Plasma lipid metabolism exemplifies the interoceptive nature of chronic migraine
Authors: Fonteh Alfred Nji , Castor Katherine , Arakaki Xianghong , Woldeamanuel Yohannes , Cowan Robert , Harrington Michael 
Published: April 2020

BackgroundMigraine is an example of an interoceptive disorder that is characterized by complex interactions between the central and peripheral nervous systems and the whole body physiology. The major central events include cortical spreading depression, amplified neuronal excitability, and dysfunction of several ion channels. These pathophysiological changes that are associated with disabling head pain may be accompanied by several body‐wide comorbidities; cardiovascular, respiratory, neurological, osteoarthritis, obesity, allergies, depression, and other psychiatric conditions. Different physiological body systems involving hormonal regulation, neurotransmitter/receptor signaling, inflammation, and oxidation may connect the interoceptive signals of chronic migraine (CM) with its comorbidities. The aim of our study is to determine if lipid metabolism is a common signaling event that underlies chronic migraine (CM) and its comorbidities.MethodsWe enrolled healthy control volunteers (CT, n=10) and CM study participants (n=15) in an IRB‐approved study. CM participants were diagnosed using the International Classification of Headache Disorders‐3ß (ICHD3ß) criteria. Plasma unesterified (UFA) and esterified fatty acids (EFA) were quantified using gas chromatography‐mass spectrometry. The groups of fatty acids detected in plasma included even chain saturated fatty acids (ecSAFA), odd chain SAFA (ocSAFA), even chain monounsaturated fatty acids (ecMUFA), odd chain MUFAs (ocMUFA), omega‐3 (n‐3), and omega‐6 (n‐6) polyunsaturated fatty acids (PUFA).ResultsUnesterified levels of three even chain ecSAFA, two ocSAFAs, the sum of ecSAFAs, sum of SAFAs, six ecMUFA, 2 ocMUFAs, five n‐3 PUFA, and five n‐6 PUFAs are higher in plasma from CM patients. The sum of all UFAs is significantly elevated in CM. Esterified levels of two ecSAFAs, sum of ecSAFAs, one ocSAFAs, the sum of all SAFAs, five ecMUFAs, three ocMUFAs, five n‐3 PUFAs, sum of n‐3 PUFAs, and three n‐6 PUFAs, are higher in CM plasma. For both UFA and EFA, only the C16:1 composition was significantly higher in CM plasma. The ratios C16:1/C16:0 and C20:4n‐6/homo‐γ‐C20:3n‐6 representative of delta‐9 and delta‐5 desaturases, respectively, are higher in CM. PHQ‐9 depression scores were lower (p =0.0041) in CT (3.6 ± 2.2) compared with CM (10.4 ± 5.9). Depression scores directly correlated with esterified nervonic acid (C24:1) and lignoceric acid (C24:0) levels.ConclusionOur studies show that plasma fatty acids are differentially metabolized in chronic migraine participants compared to healthy controls. Furthermore, plasma lipid metabolism is correlated with depression in chronic migraineurs. We propose that the complex interplay between brain‐energy regulation and the mobilization of lipids from adipose tissues is central to the interoceptive nature of chronic migraine. Therefore, understanding the key hormonal pathways, major enzymes, and signaling pathways will be crucial in unlocking complex migraine mechanisms and discovering better therapies.Support or Funding InformationRecruitment and sample collection at Stanford University School of Medicine was supported by generous gifts from the Higgins Family Trusts. Lipid analyses was supported by NIH 5R01NSO72497 and HMRI.