Original contributionEffects of mild hypoxic hypoxia on poststimulus undershoot of blood-oxygenation-level-dependent fMRI signal in the human visual cortex
Introduction
Positive blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal elicited by task activation is followed by a sustained negative signal change in T2*-weighted gradient echo (GRE) images in human visual and motor cortices [1], [2], [3], [4], [5]. The negative signal deflection in T2*-weighted BOLD fMR images, which typically shows an amplitude ratio of 1 to 3 relative to the positive BOLD signal, is commonly referred to as the poststimulus undershoot [1], [2], [3]. This is an example of transient features of the BOLD effect [4]. Previous BOLD fMRI studies have shown that the poststimulus undershoot appears after brief (seconds) [5], [6], intermediate (tens of seconds) [6], [7], [8] or exhaustive (minutes) [1], [2] stimulation paradigms. High spatial resolution BOLD fMRI has shown that the poststimulus undershoot is expressed throughout the layers of cat visual cortex area 18 [9].
Frahm et al. [1], [2] showed that cerebral blood flow (CBF) returns to baseline within seconds after termination of visual stimulation when the BOLD poststimulus undershoot is maximal. In agreement with these data, it has been shown that neither primary hand [7] nor supplementary [10] motor cortices show CBF undershoot after termination of finger tapping. Frahm et al. [1], [2] deduced from their MR findings that oxidative metabolism proceeds at a high level promptly after brain stimulation, yet CBF is at baseline, leading to a state they named “negative uncoupling.” Recently, Lu et al. [8] used multimodal fMRI methods to quantify oxygen extraction fraction (OEF), CBF and cerebral blood volume (CBV) in conjunction with BOLD fMRI scans in human visual cortex. They observed that OEF and, therefore, also cerebral metabolic rate of oxygen (CMRO2) stayed elevated for a substantial period of time after stimulation, but both CBF and CBV returned to the baseline within seconds after stimulus termination. These observations, together with the previous ones [1], [7], argue that buildup of deoxyhemoglobin (Hb) is due to metabolic reasons. Consistent with this notion, optical imaging spectroscopy (OIS) studies of anesthetized rats have demonstrated oxyhemoglobin (HbO2) undershoot and Hb overshoot in the barrel cortex seconds after termination of the stimulus [11], [12]. A recent combined fMRI and near-infrared spectroscopy study in man showed that during BOLD poststimulus undershoot, Hb overshoot occurred at baseline CBV in the visual cortex [13]. Thus, both human fMRI and animal OIS data support the idea that the BOLD poststimulus undershoot results from a mismatch between CMRO2 and CBF in the brain during restoration of ionic and transmitter homeostasis.
Mandeville et al. [14], working with a forepaw stimulation model of anesthetized rats and using a long half-life blood pool contrast agent for imaging of hemodynamics in conjunction with T2*-weighted fMRI, found that CBV was elevated during the poststimulus phase, matching the negative deflection in the BOLD signal. Hoge et al. [15] observed a CBF undershoot after flashing goggles stimulation in the visual cortex, and they associated the CBF undershoot with a slow return of CBV poststimulus. These findings lend support to the idea that the poststimulus undershoot could, in fact, reflect hemodynamic rather than metabolic events in the brain. Given the evidence that CMRO2 is elevated in the poststimulus phase and that, at the same time, CBF proceeds at baseline [1], [8] or even lower than that [15], curtailed oxygen availability is expected to either affect BOLD undershoot, influence CBV or both. The present study was devised to address these questions in the human visual cortex in the presence of mild hypoxic hypoxia. We have used T2*-weighted fMRI and vascular-space-occupancy-dependent (VASO) fMRI [16] to examine both oxygenation (i.e., BOLD) and hemodynamic (i.e., CBV and BOLD) aspects in the human visual cortex during varying blood oxygen saturation levels. It is anticipated that these experiments would provide information from the physiological substrates of the BOLD fMRI signal transient as well as from regulation of CBV during increased energy consumption in the poststimulus phase.
Section snippets
Materials and methods
The protocol was approved by the Committee on the Ethics of Research on Human Beings of the University of Manchester and by the Manchester Local Research Ethical Committee. Six healthy volunteers (age range, 26–49 years; two females and four males) gave written informed consent before participation. Inhaled O2 content (FIO2) was either 21% (room air) or 12% (balanced with N2 in a non-rebreathing circuitry, Hans Rudolph Inc., Kansas City, USA). Oxygen saturation (Ysat used for pulse oximeter
Results
Apart from initial sensation of breathlessness, no other adverse effects were reported during exposure to 12% FIO2. The heart rate increased from 66±12 to 79±13 (P<.05). A steady-state Ysat of 0.86±0.02 was attained with 12% FIO2, which translates to a decrease in arterial O2 pressure by ∼50%. The signal-to-noise ratio (SNR) in BOLD images was 184±28 and 182±29 in normoxia and hypoxia, respectively. The respective SNR values for VASO images (TE=11 ms) were 122±12 and 118±10. Typical activation
Discussion
These results show that curtailed oxygen availability influences characteristics of positive BOLD response but has no effect on the BOLD poststimulus undershoot. The most notable effect by hypoxia is a decline in the volume of cortex showing positive BOLD during visual activation. The observation that the characteristics of BOLD poststimulus undershoot are hypoxia insensitive is rather surprising in light of evidence pointing to increased oxygen metabolism after stimulation in the visual cortex
Acknowledgments
This study was supported by grants from the Medical Research Council (UK), the Academy of Finland, the University of Kuopio Foundation, the Research Foundation of Orion Corporation and the Ella and Georg Ehrnrooth Foundation. Pasi Tuunanen was the recipient of a Marie-Curie Fellowship by the European Union during the course of the study. Expert technical help by Ms. Lisa Leahy and Mr. Barry Whitnall in MR scanning is greatly acknowledged.
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The BOLD post-stimulus undershoot, one of the most debated issues in fMRI
2012, NeuroImageCitation Excerpt :Since our original study in 2004, others have confirmed the rapid CBV changes in humans. Using visual stimulation combined with hypoxic hypoxia (Tuunanen et al., 2006), it was shown that the BOLD PSU continued much longer than CBV as measured by the VASO technology. Interestingly, while the positive BOLD effect was reduced during hypoxia, hypoxia did not affect the length and magnitude of the PSU.
Dynamic models of BOLD contrast
2012, NeuroImageCitation Excerpt :In these studies the venous CBV change was slow to develop and slow to recover, so the CBV effect was only seen with a long stimulus duration. In contrast to these results in animal models, though, a number of studies in humans failed to find evidence of a slow recovery of CBV using injected contrast agents (Dechent et al., 2011; Frahm et al., 2008), the VASO technique (Lu et al., 2004; Tuunanen et al., 2006) or near infrared spectroscopy (NIRS) (Schroeter et al., 2006), although a study with another method (VERVE) did find evidence for a slow CBV recovery (Chen and Pike, 2009). A recent study found that gradient echo and spin echo BOLD responses had nearly identical dynamic shapes, in contradiction to the prediction that extravascular signal loss around veins with elevated CBV should be partly refocused in the spin echo (Poser et al., 2011), although one needs to be careful about the interpretation of spin-echo BOLD signals (Uludag et al., 2009).
Gray matter nulled and vascular space occupancy dependent fMRI response to visual stimulation during hypoxic hypoxia
2012, NeuroImageCitation Excerpt :The most noticeable effect by hypoxic hypoxia is a decline in the number of active voxels, meaning that the size of the active brain region, as delineated by VASO or GMN fMRI, is reduced during visual stimulation in hypoxic hypoxia. This result is consistent with previous studies using both BOLD and VASO (Ho et al., 2008; Tuunanen et al., 2006a, 2006b). We show that SNR for GMN scans with TE = 10 ms, which were used to define the activated pixels, cannot account for the reduced active voxel number.
Functional MRI study of the primary somatosensory cortex in comatose survivors of cardiac arrest
2009, Experimental NeurologyThe post-stimulation undershoot in BOLD fMRI of human brain is not caused by elevated cerebral blood volume
2008, NeuroImageCitation Excerpt :Additional support for the absence of an elevated rCBV in the post-stimulation phase of human BOLD fMRI experiments stems from recent studies using the VASO technique. With the exception of the initial methodological work (Lu et al., 2003), it was shown that CBV returned to baseline shortly after the cessation of stimulation, while the BOLD signal exhibits a prominent undershoot (Lu et al., 2004; Tuunanen et al., 2006; Poser and Norris, 2007). However, it should be mentioned that – apart from measuring CBV changes and depending on the details of the chosen sequence – the VASO signal has been discussed to include components from CBF, extravascular BOLD, or the inflow of fresh spins (Donahue et al., 2006; Scouten and Constable, 2007), so that care should be taken with respect to mechanistic interpretations.