Metabolic abnormalities in the insula of patients with interictal migraine without aura: a prospective cross-sectional study

The insula plays a crucial role in the pathophysiology of patients with migraine without aura (MWoA), but the exact neurometabolic mechanisms are still unclear. This study aimed to explore possible neurometabolic mechanisms in the insula during the interictal period in MWoA patients, and neurometabolic differences between high frequency (HF) and law frequency (LF) headache patients via proton magnetic resonance spectroscopy (1H-MRS). A total of 22 MWoA patients and 22 age-, gender-, and education-matched healthy controls (HCs) were included in this prospective cross-sectional study. The subjects underwent routine T1-weighted imaging (T1WI) and single-voxel 1H-MRS scans, with the region of interest fixed in the left insula. Metabolites, including myo-inositol (Ins), N-acetyl aspartate (NAA), choline-containing compound (Cho), creatine and phosphocreatine (Cr), glutamate and glutamine (Glx), were quantified via the linear combination model (LCModel) software, and then corrected for the partial volume effect of cerebrospinal fluid (CSF). The MWoA patients were categorized into LF and HF headache groups according to their headache frequency. Metabolic differences between the groups were tested by an analysis of covariance (ANCOVA), and the clinical relevance of these metabolites was analyzed by Pearson or Spearman correlation analyses. During the interictal period of headache, the Ins (MWoA vs. HCs: 5.16±1.14 vs. 6.21±1.14, P=0.017), NAA (MWoA vs. HCs: 5.70±1.23 vs. 6.59±1.12, P=0.015), and Glx (MWoA vs. HCs: 12.88±1.63 vs. 14.36±2.17, P=0.020) concentrations were significantly decreased in the insula of the MWoA patients compared to the HCs. Further, the HF headache patients had obviously higher Cr levels than the LF headache patients (HF vs. LF: 6.16±0.67 vs. 6.01±0.91, P=0.037). The headache frequency of the MWoA patients was positively correlated with the headache-attributed lost time-90 days (HALT-90) scale (r=0.560, P=0.010) and Hamilton Depression Rating Scale (HAMD) (r=0.529, P=0.017) scores. In addition, a higher HALT-90 score was associated with a higher Cho level in the MWoA patients (r=0.654, P=0.002). The dysfunction or loss of neurons and glial cells, and excitatory neurotransmitter conversion imbalance may be the key changes in the insula of interictal MWoA patients. HF headaches are characterized by hypometabolism, which may be caused by more serious mitochondrial dysfunction.