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Blood-oxygen-level-dependent signal or (BOLD) signal measures the changes in magnetic properties of blood due to changes in brain activity to show which brain regions are active during certain tasks. The changes in magnetic properties of blood correlate with changing neuronal activity. Very active neurons require energy in the form of oxygen and glucose, which come from the blood. These neurons suck the oxygen out of the blood to make energy. Blood flow increases to these neurons to replenish oxygen and can overcompensate resulting in a net increase in oxygen, which is referred to as the hemodynamic response. The hemodynamic response depends on oxygen levels, blood flow, and blood volume. BOLD signal is measured in functional magnetic resonance imaging (fMRI). Deoxygenated hemoglobin interferes with the magnetic fields from the MRI making the image fuzzy. Oxygenated hemoglobin reduces this interference and creates a better signal, which makes that part of the brain light up.

History
The BOLD contrast mechanism was first described by Ogawa & Lee in 1990 in rat brain studies. Ogawa discovered that blood oxygen levels could be used as a contrast mechanism when imaging rat brains in a strong magnetic field. The deoxygenated hemoglobin interfered with the MRI signal resulting in images that resembled thick dark lines. The brain regions could not be identified. He concluded that BOLD contrast adds an additional feature to MRI and reveals regional neural activity by using deoxygenated hemoglobin as a contrast agent.

Use in research
fMRI machines are always measuring the changing signal strength which indicates a change in neural activity. The changing signal strength is due to oxygen levels in the blood changing which is referred to as the BOLD response. The BOLD response is what the fMRI machine is measuring to see which brain areas become activated while doing a certain task. While in the scanner, patients may be asked to perform a simple task or be presented with a stimulus, such as a smell. This allows researchers to be able to study how the brain responds to certain stimuli and which brain regions are activated while doing a task. Researchers can understand brain activation pathways in healthy brains and how this differs from people with mental illness.

BOLD response curve
Activated neurons follow the same pattern of signal change in response to a stimulus. When a neuron first becomes activated, the oxygen readily nearby in the blood is quickly sucked up, resulting in an initial dip for only a couple of seconds. Initial dip refers to the decrease in oxygenated hemoglobin when neurons first get activated and use up the available oxygen. There is some controversy regarding the initial dip because it is not consistently seen in studies. It takes a couple seconds for the blood to replenish the oxygen to that area because blood is slower than neural activity. In response to the decrease in oxygen, the blood overcompensates and carries an excess of oxygen to the neuron in an attempt to match the oxygen being used. This is referred to as the overshoot. The BOLD response remains elevated for as long as the stimulus is present, which is the positive BOLD response. The positive BOLD response is what is being measured and indicates which brain areas are activated. When the stimulus stops, an undershoot occurs which allows excess oxygen to clear out or be taken up by nearby neurons then the blood’s oxygen level normalizes.

BOLD signal reflects neuronal activation
Recent research has shown that BOLD signal depends not only on blood oxygenation but also on cerebral blood flow and cerebral blood volume. BOLD signal changes are associated with the synaptic inputs being received at the site of activation, not with the output level of firing of the neuron receiving the inputs .This means that BOLD signal reflects the synaptic activity that created neuronal connections at the site of activation, but not the firing patterns produced by the activated neurons. Positive BOLD signal change corresponds to excitatory activation .There are areas that show negative BOLD signal. This could be due to a decrease in synaptic activity relative to a control state. This is still not well understood.

Evidence
Studies have shown that BOLD signal does correlate with neural activity. Animals were injected with a virus that has a light activated ion channel. A fiber optic light was then implanted into the brain. When the light was turned on, the ion channels opened resulting in the neuron becoming activated. The BOLD signal was measured and increased while the fiber optic light was turned on. In the animals that did not get injected with the virus, there was no change in BOLD signal when the fiber optic light was turned on. This evidence shows that when a neuron is activated a positive BOLD signal is seen.

Disadvantages
BOLD signal has limited spatial resolution because the signal could be contaminated by nearby veins draining the sites of activation. The activated neurons are sending oxygenated blood to a draining vessel, which would increase the signal change. Another disadvantage is the slow response time. If the neural events to be measured are happening slowly, they can be tracked with fMRI since the measurement is in real time .When events occur in short time periods, an overlap in BOLD signals can occur which make it difficult to resolve individual signal changes. This makes it difficult to study fast brain processes, which occur in tens to hundreds of milliseconds.