A Lesson from Brain Imaging: Head Pain Is Different from Other Kinds of Chronic Pain

By Neil Andrews | April 23, 2024 | Posted in

A new neuroimaging study pinpoints differences in gray matter in those with chronic pain, especially multisite pain, compared to healthy individuals. Those who reported head pain showed unique differences compared to other chronic pain types.

For decades, scientists have been using neuroimaging to study the structure and function of the brain in people who have chronic pain, including headache disorders. While these investigations have advanced understanding of brain areas and networks associated with conditions ranging from low back pain to fibromyalgia to migraine, they also have significant limitations. For instance, imaging studies are expensive to carry out, and often include relatively small sample sizes, making it difficult to detect differences between study groups.

Now, new work from researchers at the University of Southern California (USC), Los Angeles, US, overcomes some of those earlier hurdles with the largest brain imaging study of chronic pain to date, showing differences in the brains of those with chronic pain compared to people without pain.

A team of investigators, including first author Ravi Bhatt and senior author Neda Jahanshad, examined gray matter differences – including alterations in cortical surface area, cortical thickness, and subcortical volume – in more than 20,000 participants from the UK Biobank, a biomedical database containing a wide range of data including genetic, imaging, and health information from half a million UK study participants. The team identified differences in those brain structure parameters in people with chronic pain compared to healthy control subjects, particularly in those who had pain at multiple body sites.

Of interest for the headache field, those who reported head pain had unique brain structure patterns that distinguished them from those who reported pain at other body sites.

And, notably, the researchers were able to link some of the brain differences to an increased risk of suicide, especially among those with chronic multisite pain.

The researchers “have provided some of the most comprehensive, large-sample evidence for gray matter associations with pain to date, with potential differences across body sites and associations with suicide risk. The study represents an important step in understanding how the brain changes with, and contributes to, chronic pain, and provides a launching point for future studies using converging methodologies,” wrote Tor Wager, Katerina Zorina-Lichtenwalter, and Naomi P. Friedman in an accompanying commentary.

“Every time I see a study with large datasets, I get excited, especially with neuroimaging research, which is such an expensive way of studying human disease. I think UK Biobank is such an amazing resource for looking at patterns of disease,” said Nasim Maleki in an interview with Migraine Science Collaborative.

Maleki, a brain imaging researcher at Harvard Medical School and Massachusetts General Hospital, Boston, US, who was not involved with the research, was most struck by the unique pattern of changes in those with chronic head pain, at least as defined in the study (pain present for three or more months).

“It is real what they have found – there are distinct differences that they see in those who had head pain compared to the other groups. Head pain is its own category; we cannot group it with other chronic pain conditions. Just showing that, in a very solid way, was the main strength of the study,” according to Maleki.

The research and commentary appeared in the March 1, 2024, issue of the journal Biological Psychiatry.

(Bio)banking on a large study
Bhatt, who is a graduate student working with Jahanshad at the Mark and Mary Stevens Neuroimaging and Informatics Institute at USC, told MSC that the large amount of data available in the UK Biobank spurred the new research.

“The rationale behind this study was to look at chronic pain in an extremely large sample, so we can capture large amounts of intra-individual variability and have enough statistical power to detect effects that could not be detected beforehand in smaller studies,” he said.

Bhatt added that the UK Biobank data also made it possible to reach another aim that he and his co-authors had in mind.

“Since we had such a large sample size, we then wanted to look at whether we could separate brain structure differences according to the type of pain,” he said.

Ultimately, the researchers would include nearly 22,000 UK Biobank participants who had undergone a brain MRI scan and who had also responded to questions about pain upon undergoing a scan.

Specifically, participants were asked about the types of pain they had experienced over the past month, including pain in the head, face, neck/shoulder, back, stomach/abdomen, hip or knee, as well as pain all over the body. The participants were then asked if they had suffered from pain at any of these body sites for three or more months, which the researchers used as the study’s definition of chronic pain. The investigators also obtained information about suicide attempt from inpatient records and self-report.

Half of the study participants had chronic pain, including, on the low end, 740 people with abdominal pain, all the way up to 4,551 individuals with knee pain; 1,639 reported chronic head pain. Meanwhile, 162 people reported a history of at least one suicide attempt. The other half of participants served as healthy controls.

In terms of the brain scans, the researchers focused on gray matter, which is brain tissue that contains an especially high concentration of the cell bodies of neurons, giving this tissue its color. They assessed gray matter differences by looking at three measures: cortical thickness, cortical surface area, and subcortical volume, the last of which refers to gray matter volume in brain structures beneath the cortex.

Head pain is different
First, the investigators considered those with chronic pain regardless of where in the body they reported pain. Gray matter differences throughout the brain were apparent in the chronic pain group, compared to controls. In general, most brain regions showed lower cortical surface area, with people who reported multisite pain showing the greatest difference in that measure.

The team next compared those with chronic localized pain (pain restricted to one location) to controls. Here, those who reported head pain had higher cortical thickness throughout many brain areas. This stood out, not only because the increase was much more widespread than reported in previous studies of headache and migraine, but also since pain at other body sites was not characterized by such an increase (with the exception of knee pain). Further, people with head pain did not show the lower surface area that those with pain at other body sites did.

“The signature for head pain was so vastly different from the other pain types,” said Jahanshad, the study’s senior author. “This is a unique type of pain that probably shouldn’t be combined with the other types of pain, at least when you’re looking at brain signatures. There’s something else going on within the circuitry and maybe the brain tissue that we really need to tease apart.”

However, noting that the study’s definition of chronic pain as pain lasting at least three months only provides limited information, Maleki cautioned that it’s not possible to extrapolate the current imaging findings about head pain to other kinds of headache, of which there are so many.

“The downside is that because this is not a clinical trial carefully designed to study a specific disease or disorder, a lot of information that you need to ultimately interpret what you’re seeing is not there,” Maleki said.

Finally, in terms of subcortical volume, the current study found that only those with abdominal pain showed a difference, in this case a decrease, compared to controls.

Brain imaging of chronic pain.

Significant differences in brain structure in participants reporting chronic pain across different body regions compared with control participants. Effect sizes (Cohen’s d) for surface area (A), cortical thickness (B), and subcortical volumes (C) for regions that are significant after false discovery rate correction. Red represents greater brain metric values, and blue represents lower brain metric values. Figure and caption from Bhatt et al. Biol Psychiatry. 2024 Mar 1;95(5):473-481.

An association with suicide attempt
The investigators next turned their attention to one of the most terrible consequences for some individuals with chronic pain.

“Chronic pain is such a giant risk factor for suicide. And since many brain imaging studies have established subsystems of the brain related to suicide, we wanted to see what differences in brain structure mediated a relationship between chronic pain and suicide attempt,” Bhatt said.

The team found an association of chronic pain, localized pain, multisite pain, and pain at all of the body sites considered in the study, including head pain, with suicide attempt. The greatest association was observed for abdominal pain.

Further, the results indicated that thickness of a brain structure called the precuneus mediated the relationship between chronic multisite pain and suicide attempt. That finding makes sense considering that the precuneus is part of a system for self-referential thought and the construction of feelings – a system that changes in people at increased risk of suicide.

Other brain areas also emerged as mediators of the pain-suicide attempt association. For example, the volume of the brainstem and amygdala mediated the relationship between abdominal pain and suicide attempt.

Limitations and questions for the future
One of the study’s limitations, which the authors acknowledge, is that it’s difficult to know what the brain structure differences actually reflect, considering the cross-sectional nature of the study. Do the differences in people with pain actually cause the pain? Do they reflect an adaptive response to the pain? Do they contribute to suicide attempt? Only a longitudinal study, where researchers follow subjects to see how the brain, and how the pain, changes over time could address such questions. Interestingly, longitudinal data are available in the UK Biobank, providing an opportunity to study questions of causality in the future.

Another limitation that Maleki pointed to is that the study was restricted to just one imaging modality, in this case MRI structural data. But this, too, is a limitation that could be overcome in future studies using UK Biobank data, which does include information obtained from other brain imaging modalities, including diffusion and functional MRI.

Maleki also recommended that future research include people whose pain conditions, especially in the case of headache, have been phenotyped in a more detailed way, rather than only define chronic pain on the basis that it last at least three months, which is a quite general definition.

The UK Biobank is not the only data source that could be used to address such limitations. For example, Jahanshad pointed to the Enhancing Neuroimaging Genetics through Meta Analysis, which is an international consortium that brings together a variety of researchers in order to advance understanding of brain structure, function and disease based on brain imaging and genetic data.

“The idea is to pool all of the data, including UK Biobank data, look for common and distinct signatures, and really have the largest and most well powered set of studies to look into the neuroimaging signatures of chronic pain, including migraine, back pain and other types of pain that are really prevalent and being studied in the neuroimaging field,” said Jahanshad, who noted that data from other imaging modalities will be included in this effort.

What is the end goal for such brain imaging studies? Personalized medicine is one of the aims often cited by those pursuing this research.

“Ideally, we’d be able to look at what’s the most effective treatment for an individual – that’s really why we’re trying to tease apart these groups. Maybe there’s an area of the brain that is affected in a certain individual because they have one type of pain, and maybe there are certain medications that can help. That’s where I would like to see this go,” Jahanshad said.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on Twitter @NeilAndrews

Mapping Brain Structure Variability in Chronic Pain: The Role of Widespreadness and Pain Type and Its Mediating Relationship With Suicide Attempt.
Bhatt et al.
Biol Psychiatry. 2024 Mar 1;95(5):473-481.

A New Look at Gray Matter Decreases in Chronic Pain.
Wager et al.
Biol Psychiatry. 2024 Mar 1;95(5):387-388.

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Neil Andrews is a science journalist and editor based in New York City. He has over two decades of experience covering science and medicine for expert and non-expert audiences alike. He is also the executive editor of the Migraine Science Collaborative, where he manages the day to day operations of the site. Previously he was the executive editor of the Pain Research Forum.

When not thinking and writing about neuroscience, Neil spends much of his free time on his Peloton and exploring NYC. He is also on a quest to satisfy his coffee cravings by visiting every independent coffee shop in the city. Follow him on Twitter @NeilAndrews.



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