***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Migraine is a common neurovascular condition that may be linked to hyperhomocysteinemia . We have previously provided evidence that reduction of homocysteine with a vitamin supplementation can reduce the occurrence of migraine in women . The current study examined the occurrence of migraine in response to vitamin supplementation with a lower dose of folic acid . Methods This was a 6 month r and omised , double blinded placebo controlled trial of daily vitamin supplementation containing 1 mg of folic acid , 25 mg of Vitamin B6 and Vitamin B12 , on reduction of homocysteine and the occurrence of migraine in 300 female patients diagnosed with migraine with aura .  Results Vitamin supplementation with 1 mg of folic acid , did not significantly decrease homocysteine levels ( P = 0.2 ) . The treatment group did not show a significant decrease in the percentage of participants with high migraine disability , severity or frequency at the end of the 6 month intervention ( P > 0.1 ) . Conclusion 1 mg of folic acid in combination with vitamin B6 and B12 is less effective in reducing migraine associated symptoms compared to the previously tested dosage of 2 mg folic acid in combination with 25 mg of vitamin B6 and 400 μg of vitamin B12 Background Refractory migraine is a challenging condition with great impact on health related quality of life . Intravenous ( IV ) ketamine has been previously used to treat various refractory pain conditions . We present a series of patients with refractory migraine treated with intravenous ketamine in the hospital setting . Methods Based on retrospective chart review , we identified six patients with refractory migraine admitted from 2010 through 2014 for treatment with intravenous ketamine . Ketamine was administered using a st and ard protocol starting with a dose of 0.1 mg/kg/hr and increased by 0.1 mg/kg/hr every 3 to 4 h as tolerated until the target pain score of 3/10 was achieved and maintained for at least 8 h. Visual Analogue Scale ( VAS ) scores at time of hospital admission were obtained as well as average baseline VAS scores prior to ketamine infusion . A phone interview was conducted for follow-up of migraine response in the 3 to 6 months following ketamine infusion . Results The study sample had a median age of 36.5 years ( range 29–54 ) and 83 % were women . Pre-treatment pain scores ranged from 9 to 10 . All patients achieved a target pain level of 3 or less for 8 h ; the average ketamine infusion rate at target was 0.34 mg/kg/hour ( range 0.12–0.42 mg/kg/hr ) . One patient reported a transient out-of-body hallucination following an increase in the infusion rate , which resolved after decreasing the rate . There were no other significant side effects . Conclusion IV ketamine was safely administered in the hospital setting to patients with refractory chronic migraine . Treatment was associated with short term improvement in pain severity in 6 of 6 patients with refractory chronic migraine . Prospect i ve placebo-controlled trials are needed to assess short term and long-term efficacy of IV ketamine in refractory chronic migraine Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man . Pituitary adenylate cyclase activating peptide-38 ( PACAP38 ) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers . We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients . Twelve healthy subjects and 12 migraine patients were examined in two separate studies . All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a r and omized , double-blind crossover study design . Headache was scored on a verbal rating scale ( VRS ) during hospital ( 0 - 2 h ) and post-hospital ( 2 - 12 h ) phases . Mean blood flow velocity in the middle cerebral artery ( V(MCA ) ) by transcranial Doppler ( TCD ) and diameter of the superficial temporal artery ( STA ) by high resolution ultrasonography were recorded during hospital phase in migraineurs . PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients . Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo ( P = 0.016 ) . Most of attacks ( 6 out of 7 ) occurred during the post-hospital phase [ mean time 6 h ( range 2 - 11 ) ] . Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase . In the hospital phase , the area under the curve ( AUC ) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects ( P = 0.005 ) and tended to be larger in migraineurs ( P = 0.066 ) . In the post-hospital phase , the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects ( P = 0.005 ) and migraine patients ( P = 0.013 ) . In migraine patients , PACAP38 caused a peak decrease of 16.1 % in V(MCA ) and a 37.5 % increase in STA diameter at 20 min after start of infusion . In conclusion , PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients . In migraine sufferers , PACAP38 caused delayed migraine-like attacks . The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38 Objective : To investigate resting-state functional connectivity in the salience network ( SN ) , the sensorimotor network ( SMN ) , and the default mode network ( DMN ) during migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38 ( PACAP38 ) . Methods : In a double-blind , r and omized study , 24 female migraine patients without aura received IV PACAP38 or vasoactive intestinal polypeptide ( VIP ) over 20 minutes . Both peptides are closely related and cause vasodilation , but only PACAP38 induces migraine attacks . VIP was therefore used as active placebo . Resting-state functional MRI  was recorded before and during PACAP38-induced migraine attacks and before and after VIP infusion . We analyzed data by Statistical Parametric Mapping 8 and the Resting-State fMRI Data Analysis Toolkit for Matlab in a seed-based fashion . Results : PACAP38 ( n = 16 ) induced migraine attacks and increased connectivity with the bilateral opercular part of the inferior frontal gyrus in the SN . In SMN , there was increased connectivity with the right premotor cortex and decreased connectivity with the left visual cortex . Several areas showed increased ( left primary auditory , secondary somatosensory , premotor , and visual cortices ) and decreased ( right cerebellum and left frontal lobe ) connectivity with DMN . We found no resting-state network changes after VIP ( n = 15 ) . Conclusions : PACAP38-induced migraine attack is associated with altered connectivity of several large-scale functional networks of the brain This study estimates the 1-year prevalence of migraine in adults in Engl and in relation to the major demographic variables of age , gender and ethnicity , and describes some of its features , including aspects of consequential disability . A telephone survey was conducted of a r and om sample ( n = 4007 ) of the population aged 16 - 65 years of mainl and Engl and using a previously vali date d diagnostic interview . The response rate was 76.5 % . Overall , 7.6 % of males and 18.3 % of females reported migraine with or without aura within the last year meeting diagnostic criteria closely approximate to those of the International Headache Society . Prevalence of migraine varied with age , rising through early adult life and declining in the late 40s and early 50s . Prevalence was higher in Caucasians than in other races . Attack rates were ≥ 1/month in most migraineurs , and most experienced interference with daily activities in ≥ 50 % of their attacks . On average , an estimated 5.7 working days were lost per year for every working or student migraineur , although the most disabled 10 % accounted for 85 % of the total . Results were in keeping with those from surveys in other countries . If these findings in mainl and Engl and are projected to the entire UK population , we estimate that 5.85 million people aged 16 - 65 years experience 190 000 migraine attacks every day and lose 25 million days from work or school each year because of them . Migraine is an important public health problem in the UK , associated with very substantial costs OBJECTIVE The aim of this study was to determine the relationship of high daily monosodium glutamate ( MSG ) consumption with glutamate concentrations in jaw muscle , saliva , and serum , and muscle pain sensitivity in healthy participants . METHODS A r and omized , double-blinded , placebo-controlled study was conducted to investigate the effect of repetitive consumption of high-dose MSG on glutamate concentration in the masseter muscles measured by microdialysis and muscle pain sensitivity . In five contiguous experimental daily sessions , 32 healthy participants drank MSG ( 150 mg/kg ) or NaCl ( 24 mg/kg ) diluted with a 400 mL soda . The concentrations of glutamate before and after the ingestion were assessed in dialysate and plasma sample s on the first and last days . Saliva glutamate concentration was assessed every day . Pressure pain threshold , pressure pain tolerance , autonomic parameters ( heart rate , systolic and diastolic blood pressures ) and reported side effects also were assessed . RESULTS No significant change was noted in the baseline concentration of glutamate in the masseter muscle , blood , or saliva , but the peak concentration in the masseter muscle increased significantly between day 1 and 5 . A statistically significant increase in systolic and diastolic blood pressures after MSG administration was observed , as well as a significantly higher frequency of reports of nausea and headache in the MSG group . No robust effect of  MSG on muscle sensitivity was found . CONCLUSION Interstitial glutamate concentration in the masseter muscle is not highly disturbed by excessive repetitive intake of MSG in healthy man Glutamatergic hyperactivity is implicated migraine pathogenesis . Also , LY293558 , an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate ( KA ) receptor antagonist , is effective in pre clinical models of migraine . We therefore tested LY293558 in acute migraine . We conducted a r and omized , triple-blind , parallel-group , double-dummy , multicentre trial of 1.2 mg/kg intravenous ( IV ) LY293558 , 6 mg subcutaneous ( SC ) sumatriptan , or placebo in the treatment of acute migraine . The primary efficacy variable was the headache response rate , i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients , 44 patients ( 20M:24F ; mean age ± SD = 40 ± 9 years ) completed the study .  Response rates were 69 % for LY293558 ( P = 0.017 vs. placebo ) , 86 % for sumatriptan ( P < 0.01 vs. placebo ) and 25 % for placebo . LY293558 and sumatriptan were superior to placebo ( P < 0.01 for all comparisons ) on all other measures of improvement in pain and migraine associated symptoms . Fifteen percent of patients who took LY293558  reported adverse events ( AEs ) ( n = 2 ; one mild , one severe ) . Fifty-three percent of patients who took sumatriptan ( n = 8 ; seven mild , one moderate ) and 31 % of those who received placebo  reported AEs ( n = 5 ; four mild , one severe ) . The efficacy and safety results of LY293558 in this small migraine proof of concept trial , together with supportive pre clinical data , provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine . Larger trials are needed to further test the hypothesis Pituitary adenylate cyclase-activating polypeptide-38 ( PACAP38 ) and vasoactive intestinal polypeptide are structurally and functionally closely related but show differences in migraine-inducing properties . Mechanisms responsible for the difference in migraine induction are unknown . Here , for the first time , we present a head-to-head comparison study of the immediate and long-lasting observations of the migraine-inducing , arterial , physiological and biochemical responses comparing PACAP38 and vasoactive intestinal polypeptide . In a double-blind crossover study 24 female migraine patients without aura were r and omly allocated to intravenous infusion of PACAP38 ( 10 pmol/kg/min ) or vasoactive intestinal polypeptide ( 8 pmol/kg/min ) over 20 min . We recorded incidence of migraine during and after infusion ( 0 - 24 h ) . Magnetic resonance angiography of selected extra- and intracranial arteries , blood sample s ( plasma PACAP38 and vasoactive intestinal polypeptide and serum tryptase ) , and 
    Output:
    
RESULTS L-kynurenine and kynurenic acid act on the glutamatergic system at the level of the second-order nociceptive neurons in the trigeminal nucleus caudalis .
Pituitary adenylate cyclase- activating polypeptide is released from the peripheral nerve endings of the trigeminal pseudounipolar neurons and causes vasodilation and mast cell degranulation , leading to consequent peripheral sensitization of the dural nociceptors .
Central ly released pituitary adenylate cyclase-activating polypeptide in the trigeminal nucleus caudalis results in the central sensitization of the second-order neurons .
The sensitization process leads to the characteristic features of migraine .
L-kynurenine , kynurenic acid , and pituitary adenylate cyclase-activating polypeptide may have fundamental roles in the initiation of migraine headache attacks