Gaba and Glutamate Changes in Pediatric Migraine

Abstract

Despite migraine being one of the top five most prevalent childhood diseases, a lack of knowledge about pediatric migraine limits effective treatment strategies; standard adult pharmaceutical therapies are less effective in children and can carry undesirable side-effects. Non-pharmacological therapies have shown some success in adults; however, to appropriately apply these in children we need to understand pediatric migraine's underlying biology. 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. Although there is indirect evidence of abnormal excitability in pediatric migraine, GABA and glutamate levels have yet to be assessed.The purpose of this study was to measure levels of GABA and glutamate in the thalamus, sensorimotor cortex and visual cortex of children with migraine using MRS. We found that children with migraine and aura had significantly lower glutamate levels in the visual cortex as compared to control children, opposite to results seen in adults. Additionally, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with a 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 paediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in the development of more effective treatments.

Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain

“…Firstly, the higher GABA+ levels observed in the migraine group compared with controls in this study were hypothesized a priori and are consistent with previous data. Previous data demonstrating this same increase in GABA/GABA+ in migraine includes pooled data from our meta-analysis, a recent high-quality study in a pediatric cohort 5 and our previous cohort study. 2 Conversely, decreased GABA+ has been reported in a single study of people with migraine 9 and related to headache severity 7 in another.…”

“…We can speculate that the increased level of GABA+ observed in the pain groups could potentially be explained by 2 proposed mechanisms. Firstly, increased GABA+ could be reflective of an adaptive response developed over time in response to pain, as proposed by Bigal et al 7 and supported by Bell et al 5 All the included participants were experiencing chronic pain of over 3 months in duration: migraine (median [IQR], 18 years, [10.5 to 25 years]), whiplash-headache (2.7 years [1.5 to 4 years]) and low back pain (5 years [2 to 12 years]). It is therefore possible that the central nervous system has affected the metabolism of GABA, the main inhibitory neurometabolite of the central nervous system, in response to the ongoing levels of pain experienced by the participant.…”

“…Two contrasting examples are migraine and low back pain. Increased GABA+ was found in adults and children with migraine compared to controls, using MRS sequences optimized to detect GABA+ 2,5 and macromolecule suppressed GABA respectively 4 . It was hypothesized that increased GABA/GABA+ levels could reflect a migraine-specific mechanism such as cortical spreading depression, neurogenic inflammation or vasodilation.…”