GABA and glutamate in pediatric migraine

Abstract

Migraine is one of the top 5 most prevalent childhood diseases; however, effective treatment strategies for pediatric migraine are limited. For example, standard adult pharmaceutical therapies are less effective in children and can carry undesirable side effects. To develop more effective treatments, improved knowledge of the biology underlying pediatric migraine is necessary. One theory is that migraine results from an imbalance in cortical excitability. Magnetic resonance spectroscopy (MRS) studies show changes in GABA and glutamate levels (the primary inhibitory and excitatory neurotransmitters in the brain, respectively) in multiple brain regions in adults with migraine; however, they have yet to be assessed in children with migraine. Using MRS and GABA-edited MRS, we show that children (7-13 years) with migraine and aura had significantly lower glutamate levels in the visual cortex compared to controls, the opposite to results seen in adults. In addition, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with higher migraine burden. We also found that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with duration since diagnosis, i.e., having migraines longer. Lower GABA levels in the sensorimotor cortex were associated with being closer to their next migraine attack. Together, this indicates that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that evidence from adults with migraine cannot be immediately translated to pediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in development of more effective treatments.

Figure 1.

Example voxel placement (top row) and overlay of all (migraine and control) MEGA-PRESS (middle row) and PRESS spectra (bottom row) for (A) thalamus, (B) sensorimotor cortex, and (C) visual cortex.

Figure 2.

Group comparisons of (A): Glx levels (F(1, 51) = 0.241, P = 0.626); (B): Glu levels (F(1, 51) = 0.001, P = 0.974); (C) GABA levels (F(1, 49) = 0.431, P = 0.515); and (D) GABA/Glx ratios (F(1,48) = 2.950, P = 0.092) in the thalamus. Each circle represents an individual subject.

Figure 3.

Group comparisons of (A) Glx levels (F(1,50) = 0.870, P = 0.356); (B) Glu levels (F(1, 50) = 1.047, P = 0.311); (C): GABA levels (F(1, 49) = 0.927, P = 0.340); and (D) GABA/Glx ratios (F(1, 47) = 1.258, P = 0.268) in the sensorimotor cortex. Each circle represents an individual subject.

Figure 4.

Group comparisons in (A): Glx levels (F(1, 48) = 1.989, P = 0.165); (B): Glu levels (F(1, 48) = 2.812, P = 0.100); (C): GABA levels (F(1, 48) = 0.582, P = 0.449); and (D) GABA/Glx ratios (F(1, 47) = 1.276, P = 0.264) in the visual cortex. Each circle represents an individual subject.

Figure 5.

Glu levels in Migraine with and without aura, and Controls. Migraine with aura had significantly lower glutamate levels in the visual cortex compared to Control (P = 0.019). There was no significant difference between Migraine without aura and control (P = 0.135) or between the Migraine with and without aura groups (P = 0.324).

Figure 6.

Associations between migraine characteristics and neurochemical levels. (A) Positive correlation between Glu in the thalamus and the number of years with migraine, controlling for age (r(18) = 0.532, P = 0.016). (B) Negative correlation between the GABA/Glx ratio in the thalamus and the number of years with migraine, controlling for age (r(17) = −0.456, P = 0.05). (C) Positive association between GABA in the thalamus and the PedMIDAS score, controlling for age (r(23) = 0.370, P = 0.068). (D) Positive correlation between GABA in the sensorimotor and the PedMIDAS score, controlling for age (r(24) = 0.514, P = 0.007). (E) Positive association between GABA in the visual cortex and the PedMIDAS score, controlling for age (r(22) = 0.361, P = 0.084). Gray shading indicates the 95% confidence intervals on the partial correlations.

Figure 7.

Negative correlation between levels of GABA in the thalamus and the position of the child in their migraine cycle, controlling for age (r(16) = −0.499, P = 0.035).