Sage Journals: Discover world-class research

Abstract

Background

Alteration in central serotonin biology has been implicated in migraine, and serotonin (5-HT) agonists have been available for more than a decade in the treatment of that condition.

Objectives

To test this hypothesis, we studied in vivo using positron-emission tomography (PET) and α-[¹¹C] methyl-L-tryptophan (α-[¹¹C]MTrp) as a surrogate marker of cerebral 5-HT synthetic rate before and after administration of eletriptan in migraine and control subjects.

Methods

Six nonmenopausal female migraine subjects with migraine without aura (MoA) and six nonmenopausal age-matched female control subjects were scanned at baseline and after oral administration of 40 mg of eletriptan. Migraine subjects at the time of PET had to have been headache free for a minimum of three days. Images of (α-[¹¹C]MTrp) brain trapping were colocalized with individual MRI images in three dimensions and analyzed.

Results

There was no difference in baseline cerebral global 5-HT synthesis between migraine and control subjects. After administration of eletriptan, there was a striking global reduction in cerebral 5-HT synthesis (K*) in the migraine group and in 22 regions of interest (ROIs). In control subjects, no significant changes were found in global cerebral 5-HT synthesis (K*) or in any of the ROIs.

Conclusions

These findings suggest in migraine an interictal alteration in the regulation mechanisms of cerebral 5-HT synthesis.

Keywords

Migraine PET cerebral serotonin eletriptan

Introduction

Serotonin (5-HT) has been suggested for several decades as a possible important neurotransmitter in migraine pathogenesis (1). Plasma 5-HT was found to be increased in ictal migraine and decreased interictally. Its metabolite 5-hyhdroxyindoleacetic acid (5-HIAA) showed changes in the opposite directions (2). 5-HIAA was also found to be increased interictally in the cerebrospinal fluid (CSF) of migraineurs, suggesting an enhanced cerebral 5-HT turnover (3). An increased rate of cerebral serotonin synthesis has been documented in migraine (4).

Electrophysiologically, abnormal intensity-dependent auditory-evoked responses documented in migraine correlate inversely with central serotonergic transmission (5). 5-HT depletion in rats enhances cortical spreading depression with an increased cortical excitability and sensitivity in trigeminal nociception (6).

Several imaging studies using positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI) have documented changes in several cerebral regions in migraine (7). A first PET study using radio-labeled oxygen had suggested some involvement of the upper brain stem structures in the pathogenesis of migraine (8). Another PET study using radio-labeled analog of tryptophan, α-[¹¹C]methyl-L-tryptophan, suggested that 5-HT neurotransmission was upregulated in migraineurs after pre-treatment with a β-blocker (4). Using the same 5-HT marker, a recent PET study in the acute phase of migraine proved an increased rate of 5-HT synthesis at the peak of the attack from a low albeit nonsignificant 5-HT synthetic rate when compared to controls in the interictal phase. Sumatriptan given at the peak of the attack induced a negative feedback on 5-HT synthesis (9).

Given the previously observed changes in the rate of 5-HT synthesis (K*) after administration of a triptan in the acute phase of migraine (9), the primary objective of the present study was to assess, with PET studies using radio-labeled tryptophan analog α-[¹¹C]methyl-L-tryptophan, if a similar effect on the rate of 5-HT synthesis (K*) could be observed following administration of serotonin agonist eletriptan in premenopausal women with migraine in the interictal phase of their disorder and in premenopausal women without migraine.

Methods

Migraine patients and control subjects

Nonmenopausal migraine patients were compared to age-matched nonmenopausal control female subjects. Migraine patients (age: mean ± SD; 30.3 ± 7.9 years; N = 6) had to have a history of migraine without aura (MoA) as defined by the 2004 International Headache Society (IHS) criteria and not fulfill the diagnostic criteria for transformed migraine (10,11). Control subjects (age: mean ± SD; 26.8 ± 7.4 years; N = 6) had no history of migraine or motion sickness and no family history of migraine, defined as no history of migraine in first-degree relatives. Exclusion criteria were defined as follows: women not using an effective method of birth control, e.g. estrogen-containing birth control medication; pregnancy; subjects intending to donate or receive blood or blood products four weeks before initiation or completion of the study; concomitant participation in clinical studies using investigational or marketed medications; prior participation in any other clinical trial with eletriptan; subjects with any systemic disease including any form of vascular disease; subjects with a history of migraine aura (MA), migrainous infarction, basilar artery migraine or familial hemiplegic migraine; subjects with alcohol or drug abuse, including analgesics and ergotamine; and subjects with PET or MRI contraindications. Six subjects were recruited in both groups. Demographic data including age, migraine days, migraine years, acute drugs and prophylactic treatment are given in Table 1. In the migraine group, four subjects had both menstrual and intermenstrual migraines, and two had migraines unrelated to their menstrual cycle. All subjects were on estrogen-containing oral contraceptive medication and the migraine patients were not and had never been on migraine prophylactic medications. All subjects underwent a general and neurological examination and on the day of the PET scan a urine pregnancy test was completed. The PET scan was performed in migraine subjects only if they had been without migraine headache for three days including prodromal symptoms and only if they were not menstruating. The time to the next migraine attack after the PET study in the migraine group was not determined. All subjects received monetary compensation for lost time and inconvenience and all gave written consent for the study, which was approved by the Research and Ethics Committee of the Montreal Neurological Institute and Hospital, and by the Institutional Review Board of McGill University.

Table 1.

Demographic data.

Demographics: Patients and control subjects
Patients	Age	Years since onset of migraine	Days per month with migraine	Acute medications	Control subjects	Age
MB	21	10	2	Sumatriptan	MA	29
LB	28	5	4	Sumatriptan	SB	35
RC	36	5	4	Naratriptan	MDH	22
SK	29	11	6	Sumatriptan	SG	28
VR	25	9	4	Sumatriptan	MM	24
NV	43	25	5	Sumatriptan + naproxen	GS	23
Mean ± S.D.	30.3 ± 7.9	10.8 ± 7.4	4.1 ± 1.32	26.8 ± 4.9
None of the patients had ever been on prophylactic medications.

PET procedures

Migraine and control subjects were submitted to two PET scans on the same day. They were examined in the morning after fasting for at least three hours. The baseline PET scan (scan 1) was performed, the subjects were then given eletriptan 40 mg orally with a glass of water and the second PET was performed approximately one hour later. In both PET studies, 70-minute dynamic scans were performed with venous blood sampling after injection of up to 13 mCi of α-[¹¹C]MTrp (controls: scan 1: 10.7 ± 0.3 mCi; scan 2: 10.1 ± 0.4 mCi; and patients: scan 1: 10.2 ± 0.6 mCi and scan 2: 9.3 ± 0.5 mCi). Up to 13 venous blood samples were drawn during the scan, at progressively longer intervals, to obtain a time-radioactivity course in plasma (input function). Five additional venous samples were drawn for high-performance liquid chromatographic (HPLC) analysis measurement of free and total plasma concentrations of tryptophan (12).

Data acquisition and co-registration of PET and MRI

PET scans were obtained with an ECAT EXACT HR + whole-body tomography scanner (Siemens Canada Inc, Toronto, Canada), which has 63 image slices at an intrinsic resolution of 5.0 × 5.0 × 5.0 mm full width at half maximum (FWHM). Images were collected and reconstructed in three dimensions (3D) using an isotropic Hanning filter of 8.1 mm FWHM, yielding images with an FWHM resolution of about 9.5 mm. The main reason for selecting this size filter was the fact that we wanted to be compatible with our other studies (13,14). Before beginning the dynamic PET scans, transmission scans were performed using ⁶⁸Ga-⁶⁸Ge source for attenuation correction. All images were smoothed using a Gaussian filter of 10.0 × 10.0 × 10.0 mm to a final resolution of ∼12.8 mm FWHM to reduce the individual variability in cortical gyral anatomy of the brain. Each subject underwent high-resolution MRI scanning (160 slices, 1 mm thick) within a mean of 15 days from the PET studies (range: 1–74 days) with a Siemens Vision scanner (1.5 T, CTI/Siemens). The MRI images were acquired in 3D, T1-weighted volumes (voxel size = 1 mm³; field of view (FOV) = 256 × 256 × 160 mm matrix; repetition time (TR) = 18 ms; echo time (TE) = 10 ms; flip angle = 30°). Co-registration of individual PET and MRI images was performed using an automatic procedure (15) that uses averaged tissue activity images obtained from the time period during five to 60 minutes of dynamic PET data, as described previously (12). The MRI images from each subject were transferred into Talairach space automatically.

Data analysis

To calculate α-[¹¹C]MTrp trapping constants (K*; μl/g/min) with venous samples, normalized input functions were estimated using the previously validated method (12). The normalized venous sinus trigeminal autonomic cephalagias (TACs) were used as the input functions for the calculation of K* images. As described previously (11), the use of this input function results in values for the brain uptake constant that are not significantly different from those calculated with the arterial input function. The functional images of the brain trapping constant K*, previously shown to be highly correlated with 5-HT synthesis in rat brain (16) and, in humans, with the constant for conversion of ¹¹C-labeled 5-hydroxytryptophan into 5-HT (17), were obtained by fitting the tissue TACs to the linearized form of the three-rate constant biological model (18). K* values were taken as a surrogate of 5-HT synthesis (16,19) as their conversion into 5-HT synthesis rates would require knowledge of the lumped constant (16), which has never been measured in humans.

Statistical analysis

Twenty-two regions of interest (ROIs) were selected using an available template (20) and corresponded to: the amygdala, caudate nucleus, anterior, medial and posterior cingulate cortex, frontal operculum, orbital, medial and superior frontal cortex, hippocampus, insular cortex, occipital cortex, globus pallidus, paracentral gyrus, parahippocampus gyrus, inferior and superior parietal gyri, putamen, supplementary motor area, temporal pole and thalamus. The 22 ROIs corresponded to the same ROIs analyzed in a previous study using a very similar protocol in the acute phase of migraine (9). These ROIs correspond to the standard Montreal Neurological Institute (MNI) protocol. In all of these regions, K* values for the left and right sides were first selected separately and since no significant left-to-right differences were found, the mean value for each region was calculated and subsequently used for statistical comparisons. Additionally, the periaqueductal gray region including the raphe nucleus was drawn by hand on the MRI image of each subject, identified as the dorsal brain stem, and transferred to the co-registered K* image. An additional analysis was performed in which the left and right ventral midbrain areas were identified and transferred to the co-registered K* values. K* values of all ROIs were calculated for each subject from K* functional image using MarsBaR software (20). The ROIs were selected to be in direct comparison with our previous study (9). All values are expressed as mean ± SEM.

Two-way repeated-measure analysis of variance (ANOVA) (RMANOVA) with Benjamini and Hochberg (21) post hoc correction was used in between scans and the left-to-right sides data comparisons (Statistica 7, StatSoft Inc, Tulson, OK, USA). Patients and controls were compared using ANOVA. Values with a p < 0.05 were considered statistically significant.

Results

There was no significant difference in the age between controls and patients (F(1,5) = 0.62; p > 0.4).

PET data: Baseline K* in control and migraine subjects

Plasma-free and total tryptophan levels (mean ± SEM) were comparable among all scans using RMANOVA with respective average concentrations control and migraine subjects of 9.7 ± 0.9 and 9.9 ± 0.8 nmol/ml (scan 1) and 9.9 ± 0.9 and 9.2 ± 0.8 nmol/ml (scan 2) of free Trp and 34.8 ± 2.2 nmol/ml and 33.0 ± 4.9 nmol/ml (scan 1) and 32.2 ± 1.6 nmol/ml and 35.9 ± 4.6 nmol/ml of total Trp. The RMANOVA revealed no significant difference between controls and patients (F(1,0) = 0.05, p > 0.8 for free Trp and F(1,0) = 0.04, p > 0.8 for total Trp), or for interaction between free or total and scan (scan*free-Trp; F(1,10) = 0.87, p > 0.4; scan*total-Trp F(1,14) = 3.6, p > 0.08). A set of representative mean images of K* obtained for scans 1 and 2 is shown in Figure 1. The global (mean ± SEM) values of K* for the whole brain were 5.0 ± 0.3 and 6.0 ± 0.6 μl/g/min for the first and second scans for control subjects (Table 2), which was not significantly different (F(1,5) = 4.39; p = 0.09), and 5.7 ± 0.3 and 4.5 ± 0.3 μl/g/min for migraine subjects (Table 3), which was significantly different (F(1,5) = 172; p < 0.0001). RMANOVA analysis indicated no overall significant difference between the first and second scan in controls (F(1,5) = 2.87; p > 0.1), but there was a significant SCAN*REGION interaction(F(22,15) = 1.7; p < 0.05) with significantly different 5-HT synthetic rates only in the frontal orbital cortex (Table 1). The significance of this region is lost after Benjamini and Hochberg post hoc correction. In the migraine patient group (Table 2) there was a significant difference between two scans (F(1,5) = 128.9; p < 0.001) and significant SCAN*REGION interaction (F(21,105) = 1.97; p < 0.02). More specifically, RMANOVA showed a decrease in K* values (p < 0.05) after eletriptan in all ROIs in patients. In patients all regions survived Benjamini and Hochberg post hoc correction. A format test of the magnitude of the drug effects also revealed that the drug effect (scan 1 compared to scan 2) is significantly greater in patients than that in the controls (F(1,10) = 19.6; p < 0.002).

Figure 1.

Images constructed from PET average K* values (μl/g/minute) comparing baseline K* values before and after administration of eletriptan in control subjects on the left side of the panel and in migraine subjects on the right side of the panel. The color bars on the side of the panel correlate with the K* values.

Table 2.

Global and regional (K*) in control subjects in selected brain areas at baseline and after administration of eletriptan.

K*	Control subjects
K*	Mean ± SEM	Mean ± SEM	F(1,5)	p
Scan 1	Scan 2
Global	5.02 ± 0.29	6.04 ± 0.56	4.39	0.090
Amygdala	7.71 ± 0.41	9.15 ± 0.58	3.15	0.136
Caudate	8.86 ± 0.39	9.15 ± 0.60	0.13	0.729
Ant_Cingul	8.58 ± 0.48	9.81 ± 0.53	4.13	0.098
Mid_Cingul	7.76 ± 0.50	9.62 ± 0.97	4.65	0.084
Post_Cingul	6.35 ± 0.66	8.04 ± 0.99	4.14	0.098
Oper_Front	7.57 ± 0.58	8.85 ± 0.72	3.34	0.127
Orb_Front	7.14 ± 0.59	9.08 ± 0.72	8.12	0.036
Mid_Front	7.74 ± 0.48	9.09 ± 0.58	4.49	0.088
Sup_Front	7.81 ± 0.53	8.95 ± 0.48	5.39	0.068
Hippocam	7.79 ± 0.42	8.50 ± 0.49	1.64	0.257
Insula	8.61 ± 0.48	10.09 ± 0.74	4.07	0.100
Occipit	7.20 ± 0.65	7.98 ± 0.91	0.60	0.475
Pallid	9.11 ± 0.38	10.32 ± 0.70	1.76	0.242
Paracentr	7.45 ± 0.49	8.34 ± 0.56	1.67	0.253
Para_Hippoc	6.36 ± 0.56	7.62 ± 0.84	2.05	0.212
Inf_Pariet	7.76 ± 0.59	9.30 ± 0.88	4.67	0.083
Sup_Pariet	7.25 ± 0.56	7.66 ± 0.88	0.20	0.674
Putam	9.38 ± 0.45	10.89 ± 0.62	3.23	0.132
Supp_Motor_area	7.36 ± 0.53	8.72 ± 1.02	2.00	0.217
Temp_pole	5.87 ± 0.41	7.30 ± 0.64	6.59	0.050
Thalam	8.44 ± 0.42	9.40 ± 0.75	1.33	0.301
Para_Aqual_Gray	7.16 ± 0.63	7.48 ± 0.59	0.12	0.739
Only Frontal Orb Cortex difference significant. The significance is lost after Benjamini and Hochberg correction.

Amy: amygdala; Caud: caudate nucleus; Cing an: anterior cingulate cortex; Cing MI: mid cingulate cortex; Cing post: posterior cingulated cortex; Fro oper: frontal operculum; Fro orb: frontal orbital cortex; Fro sup: frontal superior cortex; Hipp: hippocampus; Insu: insular cortex; Occip: occipital cortex; Pall: pallidum; Paracent: paracentral cortex; Hipp par: parahippocampal cortex; Par inf: parietal inferior cortex; Par sup: parietal superior cortex; Put: putamen; Supp mot: supplementary motor cortex; Temp pol: temporal pole; Thal: thalamus, PAG: periaqueductal gray area.

Table 3.

Global and regional (K*) in migraine subjects in selected brain areas at baseline and after administration of eletriptan.

K*	Migraine subjects
K*	Mean ± SEM	Mean ± SEM	F(1,5)	p
Scan 1	Scan 2
Global	5.66 ± 0.31	4.52 ± 0.29	172.2	4.59E-05
Amygdala	9.42 ± 0.29	7.42 ± 0.28	58.5	6.08E-04
Caudate	9.90 ± 0.67	7.96 ± 0.57	32.2	2.37E-03
Ant_Cingul	10.22 ± 0.45	8.39 ± 0.42	66.7	4.48E-04
Mid_Cingul	9.05 ± 0.51	7.61 ± 0.61	53.5	7.47E-04
Post_Cingul	7.82 ± 0.50	6.51 ± 0.65	31.0	2.57E-03
Oper_Front	8.84 ± 0.48	6.74 ± 0.53	158.2	5.64E-05
Orb_Front	7.52 ± 0.46	5.80 ± 0.72	38.9	1.55E-03
Mid_Front	8.78 ± 0.43	6.63 ± 0.37	178.0	4.23E-05
Sup_Front	8.82 ± 0.49	6.73 ± 0.41	106.4	1.47E-04
Hippocam	9.30 ± 0.46	7.45 ± 0.34	37.6	1.67E-03
Insula	9.91 ± 0.49	7.92 ± 0.46	82.5	2.71E-04
Occipit	8.08 ± 0.80	5.62 ± 0.75	44.9	1.12E-03
Pallid	10.50 ± 0.56	8.75 ± 0.83	15.3	1.13E-02
Paracentr	8.31 ± 0.52	6.59 ± 0.42	112.1	1.30E-04
Para_Hippoc	7.26 ± 0.60	5.09 ± 0.56	99.5	1.73E-04
Inf_Pariet	8.91 ± 0.76	6.58 ± 0.63	44.5	1.14E-03
Sup_Pariet	8.16 ± 0.83	5.61 ± 0.59	15.1	1.15E-02
Putam	10.93 ± 0.59	9.14 ± 0.67	22.8	4.98E-03
Supp_Motor_area	8.93 ± 0.55	6.66 ± 0.58	363.0	7.34E-06
Temp_pole	7.10 ± 0.43	5.47 ± 0.52	57.9	6.22E-04
Thalam	9.45 ± 0.56	7.24 ± 0.60	64.1	4.92E-04
Para_Aqual_Gray	8.10 ± 0.77	5.25 ± 0.72	35.9	1.85E-03
Here all differences are significant even after Benjamini and Hochberg correction.

The K* value in the interictal phase of migraine subjects and in control subjects was not statistically significant. However, after oral administration of eletriptan 40 mg (scan 2) there was a statistically significant difference between control and migraine subjects with a decrease in K* values in migraine subjects by 20.1%. Statistical significance was reached in all of the 22 regions studied as compared to interictal values (scan 1) (Table 3). In the areas defined as the dorsal brain stem that included the periaqueductal gray (PAG) and raphe nucleus, the superior parietal cortex, the parahippocampal cortex and the occipital cortex K* values decreased by respectively 35%, 31%, 30% and 30%. In control subjects, the administration showed a trend toward a global increase in K* values (20.3%) that, however, did not reach statistical significance. Statistical significance was reached in one of the 22 regions studied (scan 2) as compared to the baseline values (scan 1) (Table 2), but the significance was lost after making Benjamini and Hochberg post hoc corrections. Of interest, none of the regions that showed a higher decrease in K* in migraine subjects reached statistical significance and in particular the dorsal brain stem area showed a nonreactivity to eletriptan with a decrease in K* on the order of 4.5%. Furthermore, the regions studied that showed the lowest changes in the rate of 5-HT synthesis included the thalamus (11.4%), the superior parietal cortex (5.7%), the occipital cortex (10.8%), the hippocampus cortex (9.1%) and the caudate nucleus (3.3%).

Discussion

At baseline, we found no difference in the K* between the study and control groups. Previous studies had documented an increase in the rate of cerebral 5-HT synthesis in the interictal phase of migraine (4) or a trend toward a slight reduction (9). These differences could be explained by differences in study groups or in the method used to calculate the K* value. Indeed, our study groups consisted strictly of premenopausal women with either no migraine history as defined in the methods or strictly MoA women. Previous studies had included both genders and both types of migraine, MA and MoA, and one of these studies had calculated the K* value without integrating the influence of plasma-free or bounded tryptophan (4). Gender differences in the rate of cerebral 5-HT synthesis have been documented (22) as well as possible differences between MA and MoA (4). In addition, the influence of variable serum tryptophan concentrations on the K* value has also been documented (17). No difference in the K* has been documented in normal subjects according to their age (23).

To our knowledge, this is the first study on the effect of a triptan given orally in the interictal phase of migraine and in control subjects on the K* values taken as surrogate markers of the rate of 5HT synthesis.

Although the radioligand used in this study has no affinity for a specific 5-HT receptor, following exposure to serotonin agonist eletriptan, this study showed distinctive changes in the K* values in migraine subjects in the interictal phase of their condition with a significant reduction (16.3%) in the global K* value. In contrast, no statistically significant changes were documented in the control group. Eletriptan, a 5-HT agonist, is, among the triptans the one that has the highest lipophilicity (24). Although eletriptan’s maximal affinity is for receptors 5-HT_1B,D,F, it also shows some affinity for 5-HT_1A,1E and 5-HT₇ receptors (25). 5-HT_1A and 5-HT_1B autoreceptors are respectively predominant at the somato-dendritic sites and at the axon terminals. Their activation prevents the release of 5-HT and downregulates its synthesis. Binding at the heteroreceptors does not affect 5-HT synthesis (26,27). Eletriptan did not modify the k* in control subjects whereas the global K* was reduced after administration of eletriptan in migraine patients. A possible alteration in the 5-_HT1A and/or the 5-_HT1B autoreceptor sensibility from a sensitization process is suggested as an explanation for the documented reduction in K* following the administration of eletriptan in migraine patients. A similar reduction in the K* values was recently reported when 5-HT agonist sumatriptan was administered in the acute phase of migraine (9). In control subjects, a trend toward an effect in the opposite direction with an upregulation in K* was observed (Table 2) This trend toward an upregulation in the 5-HT synthesis in control subjects after administration of eletriptan may suggest a predominant effect on the 5-HT_1B autoreceptors leading to a positive feedback mechanism from the reduction in the amount of extracellular 5-HT agonist activity. In migraine patients, more likely sensitization of some groups of 5-HT receptors, namely autoreceptors 5-HT_1A and 5-HT_1B from a chronic hyposerotonergic state (28), could explain a negative feedback response to eletriptan.

In migraine patients, after administration of eletriptan, all brain areas studied showed statistically significant decrease, even after a post hoc correction, in the K* values. These changes were particularly more important in the dorsal brainstem area and in the occipital, superior parietal and parahippocampal cortices with values respectively at −35%, −31%, −30% and −30% when the global K* change was at −20.3% These areas of the brain have been most implicated in migraine with the early demonstration of an upper brain stem activation at the time of a migraine attack (7) and abnormalities in the sensory processing in the interictal phase of migraine (26).

In contrast, in control subjects, although the global K* value was not globally altered in a statistically significant fashion after administration of eletriptan, a trend toward an increase in the global K* value was observed (20.1%). Of interest, those areas with maximal changes documented in migraine subjects showed no significant difference in control subjects. Respectively, the dorsal brainstem, the occipital, the superior parietal and parahippocampal areas gave K* values at+4.5%, +10.8%, +5.7% and +19.8%. Given the striking changes documented in those areas in migraine subjects after administration of eletriptan and the relative non reactivity of the same areas to eletriptan in control subjects, a significant modification in the sensibility of receptors 5-HT_1B,D,F in the interictal phase of migraine is suggested in those regions of the brain.

Electrophysiologically the documented abnormalities in the intensity dependence of cortical and visual-evoked potentials (29 –31) felt to be related to an alteration in 5-HT function would suggest a similar phenomenon. A modification in 5-HT availability in migraine has also been suggested using different methods including an increased availability of a 5-HT transporter in the brain stem of migraineurs (28). Our findings add one more observation suggesting that interictally migraine is associated with an altered serotonin receptor reactivity. Such an alteration with its associated downregulation in the 5-HT synthesis and its consequential negative influence on inhibitory brain stem modulation could be interpreted as one of the contributing factors to an altered sensory threshold in the trigeminovascular system and to a dysfunctional regulation of cortical excitability (32).

The rate of cerebral 5-HT synthesis has been measured in our study using regional α-[¹¹C]MTrp trapping, which is considered a reliable acceptable method under normal and some pathological conditions (4,33,34). The global trapping of α-[¹¹C]MTrp (K*, ml/g/min) can be converted with some assumptions (35) into regional rates of brain 5-HT synthesis and the trapping is not flow dependent. We believe that this method has provided a reliable index of cerebral 5-HT synthesis in both groups studied.

In summary, our study would suggest an altered serotonin synthesis regulation in the interictal phase of migraine. Although several other markers of an altered 5-HT biosynthesis have been identified in migraine, their fundamental mechanisms remain largely unknown. The absence of difference between the study groups in the baseline 5-HT synthesis rate could be related to similar proximal rate-limiting mechanisms in migraine and in control subjects but different distal feedback mechanisms including autoreceptor sensitization.

Our study does have some limitations. First, the 5-HT radioligand used was not receptor specific, whereas the 5-HT agonist eletriptan studied had the receptor affinities described above. Our conclusions can therefore be applicable only to those 5-HT receptors. Second, the study groups included only premenopausal women all on estrogen therapy for contraception purposes, and therefore the conclusions drawn from our results cannot be generalized. Third, the PET studies were not completed at the same time of the menstrual cycle and thence the changes seen after administration of eletriptan could possibly theoretically be explained by the variability in the serotonin level within the migraine population or within the control population because of hormonal influences. If that were to be the case such variability would have been seen in the baseline scans, and those changes observed in the synthesis of 5-HT after the administration of eletriptan would have shown a scatter in both groups rather than congruous changes. Moreover, although animal studies have shown modulation of brain 5-HT concentration from the ovarian hormones at different phases of the estrus cycle, a recent PET study performed in healthy women has failed to show alteration in the 5-HT_1A and 5-HTT binding during the menstrual cycle (36). Fourth, both PET scans in any study subject were conducted on the same day, allowing for a possible session effect. However, using the same protocol, previous data have shown that the scan-rescan variability remains very small (37). In addition, the study was performed on a relatively small number of female patients; however, the number is within those used in PET studies. Because this study was conducted only in female patients, the conclusion should not be generalized for both genders. Fifth, although the migraine study subjects were required to have been migraine free for at least three days at the time of the PET study, no documentation of the following attack was kept.

Clinical implications

This study suggests an altered serotonin autoreceptor (5-HT_1A,B) sensibility in the interictal phase of migraine with an effect on serotonin synthesis regulation.

This alteration predominates in the upper brain stem and in the parietal, occipital and parahippocampal cortex.

Footnotes

Funding

This work was supported by a research grant (protocol A1601049) from Pfizer Canada (MA, PI).

Conflict of interest

Dr Aubé has received a nonconditional and unrestricted grant from Pfizer Canada to conduct this research. Dr Aubé was a member of the Pfizer Canada Advisory Board. The other authors have nothing to declare.

Acknowledgments

The authors thank Ms C Barber for nursing assistance and the staff of the Montreal Neurological Institute PET and Cyclotron-Radiochemistry Units.

References

Sicuteri

. Headache as a possible expression of deficiency of brain 5-hydroxytryptamine (central denervation hypersensitivity). Headache 1972; 12: 69–72.

Ferrari

Odink

Tapparelli

. Serotonin metabolism in migraine. Neurology 1989; 39: 1239–1242.

Kovács

Bors

Tóthfalusi

. Cerebrospinal fluid (CSF) investigations in migraine. Cephalalgia 1989; 9: 53–57.

Chugani

Niimura

Chaturvedi

. Increased brain serotonin synthesis in migraine. Neurology 1999; 53: 1473–1479.

Proietti-Cecchini

Afra

Schoenen

. Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: Demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia 1997; 17: 849–854.

Supornsilpchai

Sanguanrangsirikul

Maneesri

. Serotonin depletion, cortical spreading depression, and trigeminal nociception. Headache 2006; 46: 34–39.

May

. New insights into headache: An update on functional and structural imaging findings. Nat Rev Neurol 2009; 5: 199–209.

Weiller

May

Limmroth

. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995; 1: 658–660.

Sakai

Dobson

Diksic

. Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 2008; 70: 431–439.

10.

Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders (second edition). Cephalalgia 2004; 24(Suppl 1): 1–160.

11.

Silberstein

Lipton

Solomon

. Classification of daily or near-daily headaches: Proposed revisions to the IHS classification. Headache 1994; 34: 1–7.

12.

Nishizawa

Leyton

Okasawa

. Validation of a less invasive method for measurement of serotonin with alpha-[¹¹C] methyl-tryptophan. J Cereb Blood Flow Metab 1998; 18: 1121–1129.

13.

Kumakura

Natsume

Toussaint

. Generation of functional images of the brain trapping constant for α[¹¹C]methyl-L-tryptophan using constrained linear regression. Open Medical Imaging Journal 2011; 5: 14–25.

14.

Sakai

Nishikawa

Leyton

. Cortical trapping of α-[¹¹C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males. Neuroimage 2006; 33: 815–824.

15.

Woods

Mazziotta

Cherry

. MRI-PET registration with automated algorithm. J Comput Assist Tomogr 1993; 17: 536–546.

16.

Diksic

Young

. Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan. J Neurochem 2001; 78: 1185–1200.

17.

Leyton

Diksic

Benkelfat

. Brain regional alpha-[¹¹C]methyl-L-tryptophan trapping correlates with post-mortem tissue serotonin content and [¹¹C]5-hydroxytryptophan accumulation. Int J Neuropsychopharmacol 2005; 8: 633–634.

18.

Blomqvist

. On the construction of functional maps in positron emission tomography. J Cereb Blood Flow Metab 1984; 4: 629–632.

19.

Chugani

Musik

. Alpha[C-11]methyl-L-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab 2000; 20: 2–9.

20.

Tzourio-Mazoyer

Landeau

Papathanassiou

. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002; 15: 273–289.

21.

Benjamini

Hochberg

. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995; 57: 289–300.

22.

Sakai

Nishihawa

Leyton

. Cortical trapping of α-[¹¹C]methyl-L-tryptophan, an index of serotonin synthesis, is lower in females than males. Neuroimage 2006; 33: 815–824.

23.

Rosa-Neto

Benkelfat

Sakai

. Brain regional α-[¹¹C]methyl-L-tryptophan trapping in healthy adults: Absence of an age effect. Eur J Nucl Med Mol Imaging 2007; 34: 1254–1264.

24.

Dodick

Martin

. Triptans and CNS side-effects: Pharmacokinetic and metabolic mechanisms. Cephalalgia 2004; 24: 417–424.

25.

Strijbos

Parsons

Fugelli

. Eletriptan Pfizer. Curr Opin Investig Drugs 2002; 3: 1359–1368.

26.

McDevitt

Neumaier

. Regulation of dorsal raphe nucleus function by serotonin autoreceptors: A behavioral perspective. J Chem Neuroanat 2011; 41: 234–246.

27.

Chugani

Musik

Chakraborty

. Human brain serotonin synthesis capacity measured in vivo with α-[C-11]methyl-L-tryptophan. Synapse 1998; 28: 33–43.

28.

Schuh-Hofer

Richter

Geworski

. Increased serotonin transporter availability in the brainstem of migraineurs. J Neurol 2007; 254: 789–796.

29.

Wang

Timsit-Berthier

Schoenen

. Intensity dependence of auditory evoked potentials is pronounced in migraine: An indication of cortical potentiation and low serotonergic transmission. Neurology 1996; 46: 1404–1409.

30.

Ambrosini

Rossi

De Pasqua

. Lack of habituation causes high intensity dependence of cortical evoked potentials in migraine. Brain 2003; 126(Pt 9): 2009–2015.

31.

Afra

Proietti Cecchini

Sándor

. Comparison of visual and auditory evoked potentials in migraine patients between attacks. Clin Neurophysiol 2000; 111: 1124–1129.

32.

Pietrobon

Moskowitz

. Pathophysiology of migraine. Annu Rev Physiol 2013; 75: 365–391.

33.

Rosa-Neto

Diksic

Okasawa

. Measurement of regional alpha-[¹¹C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 2004; 61: 556–563.

34.

Okasawa

Leyton

Benkelfat

. Statistical mapping analysis of serotonin synthesis images generated in healthy volunteers using positron-emission tomography and alpha-[¹¹C]methyl-L-tryptophan. J Psychiatry Neorosci 2000; 25: 359–370.

35.

Diksic

Young

. Study of brain serotonergic system with labeled alpha-methyl-L-tryptophan. J Neurochem 2001; 78: 1185–1200.

36.

Jovanovic

Karlsoson

Cerin

. 5-HTA_1A and 5-HTT binding during the menstrual cycle in healthy women examined with [¹¹C] WAY100635 and [¹¹C] MADAM PET. Psychiatry Res 2009; 172: 31–37.

37.

Rosa-Neto

Diksic

Leyton

. Stability of alpha-[¹¹C]methyl-L-tryptophan brain trapping in healthy male volunteers. Eur J Nucl Med Mol Imaging 2005; 32: 1199–1204.

α-[ 11 C] methyl-L tryptophan-PET as a surrogate for interictal cerebral serotonin synthesis in migraine without aura

Abstract

Background

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Methods

Migraine patients and control subjects

PET procedures

Data acquisition and co-registration of PET and MRI

Data analysis

Statistical analysis

Results

PET data: Baseline K* in control and migraine subjects

Discussion

Clinical implications

Footnotes

Funding

Conflict of interest

Acknowledgments

References