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Effects of hyperoxia on resting state functional magnetic resonance imaging Ying Wei Wua,*, Cheuk Ying Tangb,c,*, Johnny Ngb, Edmund Wongb, David Carpenterb and Xiaofeng Taoa We studied the effect of oxygen inhalation during resting state functional MRI scanning in healthy control individuals. We hypothesized that resting state networks would be modified under hyperoxic conditions. Thirty-four normal volunteers were recruited for this study. All participants were scanned twice: once while breathing atmospheric air and once under hyperoxic conditions in a randomized order. Hyperoxic conditions were produced by administering 100% O2. Blood oxygen level-dependent T2* scans were obtained for each of the scans. Resting state networks were extracted using independent component analysis. A paired t-test showed that the resting state networks scans (default mode network, attention network and executive network) acquired under hyperoxic conditions had significantly higher Z-scores than scans performed under atmospheric air. Spectral analysis of the time-course signal in these networks also showed a difference in the total power of low frequencies between the two conditions. These results were reversed in the visual network. Clinical or research
Background and purpose Increasing research has been published on oxygenenhanced MRI. The applications range from studying pulmonary function [1] and tumor oxygenation [2]. Assessment of tumor hypoxia is critical to subsequent treatment strategies [3,4]. Oxygen challenge paradigms have also been used to differentiate ischemic lesions [5]. Functional MRI (MRI) relying on the BOLD (Blood Oxygenation Level Dependent) effect is ideally suited to study the effect of hyperoxic conditions on the brain. Clinical applications of fMRI have mainly been for presurgical localization imaging purposes [6]. Depending on the functional location of the tumor, different stimulation paradigms are designed to activate the region of interest [7–9]. There are several drawbacks of using paradigmdriven fMRI. One is the need for specialized peripherals to produce visual, auditory, or tactile stimuli that may not always be available in clinical MRI settings. Generally, one stimulation paradigm can only target one functional domain per scan. There are also no standardized paradigms for the various functional brain regions. Additional confounds in paradigm-driven fMRI are the need for the cooperation of the patients in performing the tasks presented; this poses complications with very sick patients, the elderly, children, and patients with altered cognitive states. 0959-4965 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
applications of oxygen-enhanced MRI need to take into account the modularly effects that hyperoxia exerts on the networks resting state functional MRI. NeuroReport 25:1186–1190 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2014, 25:1186–1190 Keywords: Default Mode Network, hyperoxia, resting state functional magnetic resonance imaging a
Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, Departments of bRadiology and Psychiatry, Mt. Sinai School of Medicine, New York, New York, USA
c
Correspondence to Xiaofeng Tao, MD, PhD, Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No.639 ZhizaoJu Road, Shanghai 200011, China Tel: + 86 21 23271699 5335; fax: + 86 21 2327 1699; e-mail: [email protected] *Ying Wei Wu and Cheuk Ying Tang contributed equally to the writing of this article. Received 3 June 2014 accepted 2 July 2014
In recent years, increasing work has been published on the use of resting state functional MRI (rsFMRI) in neuropsychiatric research [10–12]. The rsFMRI approach differs from the traditional paradigm-driven fMRI. In rsFMRI, the patients do not perform any specific task, but are told to remain at rest while fMRI data are being acquired. Using mathematical algorithms such as independent component analysis, one can then extract different spatially distinct networks that support various cognitive functions [13]. Several of these networks have consistently been reported by various groups [14–16]. Using the rsFMRI approach, one avoids potential confounds of task performance in paradigm-driven fMRI and it can be applied in situations where the patient cannot perform any task such as when they are paralyzed or are under anesthesia. It also allows one to investigate multiple brains regions simultaneously in one scan. For these reasons, rsFMRI has become a popular approach in functional brain research as well as in presurgical planning in clinical applications [17,18]. The fMRI BOLD signal is very small and is of the order of a few percent above baseline. The BOLD signal is the result of changes in local oxygenation of blood upon neuronal firing. Our group and others have reported on the effects of oxygen saturation in blood on T1, T2, and T2* relaxation rates in MRI [19,20]. The effects of oxygen on DOI: 10.1097/WNR.0000000000000239
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Effects of hyperoxia on resting state fMRI Wu et al. 1187
cerebral blood flow have been well studied before [21,22], where it has been shown that inhalation of pure oxygen causes a small decrease in cerebral blood flow. Oxygen is therefore an important modulator of the BOLD signal. Oxygen-enhanced MRI has been used before in MRI as a signal enhancer for lung imaging [23–27], renal [28], and tumor imaging [29]. Very few studies have studied the effects of oxygen on functional imaging [30,31]. In these studies, oxygen enhancement was used as a modulator of the BOLD signal similar to a paradigm-driven fMRI scan with 100% O2 as the ‘ON’ condition. Short epochs of oxygen-enhanced (‘ON’) frames were interleaved with ambient air (‘OFF’) within the same scan. In this study, we aimed to investigate the effect of continuous inhalation of 100% O2 on the functional brain networks as obtained using rsFMRI.
Methods Participants
Overall, 34 healthy volunteers (20 women, 14 men) were recruited for this study. The mean age of the participants was 26 and SD = 4.76. Informed consent was obtained from all participants before imaging. Imaging
All imaging were performed on a Philips 3T Achieva MRI (Philips Healthcare, Best, the Netherlands). A proton density/ T2-weighted, dual echo sequence was used to screen for incidental pathology (TR = 2500 ms, TE = 10, 80 ms, FOV = 23.0 cm, FA = 90°, 36 axial slices, thickness = 3 mm, skip = 1 mm, matrix size = 400 × 312). One rsFMRI baseline scan was acquired using a field echo EPI sequence with the following parameters: TR = 2000 ms, TE = 27 ms, FOV = 21.0 cm, FA = 90°, 38 slices, skip = 0.8 mm, matrix size = 88 × 86, and 300 dynamics. Each resting state scan lasted about 10 min. Each participant received two 10 min resting state scans. During one scan, they were breathing in 100% air and during the second scan they were breathing in air. The order was randomized among the participants. Pure O2 or air was administered through a standard cannula with the eyes closed.
were extracted and entered into higher-level analyses. General linear modeling and permutation-based inference testing (RANDOMISE) were used to test for group differences and symptom severity correlates of the DMN. We used a matched t-test for all the participants comparing scans during inhalation of room air and pure O2. In addition to voxelwise comparisons, we also investigated the power spectrum of the mean time-course signal in the network. We used a similar strategy as reported by Zou et al. [32] to extract the metric fractional amplitude of low frequency fluctuations (fALFF). This is a measure of the power of the frequency band that is a characteristic of the BOLD signal that supports the resting state networks. The mean time course of the DMN, VN, and AN networks was extracted and the power spectrum was computed using in-house software developed in Matlab (Matlab R2012a; The Mathworks Inc., Natick, Massachusetts, USA), and fALFF was computed accordingly. fALFF was defined as the ratio of the total low-frequency (0.01–0.08 Hz) power spectrum and the full range power spectrum. This was computed for every network and every participant for both conditions. A paired t-test was computed between air and 100% oxygen inhalation conditions for the participants using Statistica V10 (Statsoft Inc., Tulsa, Oklahoma, USA).
Results Paired t-tests between ambient air versus 100% O2 showed significant differences in all three networks, with the condition of 100% O2 yielding higher z-values. The DMN showed significant increases in the frontal and prefrontal cortices, the anterior cingulate, and portions of the superior parietal regions (Fig. 1a). The AN showed the most significant increases in the posterior parietal and prefrontal cortices. Small decreases were also detected in the portions of the anterior cingulate (Fig. 1b). The VN also showed significant decreases in the primary visual cortex (V1) (Fig. 1d). Paired t-tests between ambient air versus 100% O2 showed a significant decrease in fALFF in the DMN (P < 0.04), VN (P < 0.0004), but not significant in the AN (P = 0.77).
Analysis
Preprocessing of the functional images was performed in FSL and included motion correction (MCFLIRT), coregistration to the high-resolution T1 images (FLIRT), and nonlinear registration to the standard MNI T1 template (FNIRT). Independent component analysis was used to identify 20 unique networks of resting state activity using MELODIC [13] as implemented in FSL. The default mode network (DMN) consisting of the anterior and posterior cingulate cortex and the bilateral parietal cortices has consistently been reported before in other studies [14–16]. In addition to the DMN, the attention network (AN) and the visual network (VN) were also identified for further analysis. These three networks were identified for each participant and z-statistic images
Discussion Oxygen is essential for the proper biochemical reactions that support neuronal functions. Its homeostasis is therefore tightly controlled [33]. Because of the vascular supply and draining distribution, there is a heterogeneous distribution of oxygen saturation [34,35]. At baseline, the oxygen field is low and upon regional activation a surplus of oxygenated blood is supplied to the activation site, leading to an increase in the BOLD signal. Although under normal pathological conditions the oxygen dissociation curve predicts that the oxyhemoglobin is mostly saturated at partial pressure above 60 mm Hg, inhalation of 100% oxygen will have a modest effect on oxyhemoglobin saturation, but can increase the dissolved oxygen in arterial
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Statistical results for three rsFMRI networks. The group network (white) is superimposed on a standard anatomical MRI grayscale template. The paired t-test between hyperoxia and room air is superimposed on the network in color. Hyperoxia > air is indicated in medium to light grey and hyperoxia < air in dark grey. Only significant voxels at P < 0.05 level are shown. (a) Default mode network, (b) left and right attention network, (c) executive control network, (d) visual network. rsFMRI, resting state functional MRI.
blood several times [31]. Hyperoxic-induced changes in hemodynamics have not always been consistent; whereas some report no changes [36], others suggests increases [37] as well as decreases [38]. Although oxygen acts as a vasoconstrictor, other studies have shown that this mechanism has minimal effect on the BOLD signal [21,22]. Our results indicate that the rsFMRI scans show a higher Z-score in several of the resting state networks. These higher z-scores may have resulted from several sources. They could indicate both more coherent timesynchronous activities within the voxels of a network and less noise in the time-course signal itself. Oxygen exerts several effects on the MRI signal. Oxyhemoglobin is diamagnetic and would increase the MR signal, thereby increasing the baseline signal intensity. Animal studies have shown linear relationships of R2* with hypoxia in the brain [39]. Our group and others have also reported in a rat model an increase in T2 & T2* values under hyperoxic conditions [19,40]. Another effect of
oxygen is the shortening of T1 values of blood [19,41]. This shortened T1 might also increase the overall BOLD signal at baseline, especially with incomplete recovery of the spins at short TRs typically used in fMRI. Oxygen saturation exerts two opposing effects on the BOLD signal: on the one hand, it causes vasoconstriction (which might reduce the signal) and on the other the oxygenated blood is diamagnetic (which causes the MR signal to increase). In both the Kalamangalam and Losert studies, oxygen enhancement led to a boost in the BOLD signal [30,31]. In the study by Losert and colleagues, it was reported that oxygen enhancement led to greater than 3% single intensity change in cortical gray matter when compared with white matter (< 1%). In the study by Thulborn et al. [20], oxygen was used as a stimulus to study epileptic patients. Although not part of their analysis, they noted that during the oxygen-enhanced condition, the spontaneous BOLD signal also showed a larger variance. Our observation of higher z-scores for the networks might reflect the effect of this larger variance.
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Effects of hyperoxia on resting state fMRI Wu et al. 1189
The power spectral analysis also showed a significant difference in the fractional power of the resting state signal. Our results indicated that the fALFF was significantly lower under the hyperoxic condition in the DMN and VN networks; although not significant, the mean values were also lower in the AN. Applications of fALFF in psychiatric studies have reported both increases as well as decreases depending on the region of the brain [42–45]. Our result can be interpreted as consistent with the voxel-by-voxel comparisons. As the coherence of the resting state time signal is increased, the spread of the distribution of the power of the frequencies will decrease. This will lead to a reduced fALFF.
available for the analysis of the rsFMRI data, other factors such as heterogeneity of cerebrovascular reserve would limit its usefulness.
It is interesting to note that the inhalation of oxygen had a negative effect on the VN. Studies on the effect of caffeine on the BOLD signal in fMRI have also reported different activation patterns between the visual cortex and other gray matter regions including the frontal lobes [46]. It was suggested that caffeine might have a differential enhancing effect of executive areas versus more passive regions such as the visual cortex. Oxygen might have a similar mechanism on brain function. To obtain a consistent resting state, we instructed our participants to keep their eyes closed. Other studies have also shown a suppression of the BOLD signal under the eyes closed condition [47].
It is well known that there is an age-dependent decline in cerebral blood flow and hemoglobin oxygenation. The participants we have studied had a narrow age range. Further studies should be carried out to investigate the age-dependent effect of oxygen-enhanced rsFMRI.
Although there have been numerous studies showing the detrimental effects of hypoxia, there have also been few reports on the enhancing effects of oxygen inhalation on cognitive performance [48–50]. The enhanced cognitive abilities might also contribute toward a more coherent signaling between the distant brain regions that support the individual networks. The enhanced cognitive abilities might be reflected in the more coherent oscillations in the respective networks. This is similar to other reports on brain function and meditation, where it was found that participants who are experienced meditation practitioners show increased functional connectivity in the AN [51] and DMNs [52]. There are also numerous reports showing that meditation practitioners have higher alpha anterior–posterior electroencephalography (EEG) coherence in the alpha band during meditative states [53,54]. Although the signals of EEG and rsfMRI are of very different timescales (milliseconds vs. seconds), the electrical activity of individual neurons firing (source of the EEG signal) does give rise to the macroscopic changes in regional blood flow and oxygen consumption (source of the rsfMRI signal).
Inhaling oxygen at higher than atmospheric pressure can be toxic to the central nervous system as in the case of scuba divers breathing from 100% oxygen tanks. At high partial pressure, oxygen can cause oxidative cell damage, collapse of lungs, and seizures. At lower partial pressure, as used here, small changes in hormonal levels, heart rate, and blood pressure are common [55–57]. Moderate levels of hyperoxia could also exert effects on various substructures of the central nervous system such as the insular cortex, hypothalamus, and hippocampus [58].
Conclusion We have shown that hyperoxic conditions can modulate the various resting state networks. Our results imply that oxygen inhalation increases the time coherence in voxels within the DMN, executive network, and AN, but decreases in the VN. These results suggest that we should be cautious when interpreting rsFMRI results in oxygen-enhanced MRI or in patients with conditions that might affect oxygen delivery.
Acknowledgements This study was supported by Shanghai Municipal Education Commission research innovation grant No.12ZZ028; Outstanding academic leader of Shanghai Science and Technology Bureau (grant No.13XD1402400). Conflicts of interest
There are no conflicts of interest.
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There are some limitations in this pilot study. In this study, the 100% O2 was delivered through a cannula and should not be considered 100% as there is inevitably a small amount of room air diluted with the O2. We did not measure the respiration rate or the blood oxygen content to determine the increase in blood oxygen levels, but it has been reported before that the inhalation of pure oxygen could increase blood oxygen levels by 30% or more [48], although even if the blood oxygen content was
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Integrative systems
Effects of hyperoxia on resting state functional magnetic resonance imaging Ying Wei Wua,*, Cheuk Ying Tangb,c,*, Johnny Ngb, Edmund Wongb, David Carpenterb and Xiaofeng Taoa We studied the effect of oxygen inhalation during resting state functional MRI scanning in healthy control individuals. We hypothesized that resting state networks would be modified under hyperoxic conditions. Thirty-four normal volunteers were recruited for this study. All participants were scanned twice: once while breathing atmospheric air and once under hyperoxic conditions in a randomized order. Hyperoxic conditions were produced by administering 100% O2. Blood oxygen level-dependent T2* scans were obtained for each of the scans. Resting state networks were extracted using independent component analysis. A paired t-test showed that the resting state networks scans (default mode network, attention network and executive network) acquired under hyperoxic conditions had significantly higher Z-scores than scans performed under atmospheric air. Spectral analysis of the time-course signal in these networks also showed a difference in the total power of low frequencies between the two conditions. These results were reversed in the visual network. Clinical or research
Background and purpose Increasing research has been published on oxygenenhanced MRI. The applications range from studying pulmonary function [1] and tumor oxygenation [2]. Assessment of tumor hypoxia is critical to subsequent treatment strategies [3,4]. Oxygen challenge paradigms have also been used to differentiate ischemic lesions [5]. Functional MRI (MRI) relying on the BOLD (Blood Oxygenation Level Dependent) effect is ideally suited to study the effect of hyperoxic conditions on the brain. Clinical applications of fMRI have mainly been for presurgical localization imaging purposes [6]. Depending on the functional location of the tumor, different stimulation paradigms are designed to activate the region of interest [7–9]. There are several drawbacks of using paradigmdriven fMRI. One is the need for specialized peripherals to produce visual, auditory, or tactile stimuli that may not always be available in clinical MRI settings. Generally, one stimulation paradigm can only target one functional domain per scan. There are also no standardized paradigms for the various functional brain regions. Additional confounds in paradigm-driven fMRI are the need for the cooperation of the patients in performing the tasks presented; this poses complications with very sick patients, the elderly, children, and patients with altered cognitive states. 0959-4965 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
applications of oxygen-enhanced MRI need to take into account the modularly effects that hyperoxia exerts on the networks resting state functional MRI. NeuroReport 25:1186–1190 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2014, 25:1186–1190 Keywords: Default Mode Network, hyperoxia, resting state functional magnetic resonance imaging a
Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, Departments of bRadiology and Psychiatry, Mt. Sinai School of Medicine, New York, New York, USA
c
Correspondence to Xiaofeng Tao, MD, PhD, Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No.639 ZhizaoJu Road, Shanghai 200011, China Tel: + 86 21 23271699 5335; fax: + 86 21 2327 1699; e-mail: [email protected] *Ying Wei Wu and Cheuk Ying Tang contributed equally to the writing of this article. Received 3 June 2014 accepted 2 July 2014
In recent years, increasing work has been published on the use of resting state functional MRI (rsFMRI) in neuropsychiatric research [10–12]. The rsFMRI approach differs from the traditional paradigm-driven fMRI. In rsFMRI, the patients do not perform any specific task, but are told to remain at rest while fMRI data are being acquired. Using mathematical algorithms such as independent component analysis, one can then extract different spatially distinct networks that support various cognitive functions [13]. Several of these networks have consistently been reported by various groups [14–16]. Using the rsFMRI approach, one avoids potential confounds of task performance in paradigm-driven fMRI and it can be applied in situations where the patient cannot perform any task such as when they are paralyzed or are under anesthesia. It also allows one to investigate multiple brains regions simultaneously in one scan. For these reasons, rsFMRI has become a popular approach in functional brain research as well as in presurgical planning in clinical applications [17,18]. The fMRI BOLD signal is very small and is of the order of a few percent above baseline. The BOLD signal is the result of changes in local oxygenation of blood upon neuronal firing. Our group and others have reported on the effects of oxygen saturation in blood on T1, T2, and T2* relaxation rates in MRI [19,20]. The effects of oxygen on DOI: 10.1097/WNR.0000000000000239
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Effects of hyperoxia on resting state fMRI Wu et al. 1187
cerebral blood flow have been well studied before [21,22], where it has been shown that inhalation of pure oxygen causes a small decrease in cerebral blood flow. Oxygen is therefore an important modulator of the BOLD signal. Oxygen-enhanced MRI has been used before in MRI as a signal enhancer for lung imaging [23–27], renal [28], and tumor imaging [29]. Very few studies have studied the effects of oxygen on functional imaging [30,31]. In these studies, oxygen enhancement was used as a modulator of the BOLD signal similar to a paradigm-driven fMRI scan with 100% O2 as the ‘ON’ condition. Short epochs of oxygen-enhanced (‘ON’) frames were interleaved with ambient air (‘OFF’) within the same scan. In this study, we aimed to investigate the effect of continuous inhalation of 100% O2 on the functional brain networks as obtained using rsFMRI.
Methods Participants
Overall, 34 healthy volunteers (20 women, 14 men) were recruited for this study. The mean age of the participants was 26 and SD = 4.76. Informed consent was obtained from all participants before imaging. Imaging
All imaging were performed on a Philips 3T Achieva MRI (Philips Healthcare, Best, the Netherlands). A proton density/ T2-weighted, dual echo sequence was used to screen for incidental pathology (TR = 2500 ms, TE = 10, 80 ms, FOV = 23.0 cm, FA = 90°, 36 axial slices, thickness = 3 mm, skip = 1 mm, matrix size = 400 × 312). One rsFMRI baseline scan was acquired using a field echo EPI sequence with the following parameters: TR = 2000 ms, TE = 27 ms, FOV = 21.0 cm, FA = 90°, 38 slices, skip = 0.8 mm, matrix size = 88 × 86, and 300 dynamics. Each resting state scan lasted about 10 min. Each participant received two 10 min resting state scans. During one scan, they were breathing in 100% air and during the second scan they were breathing in air. The order was randomized among the participants. Pure O2 or air was administered through a standard cannula with the eyes closed.
were extracted and entered into higher-level analyses. General linear modeling and permutation-based inference testing (RANDOMISE) were used to test for group differences and symptom severity correlates of the DMN. We used a matched t-test for all the participants comparing scans during inhalation of room air and pure O2. In addition to voxelwise comparisons, we also investigated the power spectrum of the mean time-course signal in the network. We used a similar strategy as reported by Zou et al. [32] to extract the metric fractional amplitude of low frequency fluctuations (fALFF). This is a measure of the power of the frequency band that is a characteristic of the BOLD signal that supports the resting state networks. The mean time course of the DMN, VN, and AN networks was extracted and the power spectrum was computed using in-house software developed in Matlab (Matlab R2012a; The Mathworks Inc., Natick, Massachusetts, USA), and fALFF was computed accordingly. fALFF was defined as the ratio of the total low-frequency (0.01–0.08 Hz) power spectrum and the full range power spectrum. This was computed for every network and every participant for both conditions. A paired t-test was computed between air and 100% oxygen inhalation conditions for the participants using Statistica V10 (Statsoft Inc., Tulsa, Oklahoma, USA).
Results Paired t-tests between ambient air versus 100% O2 showed significant differences in all three networks, with the condition of 100% O2 yielding higher z-values. The DMN showed significant increases in the frontal and prefrontal cortices, the anterior cingulate, and portions of the superior parietal regions (Fig. 1a). The AN showed the most significant increases in the posterior parietal and prefrontal cortices. Small decreases were also detected in the portions of the anterior cingulate (Fig. 1b). The VN also showed significant decreases in the primary visual cortex (V1) (Fig. 1d). Paired t-tests between ambient air versus 100% O2 showed a significant decrease in fALFF in the DMN (P < 0.04), VN (P < 0.0004), but not significant in the AN (P = 0.77).
Analysis
Preprocessing of the functional images was performed in FSL and included motion correction (MCFLIRT), coregistration to the high-resolution T1 images (FLIRT), and nonlinear registration to the standard MNI T1 template (FNIRT). Independent component analysis was used to identify 20 unique networks of resting state activity using MELODIC [13] as implemented in FSL. The default mode network (DMN) consisting of the anterior and posterior cingulate cortex and the bilateral parietal cortices has consistently been reported before in other studies [14–16]. In addition to the DMN, the attention network (AN) and the visual network (VN) were also identified for further analysis. These three networks were identified for each participant and z-statistic images
Discussion Oxygen is essential for the proper biochemical reactions that support neuronal functions. Its homeostasis is therefore tightly controlled [33]. Because of the vascular supply and draining distribution, there is a heterogeneous distribution of oxygen saturation [34,35]. At baseline, the oxygen field is low and upon regional activation a surplus of oxygenated blood is supplied to the activation site, leading to an increase in the BOLD signal. Although under normal pathological conditions the oxygen dissociation curve predicts that the oxyhemoglobin is mostly saturated at partial pressure above 60 mm Hg, inhalation of 100% oxygen will have a modest effect on oxyhemoglobin saturation, but can increase the dissolved oxygen in arterial
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Statistical results for three rsFMRI networks. The group network (white) is superimposed on a standard anatomical MRI grayscale template. The paired t-test between hyperoxia and room air is superimposed on the network in color. Hyperoxia > air is indicated in medium to light grey and hyperoxia < air in dark grey. Only significant voxels at P < 0.05 level are shown. (a) Default mode network, (b) left and right attention network, (c) executive control network, (d) visual network. rsFMRI, resting state functional MRI.
blood several times [31]. Hyperoxic-induced changes in hemodynamics have not always been consistent; whereas some report no changes [36], others suggests increases [37] as well as decreases [38]. Although oxygen acts as a vasoconstrictor, other studies have shown that this mechanism has minimal effect on the BOLD signal [21,22]. Our results indicate that the rsFMRI scans show a higher Z-score in several of the resting state networks. These higher z-scores may have resulted from several sources. They could indicate both more coherent timesynchronous activities within the voxels of a network and less noise in the time-course signal itself. Oxygen exerts several effects on the MRI signal. Oxyhemoglobin is diamagnetic and would increase the MR signal, thereby increasing the baseline signal intensity. Animal studies have shown linear relationships of R2* with hypoxia in the brain [39]. Our group and others have also reported in a rat model an increase in T2 & T2* values under hyperoxic conditions [19,40]. Another effect of
oxygen is the shortening of T1 values of blood [19,41]. This shortened T1 might also increase the overall BOLD signal at baseline, especially with incomplete recovery of the spins at short TRs typically used in fMRI. Oxygen saturation exerts two opposing effects on the BOLD signal: on the one hand, it causes vasoconstriction (which might reduce the signal) and on the other the oxygenated blood is diamagnetic (which causes the MR signal to increase). In both the Kalamangalam and Losert studies, oxygen enhancement led to a boost in the BOLD signal [30,31]. In the study by Losert and colleagues, it was reported that oxygen enhancement led to greater than 3% single intensity change in cortical gray matter when compared with white matter (< 1%). In the study by Thulborn et al. [20], oxygen was used as a stimulus to study epileptic patients. Although not part of their analysis, they noted that during the oxygen-enhanced condition, the spontaneous BOLD signal also showed a larger variance. Our observation of higher z-scores for the networks might reflect the effect of this larger variance.
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Effects of hyperoxia on resting state fMRI Wu et al. 1189
The power spectral analysis also showed a significant difference in the fractional power of the resting state signal. Our results indicated that the fALFF was significantly lower under the hyperoxic condition in the DMN and VN networks; although not significant, the mean values were also lower in the AN. Applications of fALFF in psychiatric studies have reported both increases as well as decreases depending on the region of the brain [42–45]. Our result can be interpreted as consistent with the voxel-by-voxel comparisons. As the coherence of the resting state time signal is increased, the spread of the distribution of the power of the frequencies will decrease. This will lead to a reduced fALFF.
available for the analysis of the rsFMRI data, other factors such as heterogeneity of cerebrovascular reserve would limit its usefulness.
It is interesting to note that the inhalation of oxygen had a negative effect on the VN. Studies on the effect of caffeine on the BOLD signal in fMRI have also reported different activation patterns between the visual cortex and other gray matter regions including the frontal lobes [46]. It was suggested that caffeine might have a differential enhancing effect of executive areas versus more passive regions such as the visual cortex. Oxygen might have a similar mechanism on brain function. To obtain a consistent resting state, we instructed our participants to keep their eyes closed. Other studies have also shown a suppression of the BOLD signal under the eyes closed condition [47].
It is well known that there is an age-dependent decline in cerebral blood flow and hemoglobin oxygenation. The participants we have studied had a narrow age range. Further studies should be carried out to investigate the age-dependent effect of oxygen-enhanced rsFMRI.
Although there have been numerous studies showing the detrimental effects of hypoxia, there have also been few reports on the enhancing effects of oxygen inhalation on cognitive performance [48–50]. The enhanced cognitive abilities might also contribute toward a more coherent signaling between the distant brain regions that support the individual networks. The enhanced cognitive abilities might be reflected in the more coherent oscillations in the respective networks. This is similar to other reports on brain function and meditation, where it was found that participants who are experienced meditation practitioners show increased functional connectivity in the AN [51] and DMNs [52]. There are also numerous reports showing that meditation practitioners have higher alpha anterior–posterior electroencephalography (EEG) coherence in the alpha band during meditative states [53,54]. Although the signals of EEG and rsfMRI are of very different timescales (milliseconds vs. seconds), the electrical activity of individual neurons firing (source of the EEG signal) does give rise to the macroscopic changes in regional blood flow and oxygen consumption (source of the rsfMRI signal).
Inhaling oxygen at higher than atmospheric pressure can be toxic to the central nervous system as in the case of scuba divers breathing from 100% oxygen tanks. At high partial pressure, oxygen can cause oxidative cell damage, collapse of lungs, and seizures. At lower partial pressure, as used here, small changes in hormonal levels, heart rate, and blood pressure are common [55–57]. Moderate levels of hyperoxia could also exert effects on various substructures of the central nervous system such as the insular cortex, hypothalamus, and hippocampus [58].
Conclusion We have shown that hyperoxic conditions can modulate the various resting state networks. Our results imply that oxygen inhalation increases the time coherence in voxels within the DMN, executive network, and AN, but decreases in the VN. These results suggest that we should be cautious when interpreting rsFMRI results in oxygen-enhanced MRI or in patients with conditions that might affect oxygen delivery.
Acknowledgements This study was supported by Shanghai Municipal Education Commission research innovation grant No.12ZZ028; Outstanding academic leader of Shanghai Science and Technology Bureau (grant No.13XD1402400). Conflicts of interest
There are no conflicts of interest.
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There are some limitations in this pilot study. In this study, the 100% O2 was delivered through a cannula and should not be considered 100% as there is inevitably a small amount of room air diluted with the O2. We did not measure the respiration rate or the blood oxygen content to determine the increase in blood oxygen levels, but it has been reported before that the inhalation of pure oxygen could increase blood oxygen levels by 30% or more [48], although even if the blood oxygen content was
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