Genetic contribution of catechol‐O‐methyltransferase in hippocampal structural and functional changes of female migraine sufferers

Abstract

Physiological and emotional stressors are associated with or provoke each migraine attack and cause structural and functional changes in the central nervous system. The hippocampus, a limbic structure important in anxiety-related behavior, is vulnerable to long-term stress. Given that catechol-O-methyltransferase (COMT) is widely distributed in the hippocampus and its genetic variation is thought to contribute to the interindividual variability in pain perception and anxiety regulation, whether or not migraine and COMT val(158) met genotype have an interactive effect in the key brain area related to maladaptive stress, the hippocampus, is still poorly understood. Using T1-weighted and resting functional MRI, we evaluated the effect of COMT genetic variations on migraine and possible interactions between COMT and the disease in brain structure and function in 135 females with migraine without aura (MWoA) and 111 matched health controls (HC). Optimized voxel-based morphometry (VBM) and functional connectivity (FC) analyses were applied. From the whole brain VBM analysis, we found a significant disease × genotype interaction in the hippocampus, which overlapped with disease-related increase of gray matter (GM) in val homozygote migraineurs. In our results, increased GM in the hippocampus was only found in val homozygote MWoA compared to val homozygote HC. Moreover, FC between the hippocampus and the medial prefrontal cortex was significantly decreased in val homozygotes, and it was negatively correlated with self-rating anxiety scale values.Our results indicated that brain structure and function of the hippocampus are differentially affected by migraine in val homozygotes compared with met carriers.

Sex‐based differences in brain alterations across chronic pain conditions

“…In addition, patients with dysmenorrhea demonstrate greater menstrual-related increases in primary somatosensory cortex gray matter volume compared to female healthy controls (Tu et al 2013). Furthermore, additional primary sensorimotor cortical alterations including connectivity, intrinsic activity, reactivity, and perfusion have been noted in female-specific chronic pain studies (Arkink et al 2012; Burgmer et al 2012; Ellingson et al 2012; Guedj et al 2008; Guedj et al 2007; Gupta et al 2015; Kamping et al 2013; Kilpatrick et al 2014; Kim et al 2013; Lee et al 2013; Liu et al 2015a; Liu et al 2015b; Pujol et al 2014; Rahm et al 2015; Tu et al 2009). …”

Pathophysiological Bases of Comorbidity in Migraine

“…Interestingly, a specific involvement of these regions has been demonstrated in migraine patients with anxiety or depression. Functional alterations of the hippocampus (Liu et al, 2015 ) and thalamus (Wei et al, 2019 ) have been associated with the presence of anxiety in patients with migraine. Using diffusion tensor imaging, a technique that allows exploring the microstructure of brain WM tracts in vivo , Li and colleagues (Li et al, 2011 ) have shown alterations of the corpus callosum in migraine patients with anxiety or depressive disorder.…”

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

“…2-ME is synthesized by hydroxylation and subsequent O-methylation catalyzed by catechol-O-methyltransferase (COMT) [11,12]. COMT is widely distributed in the hippocampus where it catabolizes the catecholamine neurotransmitters and influences cognitive function, regulates dorsal hippocampal neurochemistry, and modulates hippocampusdependent behaviors [13,14]. Thus, 2-ME may be a metabolite of E2 also in brain structures.…”