Elevated Insula Glutamate in Migraine is Linked with Longer Headache Duration: A 7T H-MRS Study

Background & Aims

Migraine is a prevalent and highly disabling disorder, with complex neurobiological underpinnings including increased cortical and subcortical excitability[1]. This hyperexcitability may be mediated by the excitatory neurotransmitter glutamate, and recent magnetic resonance spectroscopy (H-MRS) studies have found evidence for increased glutamate/glutamine in posterior insula in chronic pain[2] and migraine[3] patients. Ultrahigh-field (e.g. 7 Tesla) MRI shows great promise for improved metabolite separability and H-MRS estimation[4]. Our study assessed posterior insula glutamate concentrations among participants with episodic migraine (MIG) and healthy volunteers (HV) using ultrahigh-field H-MRS. We hypothesized that compared to HV, MIG would show increased glutamate concentration in the posterior insula. We further hypothesized that elevated insula glutamate would be associated with greater frequency, intensity, and duration of migraine attacks.

Methods

55 participants with migraine (MIG) (51 F, 4 M, mean age = 35.1 years) and 20 healthy volunteers (HV) (19 F, 1 M, mean age = 35.6 years) were scanned in a Siemens Terra 7-Tesla MRI scanner. We used a 1H-MRS STEAM sequence in left posterior insula and obtained estimates of glutamate and glutamine concentration with LCModel[5]. We compared glutamate and glutamine concentrations between MIG and HV participants using two-tailed t-tests. Participants completed daily headache diaries electronically for at least 30 days prior to scan, reporting whether they had a headache each day, pain intensity, and headache duration. We distinguished migraine attacks from tension headaches with questions about migraine symptoms such as nausea, laterality, and aura, and only included headaches meeting migraine criteria. We examined the association between glutamate concentration in the posterior insula and migraine frequency, intensity, and duration with a series of Pearson correlation tests (? = 0.05).

Results

The mean duration of migraine attacks for MIG participants was 9.9 ± 6.9 hours (range: 2.4–33 hours). Mean migraine frequency (average migraines per month throughout enrollment period) was 4.2 ± 2.4 migraines/month (range: 0.6–10.5). Mean pain intensity (1–10, 1 being lowest and 10 being highest pain) was 5.4 ± 1.4 (range: 3.3–8.6). Participants with migraine had significantly higher glutamate concentration in the posterior insula compared to healthy controls (MIG mean = 17.1 ± 1.1 mmol/l, HV mean = 16.3 ± 1.0 mmol/l, d=0.65, p<0.05). Glutamine did not differ between the groups (MIG mean = 3.8 ± 0.9 mmol/l, HV mean = 3.9 ± 0.7 mmol/l, d=0.15, p=n.s.). Among MIG participants, there was a significant positive association between insula glutamate concentration and the mean duration of migraine attacks (r=0.41, p<0.01). No significant associations were observed between insula glutamate concentration and migraine frequency (r=-0.02, p=n.s.) or migraine pain intensity (r=0.06, p=n.s.).

Conclusions

This study found elevated glutamate concentration in the posterior insula among individuals with episodic migraine using ultrahigh-field H-MRS. Prior 3T H-MRS studies have suggested altered glutamate/glutamine levels in individuals with migraine, and our study with improved signal strength and metabolite separability offered by ultrahigh-field 7T MRI, demonstrated specific elevation of glutamate levels in the posterior insula. The association between elevated insula glutamate and migraine attack duration suggests that glutamate in this region may contribute to longer duration of migraine attacks. Furthermore, interventions targeting insular glutamate levels and cortical hyperexcitability via glutamatergic mechanisms may be able to improve patient outcomes by reducing migraine duration.

References

1. Lee, J., Lin, R.L., Garcia, R.G., Kim, J., Kim, H., Loggia, M.L., Mawla, I., Wasan, A.D., Edwards, R.R., Rosen, B.R. and Hadjikhani, N., 2017. Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine. Cephalalgia, 37(11), pp.1026-1038.

2. Zunhammer, M., Schweizer, L.M., Witte, V., Harris, R.E., Bingel, U. and Schmidt-Wilcke, T., 2016. Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity. Pain, 157(10), pp.2248-2256.

3. Harte, S.E., Clauw, D.J., Napadow, V. and Harris, R.E., 2013. Pressure pain sensitivity and insular combined glutamate and glutamine (Glx) are associated with subsequent clinical response to sham but not traditional acupuncture in patients who have chronic pain. Medical acupuncture, 25(2), pp.154-160.

4. Tká?, I., Öz, G., Adriany, G., U?urbil, K. and Gruetter, R., 2009. In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magnetic Resonance in Medicine: An Official Journal of the International Society for Magnetic Resonance in Medicine, 62(4), pp.868-879.

5. Provencher, S.W., 2001. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR in Biomedicine: An International Journal Devoted to the Development and Application of Magnetic Resonance In Vivo, 14(4), pp.260-264.

Presenting Author

Michael Datko

Poster Authors

Michael Datko

PhD

Harvard Medical School

Lead Author

Elevated Insula Glutamate in Migraine is Linked with Longer Headache Duration: A 7T H-MRS Study

Background & Aims

Methods

Results

Conclusions

References

Presenting Author

Michael Datko

Poster Authors

Michael Datko

Sarasa Tohyama

Jack H. Schnieders

Ludovica Brusaferri

Lilian Kinder

Kassandra Round

Alison Goldstein

Melaina Gilbert

Mackenzie Hyman

Frances Marin

Hannah Goodman

Danielle Giachos

Ronald Garcia

Randy Gollub

Hslinlin Cheng

Nouchine Hadjikhani

Marco L. Loggia

Zev Schuman-Olivier

Bruce Rosen

Robert Edwards

Eva Ratai

Vitaly Napadow

Topics

IASP 2024 World Congress on Pain