Hypothalamic functional MRI activity in the initiation phase of spontaneous and glyceryl trinitrate‐induced migraine attacks

Abstract

The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl‐trinitrate (GTN)‐induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level‐dependent (BOLD) response to oral glucose ingestion with 3T‐functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN‐triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between‐ and within‐group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose‐induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD‐response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN‐provoked and spontaneous migraine attacks.

Cortical glutamate and gamma-aminobutyric acid over the course of a provoked migraine attack, a 7 Tesla magnetic resonance spectroscopy study

“…Glyceryl trinitrate provocation studies have only rarely been able to provoke aura symptoms and generally provokes migraine-like attacks in over eighty percent of migraine without patients ( Ashina et al, 2013 ). In both GTN provoked and spontaneous attacks patients may experience premonitory symptoms in the preictal phase, and using neuroimaging techniques activation of hypothalamus, occipital cortex and brainstem has been demonstrated ( Ferrari et al, 2015 , Maniyar et al, 2014a , Maniyar et al, 2014b , Onderwater et al, 2020 , Schulte and May, 2016 ; van Oosterhout et al, 2021 , Weiller et al, 1995 ).…”

Functional MRI in migraine

“…Normally, the BOLD response decreases after oral glucose administration followed by a slow normalization of the BOLD response. The BOLD response was normalized significantly faster during the prodromal symptoms compared with baseline or healthy controls [22]. In another study of GTN-triggered prodromal symptoms, increased functional connectivity was found between the bilateral thalami and the right precuneus and cuneus, although there was a decreased functional connectivity between the pons and the limbic lobe.…”

“…However, it was not clear whether the patient had prodromal symptoms during the scan [21]. Changed hypothalamic activity after oral glucose ingestion was also reported in patients with prodromal symptoms as well as glyceryl trinitrate (GTN)-triggered prodromal symptoms [22]. Normally, the BOLD response decreases after oral glucose administration followed by a slow normalization of the BOLD response.…”

The premonitory phase of migraine is due to hypothalamic dysfunction: revisiting the evidence

“…Conflicting results have recently been published on hypothalamic involvement during the premonitory phase of GTN-induced migraine [ 58 , 59 ]. In one randomized, double-blind, placebo-controlled, 2-way crossover, resting-state functional MRI study [ 58 ], the authors included 25 patients with migraine who had developed GTN-induced migraine preceded by at least 3 premonitory symptoms.…”

“…Noteworthy, a thalamo-cortical dysfunction in the premonitory phase has been described by another group, but the involved cortical regions were different, and the observed findings are not comparable [ 61 ]. In another functional MRI study [ 59 ], the authors included 15 women with migraine without aura and 10 healthy women free of headache to evaluate the hypothalamic blood oxygen level–dependent (BOLD) response – a surrogate marker of neuronal activation – to oral ingestion of glucose on two separate days after overnight fasting. Patients with migraine had to be free of attacks for at least 3 days prior and 2 days after both experimental days.…”