Abstract
The functional magnetic resonance imaging (fMRI) signal results from a complex interplay of basic physiological processes, namely cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV). The ensuing change in the concentration of deoxygenated hemoglobin (dHb) affects the susceptibility of the tissue and gives rise to the so-called blood oxygenation level-dependent (BOLD) signal. The BOLD effect, together with the CBV change, which varies the amount of water protons in the extra- and intravascular space, is picked up as the fMRI signal by gradient- and spin-echo MRI sequences. In this chapter, we describe in detail the spatiotemporal properties of CMRO2, CBV, and CBF and how to model them mathematically. A special focus is on the resulting hemodynamic transients, such as the initial dip and the poststimulus undershoot. In the second half of the chapter, we review the fMRI physical mechanisms using the endogenous dHb-based contrast. In particular, we describe the relaxation rate as a function of susceptibility, diameter of blood vessels, MRI sequences, and magnetic field strength. With these parameters at hand, the fMRI signal and its intra- and extravascular contributions can be calculated from dHb and CBV changes. In summary, underlying the fMRI signal are numerous physiological and physical processes. The spatiotemporal information content of the fMRI signal, thus, depends on the dynamic properties of brain vascular and metabolic processes and the MRI parameters used (e.g., field strength, echo time, MRI sequence) to detect them.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsNotes
- 1.
Hematocrit also has a strong influence on the relaxation rate and, hence, amplitude of the fMRI signal (Silvennoinen et al. 2003). However, the change in hematocrit during activation is low. Thus, it is an important variable for intersubject comparison of the fMRI signal amplitude but not for assessing the dynamics of the fMRI signal and the activation patterns within a subject.
- 2.
We use the term ‘unmatching’ instead of the more common term ‘uncoupling’ for the transient mismatch in the relative amplitudes of the physiological variables as the latter term suggests a breakdown of the casual relationship between them, which does not have to necessarily be the case (see below).
- 3.
A promising new dynamical approach directly capable of measuring oxygen metabolism in the mitochondria is to use flavoprotein fluorescence (reviewed in Vazquez et al. 2010).
- 4.
These equations were developed in collaboration with Richard B. Buxton.
- 5.
Note, however, that this method cannot distinguish between different vascular compartments within the volume element and attributes also blood flow in the venules/veins to CBF, in contrast to standard CBF definition utilized in PET, ASL, etc. excluding venular flow.
- 6.
In contrast, Hillman et al. found that flow and volume changes occur first in the capillaries and later in the arteries (Hillman et al. 2007). Some of the contradictory findings in the literature might be explained that most of these results were obtained using intrinsic optical imaging, which is only sensitive to the first few hundred micrometers on the surface of the brain. That is, for example, an arteriolar changes occurring in a deeper layer before the capillary changes in an upper layer cannot be observed.
- 7.
However, this method assumes that the blood oxygenation in the arteries does not change, which is in contradiction to the findings of the same group using oxygen-sensitive microelectrode measurements, summarized above (Vazquez et al. 2010).
- 8.
Again, the following equations have been derived in collaboration with Richard B. Buxton.
- 9.
CBV is the parameter measured in optical imaging of intrinsic signals but is often taken as reflecting CBF as well.
- 10.
The third theoretical possibility of an initial CBF decrease has, to the best of our knowledge, not been suggested by anybody as a possible mechanism for the initial dip.
- 11.
Of course, applying many refocusing pulses as in a Carr–Purcell pulse train with very short delay periods in between the pulses or applying a large B 1 field (relative to the magnitude of the magnetic field inhomogeneity) for spin locking during this delay will reduce or even eliminate this signal loss due to dynamic averaging. Such an approach, however, would be detrimental to functional imaging signals.
References
Attwell D, Iadecola C (2002) The neural basis of functional brain imaging signals. Trends Neurosci 25:621–625
Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21:1133–1145
Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature 468:232–243
Bandettini PA, Wong EC (1995) Effects of biophysical and physiologic parameters on brain activation induced R2* and R2 changes: simulations using a deterministic diffusion model. Int J Imag Syst Technol 6(2–3):133–152
Bandettini PA, Wong EC, Hinks RS, Tikofsky RS, Hyde JS (1992) Time course EPI of human brain function during task activation. Magn Reson Med 25:390–397
Bandettini PA, Kwong KK, Davis TL, Tootell RB, Wong EC, Fox PT, Belliveau JW, Weisskoff RM, Rosen BR (1997) Characterization of cerebral blood oxygenation and flow changes during prolonged brain activation. Hum Brain Mapp 5:93–109
Barth M, Moser E (1997) Proton NMR relaxation times of human blood samples at 1.5T and implications for functional MRI. Cell Mol Biol (Noisy-le-grand) 43:783–791
Barth M, Diemling M, Moser E (1997) Modulation of signal changes in gradient-recalled echo functional MRI with increasing echo time correlate with model calculations. Magn Reson Imaging 15:745–752
Bartha R, Michaeli S, Merkle H, Adriany G, Andersen P, Chen W, Uğurbil K, Garwood M (2002) In vivo 1H2O T2 + measurement in the human occipital lobe at 4T and 7T by Carr-Purcell MRI: detection of microscopic susceptibility contrast. Magn Reson Med 47:742–750
Beckmann CF, DeLuca M, Devlin JT, Smith SM (2005) Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci 360:1001–1013
Belle V, Delon-Martin C, Massarell IR, Decety J, Le Bas J, Benabid A, Segebarth C (1995) Intracranial gradient-echo and spin-echo functional MR angiography in humans. Radiology 195:739–746
Belliveau JW, Kennedy DN, McKinstry RC, Buchbinder BR, Weisskoff RM, Cohen MS, Vevea JM, Brady TJ, Rosen BR (1991) Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254:716–719
Biswal B, Yetkin FZ, Haughton VM, Hyde JS (1995) Functional connectivity in the motor cortex of resting human brain using echo-planar Mri. Magn Reson Med 34:537–541
Biswal B, DeYoe EA, Hyde JS (1996) Reduction of physiological flucuations in fMRI using digital filters. Magn Reson Med 35:117–123
Boxerman JL, Weisskoff RM, Hoppel BE, Rosen BR (1993) MR contrast due to microscopically heterogeneous magnetic susceptibilty: cylindrical geometry. 12th Annual Meeting of the Society of magnetic Resonance in Medicine. Int Soc Magn Reson Med, New York, NY, p 389
Boxerman JL, Bandettini PA, Kwong KK, Baker JR, Davis TL, Rosen BR, Weisskoff RM (1995a) The intravascular contribution to fMRI signal change: Monte Carlo modeling and diffusion-weighted studies in vivo. Magn Reson Med 34:4–10
Boxerman JL, Hamberg LM, Rosen BR, Weisskoff RM (1995b) MR contrast due to intravscular magnetic susceptiblity perturbations. Magn Reson Med 34:555–556
Brown GG, Eyler Zorrilla LT, Georgy B, Kindermann SS, Wong EC, Buxton RB (2003) BOLD and perfusion response to finger-thumb apposition after acetazolamide administration: differential relationship to global perfusion. J Cereb Blood Flow Metab 23:829–37
Burton AC (1966) Role of geometry, of size and shape, in the microcirculation. Fed Proc 25:1753–1760
Buxton RB (2001) The elusive initial dip. Neuroimage 13:953–958
Buxton RB, Frank LR (1997) A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulation. J Cereb Blood Flow Metab 17:64–72
Buxton RB, Wong EC, Frank LR (1998) Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn Reson Med 39:855–864
Buxton RB, Uludağ K, Dubowitz DJ, Liu TT (2004) Modeling the hemodynamic response to brain activation. Neuroimage 23(Suppl 1):S220–S233
Chaimow D, Yacoub E, Uğurbil K, Shmuel A (2011) Modeling and analysis of mechanisms underlying fMRI-based decoding of information conveyed in cortical columns. Neuroimage 56:627–42
Chamberlain R, Park JY, Corum C, Yacoub E, Uğurbil K, Jack CR Jr, Garwood M (2007) RASER: a new ultrafast magnetic resonance imaging method. Magn Reson Med 58:794–799
Chen JJ, Pike GB (2009) Origins of the BOLD post-stimulus undershoot. Neuroimage 46:559–568
Cheng K, Waggoner RA, Tanaka K (2001) Human ocular dominance columns as revealed by high-field functional magnetic resonance imaging. Neuron 32:359–374
Chien D, Edelman RR (1991) Ultrafast imaging using gradient echoes. Magn Reson Q 5:31–56
Cohen ER, Uğurbil K, Kim SG (2002) Effect of basal conditions on the magnitude and dynamics of the blood oxygenation level-dependent fMRI response. J Cereb Blood Flow Metab 22:1042–1053
De Martino F, Esposito F, van de Moortele PF, Harel N, Formisano E, Goebel R, Uğurbil K, Yacoub E (2011a) Whole brain high-resolution functional imaging at ultra high magnetic fields: an application to the analysis of resting state networks. Neuroimage 57:1031–1044
De Martino F, Zimmermann J, Adriany G, van de Moortele P-F, Feinberg D, Uğurbil K, Goebel R, Yacoub E (2011b) Evidence towards columnar organization of human area MT with sub-millimetric, 3D, T2 weighted BOLD FMRI at 7 Tesla. Proc Int Soc Mag Reson Med 19:9
Devor A, Dunn AK, Andermann ML, Ulbert I, Boas DA, Dale AM (2003) Coupling of total hemoglobin concentration, oxygenation, and neural activity in rat somatosensory cortex. Neuron 39:353–359
Devor A, Tian P, Nishimura N, Teng IC, Hillman EM, Narayanan SN, Ulbert I, Boas DA, Kleinfeld D, Dale AM (2007) Suppressed neuronal activity and concurrent arteriolar vasoconstriction may explain negative blood oxygenation level-dependent signal. J Neurosci 27:4452–4459
Donahue MJ, Lu H, Jones CK, Edden RA, Pekar JJ, van Zijl PC (2006) Theoretical and experimental investigation of the VASO contrast mechanism. Magn Reson Med 56:1261–1273
Duong TQ, Kim DS, Uğurbil K, Kim SG (2000) Spatiotemporal dynamics of the BOLD fMRI signals: toward mapping submillimeter cortical columns using the early negative response. Magn Reson Med 44:231–242
Duong TQ, Kim DS, Uğurbil K, Kim SG (2001) Localized cerebral blood flow response at submillimeter columnar resolution. Proc Natl Acad Sci U S A 98:10904–10909
Duong TQ, Yacoub E, Adriany G, Hu X, Uğurbil K, Vaughan JT, Merkle H, Kim SG (2002) High-resolution, spin-echo BOLD, and CBF fMRI at 4 and 7T. Magn Reson Med 48:589–593
Duong TQ, Yacoub E, Adriany G, Hu X, Uğurbil K, Kim SG (2003) Microvascular BOLD contribution at 4 and 7T in the human brain: gradient-echo and spin-echo fMRI with suppression of blood effects. Magn Reson Med 49:1019–1027
Duyn JH, Moonen CTW, Van Yperen GH, De Boer RW, Luyten PR (1994) Inflow versus deoxyhemoglobin effects in BOLD functional MRI using gradient echoes at 1.5T. NMR Biomed 7:83–88
Edelman RE, Siewer B, Darby DG, Thangaraj V, Nobre AC, Mesulam MM, Warach S (1994) Quantitative mapping of cerebral blood flow and functional localization with echo-planar MR imaging and signal targeting with alternating radio frequency. Radiology 192:513–520
Eichling JO, Raichle ME, Grubb RL, Ter-Pogossian MM (1974) Evidence of the limitations of water as a freely diffusable tracer in brain of the Rheusus monkey. Circ Res 35:358–364
Ernst T, Hennig J (1994) Observation of a fast response in functional MR. Magn Reson Med 32:146–149
Feinberg DA, Moeller S, Smith SM, Auerbach E, Ramanna S, Gunther M, Glasser MF, Miller KL, Uğurbil K, Yacoub E (2010) Multiplexed echo planar imaging for sub-second whole brain FMRI and fast diffusion imaging. PLoS ONE 5:e15710
Fox PT, Raichle ME (1986) Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A 83:1140–1144
Fox PT, Raichle ME, Mintun MA, Dence C (1988) Nonoxidative glucose consumption during focal physiologic neural activity. Science 241:462–464
Frahm J, Merboldt K-D, Hanicke W, Kleinschmidt A, Boecker H (1994) Brain or vein-oxygenation or flow? On signal physiology in functional MRI of human brain activation. NMR Biomed 7:45–53
Frahm J, Kruger G, Merboldt KD, Kleinschmidt A (1996) Dynamic uncoupling and recoupling of perfusion and oxidative metabolism during focal brain activation in man. Magn Reson Med 35:143–148
Friston KJ, Harrison L, Penny W (2003) Dynamic causal modelling. Neuroimage 19:1273–302
Fujita N (2001) Extravascular contribution of blood oxygenation level-dependent signal changes: a numerical analysis based on a vascular network model. Magn Reson Med 46:723–734
Fukuda M, Moon CH, Wang P, Kim SG (2006a) Mapping iso-orientation columns by contrast agent-enhanced functional magnetic resonance imaging: reproducibility, specificity, and evaluation by optical imaging of intrinsic signal. J Neurosci 26:11821–11832
Fukuda M, Wang P, Moon CH, Tanifuji M, Kim SG (2006b) Spatial specificity of the enhanced dip inherently induced by prolonged oxygen consumption in cat visual cortex: implication for columnar resolution functional. MRI Neuroimage 30:70–87
Gati JS, Menon RS, Uğurbil K, Rutt BK (1997) Experimental determination of the BOLD field strength dependence in vessels and tissue. Magn Reson Med 38:296–302
Glover GH, Lai S (1998) Self-navigated spiral fMRI: interleaved versus single-shot. Magn Reson Med 39:361–368
Glover GH, Li TQ, Ress D (2000) Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med 44:162–167
Goense JB, Zappe AC, Logothetis NK (2007) High-resolution fMRI of macaque V1. Magn Reson Imaging 25:740–747
Goerke U, Moller HE, Norris DG, Schwarzbauer C (2005) A comparison of signal instability in 2D and 3D EPI resting-state fMRI. NMR Biomed 18:534–542
Goerke U, Garwood M, Uğurbil K (2011) Functional magnetic resonance imaging using RASER. Neuroimage 54:350–360
Gonzalez-Castillo J, Saad ZS, Handwerker DA, Inati SJ, Brenowitz N, Bandettini PA (2012) Whole-brain, time-locked activation with simple tasks revealed using massive averaging and model-free analysis. Proc Natl Acad Sci U S A 109:5487–5492
Goodyear BG, Menon RS (2001) Brief visual stimulation allows mapping of ocular dominance in visual cortex using fMRI. Hum Brain Mapp 14:210–217
Grinvald A, Frostig RD, Siegel RM, Bartfeld E (1991) High-resolution optical imaging of functional brain architecture in the awake monkey. Proc Natl Acad Sci U S A 88:11559–11563
Griswold MA, Jakob PM, Heidemann RM, Nittka M, Jellus V, Wang J, Kiefer B, Haase A (2002) Generalized autocalibrating partially parallel acquisitions (GRAPPA). Magn Reson Med 47:1202–1210
Grubb RL Jr, Raichle ME, Eichling JO, Ter-Pogossian MM (1974) The effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular mean transit time. Stroke 5:630–639
Gusnard DA, Raichle ME (2001) Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2:685–694
Haacke EM, Tkach JA (1990) Fast MR imaging: techniques and clinical applications. Am J Roentgenol 155:951–964
Haacke EM, Wieloposki PA, Tkash JA (1991) A comprehensive technical review of short TR, fast, magnetic resonance imaging. Magn Reson Med 3:53–170
Haase A, Frahm J, Matthaei D, Hanicke W, Merboldt KD (1986) FLASH imaging. Rapid NMR imaging using low flip angle pulses. J Magn Reson 67:258–266
Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O'Farrell FM, Buchan AM, Lauritzen M, Attwell D (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60
Harel N, Lee SP, Nagaoka T, Kim DS, Kim SG (2002) Origin of negative blood oxygenation level-dependent fMRI signals. J Cereb Blood Flow Metab 22:908–917
Harms MP, Melcher JR (2002) Sound repetition rate in the human auditory pathway: representations in the waveshape and amplitude of fMRI activation. J Neurophysiol 88:1433–1450
Harms MP, Melcher JR (2003) Detection and quantification of a wide range of fMRI temporal responses using a physiologically-motivated basis set. Hum Brain Mapp 20:168–183
Hillman EM, Devor A, Bouchard MB, Dunn AK, Krauss GW, Skoch J, Bacskai BJ, Dale AM, Boas DA (2007) Depth-resolved optical imaging and microscopy of vascular compartment dynamics during somatosensory stimulation. Neuroimage 35:89–104
Hennig J, Janz C, Speck O, Ernst T (1995) Functional spectrocopy of brain activation following a single light pulse: examination of the mechanism of the fast initial response. Int J Imag Syst Technol 6:203–208
Ho YL, Petersen ET, Zimine I, Golay X (2011) Similarities and differences in arterial responses to hypercapnia and visual stimulation. J Cereb Blood Flow Metab 31:560–571
Hoge RD, Atkinson J, Gill B, Crelier GR, Marrett S, Pike GB (1999) Stimulus-dependent BOLD and perfusion dynamics in human V1. Neuroimage 9:573–585
Hoogenraad FG, Pouwels PJ, Hofman MB, Reichenbach JR, Sprenger M, Haacke EM (2001) Quantitative differentiation between BOLD models in fMRI. Magn Reson Med 45:233–246
Horiguchi H, Nakadomari S, Misaki M, Wandell BA (2009) Two temporal channels in human V1 identified using fMRI. Neuroimage 47:273–280
Howseman AM, Grootoonk SG, Porter D, Ramdeen J, Holmes AP, Turner R (1999) The effect of slice order and thickness on fMRI activation data using multislice EPI. Neuroimage 9:363–376
Hu X, Kim S-G (1994) Reduction of physiological noise in functional MRI using navigator echo. Mag Reson Med 31:495–503
Hu X, Yacoub E (2012) The story of the initial dip in fMRI. Neuroimage 62:11037–8
Hu X, Le TH, Parrish T, Erhard P (1995) Retrospective estimation and correction of physiological fluctuation in functional MRI. Magn Reson Med 34:201–212
Hu X, Le TH, Uğurbil K (1997) Evaluation of the early response in fMRI using short stimulus duration. Magn Reson Med 37:877–884
Hyde JS, Biswal BB, Jesmanowicz A (2001) High-resolution fMRI using multislice partial k-space GR-EPI with cubic voxels. Magn Reson Med 46:114–125
Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360
Itoh Y, Suzuki N (2012) Control of brain capillary blood flow. J Cereb Blood Flow Metab 32:1167–1176
Jezzard P, Duewell S, Balaban RS (1996) MR relaxation times in human brain: measurement at 4T. Radiology 199:773–779
Kennan RP, Zhong J, Gore JC (1994) Intravascular susceptibility contrast mechanisms in tissue. Magn Reson Med 31:9–31
Kim DS, Duong TQ, Kim SG (2000) High-resolution mapping of iso-orientation columns by fMRI. Nat Neurosci 3:164–169
Kim S-G (1995) Quantification of relative cerebral blood flow change by flow-sensitive alternating inversion recovery (FAIR) technique: application to functional mapping. Magn Reson Med 34:293–301
Kim S-G, Tsekos NV (1997) Perfusion imaging by a flow-sensitive alternating inversion recovery (FAIR) technique: application to functional brain imaging. Mag Reson Med 37:425–435
Kim S-G, Hendrich K, Hu X, Merkle H, Uğurbil K (1994) Potential pitfalls of functional MRI using conventional gradient-recalled echo techniques. NMR Biomed 7:69–74
Kim SG, Hu X, Adriany G, Uğurbil K (1996) Fast interleaved echo-planar imaging with navigator: high resolution anatomic and functional images at 4 Tesla. Magn Reson Med 35:895–902
Kim T, Kim SG (2005) Quantification of cerebral arterial blood volume and cerebral blood flow using MRI with modulation of tissue and vessel (MOTIVE) signals. Magn Reson Med 54:333–342
Kim T, Kim SG (2011) Temporal dynamics and spatial specificity of arterial and venous blood volume changes during visual stimulation: implication for BOLD quantification. J Cereb Blood Flow Metab 31:1211–1222
Kim T, Hendrich K, Kim SG (2008) Functional MRI with magnetization transfer effects: determination of BOLD and arterial blood volume changes. Magn Reson Med 60:1518–1523
Kiselev VG, Posse S (1999) Analytical model of susceptibility-induced MR signal dephasing: effect of diffusion in a microvascular network. Magn Reson Med 41:499–509
Kjolby BF, Ostergaard L, Kiselev VG (2006) Theoretical model of intravascular paramagnetic tracers effect on tissue relaxation. Magn Reson Med 56:187–197
Kruger G, Glover GH (2001) Physiological noise in oxygenation-sensitive magnetic resonance imaging. Magn Reson Med 46:631–637
Kruger G, Kastrup A, Glover GH (2001) Neuroimaging at 1.5T and 3.0T: comparison of oxygenation-sensitive magnetic resonance imaging. Magn Reson Med 45:595–604
Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE (2007) Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology 242:647–649
Kwong KK, Belliveau JW, Chesler DA, Goldberg IE, Weisskoff RM, Poncelet BP, Kennedy DN, Hoppel BE, Cohen MS, Turner R, Cheng H-M, Brady TJ, Rosen BR (1992) Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A 89:5675–5679
Le Bihan D, Turner R (1991) Intravoxel incoherent motion imaging using spin echoes. Magn Reson Med 19:221–227
Lee SP, Duong T, Yang G, Iadecola C, Kim SG (2001) Relative changes of cerebral arterial and venous blood volumes during increased cerebral blood flow: implications for BOLD fMRI. Mag Reson Med 45:791–800
Leite FP, Tsao D, Vanduffel W, Fize D, Sasaki Y, Wald LL, Dale AM, Kwong KK, Orban GA, Rosen BR, Tootell RB, Mandeville JB (2002) Repeated fMRI using iron oxide contrast agent in awake, behaving macaques at 3 Tesla. Neuroimage 16:283–294
Logothetis N (2000) Can current fMRI techniques reveal the micro-architecture of cortex? Nat Neurosci 3:413–414
Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A (2001) Neurophysiological investigation of the basis of the fMRI signal. Nature 412:150–157
Lorthois S, Cassot F, Lauwers F (2011) Simulation study of brain blood flow regulation by intra-cortical arterioles in an anatomically accurate large human vascular network. Part II: flow variations induced by global or localized modifications of arteriolar diameters. Neuroimage 54:2840–2853
Lu H, Golay X, Pekar JJ, Van Zijl PC (2003) Functional magnetic resonance imaging based on changes in vascular space occupancy. Magn Reson Med 50:263–274
Lu H, Golay X, Pekar JJ, Van Zijl PC (2004a) Sustained poststimulus elevation in cerebral oxygen utilization after vascular recovery. J Cereb Blood Flow Metab 24:764–770
Lu H, van Zijl PC, Hendrikse J, Golay X (2004b) Multiple acquisitions with global inversion cycling (MAGIC): a multislice technique for vascular-space-occupancy dependent fMRI. Magn Reson Med 51:9–15
Lu H, Law M, Johnson G, Ge Y, van Zijl PC, Helpern JA (2005) Novel approach to the measurement of absolute cerebral blood volume using vascular-space-occupancy magnetic resonance imaging. Magn Reson Med 54:1403–1411
Malonek D, Grinvald A (1996) Interactions between electrical activity and cortical microcirculation revealed by imaging spectroscopy: implications for functional brain mapping. Science 272:551–554
Mandeville JB, Marota JJ (1999) Vascular filters of functional MRI: spatial localization using BOLD and CBV contrast. Magn Reson Med 42:591–598
Mandeville J, Marota J, Keltner J, Kosovsky B, Burke J et al (1996) CBV functional imaging in rat brain using iron oxide agent at steady state concentration. Annual Meeting of the International Society of Magnetic Resonance in Medicine, New York, p 292
Mandeville JB, Marota JJ, Kosofsky BE, Keltner JR, Weissleder R, Rosen BR, Weisskoff RM (1998) Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med 39:615–624
Mandeville JB, Marota JJ, Ayata C, Zaharchuk G, Moskowitz MA, Rosen BR, Weisskoff RM (1999) Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J Cereb Blood Flow Metab 19:679–689
Mandeville JB, Jenkins BG, Kosofsky BE, Moskowitz MA, Rosen BR, Marota JJ (2001) Regional sensitivity and coupling of BOLD and CBV changes during stimulation of rat brain. Magn Reson Med 45:443–447
Mandeville JB, Jenkins BG, Chen YC, Choi JK, Kim YR, Belen D, Liu C, Kosofsky BE, Marota JJ (2004) Exogenous contrast agent improves sensitivity of gradient-echo functional magnetic resonance imaging at 9.4T. Magn Reson Med 52:1272–1281
Mangia S, Tkac I, Logothetis NK, Gruetter R, Van de Moortele PF, Uğurbil K (2007) Dynamics of lactate concentration and blood oxygen level-dependent effect in the human visual cortex during repeated identical stimuli. J Neurosci Res 85:3340–3346
Mangia S, Giove F, Tkac I, Logothetis NK, Henry PG, Olman CA, Maraviglia B, Di Salle F, Uğurbil K (2009) Metabolic and hemodynamic events after changes in neuronal activity: current hypotheses, theoretical predictions and in vivo NMR experimental findings. J Cereb Blood Flow Metab 29:441–463
Mansfield P (1977) Multi-planar image formation using NMR spin echoes. J Phys C 10:L55–L58
Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS (2006) Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17:2359–2362
Masamoto K, Kurachi T, Takizawa N, Kobayashi N, Tanishita K (2003) Successive depth variations in microvascular distribution of rat somatosensory cortex. Brain Res 995:66–75
Masamoto K, Vazquez A, Wang P, Kim SG (2009) Brain tissue oxygen consumption and supply induced by neural activation: determined under suppressed hemodynamic response conditions in the anesthetized rat cerebral cortex. Adv Exp Med Biol 645:287–292
Menon RS, Ogawa S, Tank DW, Uğurbil K (1993) 4 Tesla gradient recalled echo characteristics of photic stimulation- induced signal changes in the human primary visual cortex. Magn Reson Med 30:380–386
Menon RS, Ogawa S, Hu X, Strupp JP, Anderson P, Uğurbil K (1995) BOLD based functional MRI at 4 Tesla includes a capillary bed contribution: echo-planar imaging correlates with previous optical imaging using intrinsic signals. Magn Reson Med 33:453–459
Menon RS, Ogawa S, Strupp JP, Uğurbil K (1997a) Ocular dominance in human V1 demonstrated by functional magnetic resonance imaging. J Neurophysiol 77:2780–2787
Menon RS, Thomas CG, Gati JS (1997b) Investigation of BOLD contrast in fMRI using multi-shot EPI. NMR Biomed 10:179–182
Michaeli S, Garwood M, Zhu XH, DelaBarre L, Andersen P, Adriany G, Merkle H, Uğurbil K, Chen W (2002) Proton T(2) relaxation study of water, N-acetylaspartate, and creatine in human brain using Hahn and Carr-Purcell spin echoes at 4T and 7T. Magn Reson Med 47:629–633
Mitra PP, Ogawa S, Hu X, Uğurbil K (1997) The nature of spatio-temportal changes in cerebral hemodynamics as manifested in functional magnetic resonance imaging. Magn Reson Med 37:511–518
Moeller S, Van de Moortele PF, Goerke U, Adriany G, Uğurbil K (2006) Application of parallel imaging to fMRI at 7 Tesla utilizing a high 1D reduction factor. Magn Reson Med 56:118–129
Moeller S, Auerbach E, van de Moortele P-F, Adriany G, Uğurbil K (2008) fMRI with 16 fold reduction using multibanded multislice sampling. Proc Int Soc Mag Reson Med 16:2366
Moeller S, Yacoub E, Olman CA, Auerbach E, Strupp J, Harel N, Uğurbil K (2010) Multiband multislice GRE-EPI at 7T, with 16-fold acceleration using partial parallel imaging with application to high spatial and temporal whole-brain fMRI. Magn Reson Med 63:1144–1153
Muftuler LT, Nalcioglu O (2000) Improvement of temporal resolution in fMRI using slice phase encode reordered 3D EPI. Magn Reson Med 44:485–490
Mullinger KJ, Mayhew SD, Bagshaw AP, Bowtell R, Francis ST (2013) Poststimulus undershoots in cerebral blood flow and BOLD fMRI responses are modulated by poststimulus neuronal activity. Proc Natl Acad Sci U S A 110:13636–13641
Norris DG, Zysset S, Mildner T, Wiggins CJ (2002) An investigation of the value of spin-echo-based fMRI using a Stroop color-word matching task and EPI at 3T. Neuroimage 15:719–726
Obata T, Liu TT, Miller KL, Luh WM, Wong EC, Frank LR, Buxton RB (2004) Discrepancies between BOLD and flow dynamics in primary and supplementary motor areas: application of the balloon model to the interpretation of BOLD transients. Neuroimage 21:144–153
Ogawa S (2012) Finding the BOLD effect in brain images. Neuroimage 62:608–609
Ogawa S, Lee TM (1990) Magnetic resonance imaging of blood vessels at high fields: in vivo and in vitro measurments and image simulation. Magn Reson Med 16:9–18
Ogawa S, Lee T-M, Kay AR, Tank DW (1990a) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 87:9868–9872
Ogawa S, Lee T-M, Nayak AS, Glynn P (1990b) Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med 14:68–78
Ogawa S, Tank DW, Menon R, Ellermann JM, Kim SG, Merkle H, Uğurbil K (1992) Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc Natl Acad Sci U S A 89:5951–5955
Ogawa S, Menon RS, Tank DW, Kim SG, Merkle H, Ellermann JM, Uğurbil K (1993) Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model. Biophys J 64:803–812
Ohliger MA, Grant AK, Sodickson DK (2003) Ultimate intrinsic signal-to-noise ratio for parallel MRI: electromagnetic field considerations. Magn Reson Med 50:1018–1030
Paulson OB, Hertz MM, Bolwig TG, Lassen NA (1977a) Filtration and diffusion of water across the blood-brain barrier in man. Microvasc Res 13:113–124
Paulson OB, Hertz MM, Bolwig TG, Lassen NA (1977b) Water filtration and diffusion across the blood brain barrier in man. Acta Neurol Scand Suppl 64:492–493
Pawlik G, Rackl A, Bing RJ (1981) Quantitative capillary topography and blood flow in the cerebral cortex of cats: an in vivo microscopic study. Brain Res 208:35–58
Pfeuffer J, Van De Moortele PF, Uğurbil K, Hu X, Glover GH (2002) Correction of physiologically induced global off-resonance effects in dynamic echo-planar and spiral functional imaging. Magn Reson Med 47:344–353
Polimeni JR, Fischl B, Greve DN, Wald LL (2010) Laminar analysis of 7T BOLD using an imposed spatial activation pattern in human V1. Neuroimage 52:1334–46
Poser BA, Koopmans PJ, Witzel T, Wald LL, Barth M (2010) Three dimensional echo-planar imaging at 7 Tesla. Neuroimage 51:261–266
Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, Avison M, Howseman A, Hanstock C, Shulman R (1991) Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci U S A 88:5829–5831
Pruessmann KP, Weiger M, Scheidegger MB, Boesiger P (1999) SENSE: sensitivity encoding for fast MRI. Magn Reson Med 42:952–962
Raichle ME (1987) Circulatory and metabolic correlates of brain function in normal humans. In: Plum F (ed) Handbook of physiology-the nervous system. American Physical Society, Bethesda, pp 643–674
Raichle ME (2009) A brief history of human brain mapping. Trends Neurosci 32:118–126
Sadaghiani S, Uğurbil K, Uludağ K (2009) Neural activity-induced modulation of BOLD poststimulus undershoot independent of the positive signal. Magn Reson Imaging 27:1030–1038
Segebarth C, Belle V, Delon C, Massarelli R, Decety J, Le Bas J-F, Decorpts M, Benabid AL (1994) Functional MRI of the human brain: predominance of signals from extracerebral veins. Neuroreport 5:813–816
Sheth SA, Nemoto M, Guiou MW, Walker MA, Toga AW (2005) Spatiotemporal evolution of functional hemodynamic changes and their relationship to neuronal activity. J Cereb Blood Flow Metab 25:830–841
Shmuel A, Yacoub E, Pfeuffer J, Van de Moortele PF, Adriany G, Hu X, Uğurbil K (2002) Sustained negative BOLD, blood flow and oxygen consumption response and its coupling to the positive response in the human brain. Neuron 36:1195–1210
Shmuel A, Augath M, Oeltermann A, Logothetis NK (2006) Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1. Nat Neurosci 9:569–577
Shmuel A, Chaimow D, Raddatz G, Uğurbil K, Yacoub E (2010) Mechanisms underlying decoding at 7T: ocular dominance columns, broad structures, and macroscopic blood vessels in V1 convey information on the stimulated eye. Neuroimage 49:1957–1964
Silva AC, Koretsky AP, Duyn JH (2007) Functional MRI impulse response for BOLD and CBV contrast in rat somatosensory cortex. Magn Reson Med 57:1110–1118
Silvennoinen MJ, Clingman CS, Golay X, Kauppinen RA, van Zijl PC (2003) Comparison of the depend-ence of blood R2 and R2* on oxygen saturation at 1.5 and 4.7 Tesla. Magn Reson Med 49:47–60
Sirotin YB, Hillman EM, Bordier C, Das A (2009) Spatiotemporal precision and hemodynamic mechanism of optical point spreads in alert primates. Proc Natl Acad Sci U S A 106:18390–18395
Smirnakis SM, Schmid MC, Weber B, Tolias AS, Augath M, Logothetis NK (2007) Spatial specificity of BOLD versus cerebral blood volume fMRI for mapping cortical organization. J Cereb Blood Flow Metab 27:1248–1261
Spees WM, Yablonskiy DA, Oswood MC, Ackerman JJ (2001) Water proton MR properties of human blood at 1.5 Tesla: magnetic susceptibility, T(1), T(2), T*(2), and non-Lorentzian signal behavior. Magn Reson Med 45:533–542
Springer CS, Xu Y (1991) Aspects of bulk magnetic susceptibility in in vivo MRI and MRS. In: Rink PA, Muller RN (eds) New developments in contrast agent research. European Magnetic Resonance Forum, Blonay, pp 13–25
Thulborn KR, Waterton JC, Matthews PM, Radda GK (1982) Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim Biophys Acta 714:265–270
Thulborn KR, Waterton JC, Matthews PM (1992) Dependence of the transverse relaxation time of water protons in whole blood at high field. Biochem Biophys Acta 714:265–272
Uğurbil K (2012) Development of functional imaging in the human brain (fMRI); the University of Minnesota experience. Neuroimage 62:613–619
Uğurbil K, Garwood M, Ellermann J, Hendrich K, Hinke R, Hu X, Kim SG, Menon R, Merkle H, Ogawa S, Salmi R (1993) Imaging at high magnetic fields: initial experiences at 4T. Magn Reson Q 9:259–277
Uğurbil K, Toth L, Kim DS (2003) How accurate is magnetic resonance imaging of brain function? Trends Neurosci 26:108–114
Uludağ K (2008) Transient and sustained BOLD responses to sustained visual stimulation. Magn Reson Imaging 26:863–869
Uludağ K (2010) To dip or not to dip: reconciling optical imaging and fMRI data. Proc Natl Acad Sci U S A 107:E23 (author reply E24)
Uludağ K, Dubowitz DJ, Yoder EJ, Restom K, Liu TT, Buxton RB (2004) Coupling of cerebral blood flow and oxygen consumption during physiological activation and deactivation measured with fMRI. Neuroimage 23:148–155
Uludağ K, Muller-Bierl B, Uğurbil K (2009) An integrative model for neuronal activity-induced signal changes for gradient and spin echo functional imaging. Neuroimage 48:150–165
Van De Moortele PF, Pfeuffer J, Glover GH, Uğurbil K, Hu X (2002) Respiration-induced B0 fluctuations and their spatial distribution in the human brain at 7 Tesla. Magn Reson Med 47:888–895
Van Raaij ME, Lindvere L, Dorr A, He J, Sahota B, Foster FS, Stefanovic B (2012) Quantification of blood flow and volume in arterioles and venules of the rat cerebral cortex using functional micro-ultrasound. Neuroimage 63:1030–1037
Vanzetta I (2006) Hemodynamic responses in cortex investigated with optical imaging methods. Implications for functional brain mapping. J Physiol Paris 100:201–211
Vanzetta I, Hildesheim R, Grinvald A (2005) Compartment-resolved imaging of activity-dependent dynamics of cortical blood volume and oximetry. J Neurosci 25:2233–2244
van Zijl PC, Eleff SM, Ulatowski JA, Oja JM, Ulug AM, Traystman RJ, Kauppinen RA (1998) Quantitative assessment of blood flow, blood volume and blood oxygenation effects in functional magnetic resonance imaging. Nat Med 4:159–167
van Zijl PC, Hua J, Lu H (2012) The BOLD post-stimulus undershoot, one of the most debated issues in fMRI. Neuroimage 62:1092–1102
Vazquez AL, Fukuda M, Tasker ML, Masamoto K, Kim S-G (2010) Changes in cerebral arterial, tissue and venous oxygenation with evoked neural stimulation: implications for hemoglobin-based functional neuroimaging. J Cereb Blood Flow Metab 30:428–439
Watanabe M, Bartels A, Macke JH, Murayama Y, Logothetis NK (2013) Temporal jitter of the BOLD signal reveals a reliable initial dip and improved spatial resolution. Curr Biol 23:2146–2150
Weber B, Keller AL, Reichold J, Logothetis NK (2008) The microvascular system of the striate and extrastriate visual cortex of the macaque. Cereb Cortex 18:2318–2330
Wehrli FW, MacFall JR, Schutts D, Breger R, Herfkens RJ (1984) Mechanism ofcontrast in NMR. J Comput Assist Tomogr 8:369–380
Weisskoff RM, Boxerman JL, Zuo CS, Rosen BR (1993) Endogenous susceptibility contrast: principles of relationship between blood oxygenation and MR signal change. Functional MRI of the Brain, Arlington, Virginia, pp 103–110
Weisskoff RM, Zuo CS, Boxerman JL, Rosen BR (1994) Microscopic susceptibility variation and transverse relaxation: theory and experiment. Magn Reson Med 31:601–610
Wiesinger F, Van de Moortele PF, Adriany G, De Zanche N, Uğurbil K, Pruessmann KP (2004) Parallel imaging performance as a function of field strength–an experimental investigation using electrodynamic scaling. Magn Reson Med 52:953–964
Wiesinger F, Van de Moortele PF, Adriany G, De Zanche N, Uğurbil K, Pruessmann KP (2006) Potential and feasibility of parallel MRI at high field. NMR Biomed 19:368–378
Wong EC, Buxton RB, Frank LR (1998) Quantitative imaging of perfusion using a single subtraction (QUIPSS and QUIPSS II). Magn Reson Med 39:702–708
Wong EC, Cronin M, Wu WC, Inglis B, Frank LR, Liu TT (2006) Velocity-selective arterial spin labeling. Magn Reson Med 55:1334–1341
Wu WC, Wong EC (2006) Intravascular effect in velocity-selective arterial spin labeling: the choice of inflow time and cutoff velocity. Neuroimage 32:122–128
Wu WC, Wong EC (2007) Feasibility of velocity selective arterial spin labeling in functional MRI. J Cereb Blood Flow Metab 27:831–838
Yablonskiy DA, Haacke EM (1994) Theory of NMR signal behavior in magnetically inhomogeneous tissues: the static dephasing regime. Magn Reson Med 32:749–763
Yacoub E, Le TH, Uğurbil K, Hu X (1999) Further evaluation of the initial negative response in functional magnetic resonance imaging. Magn Reson Med 41:436–441
Yacoub E, Shmuel A, Pfeuffer J, Van De Moortele PF, Adriany G, Uğurbil K, Hu X (2001) Investigation of the initial dip in fMRI at 7 Tesla. NMR Biomed 14:408–412
Yacoub E, Duong TQ, Van De Moortele PF, Lindquist M, Adriany G, Kim SG, Uğurbil K, Hu X (2003) Spin-echo fMRI in humans using high spatial resolutions and high magnetic fields. Magn Reson Med 49:655–664
Yacoub E, Van De Moortele PF, Shmuel A, Uğurbil K (2005) Signal and noise characteristics of Hahn SE and GRE BOLD fMRI at 7T in humans. Neuroimage 24:738–750
Yacoub E, Uğurbil K, Harel N (2006) The spatial dependence of the poststimulus undershoot as revealed by high-resolution BOLD- and CBV-weighted fMRI. J Cereb Blood Flow Metab 26:634–644
Yacoub E, Shmuel A, Logothetis N, Uğurbil K (2007) Robust detection of ocular dominance columns in humans using Hahn Spin Echo BOLD functional MRI at 7 Tesla. Neuroimage 37:1161–1177
Yacoub E, Harel N, Uğurbil K (2008) High-field fMRI unveils orientation columns in humans. Proc Natl Acad Sci U S A 105:10607–10612
Yang Y, Glover GH, van Gelderen P, Patel AC, Mattay VS, Frank JA, Duyn JH (1998) A comparison of fast MR scan techniques for cerebral activation studies at 1.5T [published erratum appears in Magn Reson Med 1998 Mar;39(3):following 505]. Magn Reson Med 39:61–67
Yesilyurt B, Uğurbil K, Uludağ K (2008) Dynamics and nonlinearities of the BOLD response at very short stimulus durations. Magn Reson Imaging 26:853–862
Zappe AC, Uludağ K, Logothetis NK (2008) Direct measurement of oxygen extraction with fMRI using 6% CO(2) inhalation. Mag Reson Imaging 26:961–967
Zhao F, Wang P, Hendrich K, Uğurbil K, Kim SG (2006) Cortical layer-dependent BOLD and CBV responses measured by spin-echo and gradient-echo fMRI: insights into hemodynamic regulation. Neuroimage 30:1149–1160
Zhao F, Jin T, Wang P, Hu X, Kim SG (2007a) Sources of phase changes in BOLD and CBV-weighted fMRI. Magn Reson Med 57:520–527
Zhao F, Jin T, Wang P, Kim SG (2007b) Improved spatial localization of post-stimulus BOLD undershoot relative to positive BOLD. Neuroimage 34:1084–1092
Zhu XH, Zhang N, Zhang Y, Uğurbil K, Chen W (2009) New insights into central roles of cerebral oxygen metabolism in the resting and stimulus-evoked brain. J Cereb Blood Flow Metab 29:10–8
Zimmermann J, Goebel R, De Martino F, van de Moortele PF, Feinberg D, Adriany G, Chaimow D, Shmuel A, Uğurbil K, Yacoub E (2011) Mapping the organization of axis of motion selective features in human area MT using high-field fMRI. PLoS ONE 6:e28716
Zong X, Kim T, Kim SG (2012) Contributions of dynamic venous blood volume versus oxygenation level changes to BOLD fMRI. Neuroimage 60:2238–2246
Acknowledgments
Work reported here from the Center for Magnetic Resonance University of Minnesota was supported by National Institutes of Health (NIH) Biotechnology Research Center (BTRC) grants P41 RR08079 and P41 EB015894.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer New York
About this chapter
Cite this chapter
Uludağ, K., Uğurbil, K. (2015). Physiology and Physics of the fMRI Signal. In: Uludag, K., Ugurbil, K., Berliner, L. (eds) fMRI: From Nuclear Spins to Brain Functions. Biological Magnetic Resonance, vol 30. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7591-1_8
Download citation
DOI: https://doi.org/10.1007/978-1-4899-7591-1_8
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-7590-4
Online ISBN: 978-1-4899-7591-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)