Abstract
Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.
Highlights
Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine
Tryptophan supplementation as a promising migraine treatment failed in previous studies[52,53] which may support our observation that tryptophan concentration is associated with the emotional symptoms of migraine patients but does not interfere with processes that contribute to attack generation or attack frequency
Our study demonstrated a correlation between plasma tryptophan concentration and PAG functional connectivity (PAG-FC) in migraine for the first time
Summary
Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. PAG has increased resting-state and pain induced functional connectivity with regions of nociceptive and somatosensory processing pathways in migraine patients and these connections showed association with headache frequency[17,18]. PAG functional connectivity with top-down pain modulating prefrontal cortical and limbic areas were decreased compared to non-migraineurs[19] in these studies emphasising its potential role in sensory hypersensitivity in migraine. Different serotonergic receptor activation or blockade in PAG modulated pain perception and defensive b ehaviour[39,40,41], while kynurenine injection into PAG elicited anxiolytic effect and inhibited periaqueductal gray cell activity by glutamatergic blockade[42,43] Based on these observations it can be hypothesised that PAG functional connectivity alterations in migraine might be related to tryptophan plasma concentration
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