Why do neuroscientists, including pain researchers, use brain imaging?
At the most fundamental level, neuroscientists use brain imaging as a tool to understand how the brain is organized and how it functions, and as basic science researchers, we want to understand its fundamental processes.
In the past, most of the great developments in science and medicine have come from that kind of unrestricted exploration, as opposed to directly trying to develop a treatment.
What are some of the most commonly used imaging techniques, and how do they work?
Magnetic resonance imaging (MRI) is the most commonly used technique. It is non-invasive, widely available, and relatively inexpensive. Any academic hospital will have an MRI machine for clinical use, and some have one for research.
There are two basic things you can do with MRI.
One is to look at brain structure, and the other is to look at brain function.
In terms of structure, one type of MRI scan gives very high-resolution, detailed images that allow you to measure grey matter density. Grey matter is made of the cell bodies of neurons, which look darker than other parts of neurons; the cell bodies are where neuronal activity and interactions happen.
The other type of structural MRI scan is used to see and measure white matter in the brain.
Nerve cells have long communicating tails called axons that transmit information from one neuron to another, and axons make up white matter. White matter appears white or lighter than the cell bodies, because most of the axons are insulated with a fatty substance called myelin.
The white matter acts like the highways of the brain, which communicate between the cities of the brain, made up of grey matter.
One thing you can do is investigate how strongly connected two areas of the brain are by white matter. You can also look at those connectivity pathways and measure different attributes of the pathway to see how intact or organized it is.
The other category of MRI that we use quite a lot these days is known as functional MRI, or fMRI.
For the most part, fMRI has been limited to looking at how the brain responds to a stimulus or when performing a task—how it responds when you do or experience something.
How does fMRI work?
This way of looking at brain activity relies on the BOLD effect, which stands for blood-oxygen-level-dependent.
When nerve cells are active, they require oxygen to support their activity, and that’s supplied by increasing blood flow that brings oxygen to areas of the brain.
fMRI doesn’t directly measure electrical activity of those neurons, which is how they’re actually functioning. Instead, it measures the blood oxygen and blood flow changes that occur because those neurons are active, so it’s an indirect measure of neuronal activity.
Because blood flow changes and oxygen changes are actually slow and prolonged in relation to neural activity, the technique is slow.
That’s one of the limitations of fMRI: on a temporal basis, it’s only loosely connected to the actual activity of the neurons. But that’s how we used fMRI for about 15 years.
What recent developments have emerged with the fMRI technique?
About five years ago, a new fMRI technique, called resting state functional connectivity, was developed that does not require applying a stimulus or having a subject do a task. With this new approach, we look at interactions between different areas of the brain.
In the resting brain—when you’re not doing anything in particular—the BOLD signal shows very slow oscillations. We can measure those oscillations and look for patterns that are similar between different areas of the brain.
When we see patterns that are very similar or even synchronized between two areas of the brain, we refer to that as functional connectivity.
That doesn’t mean that there is a direct connection between those two areas of the brain through a single neuron. It simply means that the two areas of the brain, from the BOLD signal perspective, show synchronized activity.
We don’t know for sure that there’s a structural connection, but functionally we refer to them as being connected—and it has been shown that, by and large, what we’re picking up with functional connectivity using MRI does reflect the structural architecture that we know is in the brain.
Why is this new technique important for the pain field?
Measuring resting state functional connectivity is very exciting for pain researchers.
Until this new technique came along, fMRI required delivery of a stimulus in order to measure brain activity, and that was not optimal for pain research for a number of reasons.
First, to understand chronic pain, we really want to see how the brain is functioning without having to deliver an additional stimulus, because chronic pain is ongoing—it doesn’t need to be evoked.
Another practical and ethical consideration is that we don’t want to add additional pain for experimental purposes to patients who are already experiencing a lot of pain.
A third reason, which is very important technically, is that the BOLD response has an upper limit—there is only so much blood flow you can have in the brain.
When people study patients with ongoing chronic pain, presumably the neurons that are related to the pain are active, and so blood flow to those areas of the brain is higher than it would normally be.
If you delivered another stimulus on top of that chronic pain, even though the neurons might become more active and patients might experience additional pain, the actual detection of that signal is hampered by this upper limit for blood flow.
What about positron emission tomography (PET) imaging—how does it differ from MRI?
PET imaging is more invasive than MRI, because it requires injection of a radioactive tracer to do your studies.
One type of PET scan can be used to indirectly track brain activity, as with fMRI, but the advantage of PET over fMRI is that, again, you don’t actually need a task or stimulus; you can just inject the tracer and see where the blood flow is higher.
The disadvantage is that the PET response is even slower than the BOLD response with MRI. PET can be used to look at responses that are ongoing, but if you wanted to look at something on a millisecond basis, you couldn’t do that.
With another type of PET scan, we take a substance that binds to a receptor and make that substance radioactive.
For this type of scan, we are looking at what’s happening at a particular receptor system in the brain, such as opiate, serotonin, or dopamine receptors. You can use the molecules that activate those receptors to look at how effective a drug is in people, for example.
What can brain imaging tell us, and what can it not tell us, about chronic pain?
The bottom line is that brain imaging can’t tell you if somebody is feeling pain—we can’t use it as a kind of mind-reading technique.
However, it can tell us what’s going on in the brain when a person is experiencing pain—when we deliver a stimulus that we know normally produces pain or activates the pain system.
What brain imaging is really good at doing right now is looking at general features that are different between two groups, for instance, a group of healthy individuals and a group of individuals that have chronic pain, if you have a large enough sample size.
For example, if we look at white matter, brain imaging can tell us that there might be something abnormal in how the white matter is organized or in how it’s connecting two areas of the brain. Imaging can also tell us if there appears to be less grey matter in an area of the brain in pain patients than in healthy people.
It can also tell us if areas of the brain are not individually functioning as they normally would, or if they’re not communicating with other areas of the brain as they normally would, either functionally or structurally.
What we can’t do yet, but what we hope to develop in the future, is to take an individual patient and say, with a high degree of certainty, that the patient is showing a certain type of pain-related abnormality,