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

Abstract and Introduction

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.

Introduction

Migraine often begins in childhood, and roughly 20% of sufferers experience their first attack before 5 years of age.[54] Early intervention can decrease migraine frequency, with those receiving earlier interventions more likely to achieve remission.[25] However, treatment strategies for children are limited, in part due to limited knowledge about pediatric migraine biology.[46] Migraine is often managed similarly in children as adults, despite evidence that children with migraine present with different symptoms.[28] Standard medications to prevent migraine in adults have shown to be no more effective than placebo in children, and may carry side effects.[28,30,54] To improve treatments for children, we need to understand the underlying biology of pediatric migraine.

There is compelling evidence that adult migraine results from an imbalance of excitation/inhibition in the brain, which changes cyclically until a migraine occurs (known as the migraine cycle).[11,12] During the interictal period, cortical excitability increases proportionally with time until the next attack. During the ictal period, or shortly thereafter, the brain returns to baseline activity and begins the cycle again.[11,12] Neurophysiological studies suggest this cortical hyperexcitability results from abnormal thalamic control,[9] resulting in altered communication in thalamocortical networks,[48] which underlie important processes in multisensory integration; this altered communication is associated with clinical migraine symptoms.[9,24] Excitability of the sensory cortices is set by activity in these thalamocortical loops. Between attacks, there is evidence that adults with migraine have reduced function in thalamocortical connectivity,[10] resulting in increased excitability in sensory and visual cortices. For example, the sensorimotor cortex of migraineurs shows enhanced responses to sensory stimuli, and the degree of enhancement correlates with headache frequency.[50] Similarly, transcranial magnetic stimulation (TMS) studies involving adults with migraine indicate visual cortex hyperexcitability.[5]

The primary neurochemicals associated with inhibition and excitation in the brain are GABA and glutamate, respectively. These can be measured in vivo noninvasively using magnetic resonance spectroscopy (MRS). A recent review of MRS studies showed that, in adults with migraine, GABA and glutamate levels are increased in multiple brain areas.[52] For example, adults with migraine show increased glutamate[2,19,45,55] and increased GABA levels[1,4] in the visual cortex, and increased glutamate in the thalamus.[2]

Despite indirect evidence of abnormal cortical excitability in children with migraine,[39,44] GABA and glutamate levels remain uninvestigated. The GABA/glutamate ratio may be used to index the inhibitory/excitatory balance and may show a stronger effect than changes in either neurochemical alone. Using advanced MRS methods, this study compares GABA and glutamate in the thalamus, sensorimotor, and visual cortices of children with and without migraine. Although the most predominant symptom of migraine is severe headache, 20% of migraine sufferers experience visual disturbances, known as aura, which is associated with increased responsiveness of the visual cortex.[26] Subsequently, GABA and glutamate levels in the visual cortex were compared between children with migraine with and without aura, and children without migraine. Finally, this study explores the association between these neurochemical levels and migraine characteristics to improve our understanding of pediatric migraine.

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