GABA and Glutamate in Pediatric Migraine

Tiffany Bell; Mehak Stokoe; Akashroop Khaira; Megan Webb; Melanie Noel; Farnaz Amoozegar; Ashley D. Harris

Disclosures

Pain. 2020;162(1):300-308. 

In This Article

Discussion

To the best of our knowledge, this is the first study to measure GABA and glutamate in pediatric migraine and one of only a few studies on migraine to consider multiple voxel locations. We found (1) migraine with aura had significantly lower Glu levels in the visual cortex compared to controls; (2) metabolite levels in the migraine group correlate with migraine characteristics; and (3) the migraine group had a higher GABA:Glx ratio in the thalamus as compared to the control group (although this did not reach statistical significance), which was primarily driven by an increase in GABA.

It has been suggested that increased glutamate is a driving force behind migraine, which is supported by the literature showing increased Glu[19,55] or Glx[2,7] in migraine in adults, including the analysis of populations of migraine with or without aura. In the one other study directly comparing glutamate levels in the visual cortex between migraine with and without aura,[55] the migraine without aura group had significantly higher Glu levels than the control group. Although the migraine with aura group also had higher levels than controls, this did not reach statistical significance. By contrast, we found a decrease in glutamate levels in the visual cortex of migraine with aura, and a trend towards decreased glutamate in migraine without aura compared to controls.

Aura in children is difficult to assess but is generally thought to have a similar presentation in adults and children.[28] Aura is thought to be caused by hypoperfusion in the occipital lobe,[18] and those who suffer from migraine with aura show higher cortical responsiveness and higher resting-level functional connectivity in the visual cortex compared to those who suffer from migraine without aura and healthy controls.[41] Therefore, our finding that children with migraine and aura show a greater difference to controls than children without aura is in line with the evidence from other imaging modalities. However, the finding of decreased levels of glutamate is unexpected, and may be a contributing factor as to why medications that are effective in adult migraineurs are not as effective in children.[38] This opposite finding emphases the need to study migraine biology in young, pediatric samples.

A change from lower glutamate levels in pediatric migraine to higher glutamate levels in adult migraine may be a result of development. Cortical excitability is known to decrease over time through pruning of glutamatergic synapses. Contingent negative variation, a measure of cortical excitability, has been shown to decrease from childhood to adulthood. Interestingly, contingent negative variation in migraine patients does not decrease as much over time as in healthy controls or in migraine patients who went into remission.[43] This implies migraine progression is related to alterations in cortical development. Synaptic pruning is triggered by GABA receptors, which increase in number at pubertal onset.[36] Subsequently, GABA alterations early in development may produce future glutamatergic alterations. Therefore, increasing our understanding of early migraine biology in pediatrics has important implications for developing targeted, early interventions, a crucial step into reducing migraine impact throughout the lifespan.

Many suggest hormonal changes are a pivotal factor in migraine due to dramatic changes in prevalence between males and females. Before puberty, there is slightly higher prevalence of migraine in males, whereas after puberty, prevalence increases dramatically in females, affecting roughly 2 females:1 male,[31] but the mechanism behind this change is not clear. We suggest the aforementioned GABA and glutamate changes are important factors. However, due to the narrow age range used in this study, the majority of participants were classed as in the pre/early stages using the pubertal status questionnaire. Therefore, although it is likely that puberty has a modulatory effect on brain development and migraine, these effects are minimized here.

In addition to higher glutamate, a recent systematic review demonstrated that adults with migraine showed higher levels of GABA in various cortical and subcortical regions.[37] In the thalamus, we found GABA/Glx to be higher in Migraine, primarily driven by higher GABA, although group comparisons did not reach statistical significance. Higher GABA levels are thought to reflect an increased inhibitory tone. Indeed, there is evidence of reduced thalamic activity in adults with migraine in between attacks,[51] which may be due to an increase in inhibition. Within the Migraine group, we found an association between higher GABA levels and higher migraine burden (measured by the PedMIDAS) in all 3 areas (although only the sensorimotor cortex reached statistical significance), indicating that children with higher GABA levels are more affected by their migraines. These higher GABA levels may reflect a compensatory mechanism in response to multiple migraines or hyperexcitability associated with migraine. We also show that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex are associated with duration since diagnosis, i.e., having migraines longer, even when controlling for current age. This suggests that these imbalances may develop over time. Indeed, there is evidence that alterations in GABA receptors influence the age of onset of migraine,[16] and adults who have suffered from migraine longer have an increased inability to habituate to stimuli.[29] Taken together, we speculate migraine is a progressive disorder leading to more irregularities in cortical excitability with development. This highlights the potential impact of early targeted interventions on migraine progression.

To control for variations in the length of each individual's migraine cycle, we created a novel metric to show, proportionally, how far a person was through their migraine cycle. This means the position in the cycle, along with changes in the brain associated with this, can be compared across people more accurately than simply looking at the number of days since their last migraine because the duration between migraines varies between people. We found that children in the migraine group with lower GABA levels in the thalamus were further in their migraine cycle, or closer in time to the next migraine. This suggests that, as the migraine cycle progresses, there is a reduction in GABAergic inhibition in the thalamus, which we speculate has a mechanistic role in the development of a migraine. Evidence in adults shows an increase in cortical excitability as the migraine cycle progresses. Cortese et al. (2017) showed a negative correlation between the resting motor threshold and the time elapsed since the last attack; as the days since the last attack increased, the resting motor threshold decreased, indicating an increase in excitability in the motor cortex. Coppola et al. (2016) showed that a reduction in lateral inhibition in the somatosensory cortex was associated with a higher number of days elapsed since the last attack. These changes in cortical excitability may be driven by changes in thalamic activity or excitability over time, evidenced in the alterations in GABA levels seen here.

A limitation of this study is that our sample generally scored less than 30 on the PedMIDAS scale, indicating migraine had a mild impact on their life. Although this may represent an abundance of migraine sufferers and may reflect the typical impact of migraine in this younger sample, it is unknown whether the findings here generalize to more severe migraines that require intensive clinical management. As we see relationships between GABA levels and PedMIDAS scores, it is possible that group differences in GABA may have been detected if our migraine sample had a higher migraine burden. In addition, the cross-sectional design of this study limits the conclusions that can be drawn; for example, although we show a relationship between GABA and migraine burden, it is unknown if GABA will increase in those whose migraine burden increases. It should also be noted that the relationship between neurotransmitter levels measured at rest using MRS and excitability of the cortex is poorly understood, with mixed findings regarding the relationship between MRS and TMS measures of excitability.[13,47] Subsequently, the conclusions regarding migraine physiology that can be drawn from this study are limited. Future studies would benefit from comparing both MRS and TMS measures in children with and without migraine.

A strength of this study is the use of a macromolecule-suppressed GABA acquisition, providing increased specificity of GABA, without the contamination of macromolecules, which can account for roughly half the GABA signal in a typical MEGA-PRESS acquisition.[20,22] However, a large voxel is needed to offset the inherent low signal-to-noise ratio for GABA,[33] resulting in partial volume effects. Tissue correction has been applied to control for metabolite relaxation effects;[34] however, the voxel will contain tissue from areas surrounding the area of interest, for example, the sensorimotor voxel contains signal from both sensory and motor regions.

In conclusion, we show alterations in excitatory and inhibitory neurotransmitter levels in children with migraine, and that these measures are associated with migraine characteristics. We show that higher GABA levels are associated with higher migraine burden, in line with the adult literature. We also show a reduction in glutamate levels in the visual cortex, the opposite of findings in adults. This highlights the need for further mechanistic studies of migraine in children, to aid in the development of more effective treatments.

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