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Abstract

In this study we aimed to assess the brain distribution of 5-HT_1A receptors in migraine patients without aura. Ten female migraine patients and 24 female healthy volunteers underwent magnetic resonance imaging and positron emission tomography using a radioligand antagonist of 5-HT_1A receptors [4-(2'-methoxyphenyl)-1-[2'-(N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine (¹⁸F-MPPF)]. A simplified reference tissue model was used to generate parametric images of 5-HT_1A receptor binding potential (BP) values. Statistical Parametrical Mapping (SPM) analysis showed increased MPPF BP in posterior cortical areas and hippocampi bilaterally in patients compared with controls. Region of interest (ROI) analysis showed a non-significant trend in favour of a BP increase patients in cortical regions identified by the SPM analysis except in hippocampi, left parietal areas and raphe nuclei. During the interictal period of migraine patients without aura, the increase of MPPF BP in posterior cortical and limbic areas could reflect an increase in receptor density or a decrease of endogenous serotonin, which could explain their altered cortical excitability.

Keywords

Migraine PET serotonin

Introduction

Migraine is a common and chronic disorder, characterized by attacks of moderate to severe headache, frequently unilateral, often associated with nausea, vomiting, photophobia or phonophobia (1) and presenting a high prevalence of depression and generalized anxiety disorder (2, 3). The involvement of serotonin (5-HT) in the pathophysiology of migraine has been documented for over 30 years.

Pharmacological agents that cause 5 HT release, such as reserpine, are able to induce a migraine attack or to increase the incidence of migraine-like headaches in migrainous patients (4, 5). Many of the pharmacological agents used to treat migraine attacks interact with serotonin and its receptors (6, 7). In particular, a recent animal study has suggested that triptans and ergot derivatives, known as agonist of 5-HT_1B/D, could also interact with 5-HT_1A receptors (8). Similarly, the preventive treatments methysergide and pizotifen, antagonists of 5-HT₂ receptors, also have a weak affinity for 5-HT_1A receptors (6, 7); in consequence, 5-HT_1A receptors may also contribute to the efficacy of some drugs used in migraine prophylaxis (9). 5-HT_1A receptor hypersensitivity is the most likely explanation for the increased prolactine response to buspirone, a 5-HT_1A receptor agonist, in migrainous patients (10). Finally, an increase of serotonin synthesis during migraine attacks has been demonstrated in vivo in patients suffering from migraine without aura using positron emission tomography (PET) and α-[¹¹C]methyl-L-tryptophan (AMT) (11) and could reflect an alteration of 5-HT synthesis via regulation of 5-HT_1A raphe autoreceptors.

5-HT_1A receptors are mostly neuronal. They are either heteroreceptors, when located in target regions of 5HT neurons with a particularly high concentration in limbic areas, or autoreceptors on the soma and dendrites of 5HT neurons in raphe nuclei, where they exert a negative feedback on serotoninergic neuron firing activity (12, 13).

The 4-(2′-methoxyphenyl)-1-[2′-(N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine (¹⁸F-MPPF) is a radiotracer antagonist of 5-HT_1A receptors that has an affinity more similar to that of 5-HT for 5-HT_1A receptors (Ki = 3.3 nM) (14) compared with other 5-HT_1A radioligands, such as ¹¹C-WAY100635. Its affinity allows its own displacement by endogenous 5-HT (15, 16). In the present study we used ¹⁸F-MPPF for PET imaging of brain 5HT_1A receptors. The aim was to assess the interictal 5-HT_1A receptor's availability, which reflects the 5HT endogenous level, in patients suffering from migraine without aura.

Methods

Patients

Data concerning patient's histories and clinical features are summarized in Table 1.

Table 1

Patients' clinical data

Patients	Age (years)	Side of migraine attacks	Antecedents	Duration of migraine (years)	Last attack migraine before PET	Attacks of migraine frequency per month	GHQ28 depression score
1	45	R	None	22	20 days	3	0
2	27	L = R	None	15	40 days	2	0
3	29	L = R	None	14	12 days	3	2
4	42	L = R	None	26	3 days	4	0
5	27	L = R	None	13	5 days	4	0
6	25	L = R	None	12	7 days	2	1
7	22	L = R	None	8	4 days	4	0
8	24	R	None	17	2 days	2	0
9	35	L = R	Meningitis at 7 years	26	15 days	3	0
10	35	R	None	19	4 days	4	2
11	43	R	None	27	3 h	4	14
12	20	L > R	None	6	3 days	3	10

R, right; L, left; PET, positron emission tomography; GHQ, General Health Questionnaire.

Twelve (right-handed) women with a diagnosis of migraine headache without aura according to the International Headache Society (1), and having suffered from migraine attacks for over 5 years, were recruited from migraine out-patients followed in the Functional Neurology Department of the Neurological Hospital Pierre Wertheimer (Lyon, France).

On the day of the PET scanning, depression and migraine symptoms were evaluated using the General Health Questionnaire (GHQ-28) and Migraine Disability Assessment Scale (MIDAS, (17)) (level 1–4), respectively.

Exclusion criteria included any other neurological disease than migraine, and a history of analgesic abuse. At the time of the PET study, none of the patients was taking prophylactic migraine treatment. All of them had been attack-free for at least 3 days preceding the PET study.

All patients gave their informed consent to the protocol, which was approved by the local ethics committee (CPP, Centre Léon Bérard, Lyon) in accordance with the Declaration of Helsinki and French regulations on Biomedical Research.

Healthy subjects

All 24 female healthy subjects (19–67 years old, mean 43.1 ± 13.3 years) from our normative database (18) were considered. As previously described, control subjects had been selected on the basis of (i) no sign or history of neurological, psychiatric, cardiovascular, pleuro-pulmonary or haematological illness, (ii) no ongoing neuroleptic, antiparkinsonian methyl-dopa, β-blocker, monoamine oxidase inhibitor-A or -B, tricyclic antidepressant, thymoregulator or antimigraine treatment, (iii) no hormone replacement therapy, and (iv) a score below the threshold for depression (< 7) for the GHQ-28.

Magnetic resonance imaging acquisition

All patients and control subjects underwent a 3-D anatomical T1-weighted sequence on a 1.5-T Siemens Magnetom scanner (Siemens AG, Erlangen, Germany). Data were acquired in the sagittal plane. The anatomical volume, consisting of 130–170 slices with 1-mm³ voxels, covered the whole brain. Magnetic resonance images (MRIs) were visually analysed by a neurologist to ensure that no brain lesion or malformation was present.

PET data acquisition and pre-processing

The methodology of tracer production, scan acquisition and data pre-processing was the same as previously described (19).

To summarize, ¹⁸F-MPPF was acquired with a CTI Exact HR+ scanner for 60 min after the injection of 151.6 MBq of ¹⁸F-MPPF (mean ± s.d., 151.6 ± 24.6 MBq). Sinograms were normalized, attenuated and scatter corrected, then reconstructed with filtered backprojection (Hanning filter: cut-off 0.5 cycle/voxel). This yielded a dynamic study of 35 volumes of 128 × 128 × 63 voxels with a voxel size of 2.04 × 2.04 × 2.42 mm³. All PET acquisitions were performed during the afternoon, and the patient's level of vigilance was supervised throughout the whole PET acquisition.

Parametric images of binding potential (BP) values as defined by (20) were obtained using a simplified reference tissue model (SRTM) introduced by (21) and validated by our group for ¹⁸F-MPPF studies (18). BP is a quantitative index combining the local density receptor and apparent in vivo affinity modulated by the extracellular endogenous serotonin concentration. Our previous study (18) confirmed that BP is a good index of local receptor concentration in normal subjects.

Using Statistical Parametrical Mapping (SPM2; Wellcome Trust Centre for Neuroimaging, UCL, London, UK) parametric images of BP were transformed into a standard space [Montreal Neurological Institute template of the ICBM Project (22)]. Normalized BP images were then smoothed using an 8 × 8 × 8-mm full-width at half-maximum isotropic Gaussian kernel to take into account interindividual anatomy variability and to improve the sensitivity of the statistical analysis (23).

BP global analysis

The BP global values were extracted for all patients and subjects using SPM. BP global values in patients were compared with BP global values in controls with Student's t-test. The significance threshold was set at P < 0.05.

Voxel-based analysis of PET data

We explored possible statistical differences between BP images of patients and controls using the linear model at each and every voxel (24). SPM2 was used on the normalized smoothed parametric BP images of patients and control subjects.

The statistical differences between patients and controls were estimated taking the age and global BP into account as covariable of no interest and using an ancova by condition. Statistical parametric maps of the t statistic (SPM_{t}) were calculated for two contrasts, controls–patients (BP decrease in patients compared with controls) and patients–controls (BP increase in patients compared with controls), with a threshold of P < 0.001 uncorrected at the voxel level. Significant clusters were then selected at a corrected level of P < 0.05 determined from a joint probability of peak height and cluster size (25).

Region of interest analysis

This analysis was carried out using an existing interactive 3-D atlas of the human brain created at the Montreal Neurological Institute (26). This atlas was obtained from a T1 MRI volume acquired from a single subject, spatially normalized into Talairach space and segmented into 90 identified structures. A set of 65 regions of interest (ROIs), including all cortical, limbic and thalamic areas, was selected from the 90 available. For the raphe nuclei, which are difficult to delineate on MRI, the contours were drawn on a MPPF-PET template by thresholding the activity at 80% of the local maximum in the brainstem (average of 50 normalized MPPF scans from our control database). The ROI was then displayed on the MRI template to verify its proper location in the periaqueductal grey matter of the brainstem.

For each patient, all ROIs were then applied on normalized and smoothed parametric BP images to extract a mean BP value for each region.

For each ROI, BP values in patients were compared with those in controls using a general linear model (SAS® software; SAS Inc., Cary, NC, USA). The group effect (patients vs. controls) was tested after adjustment for age (confounding effect). The significance threshold was set at P < 0.001 to correct for multiple comparisons.

Results

Clinical data

All patients suffered from migraine without aura and were headache free during the PET investigation. Only 10 of the 12 patients, showing a score below the threshold for depression (< 7) for the GHQ-28 and a delay of attack-free preceding the PET study inferior at 3 days, were included in the study; GHQ-28 depression scores ranged between 0 and 2 (mean ± s.d. 0.5 ± 0.85). They were aged 22–45 years (mean ± s.d. 31.1 ± 7.82).

Three patients suffered from migraine frequently lateralized on the right side, and seven did not show any predominant side for migraine (Table 1). On average, they had been suffering from migraine for 17.2 ± 6.01 years with a mean frequency of 3.1 ± 0.87 attacks per month. All patients had a MIDAS level of 3 of intensity and invalidity of their migraine. None of patients or control subjects had an MRI lesion.

BP global analysis

There was no difference in the mean BP global between patients (mean ± s.d. 0.53 ± 0.09) and controls (mean ± s.d. 0.48 ± 0.07) (P = 0.13).

SPM analysis

The contrast ‘patients–controls’ showed a significant increase of ¹⁸F-MPPF BP in seven different regions in patients compared with controls (Table 2). As illustrated in Fig. 1, these clusters were localized (i) for the left hemisphere, in the lateral parieto-occipital junction (Z_max = 6.33, k = 327, P < 0.03), the hippocampus (Z_max = 6.01, k = 1701, P < 0.001), the post-central gyrus (Z_max = 4.68, k = 957, P < 0.001) and the inferior parietal lobule (Z_max = 4.33, k = 354, P < 0.02), and (ii) for the right hemisphere, in the junction between superior temporal and middle temporal gyri (Z_max = 5.13, k = 2144, P < 0.001), the mesial aspect of the parieto-occipital junction (Z_max = 4.89, k = 1280, P < 0.001) and the hippocampus (Z_max = 4.74, k = 695, P < 0.002).

Figure 1

Statistical Parametrical Mapping results: regions showing an increase of 5-HT_1A binding potential (BP) in patients compared with 24 controls. All displayed regions had a T score thresholded at P < 0.05 after correction for multiple comparisons. Colour scale: Z score. The blue crosses are centred on significant clusters (except for the hippocampi). Statistical analysis showed seven regions with a significant increase of 5-HT_1A BP in patients in (a) left inferior parietal lobule, (b) left and right hippocampi and right junction between superior temporal and middle temporal gyri, (c) left lateral parieto-occipital junction, (d) left post-central gyrus, and (e) right internal parieto-occipital junction (cuneus and precuneus).

Table 2

Contrast ‘patients–controls’ of the Statistical Parametrical Mapping analysis

P corrected at the cluster level	k	Z score	x; y; z (mm)	Anatomical identification of Z_max
0.000	1701	6.01	−16; −8, −14	Left hippocampus
0.000	2144	5.13	64; −12; 0	Junction between right superior and middle temporal gyri
0.000	1280	4.89	6; −82; 44	Right internal parieto-occipital junction (cuneus and precuneus)
0.000	957	4.68	−34; −42; 50	Left post-central gyrus
0.001	695	4.74	26; −18; −10	Right hippocampus
0.018	354	4.33	−48; −38; 22	Left inferior parietal lobule
0.025	327	6.33	−44; −68; 18	Left lateral parieto-occipital junction

x, y, z are in Talairach coordinates, k is the cluster size (expressed in voxels).

The other contrast, ‘controls–patients’, revealed no significant decrease of ¹⁸F-MPPF BP in patients compared with controls.

ROI analysis

After adjustment for the age effect, no significant increase of mean BP in patients compared with controls was observed at P < 0.001 (Table 3). However, at an inferior P-value (P < 0.05), four ROIs showed a BP increase that was localized in the left medial occipito-temporal gyrus (P = 0.04), and right cuneus (P = 0.04), pre-cuneus (P = 0.01) and superior temporal gyrus (P = 0.03).

Table 3

Region of interest (ROI) analysis

ROI name	BP (patients) mean ± s.d.	BP (controls) mean ± s.d.	BP (patients) lsmean	BP (controls) lsmean	P-value (group effect after adjustment for age)
Amygdala L	1.10 ± 0.13	1.00 ± 0.13	1.07	1.00	0.20
Amygdala R	1.06 ± 0.13	1.01 ± 0.12	1.05	1.02	0.61
Hippocampal formation L	1.25 ± 0.16	1.16 ± 0.13	1.22	1.17	0.42
Hippocampal formation R	1.28 ± 0.19	1.15 ± 0.17	1.23	1.23	0.40
Parahippocampal gyrus L	0.79 ± 0.11	0.72 ± 0.08	0.79	0.72	0.09
Parahippocampal gyrus R	0.86 ± 0.09	0.80 ± 0.11	0.84	0.81	0.44
Cingulate region L	0.55 ± 0.09	0.56 ± 0.09	0.55	0.53	0.57
Cingulate region R	0.57 ± 0.08	0.52 ± 0.09	0.55	0.53	0.57
Insula L	0.85 ± 0.11	0.71 ± 0.13	0.82	0.73	0.07
Insula R	0.91 ± 0.13	0.78 ± 0.15	0.87	0.80	0.24
Superior temporal gyrus L	0.77 ± 0.13	0.67 ± 0.12	0.74	0.68	0.20
Superior temporal gyrus R	0.75 ± 0.12	0.62 ± 0.11	0.73	0.62	0.03
Middle temporal gyrus L	0.82 ± 0.13	0.78 ± 0.11	0.81	0.78	0.61
Middle temporal gyrus R	0.82 ± 0.14	0.74 ± 0.10	0.81	0.74	0.16
Inferior temporal gyrus L	0.79 ± 0.13	0.78 ± 0.11	0.79	0.78	0.93
Inferior temporal gyrus R	0.88 ± 0.15	0.82 ± 0.11	0.87	0.83	0.44
Medial occipitotemporal gyrus L	0.48 ± 0.11	0.39 ± 0.07	0.47	0.39	0.04
Medial occipitotemporal gyrus R	0.51 ± 0.11	0.41 ± 0.09	0.49	0.41	0.05
Lateral occipitotemporal gyrus L	0.69 ± 0.12	0.66 ± 0.09	0.68	0.67	0.75
Lateral occipitotemporal gyrus R	0.69 ± 0.12	0.60 ± 0.10	0.68	0.61	0.12
Lingual gyrus L	0.41 ± 0.15	0.35 ± 0.09	0.42	0.34	0.12
Lingual gyrus R	0.57 ± 0.15	0.51 ± 0.17	0.58	0.51	0.31
Superior occipital gyrus L	0.48 ± 0.10	0.42 ± 0.09	0.48	0.42	0.16
Superior occipital gyrus R	0.48 ± 0.11	0.40 ± 0.09	0.48	0.40	0.08
Middle occipital gyrus L	0.51 ± 0.11	0.44 ± 0.09	0.50	0.45	0.17
Middle occipital gyrus R	0.49 ± 0.13	0.45 ± 0.11	0.47	0.46	0.77
Inferior occipital gyrus L	0.48 ± 0.12	0.44 ± 0.10	0.47	0.44	0.49
Inferior occipital gyrus R	0.46 ± 0.14	0.40 ± 0.11	0.45	0.40	0.36
Occipital pole L	0.26 ± 0.11	0.27 ± 0.10	0.27	0.26	0.85
Occipital pole R	0.32 ± 0.10	0.31 ± 0.09	0.33	0.30	0.49
Precuneus L	0.67 ± 0.10	0.58 ± 0.12	0.65	0.58	0.14
Precuneus R	0.60 ± 0.11	0.48 ± 0.10	0.59	0.48	0.01
Superior parietal lobule L	0.49 ± 0.08	0.40 ± 0.11	0.47	0.41	0.16
Superior parietal lobule R	0.50 ± 0.09	0.41 ± 0.11	0.47	0.42	0.18
Inferior parietal lobule L	0.55 ± 0.13	0.45 ± 0.10	0.54	0.46	0.09
Inferior parietal lobule R	0.59 ± 0.13	0.50 ± 0.10	0.57	0.51	0.17
Cuneus L	0.46 ± 0.12	0.41 ± 0.10	0.45	0.42	0.35
Cuneus R	0.52 ± 0.11	0.43 ± 0.10	0.53	0.43	0.04
Postcentral gyrus L	0.47 ± 0.12	0.38 ± 0.09	0.45	0.39	0.13
Postcentral gyrus R	0.40 ± 0.10	0.33 ± 0.08	0.39	0.33	0.13
Precentral gyrus L	0.45 ± 0.10	0.39 ± 0.08	0.42	0.40	0.46
Precentral gyrus R	0.45 ± 0.10	0.37 ± 0.09	0.44	0.38	0.13
Superior frontal gyrus L	0.41 ± 0.11	0.36 ± 0.10	0.38	0.38	0.95
Superior frontal gyrus R	0.44 ± 0.11	0.38 ± 0.10	0.42	0.39	0.51
Middle frontal gyrus L	0.46 ± 0.11	0.42 ± 0.11	0.43	0.43	0.92
Middle frontal gyrus R	0.47 ± 0.11	0.41 ± 0.10	0.45	0.42	0.39
Inferior frontal gyrus L	0.52 ± 0.11	0.48 ± 0.09	0.52	0.48	0.38
Inferior frontal gyrus R	0.54 ± 0.10	0.47 ± 0.10	0.54	0.47	0.11
Medial frontal gyrus L	0.56 ± 0.11	0.53 ± 0.10	0.54	0.54	0.99
Medial frontal gyrus R	0.59 ± 0.10	0.51 ± 0.10	0.58	0.52	0.16
Fronto-orbital gyrus L	0.62 ± 0.10	0.57 ± 0.11	0.59	0.58	0.80
Fronto-orbital gyrus R	0.64 ± 0.11	0.62 ± 0.10	0.63	0.62	0.86
Raphe nuclei	0.23 ± 0.06	0.21 ± 0.12	0.19	0.22	0.43

Mean BP values in ROIs for patients and controls, least square means in patients and controls and P-values obtained from the General Linear Model for the group effect (patients vs. controls) after adjustment for age.

L, left; R, right, lsmean, least square mean; BP, binding potential.

BP values in raphe nuclei were not significantly different in patients and controls. No decrease of BP was observed in any ROI in migraine patients.

Discussion

Voxel-based SPM analysis of MPPF BP shows that the brain serotoninergic system is modified between attacks in migraine without aura. This interictal change consists of a MPPF BP increase in parieto-occipital, temporal and limbic areas. The ROI analysis did not confirm this MPPF BP increase at a threshold set at 0.001 to correct for multiple comparisons. This result could be due to the use of a strict P-value, and, contrary to the voxel-to-voxel approach in the SPM analysis, to the use for statistics of an average BP value within the ROI. Nevertheless, the analysis showed a non-significant trend in favour of a BP increase in migraine patients in four posterior cortical ROIs.

This increase of MPPF BP for 5-HT_1A receptors may reflect either an increase of 5-HT_1A receptor density or a reduction of endogenous serotonin release. MPPF being displaceable by endogenous 5-HT, a reduction of endogenous serotonin synthesis and release can cause an increase of MPPF binding (15, 16). Either or both mechanisms could be involved in the MPPF BP increase that we observed.

A serotonin metabolism dysfunction has been demonstrated in migraine without aura, but data concerning free plasmatic 5HT are often contradictory (27–29). Between attacks, migrainous patients were shown to have a lower plasmatic 5-HT level than controls and patients with tension headache (30).

The increased MPPF BP may reflect a low endogenous 5-HT during the attack-free period. 5-HT is considered to be an inhibitory neurotransmitter in the brain and could play a role in the central modulation of trigeminal pain. The cortical serotoninergic projections of raphe nuclei are numerous. They mainly target limbic areas, particularly the amygdala, the hippocampus and the entorhinal cortex (31), as well as parietal, occipital and frontal cortices (32, 33). 5-HT release or 5-HT-receptor-mediated transmission may contribute to the tonic suppression of nociceptive transmission (34). Recently, a PET study of 5-HT_1A receptors using the ¹¹C-WAY100635 in 11 healthy male subjects showed a negative correlation between BP and the intensity of the cold pressor pain in multiple brain areas of the pain matrix including prefrontal, cingulate and insular cortices (35). However, this study was performed only on male subjects, and we cannot exclude that the pain perception could be gender-dependent or slightly different in women subjects. Nevertheless, the localization of our MPPF BP changes, except for the hippocampi, is different from those involved in regulation of pain-related responses of this previous study, and brain areas involved in the pain matrix, in particular operculo-insular and cingulate cortex, do not show any interictal 5HT_1A receptors changes. Interictal modifications of MPPF BP are thus unlikely to reflect functional modifications of pain processing in migraine. More probably, they are linked to the interictal changes in cortical excitability reported in migrainous patients. Indeed, a decrease of serotonin synthesis may cause an alteration of cortical excitability mediated via 5-HT_1A receptors that have an inhibitory neuronal effect (36). The modifications of MPPF BP observed in posterior cortical areas in migraine patients could thus be linked to the lack of habituation of cortical responses to repetitive sensory stimulations during interictal state in migrainous patients, as demonstrated by visual and auditory-evoked potentials (AEP) studies ((37), see for a review (38, 39)). In migraine patients, the amplitudes of AEP with rising intensity show an increase that is higher than that observed in normals, with a steeper slope of the AEP vs. stimulus amplitude correlation (intensity dependence) (40–42). This intensity dependence being a valuable indicator of brain serotoninergic activity (43), this increased cortical excitability is considered to reflect a decrease in serotonin transmission. Thus, the hypothesis that the increased cortical MPPF BP that we observed in raphe cortical projection areas reflects reduced levels of endogenous 5HT would explain the interictal sensory stimulus hypersensitivity of migrainous patients.

In our study, no MPPF BP difference was observed in the raphe between migraine and control patients. Indeed, involvement of the raphe was expected in our patients. Evidence of raphe nucleus involvement in migraine is supported by lesion studies (44–46), by PET studies showing increased blood flow in the reticular or dorsal pons during the migraine attack and persistent after relief by sumatriptan (47–50), and, more recently, by serotonin transporter availability study (51).

The hypothesis that the cortical MPPF BP changes observed in our study were a consequence of reduced 5HT release at the raphe nuclei cortical terminals would have been supported by the finding of a change in raphe nuclei MPPF BP; this change would be compatible with an increased density of raphe nuclei 5HT_1A autoreceptors, known to mediate inhibitory feedback effect on 5HT synthesis (12, 13). However, we did not observe any MPPF BP change in the raphe of migrainous patients. This may be due to the small size of this structure that entails a strong partial volume effect. In our patients, we did not perform any partial volume effect correction (PVC), as partial volume effects remain the same for all subjects when regions with similar volumes are compared. The absence of PVC cannot therefore explain our results. In addition, the absence of any MPPF BP modification in raphe suggests that increased cortical and limbic MPPF BP may reflect more an increase 5-HT_1A receptor density than an increase of 5-HT_1A receptor availability.

In conclusion, this PET study has shown an increase of MPPF BP in posterior parieto-occipital and temporal cortical areas and limbic areas during the interictal period in migraine patients and has provided an argument in favour of a low brain serotonin level in migraineurs without aura between attacks. However, to rule out the possibility that our results reflect overexpression of 5-HT_1A cortical receptors between migraine attacks, it would be interesting to investigate migraine patients with PET using the ¹¹C-WAY100635 radioligand, which is insensible to endogenous serotonin changes, due to its high binding affinity with 5-HT_1A receptor.

Acknowledgements

We thank Didier Le Bars for ¹⁸F-MPPF radiosynthesis, and the CERMEP medical team for assistance.

References

1 Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd edition. Cephalalgia 2004; 24:1–160.

2 Hamelsky

Lipton

. Psychiatric comorbidity of migraine. Headache 2006; 46:1327–33.

Abbate-Daga

Fassino

Lo Giudice

Rainero

Gramaglia

Marech

Anger, depression and personality dimensions in patients with migraine without aura. Psychother Psychosom 2007; 76:122–8.

4 Panconesi

Sicuteri

. Headache induced by serotonergic agonists—a key to the interpretation of migraine pathogenesis? Cephalalgia 1997; 17:3–14.

Leone

Attanasio

Croci

Filippini

D'Amico

Grazzi

The serotonergic agent m-chlorophenylpiperazine induces migraine attacks: a controlled study. Neurology 2000; 55:136–9.

6 Hiner

Roth

Peroutka

. Antimigraine drug interactions with 5-hydroxytryptamine1A receptors. Ann Neurol 1986; 19:511–13.

7 Peroutka

. Antimigraine drug interactions with serotonin receptor subtypes in human brain. Ann Neurol 1988; 23:500–4.

8 Shields

Goadsby

. Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target? Neurobiol Dis 2006; 23:491–501.

9 Hamon

Bourgoin

[Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine. Current hypotheses]. Pathol Biol (Paris) 2000; 48:619–29.

10.

10 Cassidy

Tomkins

Dinan

Hardiman

O'Keane

. Central 5-HT receptor hypersensitivity in migraine without aura. Cephalalgia 2003; 23:29–34.

11.

11 Chugani

Niimura

Chaturvedi

Muzik

Fakhouri

Lee

Chugani

. Increased brain serotonin synthesis in migraine. Neurology 1999; 53:1473–9.

12.

12 Weissmann-Nanopoulos

Mach

Magre

Demassay

Pujol

. Evidence for the localization of 5HT1-A binding sites on serotonin containing neurons in the raphe dorsalis and raphe centralis nuclei of the rat brain. Neurochem Int 1985; 7:1061–72.

13.

13 Richer

Hen

Blier

. Modification of serotonin neuron properties in mice lacking 5-HT1A receptors. Eur J Pharmacol 2002; 435:195–203.

14.

14 Zhuang

Kung

Chumpradit

Kung

. Derivatives of 4-(2′-methoxyphenyl)-1-[2′-(N-2′-pyridinyl-p-iodobenzamido)ethyl]piperazine (p-MPPI) as 5-HT1A ligands. J Med Chem 1994; 37:4572–5.

15.

15 Rbah

Leviel

Zimmer

. Displacement of the PET ligand 18F-MPPF by the electrically evoked serotonin release in the rat hippocampus. Synapse 2003; 49:239–45.

16.

16 Zimmer

Rbah

Giacomelli

Le Bars

Renaud

. A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF binding in the rat hippocampus. J. Nucl. Med 2003; 44:1495–501.

17.

17 Stewart

Lipton

Dowson

Sawyer

. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology 2001; 56:S20–8.

18.

Costes

Merlet

Ostrowsky

Faillenot

Lavenne

Zimmer

A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. J Nucl Med 2005; 46:1980–9.

19.

Merlet

Ryvlin

Costes

Dufournel

Isnard

Faillenot

Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG. Neuroimage 2004; 22:886–96.

20.

20 Lammertsma

Hume

. Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4:153–8.

21.

Gunn

Sargent

Bench

Rabiner

Osman

Pike

Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY- 100635 for PET. Neuroimage 1998; 8:426–40.

22.

Mazziotta

Toga

Evans

Fox

Lancaster

Zilles

A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). Philos Trans R Soc Lond B Biol Sci 2001; 356:1293–322.

23.

23 Friston

Frith

Liddle

Frackowiak

RSJ

. Comparing functional (PET) images: the assessment of significant changes. J Cereb Blood Flow Metab 1991; 11:690–9.

24.

24 Friston

Holmes

Worsley

Poline

Frith

Frackowiak

RJS

. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 3:189–210.

25.

25 Worsley

Marrett

Neelin

Vandal

Friston

Evans

. A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 1996; 4:58–73.

26.

26 Kabani

MacDonald

Holmes

Evans

. 3D anatomical atlas of the human brain. Neuroimage 1998; 7:S717.

27.

27 Curran

Hinterberger

Lance

. Total plasma serotonin, 5-hydroxyindoleacetic acid and p-hydroxy-m-methoxymandelic acid excretion in normal and migrainous subjects. Brain 1965; 88:997–1010.

28.

28 Somerville

. Platelet-bound and free serotonin levels in jugular and forearm venous blood during migraine. Neurology 1976; 26:41–5.

29.

29 Ribeiro

Cotrim

Morgadinho

Ramos

Santos

de Macedo

. Migraine, serum serotonin and platelet 5-HT2 receptors. Cephalalgia 1990; 10:213–19.

30.

30 Ferrari

Odink

Tapparelli

Van Kempen

Pennings

Bruyn

. Serotonin metabolism in migraine. Neurology 1989; 39:1239–42.

31.

31 Kohler

Steinbusch

. Identification of serotonin and non-serotonin-containing neurons of the mid-brain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain. Neuroscience 1982; 7:951–75.

32.

32 Mamounas

Molliver

. Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA). Exp Neurol 1988; 102:23–36.

33.

33 Wilson

Molliver

. The organization of serotonergic projections to cerebral cortex in primates: regional distribution of axon terminals. Neuroscience 1991; 44:537–53.

34.

34 Mason

. Central mechanisms of pain modulation. Curr Opin Neurobiol 1999; 9:436–41.

35.

Martikainen

Hirvonen

Kajander

Hagelberg

Mansikka

Någren

Correlation of human cold pressor pain responses with 5-HT(1A) receptor binding in the brain. Brain Res 2007; 1172:21–31.

36.

36 Lanfumey

Hamon

. Central 5-HT1A receptors: regional distribution and functional characteristics. Nucl Med Biol 2000; 27:429–35.

37.

37 Giffin

Kaube

. The electrophysiology of migraine. Curr Opin Neurol 2002; 15:303–9.

38.

38 Schoenen

Ambrosini

Sandor

Maertens de Noordhout

. Evoked potentials and transcranial magnetic stimulation in migraine. Clin Neurophysiol 2003; 114:955–72.

39.

39 Gantenbein

Sándor

. Physiological parameters as biomarkers of migraine. Headache 2006; 46:1069–74.

40.

40 Wang

Timsit-Berthier

Schoenen

. Intensity dependence of auditory evoked potentials is pronounced in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996; 46: 1404–9.

41.

41 Afra

Proietti Cecchini

Sandor

Schoenen

. Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks. Clin Neurophysiol 2000; 111:1124–9.

42.

42 Ambrosini

Rossi

De Pasqua

Pierelli

Schoenen

. Lack of habituation causes high intensity dependence of auditory evoked cortical potentials in migraine. Brain 2003; 126:2009–15.

43.

43 Juckel

Molnar

Hegerl

Csepe

Karmos

. Auditory-evoked potentials as indicator of brain serotonergic activity—first evidence in behaving cats. Biol Psychiatry 1997; 41:1181–95.

44.

44 Raskin

Hosobuchi

Lamb

. Headache may arise from perturbation of brain. Headache 1987; 27:416–20.

45.

45 Haas

Kent

Friedman

. Headache caused by a single lesion of multiple sclerosis in the periaqueductal grey area. Headache 1993; 33:452–5.

46.

46 Veloso

Kumar

Toth

. Headache secondary to deep brain implantation. Headache 1998; 38:507–15.

47.

Weiller

May

Limmroth

Juptner

Kaube

Schayck

Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1:658–60.

48.

48 Bahra

Matharu

Buchel

Frackowiak

Goadsby

. Brainstem activation specific to migraine headache. Lancet 2001; 357:1016–17.

49.

49 Afridi

Matharu

Lee

Kaube

Friston

Frackowiak

RSJ

Goadsby

. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005; 128:932–9.

50.

50 Afridi

Giffin

Kaube

Friston

Ward

Frackowiak

RSJ

Goadsby

. A PET study in spontaneous migraine. Arch Neurol 2005; 62:1270–5.

51.

Schuh-Hofer

Richter

Geworski

Villringer

Israel

Wenzel

Increased serotonin transporter availability in the brainstem of migraineurs. J Neurol 2007; 254:789–96.

Interictal Brain 5-HT 1A Receptors Binding in Migraine Without Aura: A 18 F-MPPF-PET Study

Abstract

Keywords

Introduction

Methods

Patients

Healthy subjects

Magnetic resonance imaging acquisition

PET data acquisition and pre-processing

BP global analysis

Voxel-based analysis of PET data

Region of interest analysis

Results

Clinical data

BP global analysis

SPM analysis

ROI analysis

Discussion

Acknowledgements

References