INTRODUCTION:

Magnetic resonance imaging (MRI) is a noninvasive medical test that helps physicians to diagnose and treat medical conditions.

MRI uses a powerful magnetic field, radio frequency pulses and a computer to produce detailed pictures of organs, soft tissues, bone and virtually all other internal body structures. The images can then be examined on a computer monitor, transmitted electronically, printed or copied to a CD. MRI does not use ionizing radiation (x-rays).

Detailed MR images allow physicians to better evaluate various parts of the body and determine the presence of certain diseases that may not be assessed adequately with other imaging methods such as x-ray, ultrasound or computed tomography (also called CT or CAT scanning). Functional magnetic resonance imaging (fMRI) is a relatively new procedure that uses MR imaging to measure the tiny metabolic changes that take place in an active part of the brain.^1-3

What are some common uses of the procedure?

fMRI is becoming the diagnostic method of choice for learning how a normal, diseased or injured brain is working, as well as for assessing the potential risks of surgery or other invasive treatments of the brain.

Figure-1: Functional Magnetic Resonance Imaging [Ref: 1-3]

Physicians perform fMRI to:

· Examine the anatomy of the brain.

· Determine precisely which part of the brain is handling critical functions such as thought, speech, movement and sensation, which is called brain mapping.

· Help assess the effects of stroke, trauma or degenerative disease (such as Alzheimer's) on brain function.

· Monitor the growth and function of brain tumors.

· Guide the planning of surgery, radiation therapy, or other surgical treatments for the brain.

How should I prepare?

You may be asked to wear a gown during the exam or you may be allowed to wear your own clothing if it is loose-fitting and has no metal fasteners.

Guidelines about eating and drinking before an MRI exam vary with the specific exam and also with the facility. For some types of exams, you will be asked to fast for 8-12 hours. Unless you are told otherwise, you may follow your regular daily routine and take medications as usual.⁴ Some MRI examinations may require the patient to swallow contrast material or receive an injection of contrast into the bloodstream. The radiologist or technologist may ask if you have allergies of any kind, such as allergy to iodine or x-ray contrast material, drugs, food, the environment, or asthma. However, the contrast material most commonly used for an MRI exam, called gadolinium, does not contain iodine and is less likely to cause side effects or an allergic reaction.⁵

The radiologist should also know if you have any serious health problems or if you have recently had surgery. Some conditions, such as severe kidney disease may prevent you from being given contrast material for an MRI. If there is a history of kidney disease, it may be necessary to perform a blood test to determine whether the kidneys are functioning adequately.^6-8

Figure-2: fMRI plate [Ref: 4-8]

Women should always inform their physician or technologist if there is any possibility that they are pregnant. MRI has been used for scanning patients since the 1980s with no reports of any ill effects on pregnant women or their babies. However, because the baby will be in a strong magnetic field, pregnant women should not have this exam unless the potential benefit from the MRI exam is assumed to outweigh the potential risks. If you have claustrophobia (fear of enclosed spaces) or anxiety, you may want to ask your physician for a prescription for a mild sedative prior to the scheduled examination.

Jewelry and other accessories should be left at home if possible, or removed prior to the MRI scan. Because they can interfere with the magnetic field of the MRI unit, metal and electronic objects are not allowed in the exam room.

These items include:

· Jewellery, watches, credit cards and hearing aids, all of which can be damaged.

· Pins, hairpins, metal zippers and similar metallic items, which can distort MRI images.

· Removable dental work.

· Pens, pocketknives and eyeglasses.

· Body piercings.

In most cases, an MRI exam is safe for patients with metal implants, except for a few types. People with the following implants cannot be scanned and should not enter the MRI scanning area unless explicitly instructed to do so by a radiologist or technologist who is aware of the presence of any of the following:

· Internal (implanted) defibrillator or pacemaker

· Cochlear (ear) implant

· Some types of clips used on brain aneurysms

You should tell the technologist if you have medical or electronic devices in your body, because they may interfere with the exam or potentially pose a risk, depending on their nature and the strength of the MRI magnet.⁹ Examples include but are not limited to:

· Artificial heart valves

· Implanted drug infusion ports

· Implanted electronic device, including a cardiac pacemaker

· Artificial limbs or metallic joint prostheses

· Implanted nerve stimulators

· Metal pins, screws, plates, stents or surgical staples

In general, metal objects used in orthopedic surgery pose no risk during MRI. However, a recently placed artificial joint may require the use of another imaging procedure. If there is any question of their presence, an x-ray may be taken to detect the presence of and identify any metal objects.¹⁰ Patients who might have metal objects in certain parts of their bodies may also require an x-ray prior to an MRI. You should notify the technologist or radiologist of any shrapnel, bullets, or other pieces of metal which may be present in your body due to accidents. Dyes used in tattoos may contain iron and could heat up during MRI, but this is rarely a problem. Tooth fillings and braces usually are not affected by the magnetic field but they may distort images of the facial area or brain, so the radiologist should be aware of them.¹¹

Figure-3: fMRI procedure [Ref: 9-12]

What does the equipment look like?

The traditional MRI unit is a large cylinder-shaped tube surrounded by a circular magnet. You will lie on a moveable examination table that slides into the center of the magnet.

Some MRI units, called short-bore systems, are designed so that the magnet does not completely surround you; others are open on the sides (open MRI). These units are especially helpful for examining patients who are fearful of being in a closed space and for those who are very obese. Newer open MRI units provide very high quality images for many types of exams; however, open MRI units with older magnets may not provide this same quality. Certain types of exams cannot be performed using open MRI. For more information, consult your doctor. The computer workstation that processes the imaging information is located in a separate room than the scanner.¹²

How does the procedure work?

Unlike conventional x-ray examinations and computed tomography (CT) scans, MRI does not depend on ionizing radiation. Instead, while in the magnet, radio waves redirect the axes of spinning protons, which are the nuclei of hydrogen atoms, in a strong magnetic field. The magnetic field is produced by passing an electric current through wire coils in most MRI units. Other coils, located in the machine and in some cases, placed around the part of the body being imaged, send and receive radio waves, producing signals that are detected by the coils. A computer then processes the signals and generates a series of images each of which shows a thin slice of the body. The images can then be studied from different angles by the interpreting physician.¹³

Overall, the differentiation of abnormal (diseased) tissue from normal tissues is often better with MRI than with other imaging modalities such as x-ray, CT and ultrasound. In an fMRI examination, you will perform a particular task during the imaging process, causing increased metabolic activity in the area of the brain responsible for the task. This activity, which includes expanding blood vessels, chemical changes and the delivery of extra oxygen, can then be recorded on MRI images.

How is the procedure performed?

MRI examinations may be performed on outpatients or inpatients.

You will be positioned on the moveable examination table. Straps and bolsters may be used to help you stay still and maintain the correct position during imaging. Small devices that contain coils capable of sending and receiving radio waves may be placed around or adjacent to the area of the body being studied. For fMRI, your head may be placed in a brace designed to help hold it still. This brace may include a mask that is created especially for you. You may be given special goggles and/or earphones to wear, so that audio-visual stimuli (for example, a projection from a computer screen or recorded sounds) may be administered during the scan. If a contrast material will be used in the MRI exam, a nurse or technologist will insert an intravenous (IV) line into a vein in your hand or arm. A saline solution may be used. The solution will drip through the IV to prevent blockage of the IV line until the contrast material is injected. You will be moved into the magnet of the MRI unit and the radiologist and technologist will leave the room while the MRI examination is performed. During an fMRI exam, you will be asked to perform a number of small tasks, such as tapping your thumb against each of the fingers on the same hand, rubbing a block of sandpaper, or answering simple questions. When the examination is completed, you may be asked to wait until the technologist or radiologist checks the images in case additional images are needed.¹⁴

Your intravenous line will be removed.

MRI exams generally include multiple runs (sequences), some of which may last several minutes.

The entire examination is usually completed within 45 minutes.

MR spectroscopy, which provides additional information on the chemicals present in the body's cells, may also be performed during the MRI exam and may add approximately 15 minutes to the exam time.

What will I experience during and after the procedure?

Most MRI exams are painless, however, some patients find it uncomfortable to remain still during MR imaging. Others experience a sense of being closed-in (claustrophobia). Therefore, sedation can be arranged for those patients who anticipate anxiety, but fewer than one in 20 require it. It is normal for the area of your body being imaged to feel slightly warm, but if it bothers you, notify the radiologist or technologist. It is important that you remain perfectly still while the images are being recorded, which is typically only a few seconds to a few minutes at a time. For some types of exams, you may be asked to hold your breath. You will know when images are being recorded because you will hear tapping or thumping sounds when the coils that generate the radiofrequency pulses are activated. You will be able to relax between imaging sequences, but will be asked to maintain your position as much as possible. You will usually be alone in the exam room during the MRI procedure. However, the technologist will be able to see, hear and speak with you at all times using a two-way intercom. Many MRI centers allow a friend or parent to stay in the room as long as they are also screened for safety in the magnetic environment. You may be offered or you may request earplugs to reduce the noise of the MRI scanner, which produces loud thumping and humming noises during imaging. Children will be given appropriately sized earplugs or headphones during the exam. MRI scanners are air-conditioned and well-lit. Some scanners have music to help you pass the time. When the contrast material is injected, it is normal to feel coolness and a flushing sensation for a minute or two. The intravenous needle may cause you some discomfort when it is inserted and once it is removed, you may experience some bruising.¹⁵ There is also a very small chance of irritation of your skin at the site of the IV tube insertion. If you have not been sedated, no recovery period is necessary. You may resume your usual activities and normal diet immediately after the exam. A few patients experience side effects from the contrast material, including nausea and local pain. Very rarely, patients are allergic to the contrast material and experience hives, itchy eyes or other reactions. If you experience allergic symptoms, a radiologist or other physician will be available for immediate assistance. Manufacturers of intravenous contrast indicate mothers should not breastfeed their babies for 24-48 hours after contrast medium is given. However, both the American College of Radiology (ACR) and the European Society of Urogenital Radiology note that the available data suggest that it is safe to continue breastfeeding after receiving intravenous contrast. The Manual on Contrast Media from the ACR states:

"Review of the literature shows no evidence to suggest that oral ingestion by an infant of the tiny amount of gadolinium contrast medium excreted into breast milk would cause toxic effects. We believe, therefore, that the available data suggest that it is safe for the mother and infant to continue breastfeeding after receiving such an agent. If the mother remains concerned about any potential ill effects, she should be given the opportunity to make an informed decision as to whether to continue or temporarily abstain from breastfeeding after receiving a gadolinium contrast medium. If the mother so desires, she may abstain from breastfeeding for 24 hours with active expression and discarding of breast milk from both breasts during that period. In anticipation of this, she may wish to use a breast pump to obtain milk before the contrast study to feed the infant during the 24-hour period following the examination."

Who interprets the results and how do I get them?

A radiologist, a physician specifically trained to supervise and interpret radiology examinations, will analyze the images and send a signed report to your primary care or referring physician, who will share the results with you.

What are the benefits vs. risks?

Benefits

· MRI is a noninvasive imaging technique that does not involve exposure to ionizing radiation.

· MRI can help physicians evaluate both the structure of an organ and how it is working.

· MRI enables the discovery of abnormalities that might be obscured by bone with other imaging methods.

· fMRI enables the detection of abnormalities of the brain, as well as the assessment of the normal functional anatomy of the brain, which cannot be accomplished with other imaging techniques.

Risks

· The MRI examination poses almost no risk to the average patient when appropriate safety guidelines are followed.

· If sedation is used there are risks of excessive sedation. The technologist or nurse monitors your vital signs to minimize this risk.

· Although the strong magnetic field is not harmful in itself, implanted medical devices that contain metal may malfunction or cause problems during an MRI exam.

· There is a very slight risk of an allergic reaction if contrast material is injected. Such reactions usually are mild and easily controlled by medication. If you experience allergic symptoms, a radiologist or other physician will be available for immediate assistance.

· Nephrogenic systemic fibrosis is currently a recognized, but rare, complication of MRI believed to be caused by the injection of high doses of gadolinium contrast material in patients with very poor kidney function.

What are the limitations of fMRI of the Brain?

High-quality images are assured only if you are able to remain perfectly still or hold your breath, if requested to do so, while the images are being recorded. If you are anxious, confused or in severe pain, you may find it difficult to lie still during imaging.

A person who is very large may not fit into the opening of a conventional MRI machine. The presence of an implant or other metallic object sometimes makes it difficult to obtain clear images and patient movement can have the same effect. MRI generally is not recommended for patients who have been acutely injured; however, this is a clinical judgment. This is because traction devices and many types of life support equipment must be kept away from the area to be imaged. Furthermore, the examination takes longer than other imaging modalities (typically x-ray and CT) and the results may not be immediately available as is often necessary in trauma situations. Although there is no reason to believe that magnetic resonance imaging harms the fetus, pregnant women usually are advised not to have an MRI exam unless medically necessary. MRI typically costs more and may take more time to perform than other imaging modalities. Functional MRI is still evolving and improving. While it appears to be as accurate in finding the location of brain activity as any other method, overall there is less experience with fMRI than with many other MRI techniques. Your physician may recommend additional tests to confirm the results of fMRI if there are critical decisions to made (such as in planning brain surgery).¹⁶

Functional MRI or functional Magnetic Resonance Imaging (fMRI) is a type of specialized MRI scan. It measures 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 1–5 seconds. This hemodynamic response rises to a peak over 4–5 seconds, before falling back to baseline (and typically undershooting slightly). This leads to local changes in the relative concentration of oxyhemoglobin and deoxyhemoglobin and changes in local cerebral blood volume and in local cerebral blood flow.¹⁷

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.^4,7,8 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).⁵ 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 1992.⁶In the same year, Dr. Ogawa submitted their result on March 31 and published in July issue of PNAS.⁷ In the following year, Dr. Ogawa published the biophysics model of BOLD contrast in Biophysical Journal.⁸ Dr. Bandettini also published a further paper in 1993 demonstrating quantitative determination of functional activation maps.⁹

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.³ Hemoglobin is diamagnetic when oxygenated (oxyhemoglobin) but paramagnetic when deoxygenated (deoxyhemoglobin).¹⁰ 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.¹¹ 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.^12,13

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.¹⁴ 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.¹⁵ 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.^16,17

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).^18,19 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.²⁰ 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.²¹

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.²² Furthermore, the size of the BOLD signal increases roughly as the square of the magnetic field strength.²³ 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.^24-27 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 psycho- physiological 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.^28,29

Advantages of fMRI:

· It can noninvasively record brain signals without risks of 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.³⁰³¹

Scanning in practice: Berkeley's 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.³² 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.^33,34 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.^35,36 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.³⁷ 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.³⁸ The future importance of diffusion-based functional techniques relative to BOLD techniques is not yet clear.

Contrast MRI: 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.^39,40 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.⁴¹ 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. The ASL activation signal is believed to be dominated by changes in the capillary bed of the activated area of the cortex, wheareas the BOLD signal is likely to be dominated by changes in the oxygenation of nearby veins.

Magnetic resonance spectroscopic imaging: Magnetic resonance spectroscopic imaging (MRS) is another, NMR-based process for assessing function within the living brain. MRS takes advantage of the fact that protons (hydrogen atoms) residing in differing chemical environments depending upon the molecule they inhabit (H₂O vs. protein, for example) possess slightly different resonant properties (chemical shift). For a given volume of brain (typically > 1 cubic cm), the distribution of these H resonances can be displayed as a spectrum.

The area under the peak for each resonance provides a quantitative measure of the relative abundance of that compound. The largest peak is composed of H₂O. However, there are also discernible peaks for choline, creatine, N-acetylaspartate (NAA) and lactate. Fortuitously, NAA is mostly inactive within the neuron, serving as a precursor to glutamate and as storage for acetyl groups (to be used in fatty acid synthesis) — but its relative levels are a reasonable approximation of neuronal integrity and functional status. Brain diseases (schizophrenia, stroke, certain tumors, multiple sclerosis) can be characterized by the regional alteration in NAA levels when compared to healthy subjects. Creatine is used as a relative control value since its levels remain fairly constant, while choline and lactate levels have been used to evaluate brain tumors.

Diffusion tensor imaging: Diffusion tensor imaging (DTI) is a related use of MR to measure anatomical connectivity between areas. Although it is not strictly a functional imaging technique because it does not measure dynamic changes in brain function, the measures of inter-area connectivity it provides are complementary to images of cortical function provided by BOLD fMRI. White matter bundles carry functional information between brain regions. The diffusion of water molecules is hindered across the axes of these bundles, such that measurements of water diffusion can reveal information about the location of large white matter pathways. Illnesses that disrupt the normal organization or integrity of cerebral white matter (such as multiple sclerosis) have a quantitative impact on DTI measures.

fMRI and EEG: Functional MRI has high spatial resolution but relatively poor temporal resolution (of the order of several seconds). Electroencephalography (EEG) directly measures the brain's electrical activity, giving high temporal resolution (~milliseconds) but low spatial resolution. The two techniques are therefore complementary and may be used simultaneously to record brain activity. Recording an EEG signal inside an MRI system is technically challenging. The MRI system introduces artifacts into the EEG recording by inducing currents in the EEG leads via Faraday induction. This can happen through several different mechanisms. An imaging sequence applies a series of short radiofrequency pulses which induce a signal in the EEG system. The pulses are short and relatively infrequent, so interference may be avoided by blanking (switching off) the EEG system during their transmission. Magnetic field gradients used during imaging also induce a signal, which is harder to remove as it is in a similar frequency range to the EEG signal. Current is also induced when EEG leads move inside the magnet bore (i.e. when the patient moves during the exam). Finally, pulsed blood flow in the patient in the static magnetic field also induces a signal (called a ballistocardiographic artifact), which is also within the frequency range of interest. The EEG system also affects the MRI scan. Metal in the EEG leads and electrodes can introduce susceptibility artifacts into MR images. Care must also be taken to limit currents induced in the EEG leads via the MRI RF system, which could heat the leads sufficiently to burn the subject.

Having simultaneously recorded EEG and fMRI data, the final hurdle is to co-register the two datasets, as each is reconstructed using a different algorithm, subject to different distortions.

Nuclear neuroimaging: Before the advent of fMRI functional neuroimaging was typically performed with positron emission tomography (PET) scanners or more rarely with SPECT scanners. Niels A. Lassen and his coworkers lead the earliest efforts of functional neuroimaging, using radioactive gases to construct images of the working brain.

These nuclear imaging techniques do not use the nuclear magnetic resonance property and employ entirely different scanners.

Approaches to fMRI data analysis: The ultimate goal of fMRI data analysis is to detect correlations between brain activation and the task the subject performs during the scan. The BOLD signature of activation is relatively weak, however, so other sources of noise in the acquired data must be carefully controlled. This means that a series of processing steps must be performed on the acquired images before the actual statistical search for task-related activation can begin. For a typical fMRI scan, the 3D volume of the subject's head is imaged every one or two seconds, producing a few hundred to a few thousand complete images per scanning session. The nature of MRI is such that these images are acquired in Fourier transform space, so they must be transformed back to image space to be useful. Because of practical limitations of the scanner the Fourier samples are not acquired on a grid, and scanner imperfections like thermal drift and spike noise introduce additional distortions. Small motions on the part of the subject and the subject's pulse and respiration will also affect the images. The most common situation is that the researcher uses a pulse sequence supplied by the scanner vendor, such as an echo-planar imaging (EPI) sequence that allows for relatively rapid acquisition of many images. Software in the scanner platform itself then performs the reconstruction of images from Fourier transform space. During this stage some information is lost (specifically the complex phase of the reconstructed signal). Some types of artifacts, for example spike noise, become more difficult to remove after reconstruction, but if the scanner is working well these artifacts are thought to be relatively unimportant. For pulse sequences not provided by the vendor, for example spiral EPI, reconstruction may have to be done by software running on a separate platform. After reconstruction the output of the scanning session consists of a series of 3D images of the brain. The most common corrections performed on these images are motion correction and correction for physiological effects. Outlier correction and spatial and/or temporal filtering may also be performed. If the task performed by the subject is thought to produce bursts of activation which are short compared to the BOLD response time (on the order of 6 seconds), temporal filtering may be performed at this stage to attempt to deconvolve out the BOLD response and recover the temporal pattern of activation. At this point the data provides a time series of samples for each voxel in the scanned volume. A variety of methods are used to correlate these voxel time series with the task in order to produce maps of task-dependent activation. There are many software packages available for analysing fMRI data.⁴²

Reconstruction of MRI data needs to be tested, calibrated and confirmed. MRI can suffer from numerous artifacts that include, geometric distortions, Nyquist ghosting, and signal dropout. Medical Imaging Phantoms are used to provide a consistent geometrical source for calibration and testing purposes. Minute tumor changes can require recalibration by use of a phantom to quantify the change.

Cost of fMRI: The major cost of an fMRI experiment is the MR scanner itself. New 1.5 tesla scanners often cost between $1,000,000 USD and $1,500,000 USD. New 3.0 tesla scanners often cost between $2,000,000 and $2,300,000 USD. Construction of MRI suites can cost $500,000 USD. MRI procedures themselves can vary considerably in cost but generally fall somewhere between $400 and $3,500, depending on the facility and which region of the body is being scanned. Extremity scans (feet, hands, etc.) tend to be lower in price while body scans (including the brain) tend to be higher.

CONCLUSION:

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 2006 by Weiller C et al. indicating a 90% to 93% success rate.⁴³However, 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.

REFERENCES:

1. Roy CS, Sherrington CS. "On the Regulation of the Blood-supply of the Brain". Journal of Physiology 11 (1-2): 85–158, 1890.

2. Raichle, M. E., Mintun, M. A.. "Brain Work and Brain Imaging". The Annual Review of Neuroscience 2006.

3. Laureys, S., Boly, M., Tononi, G.: "Functional Neuroimaging" in "The Neurology of Consciousness: Cognitive Neuroscience and Neuropathology" (Laureys, S., Tononi, G. eds.), Academic Press-Elsevier: 31-42, 2009.

4. Ogawa, S., Lee, T.M., Nayak, A.S., and Glynn, P. "Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields". Magnetic Resonance in Medicine 14: 68–78, 1990.

5. Belliveau JW, Kennedy DN, McKinstry RC, Buchbinder BR, Weisskoff RM, Cohen MS, Vevea JM, Brady TJ, and Rosen BR. "Functional mapping of the human visual cortex by magnetic resonance imaging". Science 254: 716–719, 1991.

6. KK Kwong, JW Belliveau, DA Chesler, IE Goldberg, RM Weisskoff, BP Poncelet, DN Kennedy, BE Hoppel, MS Cohen, R Turner, H Cheng, TJ Brady, and BR Rosen. "Dynamic Magnetic Resonance Imaging of Human Brain Activity During Primary Sensory Stimulation". PNAS 89: 5951–55, 1992.

7. Ogawa S, Tank DW, Menon R, Ellermann JM, Kim SG, Merkle H, Ugubril K. "Intrinsic signal changes accompanying sensory stimulation: Functional brain mapping with magnetic resonance imaging". PNAS 89: 5675–79, 1992.

8. Ogawa S, Menon RS, Tank DW, Kim SG, Merkle H, Ellermann JM, Ugurbil K. "Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model". Biophysical journal 64 (3): 803–12, 1993.

9. Bandettini, P.A.; Jesmanowicz, A.; Wong, E.C.; Hyde, J.S. "Processing strategies for time-course data sets in functional MRI of the human brain". Magnetic Resonance in Medicine 30 (2): 161–173, 1993.

10. L Pauling and CD Coryell. "The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and Carbonmonoxyhemoglobin". PNAS 22: 210–6, 1936.

11. Gusnard DA, Raichle ME (2001). "Searching for a baseline: Functional imaging and the resting human brain". Nature Reviews Neuroscience 2 (10): 685–694, 2001.

12. Yablonskiy DA, Haacke EM. "Theory of NMR signal behavior in magnetically inhomogeneous tissues: the static dephasing regime". Magnetic Resonance in Medicine 32 (6): 749–63, 1994.

13. Konn D, Gowland P, Bowtell R. "MRI detection of weak magnetic fields due to an extended current dipole in a conducting sphere: a model for direct detection of neuronal currents in the brain."Magnetic Resonance in Medicine 50 (1): 40–49, 2003.

14. Magistretti PJ, Pellerin L. "Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging." Philosophical Transactions of the Royal Society of London 29 (354(1387)): 1155–63, 1999.

15. Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A. "Neurophysiological investigation of the basis of the fMRI signal.". Nature 412 (6843): 150–7, 2001.

16. Yang, G. and Iadecola, C. "Glutamate microinjections in cerebellar cortex reproduce cerebrovascular effects of parallel fiber stimulation". Am J Physiol Regul Integr Comp Physiol 271 (6): R1568–1575, 1996.

17. Bonvento, G.; Cholet, N.; Seylaz, J. "Sustained attenuation of the cerebrovascular response to a 10 min whisker stimulation following neuronal nitric oxide synthase inhibition". Neuroscience Research 37 (2): 163, 2000.

18. Kim, D.; Duong, T.; Kim, S. "High-resolution mapping of iso-orientation columns by fMRI". Nature neuroscience 3 (2): 164–169, 2000.

19. Malonek, D.; Grinvald, A. "Interactions Between Electrical Activity and Cortical Microcirculation Revealed by Imaging Spectroscopy: Implications for Functional Brain Mapping". Science 272 (5261): 551, 1996.

20. Zarahn, E. "Spatial localization and resolution of BOLD fMRI". Current Opinion in Neurobiology 11 (2): 209–212, 2001.

21. Behzadi, Y. et al. "Caffeine reduces the initial dip in the visual bold response at 3 t."Neuroimage 32 (1): 9–15, 2006.

22. Di Salle, F.; Esposito, F.; Elefante, A.; Scarabino, T.; Volpicelli, A.; Cirillo, S.; Elefante, R.; Seifritz, E. "High field functional MRI". European journal of radiology 48 (2): 138–145, 2003.

23. van der Zwaag W, Francis S, Head K, Peters A, Gowland P, Morris P, Bowtell R. "fMRI at 1.5, 3 and 7 T: Characterising BOLD signal changes.". Neuroimage 47 (4): 1425–34, 2009.

24. Roemer PB, Edelstein WA, Hayes CE, Souza SP, Mueller OM. (November 1990). "The NMR phased array.". Magn Reson Med. 16 (2): 192–225, 1990.

25. Pruessmann KP, Weiger M, Scheidegger MB, Boesiger P. "SENSE: Sensitivity encoding for fast MRI.". Magn Reson Med. 42 (5): 952–62, 1999.

26. Griswold MA, Jakob PM, Heidemann RM, Nittka M, Jellus V, Wang J, Kiefer B, Haase A. "Generalized autocalibrating partially parallel acquisitions (GRAPPA).". Magn Reson Med. 47 (6): 1202–10, 2002.

27. http://www.wired.com/wiredscience/2009/09/fmrisalmon/

28. Shmuel et al. Negative fMRI response correlates with decreases in neuronal activity in monkey visual area V1. Nature Neurosci. 9(4):569-577, 2006.

29. Logothetis, N.K.; Pauls, J; Augath, M; Trinath, T; Oeltermann, A. "Neurophysiological investigation of the basis of the fMRI signal." Nature 412 (6843): 150, 2001.

30. Magalhaes, A. Functional magnetic resonance and spectroscopy in drug and substance abuse. Top Magnetic Resonance Imaging. 3, 247-251, 2005.

31. Chen, C., Hou, B., Holodny, A. Effect of age and tumor grade on BOLD functional MR imaging in pre-operative assessment of patients with glioma. Radiology. 3, 971-978, 2008.

32. Aguirre, G., Zarahn, E., and D’esposito, M. The variability of human BOLD hemodynamic responses. Neuroimage. 8 (4), 360-369, 1998.

33. Corbetta, M., Miezin, F., Dobmeyer, S., Shulman, G., Petersen, S. Attentional modulation of neural processing of shape, color, and velocity in humans. Science. 4962, 1556-1559, 1990.

34. Haller, S., Bartsch, A. Pitfalls in fMRI. European Radiology. 19, 2689-2706, 2009.

35. Le Bihan D, et al. "Direct and fast detection of neuronal activation in the human brain with diffusion MRI". PNAS 103 (21): 8263–8268, 2006.

36. Kohno S et al. "Water diffusion slowdown in the human visual cortex on visual stimulation precedes vascular responses". Journal of Cerebral Blood Flow & Metabolism 29 (6): 1197–1207, 2009.

37. Mandl RCW et al. "Functional diffusion tensor imaging: Measuring task-related fractional anisotropy changes in the human brain along white matter tracts". PLoS ONE 3 (11): 1–10, 2008.

38. Detre, J.A., Leigh, J.S., Williams, D.S., and Koretsky, A.P. Perfusion imaging. Magn Reson Med 23, 37-45, 1992.

39. Williams, D.S., Detre, J.A., Leigh, J.S., and Koretsky, A.P. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A 89, 212-216, 1992.

40. Scott A. Huettel, Allen W. Song, Gregory McCarthy, Functional Magnetic Resonance Imaging, Sinauer Associates, 2004.

41. Richard B. Buxton, An Introduction to Functional Magnetic Resonance Imaging: Principles and Techniques, Cambridge Univ Press, 2002.

42. Roberto Cabeza and Alan Kingstone, Editors, Handbook of Functional Neuroimaging of Cognition, Second Edition, MIT Press, 2006.

43. Weiller C et al. "Role of functional imaging in neurological disorders". Journal of Magnetic Resonance Imaging 23 (6): 840–850, 2006.

Received on 19.04.2011 Modified on 18.05.2011

Research J. Pharm. and Tech. 4(8): August 2011; Page 1167-1176

Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India