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

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Migraines affect approximately 38 million people in the United States, and are the seventh‐most disabling condition in the world, as assessed by interference with the sufferer's ability to function in everyday activities 1. Although several hypotheses implicate neuronal and trigeminovascular involvement with migraine onset and progression 2, an exact pathophysiological change is yet to be identified that can explain the onset, progression, and termination of migraines.
Biochemical imbalances of Na+ in migraine have been identified in the cerebrospinal fluid (CSF) 3, brain 5, and alterations of Ca2+ and Na+ channels as well as the Na+/K+/ATPase transporter (NKAT) for the rare familial hemiplegic migraine mutation 6. However, there is limited characterization of metabolic changes during the onset and progression of migraine. It follows that the identification of specific metabolic changes may improve the understanding of migraine and open new avenues for therapy development. This study, therefore, evaluates biochemical and metabolic imbalances hypothesized to reflect how dysfunctional pathways paralleling migraine affect humans by means of a frequently studied nitroglycerin (NTG) triggered animal migraine model 5. In clinical cohorts, NTG typically triggers a mild headache that is short‐lived and stops rapidly after administration is completed, based on a short (2 min) half‐life 10. This mild, immediate headache results from the acute effects of nitric oxide (NO) as a vasodilator affecting the intra‐ and extracranial vasculature. For migraineurs, however, NTG triggers a delayed onset of central sensitization as a result of the action of NO on neuronal firing that is not observed in nonmigraineurs. This sensitization is reflected in the animal analogue.
To probe metabolic imbalances resulting from NTG exposure, in vivo proton magnetic resonance spectroscopy (1H MRS) is used in this study to assess metabolic dysfunctions reflected in the dynamic concentrations of energetics, osmolytes, and neurotransmitters. In previous studies at lower magnetic fields and in the occipital and temporoparietal regions, various metabolites have been interrogated with respect to migraine in patient populations: N‐acetyl aspartate (NAA) 12; total creatine (tCr), which includes phosphocreatine and creatine 13; total choline (Cho) 13; and Glx/GABA+, which is a mixture of spectral overlaps from gamma‐aminobutyric acid, glutamate, and glutamine 14. Decreased levels of NAA, Cho, and tCr indicate a potential effect of migraine on chronic neuronal integrity and decreased membrane turnover. However, these studies were conducted during the interictal period, and no clinical study to date has acquired 1H MRS during migraine. Preclinically, Ma et al. 15 made use of a migraine rodent model in their spectroscopy‐based study to evaluate metabolites. However, their study was performed at one time point: 90 min after establishing the onset of the migraine analogue based on behavioral characterization. Additionally, their voxels were localized in the thalamus and cerebellum, and the primary metabolites interrogated were Glx/GABA+, creatine, choline, NAA, and myoinositol. Thus, several MRS studies have reported metabolic changes in migraine patients, but study designs and results have been heterogeneous, with little consistency among findings for 1H MRS 16.
Leveraging the sensitivity and spectral dispersion benefits of high‐field MRS, the overall aim of the present study is to interrogate metabolites at 21.1 T dynamically and in vivo during acute and delayed onset of central sensitization. To enhance sensitivity while reducing individual experiment acquisitions times, relaxation‐enhanced MR spectroscopy (RE‐MRS) was used to analyze quantitative changes in brain metabolites during progression of the migraine analogue from baseline. Relaxation‐enhanced MR spectroscopy uses specifically designed radiofrequency (RF) pulses to excite metabolites of known chemical shifts over a narrow bandwidth 18.

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