The European Pain Federation (EFIC) and the European Headache Federation (EHF) hosted a special webinar, ‘Bridging the Gap: New Insights on Migraine from Pain and Headache Research’ on 18 June to mark Migraine Awareness Month.
Experts presented and discussed two newly-published studies offering fresh perspectives on migraine mechanisms and clinical management.
EFIC represents approximately 20,000 healthcare professionals and researchers across Europe, while the EHF is a non-profit organisation that works to improve awareness of headache disorders and their impact amongst governments, healthcare providers and consumers across Europe. “Pain is multidisciplinary and is a shared responsibility across multiple [medical] professions. It is really important we have this collaboration,” Sam Kynman, Executive Director at EFIC, commented while introducing the webinar.
Dr Peter Petschner, Assistant Professor, Bioinformatics Centre, Institute of Chemical Research, Kyoto University, Japan, and Department of Pharmacodynamics, Faculty of Pharmaceutical Sciences, Semmelweis University, Budapest, Hungary, outlined the findings and rationale behind his co-authored study, ‘The interictal transcriptomic map of migraine without aura’, which was published in the Journal of Headache and Pain.
The study aimed to deliver a replicable transcriptomic map of migraine without aura (MO) and its comprehensive genome to identify hypotheses for future research and clinical drug discovery.
Previous transcriptomic investigations in MO yielded inconsistent findings and remained detached from existing migraine pathophysiology theories, genetic findings and the method’s potential for drug development, he commented.
For the study Dr Petschner and colleagues recruited 30 controls and 22 MO patients without serious chronic comorbidities/regular medication intake. “We wanted to collect a very homogenous sample…. And we excluded everybody with any other comorbidity other than migraine and comorbid allergy.”
RNA-sequencing was conducted interictally at two different time points to identify replicable differential gene expression and enriched pathways. Subsequent refining and functional analyses were performed, including: 1) testing additional patient factors, 2) running genetic association analysis on migraine in the UK Biobank (UKB) and the study cohort, and 3) predicting drug binding with AutoDock Vina and machine learning to proteins of transcriptomic changes.
“[Outside of the allergy comorbidity findings] we found a lot of pathways that were significant and replicated… and they were related to non-migraine pattern mechanisms,” reported Dr Petschner.
The final results identified differences in the gene CYP26B1 as a key alteration in migraine.
Gene set enrichment analysis identified 88 replicated, significant, exclusively downregulated core pathways, including metabolic, cardiovascular, and immune system-related gene sets and 69 leading genes, like CORIN.
Logistic regression of leading genes and vitamin A pathway-related polymorphisms identified 11 significant polymorphisms in LRP1.
Confirmatory analyses excluded a substantial impact of sex, allergy, and different vitamin A/retinol intake. Binding simulations and predictions pointed to potential future drug molecules, like tetrandrine and probucol.
In summary, the study’s resulting replicable transcriptomic map of MO and functional analyses: 1) identified pathomechanisms related to metabolic, cardiovascular, and immune system-related processes on a molecular level, 2) reported gene level hits, 3) proposed novel potential aetiology, like LRP1-induced decreased retinoic acid signalling, and 4) delivered novel drug candidates for migraine.
The next speaker was Dr Kuan-Po Peng, Neurologist and Headache Specialist, Department of System Neuroscience, University Medical Centre Hamburg-Eppendorf, Germany. His research focuses on exploring the generator of cyclic changes in sensory modalities in migraine and deciphering the mechanism responsible for the efficacy of migraine treatment using psychophysical and functional imaging methods.
The study he discussed was entitled ‘Cycling sensitivity across migraine phases: A longitudinal case–control study’, and was published in the European Journal of Pain.
“How do we predict migraine? Many symptoms start before the actual migraine,” he commented, discussing the rationale for carrying out this study.
Functional neuroimaging studies indicate that central transmission of trigeminal pain may commence up to 48 hours prior to the onset of headache. Whether these cyclic changes are associated with somatosensory alteration remains incompletely understood, hence Dr Peng and colleagues have been researching the area for some time.
The present study aimed to investigate the temporal progression of somatosensory alterations preceding the onset of a migraine attack. Patients with menstrually-related migraine (n=10) and matched healthy controls (n=13) underwent consecutive daily quantitative sensory tests, commencing six days prior to the expected onset of the migraine attack and menstruation. Each subject was investigated for seven-to-11 consecutive days, resulting in 85 and 91 days of experimentation for the respective cohorts.
Electrical/heat/cold pain thresholds showed a phase-dependent decline towards the spontaneous migraine attack, which had commenced 48 hours prior to the onset of the headache. The pain thresholds further declined towards the ictal phase, with only the electrical pain threshold reaching statistical significance (ictal vs pre-ictal).
In healthy controls, the pain thresholds remained stable and unaltered during the consecutive daily measurements. In an exploratory analysis, the pain thresholds at baseline (interictal phase) were comparable between both cohorts.
Dr Peng said the data suggests the existence of a trigeminal somatosensory alteration in the pre-ictal phase of migraine, occurring up to 48 hours prior to the onset of headache. This change occurred in a chronologically synchronous manner with the brain activation in the pre-ictal phase in functional neuroimaging studies.
“As a proof of concept we have shown with clinical behaviour data that the migraine is driven by cycling sensitivity changes as demonstrated by the threshold changes,” he said.
It will be important to combine pain threshold measurement and functional neuroimaging in future studies to identify the generator behind the cyclic sensory fluctuation, ie, the potential cause of the migraine, Dr Peng concluded.
Is their significance for Dr. Penge theory that taking preventative medication could abort the entire episode .