Cortical GABA in migraine with aura -an ultrashort echo magnetic resonance spectroscopy study

Migraine is an episodic type of primary headache affecting a large proportion of the population with a female preponderance. Approximately 20% of all migraine patients experiences auras, often of the visual type [1]. Cortical spreading depression (CSD) is thought to be the physiological mechanism underlying migraine aura; hence, studies using both magnetic resonance spectroscopy (MRS) and visually evoked potentials indicate an abnormal inhibition-excitation balance [2‐6]. An unbalanced inhibition-excitation system of the brain could be driven by a γ-aminobutyric acid (GABA) – Glutamate disturbance (see [7] for a recent review on GABA and migraine). If the GABA concentrations are found to be altered in migraine patients, this could lead to new preventative approaches in migraine treatment.

Previous MRS studies have investigated change of cortical GABA in migraine patients [2‐5]. Studies were underpowered and inconclusive, MRS methods differed, and study population included a mixture of migraine patients with and without aura with large variability in headache frequency [8]. Based on prior studies by Bridge et al. [2] and Bigal et al. [5], it is possible that occipital GABA levels are reduced in frequent migraine. However, these findings have not yet been replicated. Furthermore, it is unknown whether GABA and/or glutamate levels are changed in migraine patients due to the migraine attacks, and it is also unknown if low GABA levels are part of the underlying mechanism triggering the migraine aura. Previous studies were not designed to examine if the diminished levels of GABA were due to migraine prophylactic medication.

The present study recruited mildly affected migraine patients with episodic aura of low frequency. It was hypothesized that occipital GABA levels were decreased in migraine patients as compared with healthy subjects. In order to replicate prior findings by Bridge et al. [2] and Bigal et al. [5], our primary focus was on the occipital cortex. Secondarily, the somatosensory (parietal) cortex was investigated to clarify whether any differences in the occipital cortex would generalize to other sensory areas.

The primary outcome for this study was difference in GABA/Total creatinine levels between patients with MWA and healthy matched subjects measured using Proton (H⁺) Magnetic resonance spectroscopy. Furthermore, the secondary outcome measures included comparison of total glutamate/glutamine (Glx) ratioed to total creatinine as well as additional metabolites in MWA patients and healthy controls, provided using the SPECIAL spectroscopy method.

This cross-sectional imaging study was approved by the Central Denmark Region Research Ethics Committee (case number: 1–10–72-326-15) prior to patient recruitment. All participants gave written and verbal informed consent. All patients were scanned between September 2015 and June 2016 at Aarhus University Hospital, at the Center for functionally integrative neuroscience (CFIN), using a Siemens Trio 3 T scanner dedicated for research.

Participants were recruited using posters that were on public display in Aarhus University and at Aarhus University Hospital. Firstly, participants were questioned using a semi structured questionnaire, and then secondly to establish a migraine diagnosis, a trained research assistant (TB) and a specialist neurologist (HK) screened all potential patients before study enrolment. Inclusion criteria were: Migraineurs should fulfil criteria for episodic migraine with aura and with headache (diagnosis group IHS ICHD-3 1.2.1.1 https://​www.​ichd-3.​org/​1-migraine/​), 4–20 attacks during the past year, age 18 to 50 years, no other significant illness and no medication known to affect neuronal excitability other than migraine treatment.

Patients was screened by the criteria that during the last 1 years at least 4 headache attacks with:

Typical aura with signs of vision disturbances or somatosensory disturbances eventually mild motor aura (speak difficulties, clumsiness) before or during headache, at least 4 headaches with aura episodes identified with full remission within hours-1 week.

Duration of each headache attack was reported from 4 h to 1–2 days if headache was untreated.

Typically, moderate intense headache, predominantly unilateral or eventually bilateral origin of headache, typically headache with pulsating/throbbing character. Other signs like nausea, vomiting, phono- and/or photophobia during headaches were registered, worsening during activity and improvement during rest. Participants were excluded if they reported any other neurological disorder.

Scans were performed at least 7 days after last migraine attack.

Control subjects were included in a similar fashion using a semi structured questionnaire and screening process. Inclusion criteria were: Healthy men or women, age 18–50. Exclusion criteria were any prior migraine or other headache diagnosis, any significant psychiatric diagnosis or any current neuro modulating medication. We did not collect information on any family history of migraine from the healthy subjects.

All scans were performed during the day time, from 8.00 AM to 4.15 PM, scheduled scans were performed independently of group affiliation.

Sixteen migraine patients were included, one female patient was unable to complete the scan due to claustrophobia. One migraine patient was in migraine prophylactic treatment with lamotrigine and was excluded in the final analysis. Seven patients were prescribed triptans for migraine attacks. Seventeen age- and gender-matched healthy subjects (10 women, 7 men) were included for comparison. One control data set was lost due to technical problems. The final analysis concluded a sample consisting of 14 patients (9 women, mean age of 23 (range 19–34)) and 16 healthy subjects (9 women, mean age of 23 (range 19–33)). The mean number of migraine attacks were 11.04 per year (Range 4–25 attacks/year).

The present case-control study population with 14 mildly affected patients suffering from migraine with aura (MWA) (diagnosis group IHS ICHD-3 1.2.1.1 Migraine typical aura with headache (episodic) https://​www.​ichd-3.​org/​1-migraine/​) was not able to replicate prior findings of low GABA levels in occipital cortex using functional MRI [2].

A disturbance in cortical excitatory/inhibitory balance has been suggested to contribute to the initiation of cortical spreading depression and thereby eliciting aura in MWA patients. Moreover, disturbed perception of visual stimuli has been documented in MWA patients [14] even outside of migraine attacks, which suggests an underlying disturbance in cortical function in migraineurs. To our knowledge three prior studies have investigated GABA levels using MRS in migraine patients, reporting high [3], low [2] or normal [5] GABA. The diverging results are likely due to differences in voxel placement (occipital vs parietal), MR-sequences used (MEGA-PRESS, SPECIAL), patients included (with or without aura) and disease severity. The prior studies by Bigal et al. [5] and Bridge et al. [2] both investigate occipital GABA in MWA patients (although the Bigal study included a mixed group of patients) and are thus comparable to the current study. In the study by Bigal et al. no difference was found between patients and healthy subjects, however a secondary analysis showed that GABA was lower in the patients with one or more severe migraine attacks within the last month. The recent study by Bridge et al. reported low occipital GABA levels in a cohort of MWA patients with a high frequency of migraine attacks (average 5 per month) and with several patients on migraine prophylactic treatment [2]. Taken together, the results from the two studies indicate that GABA levels are low in patients with more severe migraine. The current study investigated a group of more mildly affected patients (average of 11.04 attacks per year) undergoing MRI more than 7 days after their last registered migraine attack, making this sample very different from the patients examined by Bridge et al. In the present study GABA levels were unchanged in migraine patients with less severe affection, however the current study did not contribute with additional information regarding GABA levels in severe migraine headaches.

Using the SPECIAL MRS sequence, we also looked in to several other metabolites, such as Glutamate/Glutamine (Glx) and NAA (NAA+ NAAG). NAA levels have previously been found to be lower in migraine patients [8], we found no significant difference. As we work with the hypothesis that the migraine aura is caused by an imbalance in the excitatory-inhibitory system, glutamate could be of interest since it is one of the primary excitatory neurotransmitters in the brain, here we found no difference.

One of the major limitations of the current study is the lack of precise phenotyping, as well as the low number of participants. The study size is of concern both in this and in several previous studies and should be addresses in future studies.

Future studies should also address whether low GABA levels in severe migraine headache are due to migraine aura, or are a consequence of migraine prophylactic treatment, although evidence shows that prophylactic neuromodulators in migraine seem to elevate GABA levels [15], or are simply lowered during the migraine attack and the days after, and thus a consequence of migraine headache rather than the cause. In future studies the fact that some patients only experience unilateral MwA and, some have changing laterality would possibly enable you to use patients as internal reference, using the affected side vs the unaffected side.

Several studies suggest an imbalance in the GABA-glutamate system in migraine, the current study in mildly affected MwA patients does not support this hypothesis.

More control over patient migraine prophylactic medication would also be of great interest in future studies, in the present study no patients was taking prophylactic medication. The current available studies, the present one included show that more specific studies are needed to elucidate the nature of the different levels reported in the present study and in previous findings and their correlation to migraine.

We did not find significant difference in cerebral GABA levels between patients and healthy subjects, indicating that in relatively mild migraine with aura GABA levels in the occipital and parietal lobes are normal outside migraine attacks.