A ‘complex’ of brain metabolites distinguish altered chemistry in the cingulate cortex of episodic migraine patients

Abstract

Despite the prevalence of migraine, the pathophysiology of the disease remains unclear. Current understanding of migraine has alluded to the possibility of a hyperexcitable brain. The aim of the current study is to investigate human brain metabolite differences in the anterior cingulate cortex (ACC) during the interictal phase in migraine patients. We hypothesized that there may be differences in levels of excitatory neurotransmitters and/or their derivatives in the migraine cohort in support of the theory of hyperexcitability in migraine. 2D J-resolved proton magnetic resonance spectroscopy (1H-MRS) data were acquired on a 3 Tesla (3 T) MRI from a voxel placed over the ACC of 32 migraine patients (MP; 23 females, 9 males, age 33 ± 9.6 years) and 33 healthy controls (HC; 25 females, 8 males, age 32 ± 9.6 years). Amplitude correlation matrices were constructed for each subject to evaluate metabolite discriminability. ProFit-estimated metabolite peak areas were normalized to a water reference signal to assess subject differences. The initial analysis of variance (ANOVA) was performed to test for group differences for all metabolites/creatine (Cre) ratios between healthy controls and migraineurs but showed no statistically significant differences. In addition, we used a multivariate approach to distinguish migraineurs from healthy subjects based on the metabolite/Cre ratio. A quadratic discriminant analysis (QDA) model was used to identify 3 metabolite ratios sufficient to minimize minimum classification error (MCE). The 3 selected metabolite ratios were aspartate (Asp)/Cre, N-acetyl aspartate (NAA)/Cre, and glutamine (Gln)/Cre. These findings are in support of a ‘complex’ of metabolite alterations, which may underlie changes in neuronal chemistry in the migraine brain. Furthermore, the parallel changes in the three-metabolite ‘complex’ may confer more subtle but biological processes that are ongoing. The data also support the current theory that the migraine brain is hyperexcitable even in the interictal state.

Atypical functional connectivity between the anterior cingulate cortex and other brain regions in a rat model of recurrent headache

“…18 A molecular-level study revealed altered N-acetyl aspartate/creatinine in the ACC in migraine patients. 19 Taken together, these findings indicate that the ACC plays an important role in the pathogenesis of migraine, especially CM. The ACC is involved in chronic neuropathic pain and its associated anxiety.…”

Magnetic Resonance Imaging in Pediatric Migraine

“…A single case study is not convincing to argue that this is typical of pediatric migraineurs, although several studies of migraine in adults have shown decreased NAA in various regions of the brain; [99][100][101][102][103] one study observed an increase in NAA in the pons in episodic migraineurs, 104 and many studies have not observed any differences in NAA levels in various regions of the brain. 84,85,97,[105][106][107][108][109][110][111][112][113][114] Location, in addition to type of migraine, and migraine severity may also confound results and explain some of these discrepancies. A recent review argued that, instead of indicating neuronal loss, these reductions in NAA could indicate mitochondrial dysfunction, as mitochondria are proposed to synthesize NAA.…”

Correlation of neurochemical and imaging markers in migraine

“…Magnetic resonance spectroscopy studies demonstrated neurochemical differences mainly in the cingulate and occipital cortices in patients with migraine. 6,7 Functional MRI studies found altered activation in regions related to pain processing, and the activity of resting-state networks was also shown to be altered in migraine. 8 Several diffusion tensor imaging (DTI) studies found microstructural abnormalities of the white matter in patients with migraine in pathways related to pain sensation 9 and visual processing.…”