, CBF, and CMRO₂ with corresponding local DOS/DCS measurements demonstrated strong linear correlations (R²=0.69, 0.67, 0.67; P<0.001), permitting calibration of DOS/DCS indices. The results suggest that MRI and optics offer new tools to evaluate cerebral hemodynamics and metabolism in CHD neonates.     

Cerebral metabolic rate of oxygen in obstructive sleep apnea at rest and in response to breath-hold challenge

Obstructive sleep apnea (OSA) is associated with extensive neurologic comorbidities. It is hypothesized that the repeated nocturnal apneas experienced in patients with OSA may inhibit the normal apneic response, resulting in hypoxic brain injury and subsequent neurologic dysfunction. In this study, we applied the recently developed OxFlow MRI method for rapid quantification of cerebral metabolic rate of oxygen (CMRO₂) during a volitional apnea paradigm. MRI data were analyzed in 11 OSA subjects and 10 controls (mean ± SD apnea-hypopnea index (AHI): 43.9 ± 18.1 vs. 2.9 ± 1.6 events/hour, P < 0.0001; age: 53.8 ± 8.2 vs. 45.3 ± 8.5 years, P = 0.027; BMI: 36.6 ± 4.4 vs. 31.9 ± 2.2 kg/m², P = 0.0064). Although total cerebral blood flow and arteriovenous oxygen difference were not significantly different between apneics and controls (P > 0.05), apneics displayed reduced baseline CMRO₂ (117.4 ± 37.5 vs. 151.6 ± 29.4 µmol/100 g/min, P = 0.013). In response to apnea, CMRO₂ decreased more in apneics than controls (−10.9 ± 8.8 % vs. −4.0 ± 6.7 %, P = 0.036). In contrast, group differences in flow-based cerebrovascular reactivity were not significant. Results should be interpreted with caution given the small sample size, and future studies with larger independent samples should examine the observed associations, including potential independent effects of age or BMI. Overall, these data suggest that dysregulation of the apneic response may be a mechanism for OSA-associated neuropathology.     

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.     

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.     

The oxygen paradox of neurovascular coupling

The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO₂). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO₂ decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO₂ can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO₂. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply.