The Trigeminal Nerve and Migraine: Linking Structure to Function

A new study combines structural MRI, functional MRI, and PET imaging to connect changes in the trigeminal root entry zone to inflammation and brainstem activity in people with migraine.

The trigeminal nerve features largely in the current understanding of migraine. One of the main lines of prevailing thinking in the field is that activation and sensitization of afferent fibers projecting from the nerve to neurons and blood vessels of the cranial meninges initiates headache.

But despite its role in the pathophysiology of migraine, the trigeminal nerve has remained somewhat of a mystery. In particular, the trigeminal root entry zone, where the nerve enters the brainstem, is a very small region, and the brainstem is a small structure itself. That anatomy makes it difficult to study the structure of the nerve at the level of detail that researchers would like, and to relate nerve structure to function.

But now, a collaboration amongst researchers primarily in the Boston area is the first to use the most advanced high-resolution magnetic resonance imaging (MRI) for visualizing trigeminal nerve microstructure in people with migraine. Further, by combining this structural MRI with other imaging techniques, the group linked changes in the structure of the nerve to a molecular mechanism, in this case increased neuroinflammation, as well as to lower brainstem activity, in the migraine patients.

“I think it’s really important work. It’s the sort of work that we’ve been missing in the field, in that it really does tie together the metrics that we use typically – pain and MRI metrics – with true molecular metrics,” said Massieh Moayedi, a pain neuroimaging researcher at the University of Toronto, Canada, who was not involved with the study. “So it’s really bridging that gap between molecular mechanisms and what we see in brain structure and function. It’s a paper that allows us to really start to unpack what’s going on in migraine and lays the groundwork for developing new therapeutic targets,” he added.

For Nasim Maleki, a migraine neuroimaging investigator at Massachusetts General Hospital and Harvard Medical School, Boston, US, the most innovative aspect of the study was its methodological approach.

“Any study done on a 7 Tesla scanner is something to be super excited about,” said Maleki, referring to the magnetic field strength of the MRI used in the new research. “Most studies are done on a 3 Tesla, and when you go to 7 Tesla you can see anatomical details that you cannot see with lower-power magnets,” according to Maleki, who also was not involved with the research. “Another great aspect of this study is that it’s a multimodal approach,” she added, in reference to the study’s combination of the 7 Tesla structural imaging with functional MRI and positron emission tomography (PET).

The study appeared online ahead of print on January 28, 2025, in the journal Brain.

From changes in structure…
One challenge facing the migraine field is that migraine is a clinical diagnosis, with physicians having no way to objectively determine the presence of the disease. That was part of the rationale for the study, according to first author Sarasa Tohyama of Harvard Medical School in Boston, who performed the research as a postdoc in the lab of Vitaly Napadow, one of the senior authors of the work along with Marco Loggia and a number of other principal investigators.

For patients diagnosed with migraine, “if you take an MRI of the brain using routine clinical MRI, the MRI is typically completely normal. So there’s really no objective assessment for diagnosis and for further understanding the disease,” according to Tohyama.

That makes improved technology like 7 Tesla MRI, with its high-resolution capability, a particularly valuable tool. To put it to the test, the researchers included in their study a total of 60 people with migraine (mean age of 36 years; 55 female participants), and 20 healthy controls matched for age and sex. Patients who had migraine with aura or without aura were eligible to take part. While episodic migraine was the primary study population, those with up to 20 migraine headache days per month were eligible for the study; the mean headache frequency of participants was 9.5 days per month.

The group used 7 Tesla diffusion tensor imaging (DTI), a type of MRI that measures the movement of water molecules in tissues, to examine white matter microstructure at the trigeminal root entry zone. They calculated fractional anisotropy (FA), which is a measure of tissue connectivity, with reduced FA indicating disruption of white matter tracts.

Compared to the healthy controls, those with migraine showed significantly lower FA in the right trigeminal root entry zone. Other measures from the 7 Tesla imaging also indicated disrupted microstructure in the patients.

…to changes in neuroinflammation and brainstem activity
The group next turned to a subset of 36 patients who had undergone both DTI as well as PET. The latter is a technique that enables measurement of neuroinflammation, and the researchers used it to ask if the altered microstructure had any relationship to that process, considering previous research showing a role for neuroinflammatory mechanisms in migraine.

That was indeed the case, as there was a negative correlation between FA and the PET signal at the right trigeminal nerve root entry zone: Those with lower FA (more microstructure disruption) displayed an elevated PET signal (more inflammation).

Next up was an experiment with a third imaging modality, called functional MRI (fMRI), which measures changes in blood flow associated with brain activity. Here, the researchers electrically stimulated the right side of the forehead, targeting the ophthalmic trigeminal nerve territory. They asked subjects to rate the intensity of the stimulation before fMRI and while undergoing the electrical stimulation during fMRI. Fifty-eight patients with migraine (including 43 in the interictal phase and 15 in the ictal phase) and 18 healthy controls took part in this experiment. A subset of 51 migraine patients had undergone both DTI and fMRI.

The key result was an association between the fMRI response to the electrical stimulation and right trigeminal nerve root entry zone FA. Specifically, lower FA (more disrupted microstructure) in migraine patients was associated with lower brainstem activation in the spinal trigeminal nucleus (SpV), which mediates craniofacial pain sensation and is one of three sensory nuclei of the trigeminal nerve. This was a surprising finding, Tohyama said.

“On a group level, when you compare migraine patients and healthy controls, we find that migraine patients have hyperexcitability in the SpV. But we found that if you have greater microstructural damage, there’s reduced communication of afference to the SpV, so it’s in the opposite direction of what you would expect.”

While the authors suggest that the microstructural changes could represent a kind of physiological coping mechanism to deal with the hyperexcitability that migraine patients have, the experts who spoke to Migraine Science Collaborative said the idea is speculative, a sentiment with which the authors agree.

Finally, the researchers were intrigued that their imaging findings were strongest for the right trigeminal root entry zone. They hypothesized that perhaps this was because most of the patients might have predominantly right-sided headaches. That turned out to be true. In addition, those with right-sided headaches were more likely to meet the study’s criteria for migraine, and the average migraine pain intensity was higher in those individuals as well. However, the meaning of the laterality findings remains unclear and requires further study.

Remaining questions
All in all, the outside experts who spoke to MSC were impressed with the new work, particularly its technical prowess.

“The most convincing thing is the combination of these very high-resolution advanced technologies in an intelligent way,” said Susanne Wegener, a neurologist and imaging expert at University Hospital Zurich and the University of Zurich in Switzerland. “It’s not easy to do this kind of study,” she added.

Yet like all neuroimaging studies, which are costly and complex to carry out, the new work does have limitations, which the authors acknowledge. For instance, sample sizes were sometimes small, with, for instance, just 10 healthy controls in the PET experiment.

Additional research is also needed to build the case for altered microstructure and accompanying changes in neuroinflammation and brainstem activity as a key migraine mechanism. One study that Maleki said she would like to see is a comparison of the trigeminal root entry zone with another brain region implicated in migraine, as well as with a region not related to migraine.

She also said that having a more homogeneous sample, in terms of headache frequency and headache phenotype, for instance, could advance the story. Still, she said, “this is a great first study.”

Moayedi told MSC that one clear step for future research is to try to reproduce the findings in animal models. That could help address whether the relationships among nerve microstructure, neuroinflammation, and brainstem activity are causal relationships or not, and in what direction the relationships might go.

“Right now we have three cross-sectional findings that are interesting, but whether or not they’re completely related and are driving each other remains unknown,” Moayedi said.

As for Tohyama, she said that how the findings from the imaging experiments might change based on where patients are in the migraine cycle is one of the biggest questions for subsequent studies.

“I think there is a lot of interest in understanding ictal, versus pre-ictal, versus post-ictal imaging findings in relation to those windows. And so that’s something we’re exploring further as we’re collecting more data,” she said.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

Image credit: Rouslan/123RF Stock Photo.

Reference
Trigeminal nerve microstructure is linked with neuroinflammation and brainstem activity in migraine.
Tohyama et al.
Brain. 2025 Jan 28:awaf029. Online ahead of print.