Skip to main content
NCBI home page
Journal of Cerebral Blood Flow & Metabolism logoLink to Journal of Cerebral Blood Flow & Metabolism
. 2010 Aug 25;31(1):82–89. doi: 10.1038/jcbfm.2010.133

Basal cerebral blood volume during the poststimulation undershoot in BOLD MRI of the human brain

Peter Dechent 1,*, Gunther Schütze 2, Gunther Helms 1, Klaus Dietmar Merboldt 3, Jens Frahm 3
PMCID: PMC3049461  PMID: 20736964

Abstract

One of the characteristics of the blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) response to functional challenges of the brain is the poststimulation undershoot, which has been suggested to originate from a delayed recovery of either cerebral blood volume (CBV) or cerebral metabolic rate of oxygen to baseline. Using bolus-tracking MRI in humans, we recently showed that relative CBV rapidly normalizes after the end of stimulation. As this observation contradicts at least part of the blood-pool contrast agent studies performed in animals, we reinvestigated the CBV contribution by dynamic T1-weighted three-dimensional MRI (8 seconds temporal resolution) and Vasovist at 3 T (12 subjects). Initially, we determined the time constants of individual BOLD responses. After injection of Vasovist, CBV-related T1-weighted signal changes revealed a signal increase during visual stimulation (1.7%±0.4%), but no change relative to baseline in the poststimulation phase (0.2%±0.3%). This finding renders the specific nature of the contrast agent unlikely to be responsible for the discrepancy between human and animal studies. With the assumption of normalized cerebral blood flow after stimulus cessation, a normalized CBV lends support to the idea that the BOLD MRI undershoot reflects a prolonged elevation of oxidative metabolism.

Keywords: blood-pool contrast agent, cerebral blood volume, human brain, oxidative metabolism, poststimulation undershoot, vasovist

Introduction

Functional magnetic resonance imaging (MRI) using the blood oxygenation level-dependent (BOLD) contrast has become the most widely used neuroimaging technique to noninvasively investigate human brain function. As the BOLD contrast relies on the absolute concentration of deoxyhemoglobin, which acts as an endogenous paramagnetic contrast agent, respective signal changes do not directly reflect altered neuronal activity, but are mediated through changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and CMRO2 (cerebral metabolic rate of oxygen). The complex temporal interplay of these hemodynamic and metabolic processes is still not fully understood and is the subject of ongoing research. Although the strong positive BOLD MRI signal deflection in response to increased neuronal activity is commonly believed to be dominated by the flow-mediated supply of a surplus of oxygenated blood, which in turn leads to a local decrease in deoxyhemoglobin, the origin of the poststimulation BOLD MRI undershoot below prestimulation baseline is still controversially discussed. In the human visual cortex, it is characterized by a negative signal intensity of ∼1/3 of the positive BOLD response at ∼15 to 20 seconds after stimulus cessation (Frahm et al, 1996, 2008; Krüger et al, 1999b).

Several models of the underlying physiology have been proposed to explain the BOLD MRI undershoot. First, a signal decrease below baseline may result from a temporal uncoupling of hemodynamics and metabolism, so that normalized CBF and CBV in the presence of still elevated CMRO2 lead to the production of excess deoxygenated hemoglobin (Frahm et al, 1996; Krüger et al, 1999b; Lu et al, 2004). Alternatively, a rapid normalization of CBF and CMRO2 but elevated CBV may result in a similarly increased level of deoxyhemoglobin (Buxton et al, 1998; Mandeville et al, 1999b). In a further scenario, a decrease in CBF below baseline has also been put forward to at least add to the BOLD undershoot (Chen and Pike, 2009). However, as pointed out by Lu et al (2006), interpretations of MR-based CBF measurements may be hindered by residual BOLD contributions, which mimic a poststimulation CBF undershoot, if not carefully accounted for. Interestingly, although earlier work often reported a decrease in CBF below baseline after stimulus cessation (Chen and Pike, 2009; Hoge et al, 1999; Kim et al, 1999; Uludag et al, 2004), most recent studies provide experimental evidence for a rapid return of CBF to baseline (Ances et al, 2008, 2009; Donahue et al, 2009a, 2009b; Krüger et al, 1999b; Lu et al, 2004). Moreover, independent non-MRI evidence comes from functional transcranial Doppler sonography, in which studies of the human visual system consistently observe a rapid return of CBF to baseline after stimulus cessation (Sturzenegger et al, 1996; Topcuoglu et al, 2009).

In general, knowledge of at least two of the three mechanisms is mandatory to adequately model the BOLD MRI response after altered neuronal activity. In this study, we further characterize the temporal changes of CBV after stimulus cessation, i.e., during the phase of the poststimulation BOLD undershoot. Although human studies consistently found normalized CBV values after the end of stimulation (Blockley et al, 2009; Frahm et al, 2008; Jasdzewski et al, 2003; Lu et al, 2004; Poser and Norris, 2007; Schroeter et al, 2006; Toronov et al, 2003; Tuunanen et al, 2006), several animal experiments reported elevated CBV during the BOLD undershoot (Jones et al, 2001, 2002; Kida et al, 2007; Kim et al, 2007; Leite et al, 2002; Mandeville et al, 1998, 1999a, 1999b). One possible reason for these discrepancies is a methodological difference as most of the animal studies are based on blood-pool contrast agents with iron oxide particles (Jin and Kim, 2008; Kennan et al, 1998; Kida et al, 2007; Kim et al, 2007; Mandeville et al, 1998, 1999a, 1999b; Smirnakis et al, 2007). Thus, to investigate the impact of the specific contrast agent used for assessing CBV effects, we set up an experiment using dynamic T1-weighted three-dimensional (3D) MRI and the blood-pool contrast agent Vasovist, containing gadofosveset trisodium (Majos et al, 2009; Morton et al, 2006). Vasovist binds to blood albumin and stays in the vascular system in sufficient concentration for ∼1 hour after injection. Besides its effects on T2 and T2* relaxation processes, it shortens the T1 relaxation time (Blockley et al, 2008), which allows us to study CBV effects with a contrast agent comparable with those used in animal studies and without confounding BOLD contributions using short-echo time T1-weighted MRI. We hypothesized to find a normalized level of CBV at the time of the poststimulation BOLD undershoot as in our previous study using bolus-tracking MRI (Frahm et al, 2008).

Materials and methods

Subjects

In all, 12 human adults (age 20 to 28 years, 24.1±2.5 years, 6 males) with normal or corrected-to-normal vision and no history of neurologic or psychiatric illness participated in the study, which was approved by the ethical committee of the University of Göttingen. Written informed consent was obtained from all subjects and all experiments conformed to The Code of Ethics of the World Medical Association (Declaration of Helsinki).

Stimulation Paradigms

In all functional experiments, a black–white radial checkerboard reversing at a frequency of 8 Hz (stimulation) was contrasted with a black screen (rest), while subjects had to fixate a red cross in the middle of the screen. After an initial baseline period (32 seconds), stimulation (32 seconds) and rest periods (56 seconds) alternated 4 times for the BOLD experiment (6 minutes 24 seconds) and 6 times for CBV experiments (9 minutes 20 seconds). Stimuli were generated using Presentation 10.3 (Neurobehavioral Systems, Albany, CA, USA) and fed into a set of MR-suited LCD glasses (Resonance Technology, Northridge, CA, USA) covering a visual field of 20° in the vertical and 30° in the horizontal direction.

A total of three functional experiments were conducted. The initial BOLD and CBV experiments were performed under native conditions. The latter experiment served as a control experiment to verify the successful implementation of the dynamic T1-weighted MRI technique without confounding inflow effects. The second CBV experiment was designed to evaluate CBV changes using a blood-pool contrast agent. It was therefore preceded by an injection of 0.03 mmol/kg body weight of Vasovist (Schering, Berlin, Germany), followed by 15 mL 0.9% NaCl (DeltaSelect, Pfullingen, Germany). To allow for a uniform distribution of the contrast agent, this last experiment was started 6 minutes after contrast agent administration.

Magnetic Resonance Imaging

Magnetic resonance imaging was performed at 3 T (Magnetom TIM Trio, Siemens Healthcare, Erlangen, Germany) using an eight-channel phased-array head coil. Subjects were placed supine inside the magnet bore and wore headphones for noise protection. Vital functions were monitored throughout the experiment. Studies of BOLD MRI used a T2*-sensitive gradient-echo echo-planar imaging technique with an in-plane resolution of 2 × 2 mm2, repetition/echo time=1,000/36 milliseconds, flip angle 50°, and matrix 96 × 128. In all, 11 contiguous sections of 4 mm thickness covered the early visual areas in the occipital lobe in an oblique orientation parallel to the calcarine fissure. Cerebral blood volume measurements were performed using dynamic 3D MRI with the use of a T1-weighted fast low-angle shot sequence at 8 seconds temporal resolution. The acquisitions used a nonselective radiofrequency excitation and yielded 24 sagittal partitions of 4 mm thickness with an in-plane resolution of 3 × 3 mm2, repetition/echo time=6.7/3.1 milliseconds, flip angle 15°, matrix 66 × 84, and 6/8 partial Fourier acquisition in phase encoding. The CBV analysis was restricted to only the eight innermost partitions, which were neither compromised by inflow effects nor by spatial aliasing. For anatomic reference, a T1-weighted data set covering the whole head at 1 mm isotropic resolution was acquired using inversion-recovery 3D fast low-angle shot with repetition/echo time=2,250/3.9 milliseconds, flip angle 9°, and inversion time 900 milliseconds.

Data Analysis

Single-subject analyses were performed using Brain Voyager QX (Brain Innovation, Maastricht, The Netherlands). Preprocessing included slice time correction, 3D motion correction, and linear trend removal. Functional data sets were coregistered to the anatomic data set and transformed into the Talairach space.

In accordance with the general linear model, a box-car reference waveform representing the visual stimulation protocol was either convolved with the hemodynamic impulse response function for BOLD measurements or simply shifted by one image volume (8 seconds) for CBV measurements, and single-subject activation maps were generated at P<0.00001 corrected for multiple comparisons. For the CBV measurement without a contrast agent, a lower statistical threshold of P<0.05 corrected for multiple comparisons was used to enhance the sensitivity to even subtle signal changes which might be caused by residual inflow effects. On the basis of a conjunction analysis of the BOLD and CBV experiments with contrast agent, two regions of interest (ROIs) of 1 cm3 volume were defined in each subject. The first ROI was located in the occipital gray matter across the calcarine sulcus covering the strongly activated early visual cortex, whereas the second ROI in the posterior cingulate gray matter without expected activation served as the control (Figure 1). With regard to the ROI in the activated visual cortex, two alternative selection approaches might be feasible: either taking all activated voxels from the BOLD and CBV conjunction analyses or choosing an ROI of fixed size but with individual anatomic definition. The latter approach was realized here because it allows avoiding the inclusion of large vessels based on individual anatomy and offers the use of identical volumes for control and visual areas, as well as for different subjects. In any case, a qualitative evaluation of the two ROI selection methods revealed similar temporal response profiles for the individual signal intensity time courses.

Figure 1.

Figure 1

Open in a new tab

Sagittal T1-weighted cross-sections (single subject, x-values refer to Talairach coordinates) and overlayed activation maps (visual stimulation) from the conjunction analysis of the blood oxygenation level-dependent (BOLD) and cerebral blood volume (CBV) MRI experiments. White squares refer to regions of interest in activated early visual (left) and nonactivated posterior cingulate cortex (right). MRI, magnetic resonance imaging.

Signal intensity time courses were extracted from the ROIs. Time courses were time locked averaged with regard to stimulation onset. From the BOLD experiment, the time to peak within the 32 seconds of stimulation and the time to minimum in the poststimulation phase were calculated together with the respective signal amplitudes relative to the preceding rest period. The individual times were used to extract corresponding signal amplitudes from the CBV experiments of each subject. Finally, a group analysis (activation maps, signal intensity time courses) was performed for each of the three experiments separately.

Results

Checkerboard stimulation resulted in strong BOLD MRI activation in the visual cortex for all subjects (Figure 2A). The extracted signal intensity time courses for single subjects exhibited the well-known profile including an initial delay, a positive signal change during stimulation and, again after a short delay, a prominent poststimulation undershoot, which becomes clearly visible in the time-locked averaged signal intensity time course. Dynamic T1-weighted MRI before contrast agent administration resulted in no detectable stimulus-related changes (Figure 2B). This observation confirms the successful implementation of the technique without confounding contributions from residual inflow effects. T1-weighted MRI measurements after contrast agent injection (Figure 2C) revealed widespread activation comparable with the BOLD MRI experiment. The signal intensity time course presented with a positive signal change during stimulation. However, after the end of stimulation, the signal rapidly normalized to prestimulation baseline at the time of the poststimulus BOLD undershoot.

Figure 2.

Figure 2

Open in a new tab

Single-subject results. (Left) Sagittal T1-weighted cross-sections with overlayed activation maps and corresponding (middle) raw and (right) time-locked averaged MRI signal intensity time courses extracted from the activated visual cortex (mean±s.d.; rectangles indicate stimulation periods) from (A) the BOLD experiment, (B) the CBV experiment without contrast agent, and (C) the CBV experiment with the contrast agent administered. BOLD, blood oxygenation level dependent; CBV, cerebral blood volume; MRI, magnetic resonance imaging.

Group analyses confirmed the single-subject results. Both BOLD MRI and T1-weighted MRI with contrast agent yielded comparable activation patterns in the occipital lobe (Figure 3). Signal intensity time courses in activated visual areas revealed positive BOLD and CBV responses during stimulation and a BOLD undershoot after the end of stimulation. The CBV signal had returned to baseline at the time of the BOLD undershoot (Figure 3C). Signal intensity time courses from the posterior cingulate cortex showed no stimulus-related signal changes in any experiment.

Figure 3.

Figure 3

Open in a new tab

Group results (n=12). (Left) Averaged sagittal T1-weighted cross-sections with overlayed activation maps and corresponding time-locked averaged MRI signal intensity time courses (mean±s.d.; rectangles indicate stimulation periods) extracted from (middle) the activated visual cortex and (right) the nonactivated posterior cingulate cortex from (A) the BOLD experiment, (B) the CBV experiment without contrast agent, and (C) the CBV experiment with the contrast agent administered. BOLD, blood oxygenation level dependent; CBV, cerebral blood volume; MRI, magnetic resonance imaging.

Quantitative evaluations of BOLD and CBV signal changes in the occipital ROI resulted in a maximum BOLD signal increase of 6.0%±2.1% (mean±s.d.) at 16.7±2.4 seconds after stimulus onset (Table 1). In the poststimulation phase, the signal decreased below prestimulation baseline and reached a minimum signal intensity of −1.8%±0.4% at 17.6±3.0 seconds after the end of stimulation. The corresponding CBV signal changes (Table 1) yielded a stimulus-induced increase of 1.7%±0.4%, but no effect in the poststimulation phase (0.2%±0.3%). The control experiment without contrast agent elicited no stimulus-related signal changes, neither during nor after visual stimulation.

Table 1. Normalized maximum blood oxygenation level-dependent (BOLD) responses and cerebral blood volume (CBV)-related signal changes during stimulation and poststimulation undershoot phases.

  Stimulation
 Undershoot
Subject BOLD response (%) CBV without CA response (%) CBV with CA response (%) BOLD response (%) CBV without CA response (%) CBV with CA response (%)
1 10.0 0.5 1.8 −2.1 −0.4 0.4
2 8.2 0.3 1.7 −2.4 0.8 −0.1
3 4.0 0.0 2.2 −1.9 0.3 0.2
4 4.9 0.5 1.8 −1.3 −0.3 0.2
5 3.4 −0.7 1.3 −1.3 −0.2 0.3
6 5.8 0.4 2.0 −1.8 0.6 0.1
7 5.1 −0.2 2.2 −1.6 −0.6 0.5
8 4.4 0.2 1.7 −1.2 −0.3 −0.2
9 7.2 −0.8 1.3 −1.9 −0.6 0.1
10 8.1 −0.1 2.3 −1.8 0.1 0.2
11 6.7 −0.1 1.2 −2.6 0.2 0.1
12 3.9 −0.1 1.3 −1.4 0.4 0.9
Mean±s.d. 6.0±2.1 0.0±0.4 1.7±0.4 −1.8±0.4 0.0±0.5 0.2±0.3
Open in a new tab

CA, contrast agent.

Discussion

We successfully implemented a dynamic T1-weighted 3D MRI technique which, after the administration of the blood-pool contrast agent Vasovist, allowed us to monitor stimulus-induced signal changes related to CBV in a standard block design. Although we found positive signal changes during visual stimulation for both BOLD and CBV experiments, the poststimulation BOLD undershoot was not accompanied by increased signals in CBV-related T1-weighted MRI. After cessation of visual stimulation, the CBV response returned to baseline within at most 16 seconds. The detection of an even more rapid return was precluded by the temporal resolution of the study. This finding is in full agreement with other human studies reporting normalization of CBV to prestimulation baseline levels within 20 seconds after the end of stimulation (Donahue et al, 2009a, 2009b; Frahm et al, 2008; Lu et al, 2004).

These observations confirm our previous report using bolus-tracking MRI (Frahm et al, 2008) by a completely different methodology, with regard to both the MRI acquisition technique and the contrast agent. In view of existing theories of the poststimulation BOLD undershoot and under the assumption of a rapid return of CBF to baseline after stimulation, these findings strongly support the hypothesis of a transient uncoupling of hemodynamics (CBF and CBV) and metabolism (CMRO2) in the human visual cortex (Frahm et al, 1996). Thus, the elevated consumption of oxygen in the presence of normal delivery of oxyhemoglobin leads to an excess production of deoxyhemoglobin relative to baseline, which is then seen as a relative signal reduction (undershoot) in BOLD MRI acquisitions.

Additional support for the absence of an elevated CBV in the poststimulation phase of human BOLD MRI experiments comes from recent studies using the vascular space occupancy technique, in which it was shown that CBV returned to baseline shortly after the cessation of stimulation, whereas the BOLD signal exhibits a prominent undershoot (Donahue et al, 2009a, 2009b; Lu et al, 2004; Poser and Norris, 2007; Tuunanen et al, 2006). Other independent evidence for the lack of a CBV contribution to the poststimulation undershoot comes from optical imaging techniques. Respective human studies support normalized CBV values—represented by the measured total hemoglobin signal—during the poststimulation phase (Jasdzewski et al, 2003; Schroeter et al, 2006; Toronov et al, 2003).

Taken together, at least three different MRI techniques (i.e., bolus-tracking T2*, blood-pool contrast agent T1, and vascular space occupancy) and optical imaging studies hint at a scenario in awake human subjects, in whom the predominance of flow-related reductions of the deoxyhemoglobin level during stimulation, i.e., the positive BOLD response, is followed by a poststimulation BOLD undershoot with normalized CBV. This raises the question why opposing results have frequently been reported in animal studies (Kennan et al, 1998; Kida et al, 2007; Kim et al, 2007; Leite et al, 2002; Mandeville et al, 1998, 1999a, 1999b). Previously, we suggested interspecies differences, the need for anesthesia, and the use of long-lasting iron oxide contrast agents as candidates for the discrepant findings (Frahm et al, 2008). In this respect, these results provide evidence against the assumption that the specific nature of the contrast agent might be responsible for the conflicting results. Although Vasovist is based on gadolinium rather than on iron oxide particles as used for most animal studies, it temporarily binds to the blood albumin and also acts as a blood-pool contrast agent (Blockley et al, 2008; Majos et al, 2009; Morton et al, 2006). To which degree interspecies differences and/or influences from anesthesia have a role cannot be answered at this stage. In fact, other possible reasons have recently been put forward such as variable strength and/or variable temporal profile of CBV responses across different cortical layers (Jin and Kim, 2008; Kim and Kim, 2010; Shen et al, 2008; Smirnakis et al, 2007; Yacoub et al, 2006; Zhao et al, 2006). These effects have not been detected in human MRI studies, because the spatial resolution is usually too coarse to differentiate between cortical layers. A further idea directs to the cortical systems investigated in humans and animals as the BOLD response differs, e.g., in the visual and motor cortices (Chen and Pike, 2009; Donahue et al, 2009a). Although CBF and CBV normalize comparably fast in both visual and motor systems, the BOLD undershoot was found to return more quickly to baseline in the motor cortex (Donahue et al, 2009a). In fact, most human studies of the BOLD undershoot used visual stimulation (Blockley et al, 2009; Donahue et al, 2009b; Frahm et al, 1996; Jones et al, 1998; Krüger et al, 1999a, 1999b, 1998; Lu et al, 2004; Tuunanen et al, 2006), whereas stimulation of the somatosensory system is preferred in anesthesized animals because of technical reasons (Kennan et al, 1998; Kida et al, 2007; Kim et al, 2007; Mandeville et al, 1998, 1999a, 1999b; Shen et al, 2008). So far, no definite conclusions can be drawn about respective differences.

Concluding Remarks

The implementation of a dynamic T1-weighted 3D MRI technique allowed us to study the temporal profile of CBV-related signal changes after administration of a blood-pool contrast agent. The absence of potentially confounding inflow effects was verified using measurements without contrast agent but otherwise identical conditions: visual stimulation resulted in no detectable signal change. Complementing a previously conducted bolus-tracking study (Frahm et al, 2008), these results provide further evidence against a positive CBV contribution to the poststimulation BOLD MRI undershoot commonly observed in response to stimulation of the human visual cortex. With the assumption of a rapid normalization of CBF after stimulus cessation, this undershoot is most likely attributed to prolonged oxidative metabolism.

The authors declare no conflict of interest.

References

  1. Ances BM, Leontiev O, Perthen JE, Liang C, Lansing AE, Buxton RB. Regional differences in the coupling of cerebral blood flow and oxygen metabolism changes in response to activation: implications for BOLD-fMRI. Neuroimage. 2008;39:1510–1521. doi: 10.1016/j.neuroimage.2007.11.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ances BM, Liang CL, Leontiev O, Perthen JE, Fleisher AS, Lansing AE, Buxton RB. Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation. Hum Brain Mapp. 2009;30:1120–1132. doi: 10.1002/hbm.20574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blockley NP, Francis ST, Gowland PA. Perturbation of the BOLD response by a contrast agent and interpretation through a modified balloon model. Neuroimage. 2009;48:84–93. doi: 10.1016/j.neuroimage.2009.06.038. [DOI] [PubMed] [Google Scholar]
  4. Blockley NP, Jiang L, Gardener AG, Ludman CN, Francis ST, Gowland PA. Field strength dependence of R1 and R2* relaxivities of human whole blood to ProHance, Vasovist, and deoxyhemoglobin. Magn Reson Med. 2008;60:1313–1320. doi: 10.1002/mrm.21792. [DOI] [PubMed] [Google Scholar]
  5. Buxton RB, Wong EC, Frank LR. Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn Reson Med. 1998;39:855–864. doi: 10.1002/mrm.1910390602. [DOI] [PubMed] [Google Scholar]
  6. Chen JJ, Pike GB. Origins of the BOLD post-stimulus undershoot. Neuroimage. 2009;46:559–568. doi: 10.1016/j.neuroimage.2009.03.015. [DOI] [PubMed] [Google Scholar]
  7. Donahue MJ, Blicher JU, stergaard L, Feinberg DA, MacIntosh BJ, Miller KL, Günther M, Jezzard P. Cerebral blood flow, blood volume, and oxygen metabolism dynamics in human visual and motor cortex as measured by whole-brain multi-modal magnetic resonance imaging. J Cereb Blood Flow Metab. 2009a;29:1856–1866. doi: 10.1038/jcbfm.2009.107. [DOI] [PubMed] [Google Scholar]
  8. Donahue MJ, Stevens RD, de Boorder M, Pekar JJ, Hendrikse J, van Zijl PCM. Hemodynamic changes after visual stimulation and breath holding provide evidence for an uncoupling of cerebral blood flow and volume from oxygen metabolism. J Cereb Blood Flow Metab. 2009b;29:176–185. doi: 10.1038/jcbfm.2008.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Frahm J, Baudewig J, Kallenberg K, Kastrup A, Merboldt KD, Dechent P. The post-stimulation undershoot in BOLD fMRI of human brain is not caused by elevated cerebral blood volume. Neuroimage. 2008;40:473–481. doi: 10.1016/j.neuroimage.2007.12.005. [DOI] [PubMed] [Google Scholar]
  10. Frahm J, Kruger G, Merboldt KD, Kleinschmidt A. Dynamic uncoupling and recoupling of perfusion and oxidative metabolism during focal brain activation in man. Magn Reson Med. 1996;35:143–148. doi: 10.1002/mrm.1910350202. [DOI] [PubMed] [Google Scholar]
  11. Hoge RD, Atkinson J, Gill B, Crelier GR, Marrett S, Pike GB. Stimulus-dependent BOLD and perfusion dynamics in human V1. Neuroimage. 1999;9:573–585. doi: 10.1006/nimg.1999.0443. [DOI] [PubMed] [Google Scholar]
  12. Jasdzewski G, Strangman G, Wagner J, Kwong KK, Poldrack RA, Boas DA. Differences in the hemodynamic response to event-related motor and visual paradigms as measured by near-infrared spectroscopy. Neuroimage. 2003;20:479–488. doi: 10.1016/s1053-8119(03)00311-2. [DOI] [PubMed] [Google Scholar]
  13. Jin T, Kim S-G. Cortical layer-dependent dynamic blood oxygenation, cerebral blood flow and cerebral blood volume responses during visual stimulation. Neuroimage. 2008;43:1–9. doi: 10.1016/j.neuroimage.2008.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jones M, Berwick J, Johnston D, Mayhew J. Concurrent optical imaging spectroscopy and laser-Doppler flowmetry: the relationship between blood flow, oxygenation, and volume in rodent barrel cortex. Neuroimage. 2001;13:1002–1015. doi: 10.1006/nimg.2001.0808. [DOI] [PubMed] [Google Scholar]
  15. Jones M, Berwick J, Mayhew J. Changes in blood flow, oxygenation, and volume following extended stimulation of rodent barrel cortex. Neuroimage. 2002;15:474–487. doi: 10.1006/nimg.2001.1000. [DOI] [PubMed] [Google Scholar]
  16. Jones RA, Schirmer T, Lipinski B, Elbel GK, Auer DP. Signal undershoots following visual stimulation: a comparison of gradient and spin-echo BOLD sequences. Magn Reson Med. 1998;40:112–118. doi: 10.1002/mrm.1910400116. [DOI] [PubMed] [Google Scholar]
  17. Kennan RP, Scanley BE, Innis RB, Gore JC. Physiological basis for BOLD MR signal changes due to neuronal stimulation: separation of blood volume and magnetic susceptibility effects. Magn Reson Med. 1998;40:840–846. doi: 10.1002/mrm.1910400609. [DOI] [PubMed] [Google Scholar]
  18. Kida I, Rothman DL, Hyder F. Dynamics of changes in blood flow, volume, and oxygenation: implications for dynamic functional magnetic resonance imaging calibration. J Cereb Blood Flow Metab. 2007;27:690–696. doi: 10.1038/sj.jcbfm.9600409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kim SG, Rostrup E, Larsson HB, Ogawa S, Paulson OB. Determination of relative CMRO2 from CBF and BOLD changes: significant increase of oxygen consumption rate during visual stimulation. Magn Reson Med. 1999;41:1152–1161. doi: 10.1002/(sici)1522-2594(199906)41:6<1152::aid-mrm11>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  20. Kim T, Hendrich KS, Masamoto K, Kim SG. Arterial versus total blood volume changes during neural activity-induced cerebral blood flow change: implication for BOLD fMRI. J Cereb Blood Flow Metab. 2007;27:1235–1247. doi: 10.1038/sj.jcbfm.9600429. [DOI] [PubMed] [Google Scholar]
  21. Kim T, Kim S-G. Cortical layer-dependent arterial blood volume changes: improved spatial specificity relative to BOLD fMRI. Neuroimage. 2010;49:1340–1349. doi: 10.1016/j.neuroimage.2009.09.061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Krüger G, Fransson P, Merboldt KD, Frahm J. Does stimulus quality affect the physiologic MRI responses to brief visual activation. Neuroreport. 1999a;10:1277–1281. doi: 10.1097/00001756-199904260-00023. [DOI] [PubMed] [Google Scholar]
  23. Krüger G, Kastrup A, Takahashi A, Glover GH. Simultaneous monitoring of dynamic changes in cerebral blood flow and oxygenation during sustained activation of the human visual cortex. Neuroreport. 1999b;10:2939–2943. doi: 10.1097/00001756-199909290-00012. [DOI] [PubMed] [Google Scholar]
  24. Krüger G, Kleinschmidt A, Frahm J. Stimulus dependence of oxygenation-sensitive MRI responses to sustained visual activation. NMR Biomed. 1998;11:75–79. doi: 10.1002/(sici)1099-1492(199804)11:2<75::aid-nbm504>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  25. Leite FP, Tsao D, Vanduffel W, Fize D, Sasaki Y, Wald LL, Dale AM, Kwong KK, Orban GA, Rosen BR, Tootell RB, Mandeville JB. Repeated fMRI using iron oxide contrast agent in awake, behaving macaques at 3 Tesla. Neuroimage. 2002;16:283–294. doi: 10.1006/nimg.2002.1110. [DOI] [PubMed] [Google Scholar]
  26. Lu H, Donahue MJ, van Zijl PCM. Detrimental effects of BOLD signal in arterial spin labeling fMRI at high field strength. Magn Reson Med. 2006;56:546–552. doi: 10.1002/mrm.20976. [DOI] [PubMed] [Google Scholar]
  27. Lu H, Golay X, Pekar JJ, Van Zijl PC. Sustained poststimulus elevation in cerebral oxygen utilization after vascular recovery. J Cereb Blood Flow Metab. 2004;24:764–770. doi: 10.1097/01.WCB.0000124322.60992.5C. [DOI] [PubMed] [Google Scholar]
  28. Majos A, Bogorodzki P, Piatkowska-Janko E, Wolak T, Kurjata R, fañczyk L. Functional imaging with MR T1 contrast: a feasibility study with blood-pool contrast agent. Eur Radiol. 2009;19:898–903. doi: 10.1007/s00330-008-1210-8. [DOI] [PubMed] [Google Scholar]
  29. Mandeville JB, Marota JJ, Ayata C, Moskowitz MA, Weisskoff RM, Rosen BR. MRI measurement of the temporal evolution of relative CMRO(2) during rat forepaw stimulation. Magn Reson Med. 1999a;42:944–951. doi: 10.1002/(sici)1522-2594(199911)42:5<944::aid-mrm15>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  30. Mandeville JB, Marota JJ, Ayata C, Zaharchuk G, Moskowitz MA, Rosen BR, Weisskoff RM. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J Cereb Blood Flow Metab. 1999b;19:679–689. doi: 10.1097/00004647-199906000-00012. [DOI] [PubMed] [Google Scholar]
  31. Mandeville JB, Marota JJ, Kosofsky BE, Keltner JR, Weissleder R, Rosen BR, Weisskoff RM. Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med. 1998;39:615–624. doi: 10.1002/mrm.1910390415. [DOI] [PubMed] [Google Scholar]
  32. Morton DW, Keogh B, Lim K, Maravilla KR. Functional brain imaging using a long intravenous half-life gadolinium-based contrast agent. AJNR Am J Neuroradiol. 2006;27:1467–1471. [PMC free article] [PubMed] [Google Scholar]
  33. Poser BA, Norris DG. Measurement of activation-related changes in cerebral blood volume: VASO with single-shot HASTE acquisition. Magma. 2007;20:63–67. doi: 10.1007/s10334-007-0068-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schroeter ML, Kupka T, Mildner T, Uludag K, von Cramon DY. Investigating the post-stimulus undershoot of the BOLD signal–a simultaneous fMRI and fNIRS study. Neuroimage. 2006;30:349–358. doi: 10.1016/j.neuroimage.2005.09.048. [DOI] [PubMed] [Google Scholar]
  35. Shen Q, Ren H, Duong TQ. CBF, BOLD, CBV, and CMRO(2) fMRI signal temporal dynamics at 500-msec resolution. J Magn Reson Imaging. 2008;27:599–606. doi: 10.1002/jmri.21203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Smirnakis SM, Schmid MC, Weber B, Tolias AS, Augath M, Logothetis NK. Spatial specificity of BOLD versus cerebral blood volume fMRI for mapping cortical organization. J Cereb Blood Flow Metab. 2007;27:1248–1261. doi: 10.1038/sj.jcbfm.9600434. [DOI] [PubMed] [Google Scholar]
  37. Sturzenegger M, Newell DW, Aaslid R. Visually evoked blood flow response assessed by simultaneous two-channel transcranial Doppler using flow velocity averaging. Stroke. 1996;27:2256–2261. doi: 10.1161/01.str.27.12.2256. [DOI] [PubMed] [Google Scholar]
  38. Topcuoglu MA, Aydin H, Saka E. Occipital cortex activation studied with simultaneous recordings of functional transcranial Doppler ultrasound (fTCD) and visual evoked potential (VEP) in cognitively normal human subjects: effect of healthy aging. Neurosci Lett. 2009;452:17–22. doi: 10.1016/j.neulet.2009.01.030. [DOI] [PubMed] [Google Scholar]
  39. Toronov V, Walker S, Gupta R, Choi JH, Gratton E, Hueber D, Webb A. The roles of changes in deoxyhemoglobin concentration and regional cerebral blood volume in the fMRI BOLD signal. Neuroimage. 2003;19:1521–1531. doi: 10.1016/s1053-8119(03)00152-6. [DOI] [PubMed] [Google Scholar]
  40. Tuunanen PI, Vidyasagar R, Kauppinen RA. Effects of mild hypoxic hypoxia on poststimulus undershoot of blood-oxygenation-level-dependent fMRI signal in the human visual cortex. Magn Reson Imaging. 2006;24:993–999. doi: 10.1016/j.mri.2006.04.017. [DOI] [PubMed] [Google Scholar]
  41. Uludag K, Dubowitz DJ, Yoder EJ, Restom K, Liu TT, Buxton RB. Coupling of cerebral blood flow and oxygen consumption during physiological activation and deactivation measured with fMRI. Neuroimage. 2004;23:148–155. doi: 10.1016/j.neuroimage.2004.05.013. [DOI] [PubMed] [Google Scholar]
  42. Yacoub E, Ugurbil K, Harel N. The spatial dependence of the poststimulus undershoot as revealed by high-resolution BOLD- and CBV-weighted fMRI. J Cereb Blood Flow Metab. 2006;26:634–644. doi: 10.1038/sj.jcbfm.9600239. [DOI] [PubMed] [Google Scholar]
  43. Zhao F, Wang P, Hendrich K, Ugurbil K, Kim S-G. Cortical layer-dependent BOLD and CBV responses measured by spin-echo and gradient-echo fMRI: insights into hemodynamic regulation. Neuroimage. 2006;30:1149–1160. doi: 10.1016/j.neuroimage.2005.11.013. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cerebral Blood Flow & Metabolism are provided here courtesy of SAGE Publications

RESOURCES