Hyperoxia-induced alterations in cardiovascular function and autonomic control during return to normoxic breathing

Hyperoxia causes hemodynamic alterations. We hypothesized that cardiovascular and autonomic control changes last beyond the end of hyperoxic period into normoxia. Ten healthy volunteers were randomized to breathe either medical air or 100% oxygen for 45 min in a double-blind study design. Measurements were performed before (baseline) and during gas exposure, and then 10, 30, 60, and 90 min after gas exposure. Hemodynamic changes were studied by Doppler echocardiography. Changes in cardiac and vasomotor autonomic control were evaluated through changes in spectral power of heart rate variability and blood pressure variability. Cardiac baroreflex sensitivity was assessed by the sequence method. Hyperoxia significantly decreased heart rate and increased the high frequency power of heart rate variability, suggesting a chemoreflex increase in vagal activity since the slope of cardiac baroreflex was significantly decreased during hyperoxia. Hyperoxia increased significantly the systemic vascular resistances and decreased the low frequency power of blood pressure variability, suggesting that hyperoxic vasoconstriction was not supported by an increase in vascular sympathetic stimulation. These changes lasted for 10 min after hyperoxia (p < 0.05). After the end of hyperoxic exposure, the shift of the power spectral distribution of heart rate variability toward a pattern of increased cardiac sympathetic activity lasted for 30 min (p < 0.05), reflecting a resuming of baseline autonomic balance. Cardiac output and stroke volume were significantly decreased during hyperoxia and returned to baseline values (10 min) later than heart rate. In conclusion, hyperoxia effects continue during return to normoxic breathing, but cardiac and vascular parameters followed different time courses of recovery.     

Analysis of EEG activity in response to binaural beats with different frequencies

When two coherent sounds with nearly similar frequencies are presented to each ear respectively with stereo headphones, the brain integrates the two signals and produces a sensation of a third sound called binaural beat (BB). Although earlier studies showed that BB could influence behavior and cognition, common agreement on the mechanism of BB has not been reached yet. In this work, we employed Relative Power (RP), Phase Locking Value (PLV) and Cross-Mutual Information (CMI) to track EEG changes during BB stimulations. EEG signals were acquired from 13 healthy subjects. Five-minute BBs with four different frequencies were tested: delta band (1 Hz), theta band (5 Hz), alpha band (10 Hz) and beta band (20 Hz). We observed RP increase in theta and alpha bands and decrease in beta band during delta and alpha BB stimulations. RP decreased in beta band during theta BB, while RP decreased in theta band during beta BB. However, no clear brainwave entrainment effect was identified. Connectivity changes were detected following the variation of RP during BB stimulations. Our observation supports the hypothesis that BBs could affect functional brain connectivity, suggesting that the mechanism of BB–brain interaction is worth further study.     

Coupling Between Resting Cerebral Perfusion and EEG

While several studies have investigated interactions between the electroencephalography (EEG) and functional magnetic resonance imaging BOLD signal fluctuations, less is known about the associations between EEG oscillations and baseline brain haemodynamics, and few studies have examined the link between EEG power outside the alpha band and baseline perfusion. Here we compare whole-brain arterial spin labelling perfusion MRI and EEG in a group of healthy adults (n = 16, ten females, median age: 27 years, range 21–48) during an eyes closed rest condition. Correlations emerged between perfusion and global average EEG power in low (delta: 2–4 Hz and theta: 4–7 Hz), middle (alpha: 8–13 Hz), and high (beta: 13–30 Hz and gamma: 30–45 Hz) frequency bands in both cortical and sub-cortical regions. The correlations were predominately positive in middle and high-frequency bands, and negative in delta. In addition, central alpha frequency positively correlated with perfusion in a network of brain regions associated with the modulation of attention and preparedness for external input, and central theta frequency correlated negatively with a widespread network of cortical regions. These results indicate that the coupling between average EEG power/frequency and local cerebral blood flow varies in a frequency specific manner. Our results are consistent with longstanding concepts that decreasing EEG frequencies which in general map onto decreasing levels of activation.     

Mapping changes in cortical activity during sleep in the first 4 years of life

A coherent body of evidence supports the notion that sleep is a local and use‐dependent process. Significant changes in brain morphology and function occur in the first years of life, revealing a postero–anterior trajectory of cortical maturation. On this basis, a recent study demonstrated that regional cortical maturation between early childhood and late adolescence is reflected in regional changes of sleep slow wave activity (SWA) during non‐rapid eye movement (NREM) sleep. Our hypothesis is that changes of electroencephalogram (EEG) rhythms during sleep from birth to childhood are also mirrored by parallel regional changes in the EEG rhythms of sleep according to the assumption of a postero–anterior gradient in cortical maturation. We studied all‐night EEG of 39 healthy, full‐term, infants and children aged between 0 and 48 months, evaluating regional differences in NREM sleep. We confirmed the strictly local nature of sleep with frequency‐specific regional differences. Specifically, we found a general shift of maxima of the upper alpha activity from occipital to prefrontal regions, expressed mainly by the ~11 Hz frequency. This shift corresponds to a postero–anterior trajectory of the so‐called ‘slow spindles’. The theta and alpha EEG activity of the frontal cortex exhibits a clear, positive, correlation with age. We conclude that specific local differences during NREM sleep, parallel cortical maturation also in the first 4 years of life.     

Ongoing theta oscillations predict encoding of subjective memory type

Recent human electro-encephalography (EEG) studies show that ongoing brain states support successful encoding of human memory, including recognition. However it is not known whether ongoing cortical activity qualitatively determines different memory types at encoding. In this study, using a remember/know procedure, we measured the EEG oscillations that emerge before and during the encoding of abstract visual stimuli in episodic and non-episodic memory, focusing on the theta (2–8 Hz) and alpha (9–12 Hz) oscillation range. We found that enhanced prestimulus theta oscillations precede episodic memory encoding, compared to non-episodic encoding. The prestimulus difference appeared at frontal and temporal sites. Furthermore, the theta enhancement reappeared after stimulus onset. Enhanced upper alpha oscillations suggested increased working memory processing in the case of episodic memory. Finally, the pre- and post-stimulus theta and alpha amplitudes showed different correlation patterns for episodic and non-episodic encoding. Our results are the first to suggest that encoding of episodic memory depends on preparatory processing in the form of frontal and temporal theta oscillations.     

Influence of inspiratory threshold load on cardiovascular responses to controlled breathing at 0.1 Hz

Slow, deep breathing is being used as a self‐management intervention for various health conditions including pain and hypertension. Stimulation of the arterial baroreceptors and increased vagal modulation are among the proposed mechanisms for the therapeutic effects of slow, deep breathing. We investigated whether adding inspiratory threshold load can enhance the cardiovascular responses to controlled breathing at the frequency of 0.1 Hz, a common form of slow, deep breathing. Healthy volunteers (N = 29) performed controlled breathing at 0.1 Hz (6 breaths/minute) without load and with inspiratory threshold loads of 5 cmH₂O and 10 cmH₂O. Respiratory airflow, heart rate, and blood pressure were continuously recorded. The amplitude of the systolic blood pressure variation during respiratory cycles increased with increasing loads. Respiratory sinus arrhythmia was higher during controlled breathing at 0.1 Hz with the load of 10 cmH₂O compared to without load. Baroreflex sensitivity was not affected by loads. The effect of loads on respiratory sinus arrhythmia was mediated by increasing the amplitude of systolic blood pressure variation during respiratory cycles. These results suggest that applying small inspiratory threshold loads during controlled breathing at 0.1 Hz increases cardiac vagal modulation by this breathing exercise. This effect seems to be mediated by stronger stimulation of the arterial baroreceptors because of larger systolic blood pressure swings along the respiratory cycle. The potential benefit of long‐term practice of controlled breathing at 0.1 Hz with inspiratory threshold loads on baroreflex function and cardiac vagal control needs to be investigated, particularly in pain and hypertension patients.     

Effects of moderate hyperoxia on oxygen consumption during submaximal and maximal exercise

The present study examined the effect of hyperoxia on oxygen uptake (V˙O₂) and on maximal oxygen uptake (V˙O_2max) during incremental exercise (IE) and constant work rate exercise (CWRE). Ten subjects performed IE on a bicycle ergometer under normoxic and hyperoxic conditions (30% oxygen). They also performed four 12-min bouts of CWRE at 40, 55, 70 and 85% of normoxic V˙O_2max (ex1, ex2, ex3 and ex4, respectively) in normoxia and in hyperoxia. V˙O_2max was significantly improved by 15.0 (15.2)% under hyperoxia, while performance (maximum workload, W _max) was improved by only +4.5 (3.0)%. During IE, the slope of the linear regression relating V˙O₂ to work rate was significantly steeper in hyperoxia than in normoxia [10.80 (0.88) vs 10.06 (0.66) ml·min^–1·W^–1]. During CWRE, we found a higher V˙O₂ at ex1, ex2, ex3 and ex4, and a higher V˙O₂ slow component at ex4 under hyperoxia. We have shown that breathing hyperoxic gas increases V˙O_2max, but to an extent that is difficult to explain by an increase in oxygen supply alone. Changes in metabolic response, fibre type recruitment and V˙O₂ of non-exercising tissue could explain the additional V˙O₂ for a given submaximal work rate under hyperoxia. Electronic Publication     

Effects of pulmonary gas embolism on circulation and respiration in the dog

Summary The purpose of this investigation was to find an explanation for the arterial hypoxemia which occurs during pulmonary gas embolism in normoxic conditions. Infusion of oxygen at a rate of 3.2 ml min^–1 during constant artificial ventilation led to an increase of the normoxic shunt percentage from 2.9 to 21.8. When excluding the contribution of lung units with low ventilation-perfusion ratios to the total shunt by breathing hyperoxic gas mixtures, the remaining hyperoxic shunt percentage increased from 2.9 to only 4.3 during inhalation of pure oxygen. There was a linear relationship between this hyperoxic shunt percentage and the degree of pulmonary gas embolization as expressed by the ratio of diastolic pulmonary arterial pressure with and without embolization. A comparison of the normoxic and hyperoxic increases of shunt percentage due to pulmonary gas embolism suggests that a major part of the arterial hypoxemia in normoxic condition is due to a marked increase in the number of lung units with low ventilation-perfusion ratios, i.e., by an enhanced unevenness of the distribution of the ventilation-perfusion ratio in the lungs. A moderate increase of the physiological dead space indicates some increase of lung units with high ventilation-perfusion ratios or of the alveolar dead space. The minor increase of the hyperoxic shunt percentage, expressing venous admixture by anatomical veno-arterial and possible atelectatic shunting, is probably due to atelectatic areas in the lungs. CO₂ elimination during the same extent of pulmonary gas embolization was more impaired during hyperoxia than during normoxia. This effect may be due to the release of hypoxic vasoconstriction in lung units with low ventilation-perfusion ratios during air breathing by hyperoxia, so that more blood would be shifted to these lung units. The elimination of CO₂ from that blood is impaired because the CO₂ pressure gradient is too small to compensate for the low ventilation in these lung units.     

Preparing for hard times: Scalp and intracranial physiological signatures of proactive cognitive control

Based on reward and difficulty information, people can strategically adjust proactive cognitive control. fMRI research shows that motivated proactive control is implemented through fronto‐parietal control networks that are triggered by reward and difficulty cues. Here, we investigate electrophysiological signatures of proactive control. Previously, the contingent negative variation (CNV) in the ERPs and oscillatory power in the theta (4–8 Hz) and alpha band (8–14 Hz) have been suggested as signatures of control implementation. However, experimental designs did not always separate control implementation from motor preparation. Critically, we used a mental calculation task to investigate effects of proactive control implementation on the CNV and on theta and alpha power, in absence of motor preparation. In the period leading up to task onset, we found a more negative CNV, increased theta power, and decreased alpha power for hard versus easy calculations, showing increased proactive control implementation when a difficult task was expected. These three measures also correlated with behavioral performance, both across trials and across subjects. In addition to scalp EEG in healthy participants, we collected intracranial local field potential recordings in an epilepsy patient. We observed a slow‐drift component that was more pronounced for hard trials in a hippocampal location, possibly reflecting task‐specific preparation for hard mental calculations. The current study thus shows that difficulty information triggers proactive control in absence of motor preparation and elucidates its neurophysiological signatures.     

Does Greater Low Frequency EEG Activity in Normal Immaturity and in Children with Epilepsy Arise in the Same Neuronal Network?

Greater low frequency power (<8 Hz) in the electroencephalogram (EEG) at rest is normal in the immature developing brain of children when compared to adults. Children with epilepsy also have greater low frequency interictal resting EEG activity. Whether these power elevations reflect brain immaturity due to a developmental lag or the underlying epileptic pathophysiology is unclear. The present study addresses this question by analyzing spectral EEG topographies and sources for normally developing children and children with epilepsy. We first compared the resting EEG of healthy children to that of healthy adults to isolate effects related to normal brain immaturity. Next, we compared the EEG from 10 children with generalized cryptogenic epilepsy to the EEG of 24 healthy children to isolate effects related to epilepsy. Spectral analysis revealed that global low (delta: 1–3 Hz, theta: 4–7 Hz), medium (alpha: 8–12 Hz) and high (beta: 13–25 Hz) frequency EEG activity was greater in children without epilepsy compared to adults, and even further elevated for children with epilepsy. Topographical and tomographic EEG analyses showed that normal immaturity corresponded to greater delta and theta activity at fronto-central scalp and brain regions, respectively. In contrast, the epilepsy-related activity elevations were predominantly in the alpha band at parieto-occipital electrodes and brain regions, respectively. We conclude that lower frequency activity can be a sign of normal brain immaturity or brain pathology depending on the specific topography and frequency of the oscillating neuronal network.     

Pulmonary perfusion quantification with flow‐sensitive inversion recovery (FAIR) UTE MRI in small animal imaging

Blood perfusion in lung parenchyma is an important property for assessing lung function. In small animals, its quantitation is limited even with radioactive isotopes or dynamic contrast‐enhanced MRI techniques. In this study, the feasibility flow‐sensitive alternating inversion recovery (FAIR) for the quantification of blood flow in lung parenchyma in free breathing rats at 7 T has been investigated. In order to obtain sufficient signal from the short T₂* lung parenchyma, a 2D ultra‐short echo time (UTE) Look‐Locker read‐out has been implemented. Acquisitions were segmented to maintain acquisition time within an acceptable range. A method to perform retrospective respiratory gating (DC‐SG) has been applied to investigate the impact of respiratory movement. Reproducibilities within and between sessions were estimated, and the ability of FAIR‐UTE to identify the decrease of lung perfusion under hyperoxic conditions was tested. The implemented technique allowed for the visualization of lung parenchyma with excellent SNR and no respiratory artifact even in ungated acquisitions. Lung parenchyma perfusion was obtained as 32.54 ± 2.26 mL/g/min in the left lung, and 34.09 ± 2.75 mL/g/min in the right lung. Application of retrospective gating significantly but minimally changes the perfusion values, implying that respiratory gating may not be necessary with this center‐our acquisition method. A decrease of 10% in lung perfusion was found between normoxic and hyperoxic conditions, proving the feasibility of the FAIR‐UTE approach to quantify lung perfusion changes.     

Developmental plasticity of ventilatory control in zebrafish, Danio rerio

To determine whether development of ventilatory control in zebrafish (Danio rerio) exhibits plasticity, embryos were exposed to hypoxia, hyperoxia or hypercapnia for the first 7 days post-fertilization. Their acute reflex breathing responses to ventilatory stimuli (hypoxia, hypercapnia and external cyanide) were assessed when they had reached maturity (3 months or older). Zebrafish reared under hyperoxic conditions exhibited significantly higher breathing frequencies at rest (283+/-27min(-1) versus 212+/-16min(-1) in control fish); breathing frequency was unaffected in adult fish subjected to hyperoxia for 7 days. The respiratory responses of fish reared in hyperoxic water to acute hypoxia, hypercapnia or external cyanide were blunted (hypoxia, cyanide) or eliminated (hypercapnia). Adult fish exposed for 7 days to hyperoxia showed no change in acute responses to these stimuli. The respiratory responses to acute hypoxia, hypercapnia or external cyanide of fish reared under hypoxic or hypercapnic conditions were similar to those in fish reared under normal conditions. A subset of all fish examined exhibited episodic breathing; an analysis of breathing patterns demonstrated that fish reared under hypercapnic conditions had an increased tendency to display episodic breathing. The results of this study reveal that there is flexibility in the design and functioning of the embryonic or larval respiratory system in zebrafish.     

Local changes in the wake electroencephalogram precedes lane departures

The objective of this exploratory study is to investigate if lane departures are associated with local sleep, measured via source‐localized electroencephalography (EEG) theta power in the 5–9 Hz frequency range. Thirty participants drove in an advanced driving simulator, resulting in 135 lane departures at high levels of self‐reported sleepiness. These lane departures were compared to matching non‐departures at the same sleepiness level within the same individual. There was no correspondence between lane departures and global theta activity. However, at the local level an increased risk for lane departures was associated with increased theta content in brain regions related to motor function.     

Neural basis of implicit motor sequence learning: Modulation of cortical power

Implicit sequence learning describes the acquisition of serially ordered movements and sequentially structured cognitive information, that occurs without awareness. Theta, alpha and beta cortical oscillations are present during implicit motor sequence learning, but their role in this process is unclear. The current study addressed this gap in the literature. A total of 50 healthy adults aged between 19 and 37 years participated in the study. Implicit motor sequence learning was examined using the Serial Reaction Time task where participants unknowingly repeat a sequence of finger movements in response to a visual stimulus. Sequence learning was examined by comparing reaction times and oscillatory power between sequence trials and a set of control trials comprising random stimulus presentations. Electroencephalography was recorded as participants completed the task. Analyses of the behavioral data revealed participants learnt the sequence. Analyses of oscillatory activity, using permutation testing, revealed sequence learning was associated with a decrease in theta band (4–7 Hz) power recorded over frontal and central electrode sites. Sequence learning effects were not observed in the alpha (7–12 Hz) or beta bands (12–20 Hz). Even though alpha and beta power modulations have long been associated with executing a motor response, it seems theta power is a correlate of sequence learning in the manual domain. Theta power modulations on the serial reaction time task may reflect disengagement of attentional resources, either promoting or occurring as a consequence of implicit motor sequence learning     

Theta‐ and alpha‐power enhancements in the electroencephalogram as an auditory delayed match‐to‐sample task becomes impossibly difficult

Recent studies have related enhancements of theta‐ (∼4–8 Hz) and alpha‐power (∼8–13 Hz) to listening effort based on parallels between enhancement and task difficulty. In contrast, nonauditory works demonstrate that, although increases in difficulty are initially accompanied by increases in effort, effort decreases when a task becomes so difficult as to exceed one's ability. Given the latter, we examined whether theta‐ and alpha‐power enhancements thought to reflect effortful listening show a quadratic trend across levels of listening difficulty from impossible to easy. Listeners (n = 14) performed an auditory delayed match‐to‐sample task with frequency‐modulated tonal sweeps under impossible, difficult (at ∼70.7% correct threshold), and easy (well above threshold) conditions. Frontal midline theta‐power and posterior alpha‐power enhancements were observed during the retention interval, with greatest enhancement in the difficult condition. Independent component‐based analyses of data suggest that theta‐power enhancements stemmed from medial frontal sources at or near the anterior cingulate cortex, whereas alpha‐power effects stemmed from occipital cortices. Results support the notion that theta‐ and alpha‐power enhancements reflect effortful cognitive processes during listening, related to auditory working memory and the inhibition of task‐irrelevant cortical processing regions, respectively. Theta‐ and alpha‐power dynamics can be used to characterize the cognitive processes that make up effortful listening, including qualitatively different types of listening effort.     

EEG network connectivity changes in mild cognitive impairment — Preliminary results

Resting state EEGs were compared between patients with amnestic subtype of mild cognitive impairment (aMCI) and matched elderly controls at two times over a one year period. The study aimed at investigating the role of functional connectivity between and within different brain regions in relation to the progression of cognitive deficit in MCI. The EEG was recorded in two sessions during eyes closed and eyes open resting conditions. Functional brain connectivity was investigated based on the measurement of phase synchronization in different frequency bands. Delta and theta synchronization characteristics indicated decreased level of local and large-scale connectivity in the patients within the frontal, between the frontal and temporal, and frontal and parietal brain areas which was more pronounced 1 year later. As a consequence of opening the eyes connectivity in the alpha1 band within the parietal lobe decreased compared to the eyes closed condition but only in the control group. The lack of alpha1 band reactivity following eye opening could reliably differentiate patients from controls. Our preliminary results support the notion that the functional disconnection between distant brain areas is a characteristic feature of MCI, and may prove to be predictive in terms of the progression of this condition.     

Impairment in recognition of emotional facial expressions in Alzheimer's disease is represented by EEG theta and alpha responses

Behavioral studies have shown that the recognition of facial expressions may be impaired in patients with Alzheimer's disease (AD). The identification and recognition of a facial expression might be represented by event‐related brain oscillations. The present study aims to analyze EEG event‐related oscillations and determine the electrophysiological indicators of impaired facial expression recognition in AD patients. EEGs of 30 healthy controls and 30 AD patients were recorded during their perception of three different facial expressions (angry, happy, neutral). Event‐related power spectrum and phase locking were analyzed in the theta (4?7) and alpha (8?13 Hz) frequency bands with the EEGLAB open toolbox. There was a significant facial Expression × Group interaction (p < 0.05) for the theta power spectrum; the healthy control group had higher theta power than the AD group during the perception of angry facial expressions (p < 0.05). There was a significant hemisphere difference between the two groups (p < 0.05). There was a right hemisphere alpha power dominance in healthy subjects. However, AD patients did not have this alpha power asymmetry. The present study, for the first time in the literature, presents the electrophysiological indicators of impaired recognition of facial expression in AD patients. The current study could be a basis for future studies that will analyze emotional processing in different kinds of dementia patients, and this study may have provided indicators of electrophysiological correlates of behavioral problems observed in clinical practice.     

Topographic sleep EEG changes in the acute and chronic stage of hemispheric stroke

After stroke, the injured brain undergoes extensive reorganization and reconnection. Sleep may play a role in synaptic plasticity underlying stroke recovery. To test this hypothesis, we investigated topographic sleep electroencephalographic characteristics, as a measure of brain reorganization, in the acute and chronic stages after hemispheric stroke. We studied eight patients with unilateral stroke in the supply territory of the middle cerebral artery and eight matched controls. All subjects underwent a detailed clinical examination including assessment of stroke severity, sleep habits and disturbances, anxiety and depression, and high‐density electroencephalogram examination with 128 electrodes during sleep. The recordings were performed within 10 days after stroke in all patients, and in six patients also 3 months later. During sleep, we found higher slow‐wave and theta activity over the affected hemisphere in the infarct area in the acute and chronic stage of stroke. Slow‐wave, theta activity and spindle frequency range power over the affected hemisphere were lower in comparison to the non‐affected side in a peri‐infarct area in the patients’ group, which persisted over time. Conversely, in wakefulness, only an increase of delta, theta activity and a slowing of alpha activity over the infarct area were found. Sleep slow‐wave activity correlated with stroke severity and outcome. Stroke might have differential effects on the generation of delta activity in wakefulness and sleep slow waves (1–8 Hz). Sleep electroencephalogram changes over both the affected and non‐affected hemispheres reflect the acute dysfunction caused by stroke and the plastic changes underlying its recovery. Moreover, these changes correlate with stroke severity and outcome.     

Oxygen‐sensitive MRI assessment of tumor response to hypoxic gas breathing challenge

Oxygen‐sensitive MRI has been extensively used to investigate tumor oxygenation based on the response (R₂* and/or R₁) to a gas breathing challenge. Most studies have reported response to hyperoxic gas indicating potential biomarkers of hypoxia. Few studies have examined hypoxic gas breathing and we have now evaluated acute dynamic changes in rat breast tumors. Rats bearing syngeneic subcutaneous (n = 15) or orthotopic (n = 7) 13762NF breast tumors were exposed to a 16% O₂ gas breathing challenge and monitored using blood oxygen level dependent (BOLD) R₂* and tissue oxygen level dependent (TOLD) T₁‐weighted measurements at 4.7 T. As a control, we used a traditional hyperoxic gas breathing challenge with 100% O₂ on a subset of the subcutaneous tumor bearing rats (n = 6). Tumor subregions identified as responsive on the basis of R₂* dynamics coincided with the viable tumor area as judged by subsequent H&E staining. As expected, R₂* decreased and T₁‐weighted signal increased in response to 100% O₂ breathing challenge. Meanwhile, 16% O₂ breathing elicited an increase in R₂*, but divergent response (increase or decrease) in T₁‐weighted signal. The T₁‐weighted signal increase may signify a dominating BOLD effect triggered by 16% O₂ in the relatively more hypoxic tumors, whereby the influence of increased paramagnetic deoxyhemoglobin outweighs decreased pO₂. The results emphasize the importance of combined BOLD and TOLD measurements for the correct interpretation of tumor oxygenation properties.