Selective reduction of thalamic glutathione in migraine in the absence of detectable N-acetylaspartate alterations.

Abstract

Background: Oxidative stress has been implicated in migraine pathophysiology, but direct evidence of brain antioxidant alterations and their relationship to neuronal integrity remains limited.

Methods: We conducted a cross-sectional proton magnetic resonance spectroscopy (¹H-MRS) study measuring seven metabolites in a single thalamic voxel of 131 participants (left or right, selected for spectral quality): 36 healthy controls, 46 migraines without aura, 17 migraines with aura, and 32 tension-type headache patients.

Results: Glutathione (GSH) was the only metabolite showing significant group differences (Welch's F = 31.74, p < 0.001, η² = 0.432). Thalamic GSH was reduced in migraine without aura (1.76 ± 0.16) and migraine with aura (1.70 ± 0.13) compared to healthy controls (2.07 ± 0.20), with large effect sizes (Cohen's d = 1.70 and 2.14, respectively). N-acetylaspartate (NAA), a marker of neuronal integrity, showed no group differences (p = 0.74). Equivalence testing showed that the GSH-NAA correlation was statistically equivalent to zero within predefined bounds (TOST p = 0.015), indicating that GSH reduction occurred in the absence of a detectable linear association with NAA in this sample. GSH demonstrated good diagnostic performance (AUC = 0.895, 95% CI 0.821-0.952; sensitivity 93.7%; specificity 69.4%), validated by permutation testing (p = 0.001).

Conclusions: These findings indicate selective thalamic GSH reduction in migraine in the absence of detectable NAA alterations. These observations are consistent with reduced thalamic antioxidant capacity that is not accompanied by measurable neuronal loss, although NAA cannot exclude subtle neuronal or synaptic dysfunction. Thalamic GSH may represent a candidate biomarker that requires independent validation, and the potential of antioxidant strategies remains hypothesis-generating.