Metabolic assessment of a migraine model using relaxation-enhanced 1 H spectroscopy at ultrahigh field

Abstract

Purpose: This study evaluates biochemical imbalances in a rat model that reflects dysfunctional pathways in migraine. The high sensitivity and spectral dispersion available to ¹ H MRS at 21.1 T expands metabolic profiling in this migraine model to include lactate (Lac), taurine (Tau), aspartate, and Gly-a mixture of glycine, glutamine, and glutamate.

Methods: Sprague-Dawley male rats were administered in situ an intraperitoneal injection of nitroglycerin (NTG) to induce the migraine analogue or saline as a control. A selective relaxation-enhanced MR spectroscopy sequence was used to target upfield metabolites from a 4-mm³ voxel for 2.5 h after injection.

Results: Significant increases were evident for Lac as early as 10 min after NTG injection, peaking over 50% compared with baseline and control (normalized Lac/N-acetyl aspartate with NTG = 1.54 ± 0.65 versus with saline = 0.99 ± 0.08). Tau decreased progressively in controls over 2 h after injection, but remained elevated with NTG, peaking at 105 min after injection (normalized Tau/N-acetyl aspartate with NTG = 1.10 ± 0.18 versus with saline = 0.85 ± 0.14). Total creatine under NTG showed significant decreases with time and compared with saline; Gly demonstrated temporal increases for NTG.

Conclusions: These changes indicate an altered metabolic profile in the migraine analogue consistent with early changes in neural activity and/or vasodilation consistent with progressively enhanced neuroprotection and osmoregulation. Magn Reson Med 79:1266-1275, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Keywords: 1H MR spectroscopy; high magnetic field; lactate; migraine; nitroglycerin; taurine.

Figure 1

A) Representative images demonstrate the 4×4×4-mm voxel placement in the i) coronal ii) axial and iii) sagittal anatomical directions. B) Representative in vivo 1D RE-MRS shows metabolite peak assignment. A TE = 52 ms for the RE-MRS spin-echo (TE = 64 ms including the LASER module) and TR = 2.5 s with 256 averages was used to achieve a total scan time of 10 min. C) Representative ¹H metabolite spectra were acquired as time courses for a NTG-injected rat and D) saline-injected rat. For NTG, changes in Lac, Tau, tCr and Gly are evident compared to pre-injection baseline values; ethanol, as part of the NTG vehicle, is apparent after injection. The spectra have been plotted with sequential offsets in both frequency and vertical domains to better visualize the spectral time course.

Figure 2

A) Average lactate signal changes (mean ± SD) as a function of time after injection. Signals are normalized to NAA and pre-injection intensity values, with t=0 min representative of the pre-injection scan acquired just before IP injection. Statistical significances are †p<0.05 (LSD test) for temporal comparisons within NTG. (Blue error bars and brackets indicate NTG, whereas orange error bars indicate saline.) B) Percent difference in lactate (mean ± SD) with respect to the pre-injection value, with significance identified at *p<0.05 (Bonferroni’s test) for comparisons between NTG and saline. Abbreviations: Lac, lactate; NAA, N-acetyl aspartate; IP, intraperitoneal; SD, Standard Deviation.

Figure 3

A) Average taurine signal changes (mean ± SD) as a function of time after injection. Signals are normalized to NAA and pre-injection intensity values, with t=0 min representative of the pre-injection scan acquired just before IP injection. Statistical significances are †p<0.05 (LSD test) for temporal comparisons within NTG and ‡p<0.05 for comparisons within saline cohorts. (Blue error bars indicate NTG, whereas orange error bars and brackets indicate saline.) B) Percent difference in taurine (mean ± SD) with respect to the pre-injection value. Comparisons between NTG and saline are significant at *p<0.05 (Bonferroni’s test). Abbreviations: Tau, taurine; NAA, N-acetyl aspartate; IP, intraperitoneal; SD, Standard Deviation.

Figure 4

A) Average total creatine signal intensities (mean ± SD) as a function of time after injection. Signals are normalized to NAA and pre-injection intensity values, with t=0 min representative of the pre-injection scan acquired just before IP injection. Statistical significances are ‡p<0.05 (LSD test) for temporal comparisons within saline cohorts. (Blue error bars indicate NTG, whereas orange error bars indicate saline.) B) Percent difference in total creatine (mean ± SD) with respect to the pre-injection value. Comparisons between NTG and saline are significant at *p<0.05 (Bonferroni’s test). Abbreviations: tCr, total creatine; NAA, N-acetyl aspartate; IP, intraperitoneal; SD, Standard Deviation.

Figure 5

A) Average choline signal intensities (mean ± SD) as a function of time after injection. Signals are normalized to NAA and pre-injection intensity values, with t=0 min representative of the pre-injection scan acquired just before IP injection. Statistical significances are †p<0.05 (LSD test) for temporal comparisons within NTG and ‡p<0.05 for comparisons within saline. (Blue error bars and brackets indicate NTG, whereas orange error bars and brackets indicate saline.) B) Percent difference in choline (mean ± SD) with respect to the pre-injection value. Comparisons between NTG and saline are significant at *p<0.05 (Bonferroni’s test). Abbreviations: Cho, choline; NAA, N-acetyl aspartate; IP, intraperitoneal; SD, Standard Deviation.

Figure 6

A) Average Gly signal intensities (mean ± SD) as a function of time after injection. Signals are normalized to NAA and pre-injection intensity values, with t=0 min representative of the pre-injection scan acquired just before IP injection. Statistical significances are †p<0.05 (LSD test) for temporal comparisons within NTG. (Blue error bars and brackets indicate NTG, whereas orange error bars indicate saline.) B) Percent difference in Gly (mean ± SD) with respect to the pre-injection value. Comparisons between NTG and saline are significant at *p<0.05 (Bonferroni’s test). Abbreviations: Gly, mixture of glycine, glutamine and glutamate; NAA, N-acetyl aspartate; IP, intraperitoneal; SD, Standard Deviation.