Almost all 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 directly have been attempted (for example, measurement of the Oxygen Extraction Fraction, or OEF, in regions of the brain, which measures how much of the oxyhemoglobin in the blood has been converted to deoxyhemoglobin, 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.
Hemoglobin is diamagnetic when oxygenated but paramagnetic when deoxygenated. The magnetic resonance (MR) signal of blood is therefore slightly different depending on the level of oxygenation. These differential signals can be detected using an appropriate MR pulse sequence as blood-oxygen-level dependent (BOLD) contrast. 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 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.
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, especially glutamate.
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 responsivnesses 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 4 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.
BOLD effects are measured using rapid volumetric acquisition of images with contrast weighed by T2 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 advanced “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.
Bold fMRI Publication References
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