Clinical Studies Update: A Wide Range of Research for the Start of 2025

Recent work spans from hemiplegic migraine to classification of aura, from microRNAs to trigeminal nerve microstructure, and more.

Editor’s note: This is MSC’s latest update on recent clinical studies that we think will be of interest to our readers. The studies described below all appeared in January or February of 2025.

Learning more about hemiplegic migraine

Hemiplegic migraine was the focus of two recent clinical studies. In the first, published in Cephalalgia, researchers in Denmark looked at how variants in three genes – CACNA1A, ATP1A2, and SCN1A – associated with familial hemiplegic migraine (FHM) and epilepsy affected the risk of migraine, and the risk of epilepsy. The group refers to their work as taking a “genotype-first approach” because the study starts with genetic data and then examines potential associations of genes with migraine and with epilepsy. That is in contrast to a phenotype-first approach, which begins with patient symptoms and then characterizes the genetic profile of patients with those symptoms.

The group had data from whole-exome sequencing of more than 450,000 people in the UK Biobank database; whole exome sequencing is when all the protein-coding regions of genes are sequenced. They found an increased risk of migraine (based on in-patient diagnosis or self-report), but not epilepsy, in those who had certain heterozygous mutations in CACNA1A, ATP1A2, or SCN1A; heterozygous mutations are those in which one allele of a gene is mutated and the other is normal. In contrast, those who had homozygous mutations (mutations in both alleles) in SCN1A had an increased risk of migraine but a lower risk of epilepsy.

“These findings offer significant advancements in our understanding of the genetics of migraine and epilepsy, and enhance future ability to provide … effective, targeted and personalized care for migraine patients,” the researchers concluded.

Meanwhile, a different study, published in Neurology Genetics, followed children with hemiplegic migraine (HM) related to variants of the CACNA1A gene. The goal of this longitudinal investigation, a small study with 15 subjects from the ages of 3 to 23 and based on electronic medical records, was to see how the course of the disease may change over time throughout childhood.

Results indicated no clear patterns for when HM events occurred nor for how severe they were (overall, 25% of HM events were severe, with 75% of individuals having at least one severe HM in their lifetime). There was also no strong correlation between the severity of epilepsy, a condition that has also previously been linked to CACNA1A, and the frequency and severity of HM events. Most study participants had co-morbidities like epilepsy, neurodevelopmental traits, and brain atrophy, making treatment of HM more challenging.

“Our study emphasizes the unpredictable nature of HM with risk of future events in affected individuals that may present as severe, resulting in life-threatening consequences that require immediate intervention,” the authors concluded. “Triggers are largely unknown, with mild head trauma as an inconsistent trigger. Accordingly, in our clinical practice, we recommend that individuals with a CACNA1A variant that has potential to cause HM should be provided an action plan for HM and guidance to treat all HM events as if they could be severe.”

Better terminology for and classification of aura

Migraine with aura is a well-known subtype of migraine, where people experience symptoms including visual, somatosensory, motor, and verbal disturbances. Migraine, however, is not the only disorder where aura can be present, and so researchers behind a recent review from The Journal of Headache and Pain have proposed a new classification of aura based on its clinical etiology (rather than on its pathological cause, cortical spreading depression).

These investigators are proposing a four-part classification: Migrainous aura, to refer to aura whose clinical etiology is migraine; non-migrainous aura, where a different clinical etiology exists; aura of uncertain clinical etiology; and migrainous infarction, where the migraine aura is associated with an infarction in a corresponding brain region. The researchers say they intend for this classification system to harmonize with International Classification of Headache Disorders (ICHD)-3 criteria for diagnosing migraine with aura, and perhaps could be integrated into future ICHD-3 updates.

Why does this all matter? “In the ever-evolving field of neurology,” the study authors wrote, “refining our terminology is paramount to promoting effective communication, improving clinical care, advancing scientific research, and fostering global collaboration. Clear definitions are critical for accurate phenotyping of different clinical entities, which is a crucial step for translational mechanistic research.”

Anti-CGRP treatment and cardiovascular safety

Several papers have been published recently on the effects of migraine treatment on the cardiovascular system (see previous MSC clinical update here). A new study from JAMA Neurology keeps the focus on this area by addressing the impact that anti-CGRP monoclonal antibodies (mAbs) may have on cardiovascular safety.

The research included more than 9,000 people with migraine who were on Medicare health insurance and started the antibodies. The investigators compared them to Medicare beneficiaries who initiated onabotulinumtoxinA. Most subjects were older (an average age of 58 to 62 years) or had disability status, and were mostly female and White. How long it took for subjects to experience their first myocardial infarction or stroke served as the study’s primary outcome.

No differences were seen between groups in the primary outcome, including when considering MI and stroke as a composite outcome, or when evaluating MI and stroke risk separately. Nor were there differences in a number of secondary outcomes, including hypertensive crisis, peripheral revascularization, or Raynaud phenomenon.

The researchers wrote that one notable aspect of the study is the inclusion of older adults and those with disability status, since those individuals are underrepresented in randomized trials.

“It is imperative to thoroughly assess CVD [cardiovascular disease] events associated with anti-CGRP mAbs compared to other migraine treatments, particularly among individuals at high risk of CVD,” the authors wrote in their discussion. “Our findings indicate no significant differences in the risk of CVD events between those initiating anti-CGRP mAbs and onabotulinumtoxinA. This suggests that anti-CGRP mAbs can be considered a viable option for preventing migraine in older adults and patients at high risk of CVD.”

MicroRNAs and migraine

MicroRNAs (miRNAs) are small, single-stranded, non-coding RNA molecules that control gene expression – the turning on or off of genes. A recent study, published in Brain, of more than 300 participants sought miRNA “signatures” that might distinguish people with episodic migraine from healthy controls, and that might also reflect different stages of migraine, including interictal migraine, ictal migraine, and chronic migraine.

The authors reported microRNA signatures that were higher or lower in subjects with migraine, compared to controls. And, interestingly, four different miRNA signatures were differentially expressed only during the ictal stage of episodic migraine, and not during interictal or chronic migraine, again compared to controls. Additional analysis pointed to prolactin and estrogen as key mediators of these differences. The team also used data on the genetic susceptibility to migraine and created a prediction model that combined those data with the miRNA findings. They found that this composite microRNA-genetic risk score (GRS) model did well at differentiating those with migraine from controls.

“[B]y combining genetic information, we established composite miRNA-GRS models that could differentiate patients from controls with high accuracy, heralding the promising future of integrating genetic and miRNA information to formulate precision medicine in migraine,” according to the authors in their discussion.

Goings-on in the trigeminal nerve during migraine

In a new study published in Brain, researchers combined a number of the latest imaging techniques to investigate white matter microstructure, and inflammation, of the trigeminal nerve, and activation of the brainstem, during migraine. This work, which included 60 people with migraine and 20 healthy controls, identified differences in these measures. Overall, the multimodal imaging approach was a key strength of the study, showing that it can be used to study trigeminal nerve microstructure.

Those with migraine exhibited reduced fractional anisotropy, a structural magnetic resonance imaging (MRI) measure that reflects the integrity of white matter, in this case in the root entry zone of the trigeminal nerve. Accompanying that change was elevated inflammation at the root entry zone, as indicated by positron emission tomography (PET) imaging. Finally, according to results from another MRI technique (functional MRI), those with migraine showed less activation in the spinal trigeminal nucleus in response to innocuous electrical forehead stimulation targeting the ophthalmic trigeminal nerve territory.

These findings, which indicate both structural and functional changes of the trigeminal nerve in people with migraine, “are compatible with the trigeminovascular hypothesis of migraine, demonstrating the fundamental role of the trigeminal nerve in this complex and difficult-to-treat neurological disorder, and supporting a linkage between peripheral and central factors,” the authors wrote.

A review on a neglected topic

Women are much more likely to have migraine than men – but men have it, too. A recent review article published in The Journal of Headache and Pain draws attention to this issue. The authors discuss the clinical presentation of migraine in men, and pathophysiological differences between men and women, including differences in brain structure, the trigeminovascular system, and pain modulation and processing.

The work also looks at the role of sex hormones in men, as well as treatment aspects specific to men, among many other topics. For an up-to-date perspective on a wide range of considerations of migraine in men, this review will serve readers well.

Suicide and headache

A paper from JAMA Neurology presented results from a population-based cohort study addressing the risk of attempted suicide, and completed suicide, in people diagnosed with headache disorders including migraine, tension-type headache (TTH), trigeminal autonomic cephalalgias (TACs), and post-traumatic headache disorder. The research included nearly 120,000 people with headache (70% female) and nearly 600,000 matched controls without headache.

Attempted and completed suicide risk was consistently elevated in those with headache. The 15-year absolute risk of attempted suicide in the headache group was 0.78%, compared to 0.33% in the matched control group. The 15-year absolute risk of completed suicide was 0.21% in the headache group versus 0.15% in the control group. The researchers also found that the risk of attempted and completed suicide was consistently elevated over time, not only at 15 years but at five and 10 years as well.

Additional analyses showed that those with headache were roughly twice as likely to have attempted suicide, and approximately 1.5 times as likely to have completed suicide, compared to controls. Overall, all types of headache were associated with an increased risk of attempted and completed suicide, though the associations were strongest for the TACs and post-traumatic headache.

The research extends previous observations about suicide risk to a broader range of headaches, as the authors wrote. “The risk of suicide associated with migraine and TACs, such as cluster headache, is widely recognized. Our results further suggest a strong and persistent association with attempted and completed suicide across headache disorders including TTH—a highly prevalent primary headache disorder typified by its mild to moderate intensity—suggesting that even patients with milder headaches may experience elevated suicide risk.”

 If you are having thoughts of suicide, call or text 988 to reach the 988 Suicide & Crisis Lifeline. For those who live outside of the US, visit the International Association for Suicide Prevention to find a helpline.

An inflammatory component of cluster headache

Researchers in Denmark are building the case for the immune system’s role in cluster headache (CH). In work published in Annals of Neurology, the team performed a prospective case-control study looking at plasma levels of almost four dozen cytokines in patients and matched controls. The study included those with chronic CH (CCH), individuals with episodic CH (ECH) in bout, and people with ECH in remission.

The team saw changes in 13 cytokines in the ECH in bout group, three in the ECH in remission group, and 10 in the CCH group compared to controls. The authors drew attention to oncostatin M, which was elevated in all of the CH groups. Oncostatin M, a cytokine belonging to the interleukin-6 family, is known to be involved in pain, and its receptor is present in the trigeminal ganglion. Meanwhile, tumor necrosis factor superfamily [TNFSF] 12 was lower in all three types of CH compared to controls. Further, the group emphasized the finding of distinct patterns of changes in cytokines between CCH and ECH in bout, particularly in interleukin-1 beta (IL-1β), which was associated with CCH but not ECH in bout.

“Despite CH attacks presenting identically in ECH in bout and in CCH,” the authors wrote, “we observed distinct alterations of the immune system between ECH in bout and CCH, showing that the direction of upregulation and downregulation seems [to be] in opposing directions. In addition, higher IL-1β was associated with chronic, rather than ECH in bout. The clinical implication needs further research, but the finding could further our understanding of the observed differences in preventive treatment response and of the transition between ECH and CCH.”

Efficacy of gepants for acute treatment in males

A secondary analysis of eight randomized clinical trials testing ubrogepant or atogepant, two CGRP receptor antagonists, in people with migraine is the focus of a recent study in Cephalalgia. The key finding was that both females and males showed similar responses to these gepants for acute and preventive treatment of migraine.

“It has been suggested that the available data do not support the effectiveness of CGRP receptor antagonists (ubrogepant, rimegepant, and zavegepant) for the acute treatment of migraine in males. [In the new study], [t]he available data provide evidence that the CGRP receptor antagonists ubrogepant and atogepant show similar efficacy in the acute and preventive treatment of migraine, respectively, in males and females,” the authors wrote in their discussion.

A new non-pharmacological treatment

The migraine field has seen some notable success in developing new drugs to treat the condition, most notably with the advent of anti-CGRP therapies. But a need for non-drug treatments remains, considering the many patients who don’t respond to currently available drugs, who may have undesirable side effects, or who may simply prefer non-pharmacological treatments.

Along those lines, a recent randomized trial published in Neurology reports positive results of the Chordate System, which delivers kinetic oscillation stimulation. The idea behind this neuromodulation approach is that the delivery of mechanical pressure, using an inflated catheter and vibration, into the nasal cavity produces cranial autonomic symptoms, thereby modulating the trigemino-autonomic reflex.

This double-blind trial in patients with chronic migraine (CM) found that the intervention produced a significantly greater reduction in monthly headache days, the study’s primary endpoint, compared to sham (no vibration) treatment (-3.5 days vs. -1.2 days), both throughout six weeks of active treatment and during a four-week follow-up period. The headache group included 67 subjects, with 65 subjects in the sham group. Adverse events were similar between groups.

“The Chordate [S]ystem may therefore represent a valuable addition to the therapeutic portfolio of preventive treatments for CM, and due to its nonpharmacologic mechanism of action, it is particularly suitable for patients who are worried about systemic side effects,” the authors concluded.

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

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