Functional magnetic resonance imaging or functional MRI (fMRI) is a type of specialized MRI scan used to measure the hemodynamic response (change in blood flow) related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging. Since the early 1990s, fMRI has come to dominate the brain mapping field due to its relatively low invasiveness, absence of radiation exposure, and relatively wide availability.

Background

Since the 1890s it has been known that changes in blood flow and blood oxygenation in the brain (collectively known as hemodynamics) are closely linked to neural activity. When neural cells are active they increase their consumption of energy from glucose and switch to less energetically effective, but more rapid anaerobic glycolysis. The local response to this energy utilization is to increase blood flow to regions of increased neural activity, which occurs after a delay of approximately 1–2 seconds. This hemodynamic response rises to a peak over 4–6 seconds, before falling back to baseline (and typically undershooting slightly). This leads to changes in local cerebral blood volume and local changes in the local concentration of oxyhemoglobin that are detectable through their paramagnetic effects.

History

Blood-oxygen-level dependence (BOLD) is the MRI contrast of blood deoxyhemoglobin, first discovered in 1990 by Seiji Ogawa at AT&T; Bell labs. Ogawa and colleagues had recognized the potential importance of BOLD for functional brain imaging with MRI, but the first successful fMRI study was reported by John W. Belliveau and colleagues in 1991 using an intraveneously administered paramagnetic contrast agent (Gadolinium). Using a visual stimulus paradigm, localized increases in blood volume (32 +/- 10 percent, n = 7 subjects) were detected in the primary visual cortex. In 1992, three papers were published using endogenous BOLD contrast MRI. One was submitted by Peter Bandettini at the Medical College of Wisconsin on February 5, revised March 31, accepted March 31 and published in the June 1992 issue of Magnetic Resonance in Medicine (MRM). The second by Kenneth Kwong and colleagues also applied BOLD to image human brain activities with MRI and was submitted on March 26 and published in the June issue of PNAS in 1992. In the same year, Dr. Ogawa submitted their result on March 31 and published in July issue of PNAS. In the following year, Dr. Ogawa published the biophysics model of BOLD contrast in Biophysical Journal. Dr. Bandettini also published a further paper in 1993 demonstrating quantitative determination of functional activation maps.

Physiology

As neurons do not have internal reserves for glucose and oxygen, more neuronal activity requires more glucose and oxygen to be delivered rapidly through the blood stream. Through a process called the hemodynamic response, blood releases glucose to neurons and astrocytes at a greater rate than in the area of inactive neurons. It results in a surplus of oxyhemoglobin in the veins of the area and distinguishable change of the local ratio of oxyhemoglobin to deoxyhemoglobin, the "marker" of BOLD for MRI. The magnetic resonance (MR) signal of blood is therefore slightly different depending on the level of oxygenation. Higher BOLD signal intensities arise from increases in the concentration of oxygenated hemoglobin since the blood magnetic susceptibility now more closely matches the tissue magnetic susceptibility. By collecting data in an MRI scanner with sequence parameters sensitive to changes in magnetic susceptibility one can assess changes in BOLD contrast. These changes can be either positive or negative depending upon the relative changes in both cerebral blood flow (CBF) and oxygen consumption. Increases in CBF that outstrip changes in oxygen consumption will lead to increased BOLD signal, conversely decreases in CBF that outstrip changes in oxygen consumption will cause decreased BOLD signal intensity. The signal difference is very small, but given many repetitions of a thought, action or experience, statistical methods can be used to determine the areas of the brain which reliably show more of this difference as a result, and therefore which areas of the brain are active during that thought, action or experience.

Almost all current fMRI research uses BOLD as the method for determining where activity occurs in the brain as the result of various experiences, but because the signals are relative and not individually quantitative, some question its rigor. Other methods which propose to measure neural activity more directly have been attempted (for example measurement of the Oxygen Extraction Fraction (OEF) in regions of the brain, which measures how much of the oxyhemoglobin in the blood has been converted to deoxyhemoglobin or direct detection of magnetic fields generated by neuronal currents), but because the electromagnetic fields created by an active or firing neuron are so weak, the signal-to-noise ratio is extremely low and statistical methods used to extract quantitative data have been largely unsuccessful as of yet.

Neural correlates of BOLD

The precise relationship between neural signals and BOLD is under active research. In general, changes in BOLD signal are well correlated with changes in blood flow. Numerous studies during the past several decades have identified a coupling between blood flow and metabolic rate; that is, the blood supply is tightly regulated in space and time to provide the nutrients for brain metabolism. However, neuroscientists have been seeking a more direct relationship between the blood supply and the neural inputs/outputs that can be related to observable electrical activity and circuit models of brain function.

While current data indicate that local field potentials, an index of integrated electrical activity, form a marginally better correlation with blood flow than the spiking action potentials that are most directly associated with neural communication , no simple measure of electrical activity to date has provided an adequate correlation with metabolism and the blood supply across a wide dynamic range. Presumably, this reflects the complex nature of metabolic processes, which form a superset with regards to electrical activity. Some recent results have suggested that the increase in cerebral blood flow (CBF) following neural activity is not causally related to the metabolic demands of the brain region, but rather is driven by the presence of neurotransmitters, like glutamate, serotonin, nitric oxide, acetylcholine, dopamine and noradrenaline.

Some other recent results suggest that an initial small, negative dip before the main positive BOLD signal is more highly localized and also correlates with measured local decreases in tissue oxygen concentration (perhaps reflecting increased local metabolism during neuron activation). Use of this more localized negative BOLD signal has enabled imaging of human ocular dominance columns in primary visual cortex, with resolution of about 0.5 mm. One problem with this technique is that the early negative BOLD signal is small and can only be seen using larger scanners with magnetic fields of at least 3 Tesla. Further, the signal is much smaller than the normal BOLD signal, making extraction of the signal from noise more difficult. Also, this initial dip occurs within 1–2 seconds of stimulus initiation, which may not be captured when signals are recorded at long repetition (TR). If the TR is sufficiently low, increased speed of the cerebral blood flow response due to consumption of vasoactive drugs (such as caffeine) or natural differences in vascular responsiveness may further obscure observation of the initial dip.

The BOLD signal is composed of CBF contributions from larger arteries and veins, smaller arterioles and venules, and capillaries. Experimental results indicate that the BOLD signal can be weighted to the smaller vessels, and hence closer to the active neurons, by using larger magnetic fields. For example, whereas about 70% of the BOLD signal arises from larger vessels in a 1.5 tesla scanner, about 70% arises from smaller vessels in a 7 tesla scanner. Furthermore, the size of the BOLD signal increases roughly as the square of the magnetic field strength. Hence there has been a push for larger field scanners to both improve localization and increase the signal. A few 7 tesla commercial scanners have become operational, and experimental 8 and 9 tesla scanners are under development.

Technique

BOLD effects are measured using rapid volumetric acquisition of images with contrast weighed by T1 or T2*. Such images can be acquired with moderately good spatial and temporal resolution; images are usually taken every 1–4 seconds, and the voxels in the resulting image typically represent cubes of tissue about 2–4 millimeters on each side in humans. Recent technical advancements, such as the use of high magnetic fields and multichannel RF reception, have advanced spatial resolution to the millimeter scale. Although responses to stimuli presented as close together as one or two seconds can be distinguished from one another, using a method known as event-related fMRI, the full time course of a BOLD response to a briefly presented stimulus lasts about 15 seconds for the robust positive response.

fMRI studies draw from many disciplines

fMRI is a highly interdisciplinary research area and many studies draw on knowledge in several fields:

Physics: Physical principles underlie fMRI signals and many studies require an understanding of these underlying principles.

Psychology: Almost all fMRI studies are essentially cognitive psychological, cognitive psychophysiological, and/or psychophysical experiments in which the MRI scanner is used to obtain an extra set of measurements in addition to behavioral or electroencephalographic measurements.

Neuroanatomy: The fMRI signals can be put into the context of previous knowledge only with an understanding of the neuroanatomy.

Statistics: Correct application of statistics is essential to "tease out" observations and avoid false-positive results.

Electrophysiology: Familiarity with neuronal behavior at the electrophysiological level can help investigators design a useful fMRI study.

Advantages and Disadvantages of fMRI

Like any technique, fMRI has advantages and disadvantages, and in order to be useful, the experiments that employ it must be carefully designed and conducted to maximize its strengths and minimize its weaknesses.

Advantages of fMRI

It can noninvasively record brain signals without risks of ionising radiation inherent in other scanning methods, such as CT or PET scans.

It has high spatial resolution. 2–3 mm is typical but resolution can be as good as 1mm.

It can record signal from all regions of the brain, unlike EEG/MEG which are biased towards the cortical surface.

fMRI is widely used and standard data-analysis approaches have been developed which allow researchers to compare results across labs.

fMRI produces compelling images of brain "activation".

Disadvantages of fMRI

The images produced must be interpreted carefully, since correlation does not imply causality, and brain processes are complex and often non-localized.

Statistical methods must be used carefully because they can produce false positives. One team of researchers studying reactions to pictures of human emotional expressions reported a few activated voxels in the brain of a dead salmon when no correction for multiple comparisons was applied, illustrating the need for rigorous statistical analyses. The BOLD signal is only an indirect measure of neural activity, and is therefore susceptible to influence by non-neural changes in the body. This also means that it is difficult to interpret positive and negative BOLD responses BOLD signals are most strongly associated with the input to a given area rather than with the output. It is therefore possible (although unlikely) that a BOLD signal could be present in a given area even if there is no single unit activity.

fMRI has poor temporal resolution. The BOLD response peaks approximately 5 seconds after neuronal firing begins in an area. This means that it is hard to distinguish BOLD responses to different events which occur within a short time window. Careful experimental design can reduce this problem. Also, some research groups are attempting to combine fMRI signals that have relatively high spatial resolution with signals recorded with other techniques, electroencephalography (EEG) or magnetoencephalography (MEG), which have higher temporal resolution but worse spatial resolution.

fMRI has often been used to show activation localized to specific regions, thus minimizing the distributed nature of processing in neural networks. Several recent multivariate statistical techniques work around this issue by characterizing interactions between "active" regions found via traditional univariate techniques.

The BOLD response can be affected by a variety of factors, including: drugs/substances; age, brain pathology; local differences in neurovascular coupling; attention; amount of carbon dioxide in the blood; etc.

For these reasons, Functional imaging provides insights into neural processing that are complementary to insights of other studies in neurophysiology.

Scanning in practice

4T fMRI scanner.]] Subjects participating in a fMRI experiment are asked to lie still and are usually restrained with soft pads to prevent movement from disturbing measurements. Some labs also employ bite bars to reduce motion, although these are unpopular as they can be uncomfortable. Small head movements can be corrected for in post-processing of the data, but large transient motion cannot be corrected. Motion in excess of around 3 millimeters results in unusable data. Motion is an issue for all populations, but most especially problematic for subjects with certain medical conditions (e.g. Alzheimer's Disease or schizophrenia) or with young children. Participants can be habituated to the scanning environment and trained to remain still in an MRI simulator.

An fMRI experiment usually lasts between 15 minutes and an hour. Depending on the purpose of study, subjects may view movies, hear sounds, smell odors, perform cognitive tasks such as n-back, memorization or imagination, press a few buttons, or perform other tasks. Researchers are required to give detailed instructions and descriptions of the experiment plan to each subject, who must sign a consent form before the experiment.

Safety is an important issue in all experiments involving MRI. Potential subjects must ensure that they are able to enter the MRI environment. The MRI scanner is built around an extremely strong magnet (1.5 teslas or more), so potential subjects must be thoroughly examined for any ferromagnetic objects (e.g. watches, glasses, hair pins, pacemakers, bone plates and screws, etc.) before entering the scanning environment.

Related techniques

Aside from BOLD fMRI, there are other related ways to probe brain activity using magnetic resonance properties:

Diffusion based functional MRI

Neuronal activity produces some immediate physical changes in cell shape that can be detected because they affect the compartment shape and size for water diffusion. A much improved spatial and temporal resolution for fMRI data collection has now been achieved by using diffusion MRI methodology that can detect these changes in neurons. The abrupt onset of increased neuron cell size occurs before the metabolic response commences, is shorter in duration and does not extend significantly beyond the area of the actual cell population involved. This technique is a diffusion weighted technique (DWI). There is some evidence that similar changes in axonal volume in white matter may accompany activity and this has been observed using a DTI (diffusion tensor imaging) technique. The future importance of diffusion-based functional techniques relative to BOLD techniques is not yet clear.

Contrast MR

An injected contrast agent such as an iron oxide that has been coated by a sugar or starch (to hide from the body's defense system), causes a local disturbance in the magnetic field that is measurable by the MRI scanner. The signals associated with these kinds of contrast agents are proportional to the cerebral blood volume. While this semi-invasive method presents a considerable disadvantage in terms of studying brain function in normal subjects, it enables far greater detection sensitivity than BOLD signal, which may increase the viability of fMRI in clinical populations. Other methods of investigating blood volume that do not require an injection are a subject of current research, although no alternative technique in theory can match the high sensitivity provided by injection of contrast agent.

Arterial spin labeling

Arterial Spin Labelling (ASL), also known as arterial spin tagging, is an MRI technique capable of measuring cerebral blood flow (CBF) in vivo. ASL is capable of providing cerebral perfusion maps, without requiring the administration of a contrast agent or the use of ionising radiation, as it uses magnetically-labelled endogenous blood water as a freely-diffusible tracer. It was first proposed in 1992 and has since benefited from a number of modifications aimed at improving its robustness. ASL can monitor changes in CBF with activation and fMRI studies can therefore be conducted using ASL instead of relying on the BOLD effect. ASL fMRI is less popular than BOLD, as it suffers from a lower signal to noise ratio, can be less sensitive to weak stimuli and its temporal resolution is poorer than in BOLD studies. On the plus side, it can provide quantitative measures of a single well-defined parameter, CBF, whose baseline value can also be determined in the same experiment. It has also been found to outperform BOLD in terms of stability to slow signal drifts and localization of the activation area.

Commercial use

Most fMRI scans are for research or clinical use. Commercial use is limited. However, a few companies have been set up that attempt to sell fMRI specific hardware or services for research or clinical use.

At least two companies have been set up to use fMRI in lie detection (No Lie MRI, Inc and Cephos Corporation).

In using fMRI techniques for use in lie detection, activated areas of the brain are observed while the subject is making a statement. Depending on what regions are the most active, the technician might determine whether a subject is telling the truth or not. Since a specific combination of brain functions are needed in order to tell a lie, the simultaneous activation of these regions often indicates deception. This technology is in its early stages of development, and many of its proponents hope to replace older lie detection techniques.

In clinical trials, the usage of fMRI as a method of lie detection has appeared reliable, with studies from 2005 by Kozel et al. indicating a 90% to 93% success rate.

However, there is still a fair amount of controversy over whether these techniques are reliable enough to be used in a legal setting. Some studies indicate that while there is an overall positive correlation, there is a great deal of variation between findings and in some cases considerable difficulty in replicating the findings.

See also

Brain Mapping

Issues in fMRI

Brain function

Event related fMRI

SEEP fMRI

List of neuroscience databases

Functional neuroimaging

References

Textbooks

Scott A. Huettel, Allen W. Song, Gregory McCarthy, Functional Magnetic Resonance Imaging, Sinauer Associates, 2004, ISBN 0-87893-288-7

Richard B. Buxton, An Introduction to Functional Magnetic Resonance Imaging: Principles and Techniques, Cambridge Univ Press, 2002, ISBN 0-521-58113-3

Roberto Cabeza and Alan Kingstone, Editors, Handbook of Functional Neuroimaging of Cognition, Second Edition, MIT Press, 2006, ISBN 0-262-03344-5

Journal articles

External links

www.mri-tutorial.com- MRI-TUTORIAL.COM | A free learning repository about neuroimaging

RadiologyInfo- The radiology information resource for patients: Functional Magnetic Resonance Imaging of the Brain

Introduction to FMRI from the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, Oxford University

BrainMapping.ORG project Community web site for information Brain Mapping and methods

fMRI Videos RadiologyTube.com - a collection of fMRI videos

fMRI Methods Wiki - with advice on how to report on fMRI studies

fMRI entry at Scholarpedia

Category:Magnetic resonance imaging Category:Neuroimaging Category:Cognitive science

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