Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients

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.

Citalopram Neuroendocrine Challenge Shows Altered Tryptophan and Kynurenine Metabolism in Migraine

“…In this study, the TRP concentration was not significantly higher in the migraine group, but it tended to be higher compared to controls at both blood samplings. Our results are consistent with previous studies reporting elevated TRP concentration in episodic [ 12 , 15 ] and chronic migraine patients [ 13 , 14 ]. However, there are some studies reporting the opposite results [ 16 , 17 ].…”

“…However, in our previous study, we did not find any correlation between migraine indicators (attack frequency and age at onset) and plasma TRP concentration, but an association between TRP concentration with depressive symptoms and trait-anxiety was apparent in migraine patients [ 15 ], which in turn may affect the recurrence of attacks and the processing of pain stimuli. Moreover, the increased plasma TRP concentration (corrected for plasma LNAA concentration) was associated with decreased functional connectivity of periaqueductal gray matter with regions implicated in fear-cascade and pain processing but increased functional connectivity with frontal emotion and pain regulating areas, thereby supporting TRP having an important role in optimizing stress coping [ 15 ]. Our previous results might suggest that serotonergic pathways synthetized from TRP could be more responsible for emotional symptoms and stress-processing in migraine than for the attack generation itself.…”

“…Increased plasma TRP/LNAA ratio was detected in interictal episodic migraine without aura patients compared to healthy controls at two independent blood samplings. To the best of our knowledge, our study is the first investigation of plasma TRP/LNAA ratio in migraine patients, as previous studies only reported results related to plasma TRP concentration [ 12 , 13 , 14 , 15 , 16 , 17 , 64 ]. In this study, the TRP concentration was not significantly higher in the migraine group, but it tended to be higher compared to controls at both blood samplings.…”

“…In migraine patients, TRP and TRP/LNAA plasma concentration did not increase from the citalopram neuroendocrine challenge. A likely explanation for this observation is that the already-elevated TRP concentration in migraine patients, which might be necessary to sustain the interictal phase or could be a sign of increased stress sensitivity [ 15 ], could not be elevated further by the acute activation of the sympathetic nervous system. Moreover, the induction of IDO and TDO enzymes may also be less effective, since enzymes of the KYN pathway are expressed in a reduced manner in migraine, resulting only in a modest increase in KYN plasma level [ 67 ].…”

“…The ratio of TRP/LNAA is widely used to describe the portion of TRP uptake to the brain; however, plasma TRP/LNAA ratio in migraine has not been investigated yet. Studies concerning the blood TRP concentration of migraine patients are not consistent; both higher [ 12 , 13 , 14 , 15 ] and lower [ 16 , 17 ] TRP concentrations were reported in migraineurs compared to controls. Furthermore, migraine patients are suggested to be sensitive to TRP concentration changes; thus, TRP depletion induces intense headache, nausea, and photophobia in migraineurs [ 18 ].…”