The Brain in Pain

Davis_HeadshotKaren Davis, PhD, is a Senior Scientist at the Krembil Research Institute and Professor at the University of Toronto, Canada. Davis uses brain imaging to understand how pain affects the brain’s structure and function. She spoke recently by phone with freelance journalist Stephani Sutherland to discuss how brain imaging works, and what it can—and can not—tell us about pain in the brain. Below is an edited transcript of their conversation.  

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. That said, there are also translational neuroscience researchers trying to bridge the gap between pure scientific discovery and the ways that we can apply new knowledge to clinically important questions. There are also clinical pain specialists who are asking very direct questions regarding treatments for chronic pain–whether there is a way to use brain imaging to track whether a drug works, for instance, or how that drug works.

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. We use structural MRI to look at the density of the cells in the brain—it’s commonly used to measure how thick the cortex is, for instance, or the amount of grey matter in areas beneath the cortex.

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. For example, if you look at a flash of light that occurs for one second, the blood flow response to that flash will occur in the corresponding brain area for about ten to 12 seconds. 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.

Then, we make the assumption that those two brain areas are working toward a common cause, because they’re doing the same thing at the same time. 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 instance, if you want to follow what’s happening to opiate receptors in the brain in various situations, you can tag—or make radioactive—a substance that binds to opiate receptors. 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. Based on some assumptions, we can infer what we think is going on. 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.

Why can’t brain imaging accomplish this yet?

There are several reasons. We have to remember that a person who has chronic pain often doesn’t have chronic pain in isolation from other problems. For instance, if you take people who have low back pain, their mobility will probably be reduced from normal levels, and their level of fitness has probably gone down because they are unable to exercise. They may also have a certain level of anxiety or depression, or show differences in how they see the world in terms of injustice, fear or frustration. So there are many issues surrounding quality-of-life and personality factors that arise if you have been trying to cope with chronic pain for a period of time.

Also, when you image the brain, you image everything in the brain. And, the systems in the brain that convey information about pain are not specific to pain; they also convey information about many other systems like attention, depression, fear, memory—all sorts of things. When we see an abnormality in the brain, we don’t know with certainty that it’s only due to the pain part of the chronic pain, as opposed to things that might be happening that are related to dealing with and suffering from chronic pain. This is one of the real problems; we don’t know if we are seeing the driving force of pain, of if we’re seeing the outcome of pain.

What are the other challenges?

The other big problem with measuring chronic pain in an individual patient is that we need to understand with a good degree of certainty what the range of normal brain structure and function is. That is very difficult, because we are now recognizing that there are many situations of “normal,” depending on many factors such as age, sex, and ethnicity. What would appear to be a normal response in a 21-year-old male, for instance, might be completely different in the brain of a 55-year-old female. People use different parts of their brain in different ways, and they might use their brain differently to cope with pain or react to pain. When we study pain, we need to understand all those different types of normal before we start making any judgment that something is abnormal.

Another challenge is that different types of pain are different from each other—even different types of acute pain. For example, superficial skin pain feels a certain way, and, in terms of brain mechanisms, that will show up differently than a stomach ache, which has different emotions, levels of unpleasantness and fears. In the same way, chronic pain would be quite different, and there are many different types of chronic pain.

What has imaging told us that has had the biggest impact on our understanding of how the brain processes pain?

What we have learned from imaging is how complex pain is—how many different aspects of the brain are involved in pain, not only in the fundamental “ouch” of pain, but also in all the other sensory, intensity, and emotional overlays that create that complex feeling. With today’s slow imaging techniques, we can’t really separate out these things in the brain, but hopefully someday we will be able to do so with fast techniques that are better linked to the electrical response and activity of neurons. There are so many exciting computational approaches being developed that I think in ten years we will be in a completely different place than we are now.

What other questions about pain might brain imaging be able to answer in the future?

How is it that we can experience pain similarly, but have many different underlying brain mechanisms at work? How is it that some people can cope with pain differently than others can? What are the brain mechanisms underlying our ability to cope with pain, to recover from an injury, or respond to a treatment—be it a drug treatment, surgical approach, or a cognitive behavioral therapy? If we can tap into those mechanisms, then we can start to help people.