NeuroImage 61 (2012) A3–A11

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NeuroImage
journal homepage: www.elsevier.com/locate/ynimg

Review

Functional MRI: A confluence of fortunate circumstances

Peter A. Bandettini ⁎
Section on Functional Imaging Methods, Functional MRI Core Facility, National Institute of Mental Health, 10 Center Dr., Rm 1D80, Bethesda, MD 20892, USA

a r t i c l e i n f o a b s t r a c t

Article history: Functional MRI has existed for about twenty years and by almost all measures has been incredibly successful.
Received 25 January 2012 What are the reasons behind this success? In this review, eight extremely fortunate circumstances came to-
Accepted 27 January 2012 gether to produce BOLD based fMRI as we know it today. They are as follows: 1. The MRI signal, 2. The MRI
Available online 6 February 2012
relaxation rates, 3. The oxygen-dependent magnetic susceptibility of blood, 4. Neuronal–hemodynamic cou-
pling, 5. The spatial scale of brain activation, 6. The prevalence of scanners able to perform echo planar imag-
Keywords:
Functional MRI
ing (EPI), 7. The parallel development of computing power, and 8. The very large group of neuroscientists
Brain imaging who, pre-1991, were perfectly poised, willing, and able to exploit the capability of fMRI. These circumstances
fMRI are discussed in detail. The desired goal of this review is primarily to convey the field of fMRI from the per-
Blood susceptibility spective of what was critically important before, during and after its inception and how things might have
BOLD been if these circumstances would have been different. While there are many instances where circumstances
MRI could have been better, it is clear that they worked out extremely well, as the field of fMRI, a major aspect of
Neurovascular coupling functional neuroimaging today, is thriving.
Published by Elsevier Inc.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A3
The MRI signal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A4
The MRI relaxation rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A5
The oxygen-dependent magnetic susceptibility of blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A5
Neuronal–hemodynamic coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A6
The spatial scale of brain activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A8
The prevalence of scanners able to perform EPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A8
Parallel development of computing power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A8
The neuroscience community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A9
Trajectory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A9
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A10
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A10

Introduction
Functional MRI has existed for about twenty years. The first man-
uscript demonstrating MRI-based mapping of human brain activation
was published in November of 1991 by Belliveau et al. (1991) with
the now iconic figure on the cover of that issue of Science. This result
showed that with the use of gadolinium as an indicator of activation-
related blood volume changes, blood volume increases in the visual
cortex associated with visual stimulation could be imaged. The first
successful experiments to determine if brain activation could be
⁎ Fax: + 1 301 402 1370.
E-mail address: bandettini@nih.gov.
URLs: http://fim.nimh.nih.gov/, http://fmrif.nimh.nih.gov/.
observed using MRI but without any exogenous contrast agents
were carried out independently early in 1991 by the research groups
at Massachusetts General Hospital (Kwong, 2012) and the University
of Minnesota (Ugurbil, 2012), and the first papers using blood oxy-
genation level dependent (BOLD), as coined by Ogawa et al. (1990),
were published in the early summer of 1992 (Bandettini et al.,
1992; Kwong et al., 1992; Ogawa et al., 1992). The Medical College
of Wisconsin group obtained their first successful fMRI results in
Sept of 1991 and managed to publish the first BOLD - based fMRI
result in June of 1992. Those were exciting times to say the least. I
was fortunate enough to be part of early fMRI efforts at the Medical
College of Wisconsin (Bandettini, 2012). To a large extent the excite-
ment has steadily grown and spread, as today, the use of BOLD con-
trast based fMRI has continued to grow in just about all measurable

1053-8119/$ – see front matter. Published by Elsevier Inc.

doi:10.1016/j.neuroimage.2012.01.130
A4 P.A. Bandettini / NeuroImage 61 (2012) A3–A11

ways. The emergence and incredible success of fMRI were the result
of the confluence of many different circumstances which essentially
simmered for years until coming together in the early 90s. These
circumstances ranged from the fundamental physical principles of
NMR and MRI, recently emergent MRI technology, principles of
biochemistry, neuroscience, cerebral physiology, the medical imaging
industry, and perhaps our own natural penchant for topographical
information.
After 1991, fMRI grew at an increasingly rapid rate, catalyzed by the
simple fact that it was a method that worked extremely well from the
start! It was relatively easy to obtain very clear and reproducible brain
activation results. Currently, as of Dec 8, 2011, according to the Scopus
search utility, 22,251 articles or reviews have been published having
the terms fMRI or functional MRI in the title, abstract, or keywords.
The rate of fMRI publication is now in excess of 2500 papers per year,
as shown in Fig. 1. The number of papers published by the journal
NeuroImage has grown in parallel with the use of fMRI, as currently, it
is publishing over 1000 papers per year. The largest fraction of the pre-
sentations at the Organization for Human Brain Mapping (OHBM)
Meeting is fMRI related, so the growth in fMRI studies is somewhat
reflected in the growth of the OHBM meeting attendance, shown in
Fig. 2. The range of applications is immense, including basic neurosci-
ence, cognitive psychology, genetics, and neurology.
Application-enabling technology has continued to grow. We have
more robust and available processing platforms, higher field
strengths, better RF coil systems, and more sophisticated pulse se-
quences and data acquisition strategies. We understand the BOLD sig-
nal much better, though not yet perfectly. The field is currently in the
process of squeezing every last bit of useful information from the time
series signal — even tapping into the so-called “resting state” signal to Fig. 2. The attendance at the Organization for Human Brain Mapping Meetings since
the first meeting in Paris in 1995. The attendance has approximately quadrupled
derive a new treasure-trove of new and potentially useful informa-
since the first few years.
tion regarding the functional organization of the brain as well as po-
tentially clinically relevant information.
Functional MRI has been one of the greatest methodological suc- The idea for this review started as a lecture that I first gave in 2006
cess stories in science in the past 20 years. How could this have hap- in Dubrovnik, Croatia at a conference celebrating the 150th anniver-
pened? The focus of this review is on the fortunate circumstances that sary of the birth of Nikola Tesla. When the lecture was given, it was
have come together so well to produce fMRI and specifically fMRI also about the 15th anniversary of the first successful experiments
using BOLD contrast as we know and love today (Bandettini, 2007). using BOLD contrast for fMRI. That lecture was about what had to
come together to create fMRI. Recently, the development of this
idea was further motivated by Robert Weisskoff's first-person histor-
ical perspective article on dynamic susceptibility imaging (Weisskoff,
2012), in which he starts by mentioning off-hand the sheer improba-
bility of MRI. I decided to expand on this idea and write a complete
perspective of this confluence of fortunate circumstances.
The circumstances are as follows: 1. The MRI signal, 2. The MRI re-
laxation rates, 3. The oxygen-dependent magnetic susceptibility of
blood, 4. Neuronal–hemodynamic coupling, 5. The spatial scale of
brain activation, 6, The prevalence of scanners able to perform echo pla-
nar imaging (EPI), 7. The parallel development of computing power,
and 8. The very large group of neuroscientists who, pre-1991, were per-
fectly poised, willing, and able to exploit the capability of fMRI.
Each of these circumstances is discussed below in the context of
the field of fMRI. Within each of these descriptions are further exam-
ples of how, if they were only slightly different, fMRI would have been
either non-existent or in a very different state than it is now. Lastly,
while we, as a community, are mostly lucky, we are not quite as
lucky as we could have been in many circumstances. I'll mention
these “only-if” circumstances as well!

The MRI signal

Water molecules contain two hydrogen atoms. Most MRI involves

Fig. 1. Based on a literature search using Scopus, with search terms “fMRI” or “function-
al MRI” and limiting the papers to only articles or reviews, this shows a very steady in-
crease in papers published since 2001. An initial jump in the numbers occurred in 1996
to 1997 when echo planar imaging, a tool that is critical to fMRI, became available on
clinical scanners.
the detection and measurement of hydrogen or, rather, protons. It's of
course fortunate for MRI that water is so abundant in our bodies since
the MRI signal that we are so dependent on arises as a infinitesimal
imbalance in energy between proton spin states. As eloquently
 P.A. Bandettini / NeuroImage 61 (2012) A3–A11
described by Weisskoff (2012): “It still seems remarkable to me that
an entire segment of the medical imaging industry could be built on
something as unlikely as MRI… The small energy difference between
the spin up and spin down state for the protons even in at 1.5 T field
creates a net polarization of only a few protons per million, and ev-
erything we see in MRI (and fMRI) is the result of that small differ-
ence.” We are able to measure only those few in a million protons.
A tiny signal that give so much information.
We are also fortunate that the resonant frequency of water in typ-
ically used fields is in the harmless radiofrequency (RF) range. MRI
coils apply RF pulses to excite the protons so that imaging may take
place. If this frequency were any higher – perhaps a single order of
magnitude – we would quickly reach RF power deposition limits.
We are now just starting to approach some RF power limits for cer-
tain RF intensive pulse sequences at 3 T and higher. This might be a
prohibitive limit at fields above 7 T which we will inevitably explore.
In addition, RF wavelengths, as they shorten with higher frequencies,
provide a source of image artifact at higher field strengths as they
begin to approach the size of a human head. So, MRI might have
been a bit easier if the resonant frequencies and corresponding wave-
lengths would have been just a bit lower and longer respectively, but
of course we are effectively working around these issues at this time.
The MRI relaxation rates
The amount of time for the spin system – in this case, protons – to
reach equilibrium after being excited by RF power, is defined primarily
by the relaxation rates T1, T2, and T2* (Mitchell and Cohen, 2004). T2* is
the rate of transverse relaxation, shorter than longitudinal relaxation
rates determined by T1, and due to macroscopic field inhomogeneities
causing spins to precess at slightly different frequencies, leading to
dephasing. Faster dephasing causes faster T2* decay and thus lower
signal at a given echo time (TE). T1 is the rate at which the system re-
covers longitudinal relaxation to reach equilibrium after an RF pulse,
and T2 is the rate in which the system loses transverse signal after an
excitation RF pulse and a refocusing pulse that mostly nullifies T2*
effects. T2 is also known as the transverse relaxation rate. T1 is on the
order of hundreds of milliseconds to seconds and T2 is on the order of
milliseconds to tens of milliseconds. As mentioned, T2* is shorter than
T2. These relaxation rates depend very much on their local environ-
ment, thus allowing exquisite differentiation of tissue types based on
these parameters. This amazing effect, coupled with the Nobel Prize
winning invention of spatial encoding by Lauterbur (1973) and
Mansfield (1977), has allowed MRI to flourish in the clinical setting. It
works incredibly well and is non-invasive and easy to use.
MRI is highly effective in pinpointing tumors, edema, and brain le-
sions of all types. The first clinical MRI scanner appeared in about
1984. Today, the average hospital has at least a handful of MR scan-
ners. Independent MRI clinics have been rapidly cropping up as
well. The clinical world that utilized MRI was, by 1991, poised and
ready to spread fMRI once it emerged.
If T1's were just a bit slower, or in other words, if spin systems (i.e.
body tissues in a magnetic field) took longer to return to their initial
magnetization once given an RF pulse, most imaging at the signal to
noise (SNR) levels that we currently enjoy would take much longer
since we would have to wait a longer time between RF excitation
pulses to allow the system gain back some of its magnetization. We
could also image at lower flip angles but the low SNR would still be
an obstacle. So if T1 were, say 10 s, we would be forced to sacrifice
SNR (less magnetization at steady state at a given TR and flip angle)
or have to wait much longer to gain back our SNR. It's possible that
these limits might be prohibitive for widespread use.
On the other hand, if T2 (or T2*) were any shorter, we might not
be able to image at all as the signal would decay away before we
could apply the appropriate magnetic field gradients to spatially en-
code the data. Currently, sparse radial paths through raw data space
A5
(or k-space) are required for imaging tissue with extremely short
T2 or T2* values, thus severely limiting image resolution.
How is fMRI fortunate with regard to relaxation rates? While we are
very fortunate T2 and T2* values are not too short, echo planar imaging
(EPI) which relies on rapidly switching the spatial encoding images to
image an entire plane in one echo (hence the name), is a sequence
that would have been hit particularly hard by shorter transverse relax-
ation rates. Since fMRI relies on EPI, it too would suffer greatly if T2*
were much shorter. Maximum achievable matrix size at these very
short T2* values, and while using single shot EPI, early on would have
been perhaps 16× 16, thus severely limiting the early advantage that
fMRI had over lower resolution brain imaging methods.
On the other hand, EPI would have benefited tremendously if the
transverse relaxation rate were just a bit longer. Instead of a typical
20 to 50 ms T2*, if we had a 200 ms T2*, our echo planar images
would have initially, back in the early 90s, been on the order of
256 × 256 matrix size rather than 64 × 64 matrix size. This 20 to
50 ms was just enough for standard EPI to create a relatively low res-
olution image that is still higher resolution than most other tech-
niques. After 20 years, we have started to make some headway in
resolution by the application of partial k-space reconstruction
(Jesmanowicz et al., 1998), multi-coil parallel acquisition (Pruessmann
et al., 1999; Sodickson, 2000), and multiplexed excitation (Feinberg et
al., 2010; Setsompop et al., 2006). Unfortunately, it's likely that even
though we are now able to physically drive the spatial encoding gra-
dients much faster, some hard limits have been set by neurobiology.
If peripheral nerve fibers experience too fast of a change in magnetic
field, they are triggered to fire as if in response to a jolt of electricity.
This can cause extreme discomfort, and of course can be life threat-
ening if the nerves happen to be in the heart. Fortunately, the thresh-
old for this type of triggered firing is much higher within the brain
itself — so there are no seizure threats. Therefore, with regard to gra-
dient induced limits on imaging, we are not so lucky that the nerves
in our bodies can't tolerate too high of a gradient switching rate even
though gradient coil technology has finally progressed such that we
could go much faster if the body allowed it.
The oxygen-dependent magnetic susceptibility of blood
The unique property of blood, fundamental to fMRI contrast, is
that the level of blood oxygenation directly influences the MRI signal.
It's an endogenous contrast agent that appears (by reducing the MRI
signal) when blood is deoxygenated and disappears (by allowing a
higher MRI signal) when blood is fully oxygenated. Oxygen is trans-
ported in the blood primarily by hemoglobin within red blood cells.
The oxygen-sensitive magnetic susceptibility of hemoglobin influ-
ences the blood susceptibility. If unbound and exposed, hemoglobin
is paramagnetic, causing hemoglobin, red blood cells containing he-
moglobin, and blood vessels containing the red blood cells to become
slightly more paramagnetic, or more correctly, just a bit less diamagnet-
ic than the rest of plasma and tissue throughout the body (Pauling and
Coryell, 1936). Objects of different susceptibility, when experiencing a
magnetic field, concentrate the field different amounts, thus causing
a small magnetic field distortion at their interfaces. Protons that
experience different magnetic fields within an imaging voxel will
precess at different frequencies. After a short amount of time,
depending on how different the magnetic fields are, their phases
will cancel thus reducing the overall signal. Needless to say, aside
from the unique oxygen transport properties of blood being likely es-
sential to all animal physiology as we know it, the oxygen-sensitive
magnetic susceptibility of blood is essential to BOLD contrast. With-
out this unique effect, BOLD would not exist.
The susceptibility modulation of blood was first described by Linus
Pauling (Pauling and Coryell, 1936). The modulation of blood oxygen-
ation on NMR relaxation properties was first measured by Keith
Thulborn (Thulborn et al., 1982). During this time, a number of groups
A6 P.A. Bandettini / NeuroImage 61 (2012) A3–A11
made similar observations (Fabry and San George, 1983). These obser-
vations were followed by the seminal work of Ogawa et al. describing
the effect, in vivo, of changes in blood oxygenation (Ogawa et al.,
1990). Shortly after this observation, Turner observed a similar effect
in cats (Turner et al., 1991). During this time, Belliveau et al. at the
Massachusetts General Hospital were pioneering the use of sequential
injections of an exogenous paramagnetic contrast agent, gadolinium,
to characterize the increase in blood volume in activated visual cortex
(Belliveau et al., 1991). This was published in 1991, but a second rev-
olution happened during the spring through fall of 1991. This is when
at least three groups were making their first observations of brain ac-
tivation using BOLD contrast. MGH, with the driven and talented ex-
perimentalist Ken Kwong, had their first successful results in May of
1991 (Kwong, 2012), Minnesota, backed by Ogawa's suspicion that
BOLD contrast could tell much more than if an unfortunate rat or cat
were suffocating or not, had their first successful results (Ugurbil,
2012) shortly following MGH (although this relative timing still some-
what contentious). The MCW group, learning of the MGH results in
August of 1991, and having been developing software and hardware
that would lend itself perfectly to the desired more-stable time series
imaging with EPI, obtained their first successful results on Sept 16,
1991, demonstrating clear motor cortex activation (Bandettini,
2012). Other groups followed quickly. The Yale group (Blamire et al.,
1992), Jens Frahm's group in Germany (Frahm et al., 1992), and the
NIH (Turner et al., 1993) all produced successful results relatively
quickly.
Only a handful of groups had the appropriate hardware and soft-
ware to perform time series data collection with fMRI. No other ven-
dor than perhaps the relatively small companies of ANMR and SMIS
sold EPI capability at this time. The fMRI world would have evolved
differently if the major vendors decided that time series EPI acquisi-
tion was not an important feature to include. Interestingly, while
EPI was widely introduced commercially in about 1996, the primary
reason for this introduction was likely cardiac imaging, where a
potential clinical market was identified. While clinical cardiac imaging
still does not utilize EPI as much as anticipated in the early 1990's,
fMRI had caught on just enough to perhaps influence the markets –
persuading vendors to keep EPI as a boutique – non clinical – feature.
Finally, one other fortunate circumstance with regard to blood is
the spatial scale of red blood cells and vessels. The field perturbation
physical dimensions are on the same order or slightly larger than the
distance a water molecule diffuses in the typical echo time (TE) — about
5 to 50 μm. If the size of the these field distortions were smaller – say, on
the scale of individual molecules – then we would be in the “fast
exchange” regime where all diffusing spins experience the same aver-
age magnetic field in an echo time, and have minimal dephasing, thus
no BOLD signal change. Depictions showing the relative scale of vessels
and the relative effects of diffusion coefficient relative to scale are
shown in Figs. 3 and 4, respectively.
Fig. 3 shows the relative scales of red blood cells within vessels, and
Fig. 4 shows a diagram of the relative sensitivity of spin-echo (as shown
by dR2, which is equivalent to the change in 1/T2) and Gradient-echo
(as shown by dR2* which is equivalent to the change in 1/T2*) to various
compartment sizes. Note that as the compartment size falls below 3 μm,
the change in relaxation rate falls off precipitously. So, we are lucky
that red blood cells and vessels are large enough – and our water diffu-
sion coefficient small enough – to actually cause susceptibility-related
dephasing.
Neuronal–hemodynamic coupling
An increase in brain activation is accompanied by a local increase in
brain metabolism, blood flow, and blood volume. We know that these
neuronal activity induced hemodynamic changes are extremely consis-
tent and robust, and we uncovered many possible mechanisms by
which they occur, but we still don't definitively know why flow
Fig. 3. The spatial scale of the primary BOLD contrast susceptibility contrast sources.
The red blood cell, venules and capillaries, and large draining veins all contribute to
BOLD contrast. It should be noted that within the large draining veins, a large source
of susceptibility contrast is intravascular small compartment (red blood cell) effects.
increases! As a result of this yet unexplained flow increase, blood
oxygenation also increases (Fox and Raichle, 1986). Again, it's not un-
derstood if the reason for the flow increase is to increase oxygen deliv-
ery since there is evidence that, even without flow increases, and
at much lower blood oxygenation levels, neurons function normally.
Nevertheless, flow increases lead to an overabundance of oxygenated
blood delivered to a region of activated neurons which leads to a change
in amount of susceptibility-related dephasing, causing the T2* weighted
signal to increase. The flow chart of events is shown in Fig. 5. The two
highly fortunate circumstances of this sequence are boxed.
One explanation is that neurovascular coupling is on a larger scale
than the area of increased metabolism, thus the “entire garden is
watered for the sake of one thirsty flower.” 1 Another explanation is
that delivery of oxygen from blood to tissue is diffusion limited and
therefore inefficient. To provide enough oxygen to the furthest acti-
vated neuron from the blood vessel, the oxygenation of the blood
would have to increase to a level above baseline. A recent article
has been published that is in support of this hypothesis (Devor et
al., 2011), although the mechanism is hypothesized to be feed for-
ward, which is puzzling. More work obviously needs to be done.
Another hypothesis is that flow increases for an entirely different rea-
son than to increase oxygen delivery, and the subsequent local
increase in oxygenation of the blood is an epiphenomenon and non-
essential. When the flow response is suppressed, BOLD contrast
based activation has the opposite sign, as the increase in metabolic
rate extracts more (but not prohibitively more) oxygen from the
blood. This has been shown in animal models and in subjects who
were flow-compromised (Rother et al., 2002).
The overabundance of oxygenated blood and the corresponding
reduction of deoxygenated blood in activated regions of the brain
are absolutely fundamental to all of BOLD contrast. If the flow in-
crease caused a delivery of oxygen that precisely matched metabolic
need, there would be no change in blood oxygenation — or perhaps
only transient changes in some regions. Functional MRI would likely
still exist as we have the capability to measure flow (Kim and
Tsekos, 1997; Williams et al., 1992), flow changes (Kwong et al.,
1992) and what appears to be blood volume changes noninvasively
1
The first I heard this quote was from Ulrich Dirnagl while at a meeting in Akita,
Japan in 1996. I've heard it many other times, so I'm not certain who originated it.
 P.A. Bandettini / NeuroImage 61 (2012) A3–A11
Fig. 4. A depiction of the relative sensitivities of spin-echo (shown as dR2) and gradient-
echo (shown as dR2*) sequences to BOLD contrast. This shows several important aspects
of BOLD contrast. First, as the compartment size becomes smaller — below 3 μm, the in-
duced effect is lower. At a compartment size about that of a veinuoles, spin-echo effects
are maximized. At compartment sizes above 15 μm, gradient-echo sequences remain high-
ly sensitive while spin-echo sequences become less sensitive again. The reason for the dif-
ferences in the curves is because spin-echo sequences rely on diffusion of spins through
gradients to cause irreversible dephasing. Maximum dephasing occurs when the scale of
the perturbation in magnetic field approximately matches the diffusion distance.
(Lu et al., 2003). Perfusion measure is generally more quantitative
and stable (Aguirre et al., 2002), but suffers limitations in sensitivity,
speed, and ease of use. If fMRI were limited to perfusion measures, it's
growth would likely be a pale comparison to what it is now. So,
because of this yet to be fully understood increase in flow and there-
fore blood oxygenation with brain activation we are all extremely
fortunate.
While there is only some evidence to the contrary (Ances et al.,
2008) it appears that hemodynamic coupling is mostly uniform
throughout the brain. Therefore it is likely that no “invisible areas”
exist where metabolism and flow are matched — or where flow
does not change locally with activation, causing BOLD to stay
unchanged or decrease. That said, this possibility is difficult rule out
entirely. From a pragmatic standpoint (and almost all fMRI people
are hearty pragmatists), it has not been an issue.
The hemodynamic response is also extremely well behaved. It
does not habituate (Bandettini et al., 1997). Therefore long or rapidly
repeated stimulation is possible. Any habituation that is seen is there-
fore surmised to be neuronal. In fact, an entire paradigm class has
emerged called fMRI-adaptation that makes use of the fact that
Fig. 5. A flow chart depiction of the cascade of neuronal, physiologic, and physical events
that come into play when BOLD contrast is observed. The boxed effects are what I have
denoted as extremely fortunate and highly critical for BOLD-based fMRI to exist.
A7
neurons, when given similar stimuli will show less activity with rep-
etition (Grill-Spector et al., 1999). This approach allows the titration
of activity associated with specific neuronal pools within voxels.
The hemodynamic response is mostly linear (Boynton et al.,
1996). When duration of stimuli is modulated within time periods
above two second duration, the hemodynamic response builds in a
linear manner (Birn and Bandettini, 2005; Birn et al., 2001). With
stimuli durations below two seconds, the BOLD response behaves in
a manner that is superlinear or larger than one would expect from a
linear system. In this linear regime, with rapid event related fMRI,
the hemodynamic response to individual stimuli can therefore be
deconvolved from the time series signal if the neuronal input function
is known (Dale and Buckner, 1997).
While we are extremely fortunate to have this robust hemody-
namic coupling that causes BOLD contrast to increase in a somewhat
uniform manner both in time and across the brain, it is also because of
the hemodynamics that BOLD is still not the perfect answer to all neu-
roimaging needs. It takes about 4 to 6 s from blood to flow from arter-
ies to arterioles to capillaries to venules to veins. The delay from a
change in oxygenation in capillaries to veins is also on the order of
seconds. Since veins contribution substantially to the fMRI signal,
any variation in their distribution contributes to the variation in the
BOLD signal. Veins not only show variable latencies in which the ox-
ygenated blood flows, but also are inhomogeneously distributed
throughout the brain relative to the imaging voxel size, causing
some voxels to have a much higher fraction of venous blood. Fig. 6
shows a cartoon of the variable distribution of vasculature as it is
sampled by imaging voxels. Note that some voxels have a very high
fraction of blood within them. These large vein effects likely would
show the largest and the most delayed signal change. This inhomoge-
neous distribution of venous blood leads to a large spatial and tempo-
ral inhomogeneity of BOLD contrast, such that we cannot say, with a
single task modulation, that a larger signal change implies more neu-
ronal activity or that a shorter latency implies do an earlier onset of
neuronal activity (Bandettini, 1999). While the community has de-
veloped methods for identifying and masking vein effects (i.e.
(Bandettini and Wong, 1997)), none of these solutions are easily
implemented or truly effective. Nevertheless, for most fMRI applica-
tions, this problem is not significant since the results do not depend
on eliminating downstream vein effects (Fig. 6).
The spatial resolution of the fMRI signal, as determined by the he-
modynamic point spread function is in the range of 3 mm at low field
strengths (Engel et al., 1997) and just over 2 mm at 7 T (Shmuel et al.,
2007). The highest functional resolution obtained has been on the
order of orientation columns (sub-millimeter) (Yacoub et al., 2008).
At high field — which increases SNR and reduces some of the intravas-
cular large vessel signal, larger vessels may not have as much influ-
ence on the BOLD signal change characteristics. The use of spin-
echo sequences, while imperfectly removing some large vessel effects
(intravascular signal is still present in spin-echo sequences) may give
more precision but at the expense of a sacrifice of about a factor of
four in functional contrast to noise.
The temporal resolution can be defined in many ways (Bandettini,
1999), but with regard to resolving the relative onsets of two differ-
ent regions, the temporal resolution is on the order of seconds
(Formisano and Goebel, 2003; Lee et al., 1995). More precision can
be obtained when the question is not which region turned on first
but if the timing of a given region is modulated by the timing of a
task. For this question, the precision can be as high as 50 to 100 ms
(Bellgowan et al., 2003; Menon et al., 1998). Other novel approaches
which rely on the inhibitory interaction of different regions (i.e. left
and right somatosensory cortex) have been able to probe, with milli-
second accuracy, the timing of the inhibitory input from one region to
another (Ogawa et al., 2000).
One highly under-appreciated yet highly fortunate aspect of the
hemodynamic effect is that it does smooth the response in time and
A8 P.A. Bandettini / NeuroImage 61 (2012) A3–A11
Fig. 6. A depiction of how the vasculature is sampled by MRI voxels. Note that the blood
volume distribution across voxels is highly inhomogeneous. This inhomogeneity is the
primary contributor to the spatial inhomogeneity of magnitude and latency of the signal
change as large vessels are most likely to fill a voxel (thus boost the fMRI signal) and show
a delayed BOLD fMRI signal change (as they are downstream from the region of activation).
space. If we were able to use MRI to look at neuronal activity directly —
bypassing the hemodynamic effect, it's likely that our relatively slow
and sparse (TR typically is between 500 ms and 3 s, and the acquisi-
tion window is about 20 ms) temporal sampling would miss most of
the interesting transient neuronal activity. For example, if a volume
consisting of 15 slices is collected each second, each slice would be
collected over only about 20 ms. This implies that 20 ms out of the en-
tire second of imaging is sampled — about 1/50th of the time series
data. Most of the interesting signal would be missed. So, ending this
section on a good note, we are quite lucky that we have this hemody-
namic system which temporally and spatially integrates neuronal ac-
tivity to a temporal and spatial scale that we are able to effectively
sample using MRI. In fact, the temporal and spatial hemodynamic
“point spread function,” while considered an inconvenience for the
most part, is actually somewhat matched to the spatial and temporal
resolution of time series MRI, allowing us to robustly detect very tran-
sient neuronal activity in very small pools of neurons on a spatial and
temporal scale that is much finer than the resolution at which we can
currently image.
The spatial scale of brain activation
Brain activation occurs on many spatial and temporal scales. Nev-
ertheless, some of the seemingly most significant functional “mod-
ules” appear to be organized on spatial scales of millimeters to
centimeters. This scale is a relative match to the resolutions that we
can realistically achieve with EPI. Fig. 7 shows these scales 2 and cor-
responding BOLD contrast fMRI images. The lower central figure is
one of the first maps of ocular dominance columns from Cheng et
al. (2001). The figure on the lower right is the first ever human orien-
tation column map obtained with fMRI. It was obtained at 7 T by
Yacoub et al. (2008).
This matching of scales is extremely fortunate. If the primary orga-
nization were only, say on a globally distributed columnar level scale
2
The diagrams showing layers and columns were obtained from http://www.
thebrain.mcgill.ca.
or lower, fMRI would likely have not achieved enough early success to
catch on. We needed the large blobs of activation for fMRI to work so
well. Now that fMRI is established, we are able to figure out ways of
looking into finer scales.
As mentioned above, fMRI methods can be used to discern activa-
tion of specific neuronal pools – even smaller than columns – within
voxels. The method known as fMRI-adaptation relies on the rapid ha-
bituation of specific populations of neurons to repeated stimuli, thus
causing the fMRI signal driven by these sub-voxel populations to de-
crease (Grill-Spector et al., 1999).
There is also evidence from studies of columnar activation decod-
ing that sub-voxel activation can be discerned in another manner
known as “pattern-effect” fMRI (Haxby et al., 2001). This capability
is likely possible because of a lower spatial frequency distribution –
either of the neuronal distributions or of the draining vasculature
(Kriegeskorte et al., 2010) – of high frequency functional organization
(Kriegeskorte and Bandettini, 2007). Studies using “pattern-effect”
mapping are rapidly emerging as an effective strategy for going
beyond more standard fMRI approaches in which the center of mass
of centimeter-sized regions are localized (Kamitani and Tong, 2005).
The prevalence of scanners able to perform EPI
As implied previously in this review, if fMRI relied on equipment
that was not part of the standard clinical MRI scanner product of
the large vendors — GE, Siemens, and Philips, the field would be
much less active. Functional MRI has hugely benefitted from the over-
whelming success of MRI, such that scanners – most equipped with
EPI and therefore fMRI capability – are ubiquitous throughout most
of the developed world. In 2002, it was reported that there were
20,000 systems in the world. In 2009, according to the Organization
for Economic Co-Operation and Development (OECD), there are
over 7950 MRI scanners in the US, which is equivalent to 25.9 MRI
machines per million people or one scanner every 39,000 people.
Once EPI became common on MRI scanners in about 1996, every clin-
ical scanner in the world suddenly became a perfectly capable fMRI
scanner. This capability allowed the field to essentially leverage the
already thriving and still rapidly growing clinical imaging demand
in order to grow so rapidly. Within a few years of the inception of
fMRI, any researcher, with a bit of work in setting up the appropriate
subject interface devices and in learning how to carry out the right
pulse sequence and data processing, could buy (or obtain for free) a
few hours of scan time on a hospital clinical scanner and perform
fMRI. Of course this easy access led to perhaps a wider range of qual-
ity in fMRI studies, but overall, has been extremely healthy for the
field! Looking at Fig. 1, the sharp increase in the slope of the curve
can be seen between 1996 and 1997, which corresponds to the year
just following when EPI capability became available on most clinical
scanners.
Parallel development of computing power
As time series EPI data are acquired at every higher temporal reso-
lution, spatial resolution, and efficiency (i.e. more data per unit time),
it's interesting to note that computational speed, memory, and disk
space are increasing at a rate that has kept up if not slightly surpassed
the needs of fMRI. Historically, a bottleneck has been the time it takes
to reconstruct from raw “k-space” data, time series image data. If it is
acquired with multiple coils (each coil produces an entire indepen-
dent dataset), or with the use of spiral acquisition that utilizes
computationally-demanding regridding, researchers have found
themselves either choosing to either wait about 10 min between
runs or to reconstruct the data offline at a later time. While these is-
sues come up — especially with sub-millimeter voxel size, 128 slice
per second, 32 channel acquisition EPI approaches, computational
power has mostly increased to solve this delay issue. Typically,
 P.A. Bandettini / NeuroImage 61 (2012) A3–A11
Fig. 7. Some of the spatial scales of brain organization. We are fortunate that these spatial scales, from regions such as the motor cortex to finely interleaved tissue such as orien-
tation columns, are all within the imaging capability of MRI and fMRI. Top row is from http://www.thebrain.mcgill.ca.
computational power used in fMRI reconstruction has lagged behind
what is available to the public by about two or more years since each
scanner upgrade, which spends about two years in development, has
a life cycle that has to adhere to the computational platform available
when it was being developed. For most EPI and even spiral imaging,
real time acquisition, reconstruction, display, and calculation of
updated functional images can be performed. Hence, true real time
fMRI – perhaps critical to the ultimate impact that fMRI has on the
clinical world – is able to be performed robustly today.
The neuroscience community
Lastly, one more ingredient that was of course beneficial to the field of
fMRI was the very large community of scientists who were primed to
jump in and start performing experiments. They had already developed
paradigms for their behavioral studies, or, if they were lucky, for their
positron emission tomography (PET), electro-encephalography (EEG)
or magneto-encephalography (MEG) or optical imaging or single unit re-
cording experiments. In the moments just before the first fMRI results
were reported, the disciplines of basic neuroscience, cognitive neuro-
science, and cognitive psychology to name a few, had thousands of
researchers that were pursuing avenues of research that would directly
benefit from non-invasively observing brain activation in animals and
in individuals, populations of healthy subjects, as well as those suffering
from neurologic, developmental, and other disorders. Previous methods
provided information but did not quite hit the “sweet spot” of availability,
ease of use, resolution, relatively low cost, non-invasiveness, and signal
fidelity and information content. At this moment that fMRI began, a
substantial amount complementary information regarding what was
happening on a systems level in human brains could be obtained.
Trajectory
In 1992, a handful of centers were using fMRI. These were
Massachusetts General Hospital (MGH), The University of Minnesota,
The Medical College of Wisconsin (MCW), Yale University, the National
A9
Institutes of Health, and the Max Planck Institute in Göttingen, Germa-
ny. Siemens had a resonant EPI system running in Erlangen. The compa-
ny ANMR sold a few resonant EPI systems that were retrofitted in GE
scanners before being bought by GE. In about 1993, a company called
SMIS sold a separate EPI console and gradients to be used in parallel
with current systems. Yale had a home-built gradient coil for EPI, as
did the NIH in the early stages of fMRI. In about 1993, Medical Advances
started to market a version of the low-inductance local head gradient
coil that was built by Eric Wong of the MCW group. The National Insti-
tutes of Health bought one of these. In 1996, everything changed when
EPI quickly became commonplace as it was now being sold on clinical
scanners. At this time fMRI studies increased rapidly.
In 1995, the first Organization for Human Brain Mapping meeting
was held in Paris. The inception of this meeting at this critical time
also helped catalyze and spread the use of fMRI. At this meeting,
PET and other modalities were the dominant methods. Within a few
years, fMRI took the lead as the most commonly used technique for
assessing, mapping, and comparing brain function.
The seeds of another revolution were planted as early as 1995
when Biswal et al., reported that the fMRI signal measured when
the subject was doing nothing at all contained information within
the time series fluctuations (Biswal et al., 1995). This was a unique
discovery but was largely ignored as a curious observation and per-
haps an artifact until a critical tipping point occurred in about 2005.
At this time, not only were scanners reaching a standard of stability
that was higher than ever before, but also, because of RF coil hard-
ware improvements and data analysis improvements, this resting
state information could be obtained much more easily by more peo-
ple. Once these improvements were coupled with a growing number
of people looking for complementary approaches to activation-
related studies, the field of resting state fMRI exploded — just as
fMRI itself did a few years earlier. While many studies have shown
the utility and power of using resting state data, 3 we still don't
3
The term “resting state” is quite contentious. In fact, it's likely not resting state, but
spontaneously activated neuronal networks.
A10 P.A. Bandettini / NeuroImage 61 (2012) A3–A11
know what functional role these correlated, very low frequency fluc-
tuations have. Likewise, we are finding very reproducible networks of
correlated activity in the brain and don't know what their functional
roles are. The most well known network so far is the default mode
network. This has been a rich catalyst for research as it appears to
be modulated by a wide range of cognitive states and tasks and is po-
tentially a sensitive indicator of both neurologic and psychiatric dis-
orders (Buckner et al., 2008).
Like fMRI itself, incomplete knowledge of the underlying neuronal
and hemodynamic mechanism has not slowed down rate of produc-
tion from groups around the world. Research on resting state fMRI
is showing converging evidence that these fluctuations are important
and useful both for understanding healthy brain and clinical popula-
tions. With regard to resting state, there is still a huge amount of
work to be done as we are not only trying to figure out what the sig-
nal means, but are also just beginning to develop robust methods for
processing this highly multi-dimensional data.
Functional MRI use appears to be moving away from the determi-
nation of where specific regions of activation are occurring on a rela-
tively coarse spatial scale, as averaged across large groups of subjects
for specific tasks or arrays of tasks. Rather, studies are being per-
formed at high fields, at higher resolutions (which defy spatial nor-
malization across subjects — for instance, how does one spatially
normalize to average ocular dominance columns across multiple sub-
jects?), and looking at resting state activity. It appears that network
analysis of brain activation or resting state will emerge, as this ap-
proach might prove more meaningful than that which has historically
involved placing regions of activation into spatial coordinates. Con-
tinuing on this trajectory, the interaction of more rigorous modeling
of brain activation networks with fMRI data during activation and
resting state should keep the field quite busy for years to come as
these trends are just starting to pick up momentum and relevance
in the clinical world and beyond. With more robust real time
methods, and more meaningful interpretation of signal changes for
individual subjects, fMRI is certain to make clinical inroads at an in-
creasing rate.
Conclusion
The emergence and explosive growth of fMRI have been exciting
and fulfilling to those of us who have been active in the field since the
beginning. It continues to grow in sophistication and utility at a rate
that shows no sign of decreasing. The key factors that came together in-
clude: 1. The MRI signal itself — an incredible discovery that still far sur-
passes fMRI in impact on the world, 2. MRI relaxation rates — any
different and imaging might be much more difficult if not impossible.
3. The magnetic susceptibility of blood — without this unique oxygena-
tion sensitivity of the susceptibility blood, BOLD would not exist, 4. Neu-
ronal–hemodynamic coupling — again, without this still incompletely
understood mechanism by which oxygenation consistently increases
with brain activation, fMRI would not nearly be as useful or as easy to
use. The hemodynamic response actually temporally and spatially inte-
grates the neuronal activity such that it can be observed using the
coarse and sparse sampling of MRI, 5. The spatial scale of brain activa-
tion — this scale matches the spatial scale of what we can image at the
speeds necessary to perform fMRI, 6 The prevalence scanners able to
perform echo planar imaging (EPI) — In about 1996, EPI was added to
clinical scanners in anticipation of potential clinical applications but
not necessarily for fMRI. Nevertheless, the primary beneficiary was
fMRI — which still has very limited, but a growing number of clinical ap-
plications, 7. The parallel growth of computing memory and speed, and
8. A very large group of neuroscientists who, pre-1991, were poised to
exploit the capability of fMRI to more deeply address their questions re-
lated to the functional organization of healthy and diseased brains. This
group literally stopped and switched to fMRI from what they were
doing within only a few years or less. Most researchers who have
made this relatively risky jump into fMRI in the early days have benefit-
ted, and the field of neuroscience, in its broadest sense, has grown tre-
mendously because of it as well. Since so many circumstances
converged in just the right manner, all of us who are working on
fMRI – either developing it or applying it – are very lucky and will be
very busy for many years to come!
Acknowledgments
This work was funded by the Intramural Research Program of the
National Institute of Mental Health.
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