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WHAT DOES fMRI TELL US ABOUTNEURONAL ACTIVITY?
David J. Heeger and David Ress
In recent years, cognitive neuroscientists have taken great advantage of functional magnetic
resonance imaging (fMRI) as a non-invasive method of measuring neuronal activity in the humanbrain. But what exactly does fMRI tell us? We know that its signals arise from changes in local
haemodynamics that, in turn, result from alterations in neuronal activity, but exactly how neuronal
activity, haemodynamics and fMRI signals are related is unclear. It has been assumed that thefMRI signal is proportional to the local average neuronal activity, but many factors can influence
the relationship between the two. A clearer understanding of how neuronal activity influences thefMRI signal is needed if we are correctly to interpret functional imaging data.
EXTRASTRIATE CORTEX

All visually responsive areas ofcortex except the primary visualcortex.

Department of Psychology,
450 Serra Mall, Building 420,
Stanford University,
Stanford, California 94305,
USA.
Correspondence to D.J.H.
e-mail: heeger@stanford.edu
DOI: 10.1038/nrn730

Functional magnetic resonance imaging (fMRI)1–5 has
revolutionized cognitive neuroscience over the past
decade. fMRI takes advantage of the coupling between
neuronal activity and haemodynamics (the local control of blood flow and oxygenation) in the brain toallow the non-invasive localization and measurement ofbrain activity (BOX 1). This technique is allowing a newera of research, complementary to more invasive techniques for measuring neuronal activity in animal models, to explore the function and dysfunction of thehuman brain. However, the ultimate success of thisresearch depends on the relationship between the fMRI
signal and the underlying neuronal activity. The vascular source of the fMRI signal places important limits on
the usefulness of the technique. Although we know thatthe fMRI signal is triggered by the metabolic demandsof increased neuronal activity, the details of this process
are only partially understood (BOX 2). Consequently, thisissue has emerged as one of the most important areas inneuroscience.
Understanding the relationship between fMRI andneuronal responses is particularly important becausesome fMRI and neurophysiology experiments haveyielded apparently conflicting results. One example
concerns the role of primary visual cortex (V1) in spatial attention6. Our ability to perform a visual discrimination task improves when we are cued to attend,
without moving our eyes, to the spatial location of therelevant stimulus. Shifts in attention are correlatedwith systematic changes in activity in a number ofbrain areas. Although some theories posit that attention is mediated by selection very early in the visual
pathways, attentional effects have been notoriously
difficult to measure using single-unit electrophysiology in area V1 of the monkey brain7,8. By contrast,
robust attentional effects have been readily measurablewith fMRI in human V1, and attentional effects in
EXTRASTRIATE CORTICAL AREAS (such as V4) seem to be considerably larger in human fMRI experiments than inmonkey electrophysiology experiments9,10. Is this due
to a species difference, or does it indicate a differencein what is being measured? For example, the fMRI signal might reflect not only the firing rates of the local
neuronal population, but also subthreshold activity,
simultaneous excitation and inhibition, or modulatory inputs (such as feedback from distant, higherlevel areas of visual cortex) that might not evoke spikes.
In addition, the fMRI signal might reflect changes inneuronal synchrony without a concomitant increase
in mean firing rate11. A further complication is thatfMRI signals reflect the pooled activity of a very large
number of neurons; modulations in the fMRI
responses could be caused by either large changes in
the firing rates in a small subpopulation of neurons,
or small changes in the firing rates in a much larger
subpopulation of neurons12.

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Box 1 | BOLD fMRI

In this review, we examine our current understandingof how the fMRI signal relates to neuronal responses, inthe context of a simple linear transform model. We begin
by defining the model, and then discuss experiments thathave evaluated three crucial implications of the model:that fMRI responses should show temporal summation,that the time course and amplitude of the fMRI
responses should be predictable from the underlying
neuronal responses, and that the fMRI responses should
be colocalized with the underlying neuronal activity.
The linear transform model

The central assumption guiding inferences that are
made from fMRI data about neuronal activity has beenthat the fMRI signal is approximately proportional to ameasure of local neural activity, averaged over a spatial
extent of several millimetres and over a time period ofseveral seconds13,14 (FIG. 1). We will refer to this as thelinear transform model of the fMRI signal. Note that thelinear transform model allows the possibility of an arbitrarily complex, nonlinear relationship between thestimulus and the neuronal activity. To evaluate
the model, one must either measure the underlying
neuronal activity (as in the direct comparisons of fMRI
and electrophysiological measurements discussedaAstrocyte

SynapseGlutamate
Glutamate

GlucoseCapillary

O2?

GlucoseO2

Glucose• More Hb• Faster dephasing• Weaker MRI signal• Less Hb• Slower dephasing• Stronger MRI signalbHb-induceddephasing

ExciteAcquire image

MRI emission

The fundamental signal for blood oxygen level dependent (BOLD) functional magnetic
resonance imaging (fMRI) comes from hydrogen atoms, which are abundant in the watermolecules of the brain. In the presence of a magnetic field, these hydrogen atoms absorb
energy that is applied at a characteristic radio frequency (~64 MHz for a standard,clinical 1.5-Tesla MRI scanner). After this step of applying radio-frequency excitation,
the hydrogen atoms emit energy at the same radio frequency until they gradually returnto their equilibrium state. The MRI scanner measures the sum total of the emitted radiofrequency energy. The measured radio-frequency signal decays over time, owing tovarious factors, including the presence of inhomogeneities in the magnetic field. Greater
inhomogeneity results in decreased image intensity, because each hydrogen atom
experiences a slightly different magnetic field strength, and after a short time has passed(commonly called T2*), their radio-frequency emissions cancel one another out. BOLD
fMRI techniques are designed to measure primarily changes in the inhomogeneity of themagnetic field, within each small volume of tissue, that result from changes in blood
oxygenation. Deoxy- and oxyhaemoglobin have different magnetic properties;
deoxyhaemoglobin is paramagnetic and introduces an inhomogeneity into the nearby
magnetic field, whereas oxyhaemoglobin is weakly diamagnetic and has little effect.
Hence, an increase in the concentration of deoxyhaemoglobin would cause a decrease inimage intensity, and a decrease in deoxyhaemoglobin would cause an increase in image
intensity (see figure; Hb, haemoglobin).
The emerging model of the haemodynamic response (BOX 2) posits that there are threephases of the BOLD fMRI response to a transient increase in neuronal activity: an initial,
small decrease in image intensity below baseline (during the initial period of oxygen
consumption), followed by a large increase above baseline (an oversupply of oxygenatedblood, which is only partially compensated for by an increase in deoxygenated venous
blood volume), and then by a decrease back to below baseline again (after the oversupplyof oxygenated blood has diminished, it still takes some time for the blood volume toreturn to baseline). The BOLD fMRI signal also depends on the inflow of fresh blood thathas not experienced the same history of radio-frequency excitation. This inflow effect, byitself (in the absence of any of the aforementioned changes in deoxyhaemoglobin
concentration), would appear as an increase in image intensity, and it adds to the increasein image intensity during the second phase of the response. The figure shows the proposed
relationship between synaptic activity, neurotransmitter recycling and metabolic demand(part a), and the effect of deoxyhaemoglobin on the MRI signal (part b).

Timebelow), or rely on what is already known about the neuronal activity (as in the temporal-summation experiments discussed below). Although the model is at best
an approximation of the complex interactions between
neuronal activity, metabolic demand, and blood flow
and oxygenation, it nonetheless serves as a useful platform on which to build. If the linear model were a satisfactory approximation, it would greatly simplify the
analysis and interpretation of fMRI data. The relationship between fMRI and neuronal responses would becharacterized completely and simply by the haemodynamic impulse response function (HIRF); that is, thefMRI response that results from a brief, spatially localized pulse of neuronal activity. Furthermore, one could
estimate the underlying neuronal activity from fMRI
measurements (FIG. 1). In fact, many fMRI studies haverelied on the linear transform model, using measurements of the temporal component of the HIRF to estimate the underlying neuronal activity. However, thesemeasurements of the HIRF would be worthless if thelinear transform model were not a valid approximation.
To be useful, the linear transform model must approximate the detailed relationship between the fMRI data
and the neuronal activity. That relationship depends on
three main factors, as outlined below.

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REVIEWSFirst, the relationship between fMRI and neuronal
responses depends on the fMRI acquisition technique.
Most fMRI experiments measure a blood oxygen level
dependent (BOLD) response. BOLD fMRI provides amixed signal that depends on blood flow, blood volume
and blood oxygenation (BOXES 1 and 2). Some of thesignal derives from changes within larger draining veins,some from smaller venules and capillaries, and somefrom extravascular sources15–17. Variations of the technique can be used to emphasize or de-emphasize one or
another of these components. The intravascular signals
are suppressed at higher magnetic field strengths

Box 2 | Haemodynamics and metabolism
The emerging model of the haemodynamic response posits that an increase in neuronal activity results in an initial
increase in oxygen consumption owing to increased metabolic demand; this changes the concentrations of oxy- anddeoxyhaemoglobin in the nearby vasculature, increasing the concentration of deoxyhaemoglobin while decreasing theconcentration of oxyhaemoglobin66–68. The increased neuronal activity also triggers, after a delay of ~2 s, a large
increase in local blood flow. This increase in blood flow provides a roughly proportional increase in glucose
consumption, but it actually overcompensates for the amount of oxygen being extracted, so that an oversupply ofoxygenated blood is delivered69,70. The increased flow also causes vasodilation of the venules and veins, because of theirballoon-like elasticity, which results in an increase in (mostly deoxygenated) venous blood volume71–74.
Empirical tests of this model of the haemodynamic response have relied on various methods to measure separately
blood volume, flow, oxygenation and magnetic susceptibility36,66,68,74–82. A particular emphasis has been placed on the
proposed initial phase of oxygen consumption, before the inflow and volume effects take place. The importance of the‘initial dip’, as it has come to be called, is that it should be more closely related to the neuronal activity than the other,more sluggish components of the haemodynamic response66. Much of the empirical evidence for the initial dip comesfrom optical-imaging studies66–68,82. There are also some reports of the initial dip using BOLD fMRI63,83–85 and magnetic
resonance spectroscopy86. However, the initial dip is highly controversial in both the optical-imaging and fMRI literature,
because it has not always been found64,65,81,87.
It is widely believed that increased blood flow follows directly from increased synaptic activity. The rationale for this isbased on the following two observations. First, as mentioned above, blood flow increases in proportion to glucose
consumption70. Second, glucose metabolism is linked to synaptic activity88–91. It has also been suggested that increases inbrain activation are supported by glycolysis (non-oxidative glucose metabolism)69,70. This would explain the observed
proportionality between blood flow and glucose consumption, along with the mismatch between blood flow andoxygen consumption. In particular, astrocytes have a crucial role in neurotransmitter recycling, using energy to clear
glutamate from the extracellular space and convert it to glutamine. Astrocytes surround both synapses andintraparenchymal capillaries, and the release of glutamate at an excitatory synapse triggers a concomitant uptake of
glucose by the astrocytes from the blood. Astrocytes rely on glycolysis to achieve their neurotransmitter recycling
function (consuming glucose and releasing lactate)89. In summary, the blood flow change has been proposed to deliver
the level of glucose required by the astrocytes, regardless of blood oxygenation.
An alternative view is that the blood flow response serves to deliver the level of oxygen required by the neurons.
According to this view, the apparent mismatch between blood flow and oxygen consumption is a necessary consequenceof how the oxygen is delivered; a disproportionately large change in blood flow is required to support a small change inoxygen metabolism, because extraction (by passive diffusion) of oxygen from the blood is less efficient at higher flow
rates92–94. This alternative view is supported by three further considerations. First, oxygen consumption does increase
with neuronal activity, although to a lesser extent than does blood flow36,95. Second, estimates of the metabolic costs ofbrain activity show that most of the energy is used by the neurons and that their energy usage depends strongly on
firing rates; only a small percentage of the energy is used for neurotransmitter recycling by the astrocytes96. The neurons
rely on oxidative metabolism of lactate, whereas the astrocytes rely on non-oxidative glycolysis89. It would make sense,
therefore, for the haemodynamic response to support the need for oxygen. Third, it has been proposed that astrocytes
might rely on their in-built stores of glycogen to provide energy during transient periods of strong neuronal activity,
obviating the need for increased glucose delivery97.
Resolving these views will surely depend on learning more about the detailed cellular and molecular mechanisms thatcause the increase in blood flow89,98. Although the blood flow response is correlated with glucose consumption undernormal circumstances, it might be caused by something else. Likewise, the blood flow response is correlated with, but
not necessarily causally related to, oxygen consumption. These suspicions are highlighted by evidence that the bloodflow response is not affected by sustained hypoxia (decreased blood oxygen), nor by hypoglycaemia (decreased blood
glucose)99,100. Furthermore, it is important to keep in mind that the blood flow response, whatever its purpose, isremarkably slow relative to the underlying changes in neuronal activity: the brain has typically done its thing andmoved on before the vasculature responds.
Various signals have been proposed to cause the blood flow response89,98; we mention three possibilities. First, theresponse might be triggered by lactate (released by the astrocytes), implying a tight link between the fMRI signal andsynaptic activity. Second, it might be triggered by a diffusible by-product of neuronal spiking; for example, by nitricoxide. Indeed, the blood flow response is reduced by blocking nitric oxide synthase while preserving the normal level of
glucose metabolism101. A third possibility is that the blood flow response might be triggered within the blood vessels
themselves, in response to transient decreases in oxygenation (the initial dip). Of course, these three processes might
operate together and with other mechanisms.

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Time (s)Figure 1 | The linear transform model of fMRI responses. Top row: hypothetical plots ofaverage neuronal activity over time. Bottom row: corresponding functional magnetic resonanceimaging (fMRI) responses. Left: hypothetical haemodynamic impulse response function (HIRF)
measured as the response to a brief pulse of neuronal activity. Right: the fMRI response when the
average neuronal activity alternates (at specific times) between three different states (high,medium and low), with brief transients each time it switches from one state to another. Given themeasured time course of neuronal activity, it is possible to compute (using convolution) the timecourse of the fMRI response. Most fMRI studies go the other way, to infer the underlying neuronal
activity from the fMRI response. In the example shown, it is possible to estimate (using linear
regression, given the HIRF) the relative amplitudes of the neuronal activity in each of the threestates, along with the amplitude of the transients.

because of the intrinsic inhomogeneity in the magnetic
field within larger vessels. The acquisition can be modified to de-emphasize the BOLD signals from larger
vessels, by suppressing signals that are associated withhigher flow velocities15,18. Other fMRI techniques havebeen developed that separately measure different components of the haemodynamic response: perfusionbased fMRI measures blood flow19,20, compounds can beinjected into the blood stream to allow the measurement of blood volume21, and diffusion-based fMRI
techniques promise to measure changes in neural andglial cell swelling that occur with excitation22. So far,there has been only a modest amount of work towards
quantifying the relationships between these different
fMRI techniques (for example, see REFS 20,23,24).
Second, the relationship between fMRI and neuronal
responses depends on the behavioural and stimulation
protocols, and on the fMRI data-analysis methods. In theearly days of fMRI there was some concern that the signal
was derived entirely from large draining veins, and consequently that it would provide misleading information
about the spatial localization of neuronal activity. For
example, presenting visual stimuli at two nearby locationsin the visual field evokes neuronal activity at two nearby
locations in retinotopic visual areas such as V1. If the
fMRI signal were evident only in the large vessel(s), which
drain the blood from V1, then it would not be possible todistinguish between these two nearby foci of neuronal
activity. Rather, the activity evoked by both visual stimuli
would seem to be displaced to the location of the drainingvein(s). To a large degree, this issue was resolved by adopting appropriate experimental protocols. Retinotopic
maps are now routinely measured in the visual cortex
using stimuli that move through the visual field, thereby
evoking a travelling wave of neuronal activity across thefolded grey matter surface25. Signals in a large draining
vein, one that drains from the region of grey matter that
corresponds to a large fraction of the retinotopic map, arede-emphasized because the blood flow and oxygenationin those vessels are roughly constant throughout theexperiment. By using this travelling-wave technique, andby restricting the data analysis to the grey matter, it is possible to distinguish activity that is separated by less than
1.5 mm in the cortex25 (fMRI techniques have advanced
considerably since these initial measurements werereported in 1994, allowing even finer spatial resolution, as
discussed below). Hence, the experimental protocol
might be crucial for obtaining precise spatial localizationof functional activity, a point that we will return to later.
There are surely a number of further issues concerning
the experimental protocol and data analysis that canaffect the fidelity of the fMRI measurements. It is therefore important, each time a new protocol is developed, tomeasure the relationship between the fMRI signals andthe underlying neuronal activity.
Third, the relationship between fMRI and neuronal
responses depends on how the neuronal activity itself ismeasured and quantified. Consider recording the simultaneous activity of a large number of individual neurons
within a region of cortex (several millimetres) and overa period of time (several seconds). What component of
the neuronal activity would be most predictive of the
fMRI signal? The various possible measurements ofneuronal activity include: the average firing rate of all of
the neurons; the average firing rate of a subpopulationof neurons; synchronous spiking activity across the neuronal population; the local field potential (LFP); the current source density; some measure of local average
synaptic activity; or some measure of the subthresholdelectrical activity. What is the relationship between thesedifferent measures of neuronal activity, and how are
they each related to the fMRI signal? New experiments
are just beginning to shed light on this question (BOX 3).
Temporal summation of fMRI responses

In a typical experiment, a time-series of BOLD fMRI
images are collected while a stimulus or cognitive task issystematically varied. If the stimulus or task variations
evoke a large enough change in blood flow and oxygenation in a certain brain region, then the image
intensity in that region will modulate (by as much as±5%, but typically by less than this) over time about its
mean intensity value.
According to the linear transform model, it should
be possible to predict the response to a long stimulus
presentation by summing the responses to shorter
stimuli (FIG. 2). For example, the response to a 12-s stimulus is predicted by summing the response to a 6-s
stimulus with a copy of the same response delayed by
6 s. Note that this allows the possibility of an arbitrarily
complex, nonlinear relationship between the stimulus
and the neuronal activity. Whatever the neuronal activity
is for the first 6 s, as long as it is identical for the second
6 s, it should be possible to predict the fMRI response toa pair of back-to-back stimuli, given the response to one
stimulus presentation.

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Box 3 | Local field potential and multi-unit activity
What is known about the local field potential (LFP; low-frequency component of the electrophysiological signal) andmulti-unit activity (MUA), and how each relates to processing in the cerebral cortex? The MUA is believed to reflect the
spiking activity of neurons near the electrode tip (within ~200 µm)102,103. The LFP, on the other hand, is believed toreflect the superposition of synchronized dendritic currents, averaged over a larger volume of tissue104.
The role of synchronized neuronal signals, including that inferred from LFP measurements, has been a source ofheated debate and considerable controversy105–107. Regardless of its functional role, it is conceivable that neuronalsynchrony (and hence LFP) could increase without a concomitant increase in mean firing rate11.
However, the LFP is expected under many circumstances to be highly correlated with local average firing rates. Most
synapses (both excitatory and inhibitory) can be traced to a local network of connections that originates in the nearby
cortical neighbourhood, leaving only a small minority of inputs from more remote cortical and subcorticalstructures108–110. So, local spiking activity, synaptic activity and dendritic currents should all covary. Moreover, althoughsome studies have found that the LFP includes contributions from distant sources104, others have found that it is dominatedby the activity of nearby neurons111–113. Methodological choices can make a huge difference, such as whether the LFP
recording is single-ended (referenced to a remote ground) or differential (referenced to another electrode or epidural
silverball) (P. Fries, personal communication). The former method can provide a localized measure of neuronal activity; forexample, in area MT, the stimulus selectivity of the LFP is similar to those of the MUA and single-unit responses(G. DeAngelis and W. T. Newsome, personal communication). The latter method is crucially dependent on the relative
positions of the two recording sites. If they are just embracing a cortical column, the measure is called a ‘transcortical fieldpotential’, and provides the best localization available with LFP112,113. However, if the reference is a distant epidural
silverball, the LFP picks up a more global signal that is strongly correlated with scalp electroencephalography (EEG).
In summary, the LFP is believed to reflect inputs and intracortical activity, but is often (but not always) correlated withthe output spiking activity in single- or multi-unit recordings.

Temporal summation holds up well in some experiments, but not in others13,20,24,26–33. The failure can betraced to the fact that very short stimulus presentations
evoke disproportionately large fMRI responses, compared with what is expected from the responses to longstimulus presentations. One possible explanation for
the failure of temporal summation is that althoughblood flow might indeed be proportional to the underlying neuronal activity, BOLD fMRI signals might have

Response to 6-s stimulus

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resonance imaging (fMRI) responses from the visual cortex for 6- and 12-s stimulus presentations.
Right: the procedure for measuring temporal summation, by comparing the responses to the twodifferent stimulus durations. BOLD, blood oxygen level dependent. Modified with permission from
REF. 13 © 1996 Society for Neuroscience.

an inherently nonlinear dependence on flow (see BOX 2
and REFS 20,34). In particular, the BOLD effect mightsaturate at high levels of blood flow because further
increases in flow would cause negligible decreases in
the concentration of deoxyhaemoglobin20,35,36. Consequently, a moderately strong stimulus might evoke anear-maximal fMRI response, leaving very little room
to reveal any further change in fMRI signal in response
to a stronger stimulus that is known to evoke moreneuronal activity. Indeed, there is some evidence thatflow might show temporal summation even when
BOLD fMRI fails to do so20.
An alternative possibility is a failure in the design ofthe experiments, rather than a failure of temporal summation itself. These experiments were all completed inprimary sensory and motor cortical areas, mostly in V1,
where short-duration stimuli are expected to give disproportionately large neuronal responses for at least
three reasons. First, V1 neurons show large transient
responses after stimulus onset, which rapidly decreaseover a period of several hundred milliseconds37. Second,
V1 neurons adapt; their responses decrease gradually
over time after prolonged (4–30 s) stimulation38. Third,
V1 responses are boosted by attention (see above), andstimulus onsets are likely to engage attention automatically. Hence, very short stimulus presentations evoke
disproportionately large neural responses, which,according to the linear transform model, should in turnevoke disproportionately large fMRI responses. Somestudies have included a post-hoc analysis to account for
the expected response transients13,20,33, but experiments
have not yet been carried out that measure the temporalsummation of the fMRI responses while explicitly controlling or compensating for response transients, adaptation and attention. So, the temporal-summation
experiments completed so far are inconclusive because

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Time (s)Figure 3 | Neuronal versus fMRI responses. a | Haemodynamic impulse response functions(HIRFs) estimated from two (red and blue curves) different recording sites. b | Comparison of themeasured functional magnetic resonance imaging (fMRI) response with that predicted (using thelinear transform model and the estimated HIRF) from the local field potential (LFP) (BOLD, blood
oxygen level dependent; s.d., standard deviation). Stimulus was a full-field, rotating, checkerboard
pattern that varied in contrast over time. Dark turquoise rectangles: contrast level over time. Light
turquoise: measured neuronal activity (LFP). Red curve: measured fMRI response. Blue curve:
predicted fMRI response. Reproduced with permission from REF. 50 © 2001 Macmillan
Magazines Ltd.

the reported failures of the linear transform model
might actually be failures of the assumptions underlying
the test, not failures of temporal summation itself.
Comparison of fMRI and neuronal responses

A second implication of the linear transform modelis that the time course and amplitude of the fMRI
responses should be predictable from the underlying
neuronal responses.
Two studies have compared human fMRI and monkey single-unit data to infer that fMRI signals are
directly proportional to average neuronal firing rates39,40.
The first of these studies compared single-unit data
recorded in monkey MT, an extrastriate area of visualcortex that is specialized for visual motion processing,with fMRI measurements in human MT+ (the MTcomplex, also known as V5), a motion-responsive cortical region that is widely believed to be homologous withmonkey MT along with adjacent motion-sensitive
areas41,42. MT neurons are sensitive to the strength, or
coherence, of the motion signal. In a stimulus that consists of a field of moving dots, motion coherence can bevaried parametrically from 0% (in which each dot
moves in a random direction) to 100% (in which all
dots move in the same direction). The responses of MT
neurons to such stochastic motion stimuli have been
extensively characterized43. Using this large database of
single-unit recordings, Rees et al.39 calculated that the
average neuronal firing rate across a large population of
MT neurons would be expected to increase linearly withcoherence. They then confirmed that the fMRI
responses in human MT+ also increased approximately
linearly with motion coherence, indicating a proportionality between fMRI signals and average firing rates.
Motivated by their report, we carried out a similar
analysis of some of our previously reported measurements of the activity in human and monkey primaryvisual cortex (V1)40,44,45. We used stimulus contrast as theindependent variable, because nearly all V1 neurons(along with most neurons in other early visual areas)
increase their firing rates monotonically with contrast.
We would expect, therefore, that if the fMRI signals were
proportional to average firing rates, then they too would
increase monotonically with stimulus contrast. We
analysed the responses of a large database of macaque V1
neurons to stimuli of varying contrasts, orientations,directions and spatiotemporal frequencies. From thisdatabase of individual V1 neurons, we estimated theaverage firing rate in monkey V1, as a function of contrast, for the specific stimulus pattern that had been usedin the fMRI experiments. The fMRI and average firingrate response curves superimposed, again indicating a
proportional relationship between fMRI response andaverage firing rate. However, both of these studies relied
on a series of computations to estimate the average neuronal activity from the electrophysiological data.
Moreover, they compared data not only from different
areas of cortical tissue, but also from different brains in
two different species.
Several studies have found generally good agreement
between the amplitudes of fMRI and electroencephalographic (EEG) signals, in both humans and anaesthetized rats27,46. Likewise, blood flow measured with thelaser Doppler flow technique has been reported to behighly predictable from EEG and LFP measurements47–49.
See BOX 3 for a discussion of how the EEG and LFP
measurements relate to the spiking activity of neurons.
A recent, seminal study by Logothetis et al.50 evaluatedthe linear transform model by comparing simultaneously
recorded fMRI and neuronal signals in the anaesthetizedmonkey. Neuronal activity was recorded with a microelectrode in V1, and analysed to measure multi-unit
activity (MUA) and LFP, which were extracted from different frequency bands of the raw electrophysiologicalsignal (LFP, 40–130 Hz; MUA, 300–1,500 Hz). For eachrecording site, the fMRI data were analysed over a small(approximately 2 × 2.5 × 7 mm) region of grey mattersurrounding the electrode tip.
Logothetis et al. examined how well they could predict
the fMRI measurements from the LFP and MUA measurements (FIG. 3). They measured baseline activity in theabsence of visual stimulation at each recording site to estimate the HIRFs separately for the MUA and LFP (themethod they used to estimate the HIRFs relied on having
simultaneous fMRI and electrophysiological measurements). They then used separate measurements of visually evoked activity to evaluate the linear transformmodel, by comparing the visually evoked fMRI responses
with those predicted from the MUA and LFP signals(according to the linear transform model, given the estimated HIRFs). At some recording sites, the linear transform model predicted the measured fMRI responses well,
explaining more than 90% of the variance in the fMRI
signals. However, at other recording sites, the LFP and
MUA signals were very poor predictors of the fMRI
responses.At those sites where the LFP was a good predictor of the fMRI responses, MUA also tended to be a goodpredictor (N. K. Logothetis, personal communication).

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Geometric centre.

On average, the LFP was slightly better than MUA at predicting the fMRI responses (although this difference wasstatistically significant, the LFP accounted for only 7.6%
more of the variance in the fMRI responses than did the
MUA). The data indicate that this difference related to thetransient nature of the MUA. Around one-quarter of therecording sites showed transient MUA responses that
returned to baseline within 2–4 s even though the stimulus stayed on for much longer. The LFP and fMRI signals
from the same sites were both sustained throughout thestimulus presentations, which lasted for up to 20 s.
On the basis of these results, Logothetis et al. concluded that BOLD fMRI signals “reflect the input andintracortical processing of a given area rather than its
spiking output.” Specifically, the data reported in mostsingle-unit electrophysiological experiments reflect theactivity of a biased sample of neurons, mostly large
pyramidal cells that send projections to other brain
areas. BOLD signals, they argue, also reflect the activityof incoming fibres, interneurons, and recurrent excitatory or inhibitory activity, rather than just ‘output’ firing
rates of the pyramidal cells (N. K. Logothetis, personalcommunication). Under some conditions, the intracortical processing within a region of cortical tissue will behighly correlated with the output spiking activity of the
pyramidal cells. For example, the inputs, intracorticalactivity and outputs in V1 all increase monotonicallywith stimulus contrast (see above). But there might besome circumstances in which there is a decoupling of
inputs and intracortical processing from output activity.
For example, the strong attentional signals (mentioned
above) measured with fMRI in early visual cortical areas
might reflect subthreshold activity arising from modulatory inputs that do not evoke spikes in the output
pyramidal cells. The interpretation of the fMRI results
depends crucially, therefore, on the extent to which theoutput from a cortical area can be decoupled fromthe intracortical activity within that area.
An example of such a decoupling of inputs from outputs was reported by Mathiesen et al.47, who comparedblood flow, LFP and spiking activity in the cerebellum ofanaesthetized rats, while electrically stimulating inputs tothe cerebellum. The crucial condition involved stimulating the cerebellar parallel fibres that evoke monosynaptic
excitatory postsynaptic potentials and disynaptic
inhibitory postsynaptic potentials in Purkinje cells, theprimary output neurons of the cerebellar cortex. By taking advantage of this specialized cerebellar circuitry, they
provided strong synaptic excitation, including excitationof inhibitory interneurons, with little or no change in the
net activity of the Purkinje cells. Nevertheless, blood flowand LFP increased.
Perhaps the most important result in the Logothetis
et al. study concerns the large differences across recordingsites. This raises a number of questions. Are the estimated
HIRFs stable across recording sites? Is the fMRI signal lesswell predicted by neuronal activity at some sites than atothers because of their proximity to larger veins? In thiscontext, it is also important to note that the stimuli were
presented in the commonly used block-alternation
design, with relatively long (4–24 s) intervals of a full-field

checkerboard pattern that alternated with intervals of a
blank (uniform grey) field. The results might differ if a
rapid series of brief (~1 s) stimulus presentations is used
(N. K. Logothetis, personal communication). Under suchconditions the transient activity would dominate, thereby
increasing the correlation between the LFP, MUA andsingle-unit activity, and causing each of these measures tobe more predictive of the fMRI responses. This would be
welcome news because a growing number of fMRI
experiments have been using such a rapid sequence ofstimulus presentations with brief inter-trial intervals30,51.
A final result from the Logothetis et al. study is thatfMRI and neuronal responses were not simply proportional to one another. A 12% stimulus contrast evokedabout half the maximum fMRI response but much lessthan half the maximum LFP and MUA. This implies
that there is a monotonic but nonlinear relationshipbetween the fMRI signal and neuronal responses, suchthat the fMRI responses increase more rapidly than neuronal responses at low contrasts, but less rapidly at highcontrasts. For example, the fMRI signal might include acontribution of asynchronous, subthreshold activity thatis not visible in LFP or MUA measurements. However,just the opposite result was observed in a comparison of
LFP and blood flow (measured with the laser Doppler
flow technique) in the somatosensory cortex of theanaesthetized rat. No blood flow response was elicited at
low levels of neuronal activity, whereas flow increased inproportion to LFP above a certain threshold level49. This
indicates that flow increases more slowly than neuronal
activity at low levels of activity, but that flow increases at
a greater rate for higher levels of activity.
Despite the nonlinear relationships observed between
LFP and either flow or BOLD signals, single-unit firing
rates seem to be roughly proportional to BOLD fMRI
signals. Isolated V1 neurons reach half their maximum
firing rate at ~10–15% contrast on average40,45, consistent
with the fMRI measurements reported by Logothetis
et al. and with other fMRI measurements in humans40,44,
but in contrast to the LFP and MUA measurements
reported by Logothetis et al.
Colocalization of fMRI and neuronal activity

A third implication of the linear transform model is thatthe fMRI responses should be colocalized with theunderlying neuronal activity. This has been explored inboth human and monkey brains.
Several studies of patients undergoing neurosurgery
have reported general agreement between sensorimotor
maps measured with fMRI and intraoperative corticalsurface recording, cortical stimulation and optical imaging52–56. This has obvious and important implications
for pre-surgical planning. However, Cannestra et al.56
point out that the precision of the concordance depends
crucially on the fMRI data-analysis techniques. As istypical of many fMRI studies, they used a model of the
HIRF to analyse their data and localize regions of activity. Using one model of the HIRF, the CENTROID of fMRI
activity was on average more than 1 cm from the centroid of intrinsic optical-imaging activity. A slight modification to the HIRF, including an initial dip (BOX 2),

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REVIEWS
yielded a marked improvement such that the centroids
were separated by ~2 mm on average.
Disbrow et al.57 reported a profound discordance
between fMRI and electrophysiological recordings ofsomatosensory cortical maps in the anaesthetizedmonkey. Although it was possible to use fMRI to determine the gross organization of body-part representations,
there were important differences between the two maps.
First, in only about half of the measurements were thecentroids of fMRI activity located within the respective
hand and face representations obtained electrophysiologically, and the mean distance between map centres (fMRI
versus electrophysiology) was ~1 cm. Second, the fMRIdefined cortical maps were considerably larger than themaps that were obtained on the basis of microelectroderecordings.
Wandell et al.58, on the other hand, reported excellent
agreement between the locations and retinotopic mapsof monkey V1, V2, V4 and MT, as measured by fMRI,
and those expected from the electrophysiological literature. This difference between the accuracy of thesomatosensory and visual maps might reflect a fundamental difference in the basis of the haemodynamic
responses in these two cortical areas. Or it might be asimple consequence of differences in the experimental
methods; Wandell et al. used the travelling-wave stimulus to measure the retinotopic maps in visual cortex,
whereas as Disbrow et al. presented tactile stimuli using
a block-alternation design with relatively long (~20 s)intervals of stimulation versus rest.
Further evidence for the colocalization of fMRI andneuronal signals comes from experiments in which
fMRI has been used to image ocular dominance andorientation columns59–63. Although some of these papers
have provoked considerable controversy (for example,
REFS 64,65), others are compelling and would not havebeen possible unless the signals were properly localized
to within a fraction of a millimetre.
Conclusions

We started this review by describing the linear transformmodel, which has been a common assumption in theinterpretation of fMRI studies. Does the evidence indicate

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that this model is a reasonable and useful approximation?
The answer is ‘yes’ for some recording sites, in some brain
areas, using certain experimental protocols. But theanswer is ‘no’ under other circumstances.
After ten years of fMRI studies, there is still much tolearn about the source of these signals. In particular, further measurements that compare fMRI and neuronalsignals are needed. The specifics of the experimental protocols are important and, hence, should be systematicallyvaried. Clearly, we need to know more about the relationships between the different measures of neuronal activity,
single- and multi-unit spiking activity, and LFP, to determine whether they reflect different aspects of neuronal
function. For example, it would be helpful for neurophysiologists routinely to digitize the entire electrophysiological signal, not just the spike times, to determine whether
or not, and under which circumstances, the intracorticalactivity within a cortical area (for example, as represented
by the LFP or MUA) might be decoupled from the output
spiking activity of isolated single units. It would also be
helpful to compare measurements of local average firing
rates with local average synaptic activity, because synaptic
activity has been identified as being linked with metabolic
demand (BOX 2), although it is not clear exactly how average synaptic activity could be measured directly. In addition, it would be informative to measure the fMRI signal
in the absence of spikes — for example, by cooling thecortex — to determine how much of the signal is induced
exclusively by the inputs to a cortical area.
This review has raised more questions than answers.
Although these questions are motivated by methodological considerations, many of them bear on fundamental
issues concerning cortical circuitry and the ways in whichlarge populations of neurons represent information in thebrain. With any new technique, it takes some time to sortout the methodological details. MRI offers a huge amountof flexibility — good news, because it should allow us torefine the methods to measure precisely the underlying
neuronal activity, but also bad news, because it might takea while for us to converge on those methods. fMRI provides a new and different picture of brain function, complementary to other techniques; although this presentsa challenge, it will also prove to be of great benefit.

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Acknowledgements
We thank W. Newsome, G. DeAngelis, P. Fries, B. Wandell, G.
Rees, R. Buxton, P. Bandettini, G. Glover, G. Boynton, M. Raichle
and N. Logothetis for detailed comments on this manuscript. The
authors are supported by grants from the National Eye Institute andthe Human Frontier Science Program.

Online links
FURTHER INFORMATION
Encyclopedia of Life Sciences: http://www.els.net/
brain imaging: observing ongoing neural activity | magnetic
resonance imaging
MIT Encyclopedia of Cognitive Sciences:
http://cognet.mit.edu/MITECS/
electrophysiology, electric and magnetic evoked fields | magnetic
resonance imaging
Access to this interactive links box is free online.

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