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Abstract

Background

Migraine is one of the most common and disabling of all medical conditions, affecting 16% of the general population, causing huge socioeconomic costs globally. Current available treatment options are inadequate. Serotonin is a key molecule in the neurobiology of migraine, but the exact role of brain serotonergic mechanisms remains a matter of controversy.

Methods

We systematically searched PubMed for studies investigating the serotonergic system in the migraine brain by either molecular neuroimaging or electrophysiological methods.

Results

The literature search resulted in 59 papers, of which 13 were eligible for review. The reviewed papers collectively support the notion that migraine patients have alterations in serotonergic neurotransmission. Most likely, migraine patients have a low cerebral serotonin level between attacks, which elevates during a migraine attack.

Conclusion

This review suggests that novel methods of investigating the serotonergic system in the migraine brain are warranted. Uncovering the serotonergic mechanisms in migraine pathophysiology could prove useful for the development of future migraine drugs.

Keywords

Serotonin neurobiology of migraine molecular imaging electrophysiology brain

Introduction

Migraine is a common, disabling and socioeconomically costly disorder characterised by recurrent attacks of throbbing, severe headache accompanied by multisensory symptoms (1,2). It affects 16% of the world’s population and ranks seventh highest among all causes of disability (3). The pathophysiology of migraine is complex and most likely involves peripheral mechanisms, such as sensitised perivascular trigeminal nociceptors (4), abnormal cortical sensory processing (5) and altered central pain modulation (6).

The serotonergic system in the brain has its origin in the raphe nuclei of the brainstem. From here, serotonergic neurons project to nearly every region of the central nervous system (CNS) (Figure 1), including the primary sensory cortex, the thalamus, the trigeminal nuclei and the dorsal horns of the spinal cord (7). Serotonin acts through several different receptor subtypes (see Table 1) (8) and is involved in many psychophysiological functions such as sleep, mood, appetite and pain modulation (9).

Figure 1.

The serotonergic system in the brain. Schematic drawing depicting the serotonergic projections from the raphe nuclei. The raphe nuclei are divided into the rostral and the caudal groups.

The role of serotonin (5-hydroxytryptamine (5-HT)) in migraine pathophysiology has been a matter of discussion for decades. In the early 1960s, it was observed that during migraine attacks the urinary excretion of the main metabolite of serotonin, 5-hydroxyaindoleacetic acid, was increased (10,11). Other early studies found low plasma serotonin content between attacks and increases during attacks (12,13). These observations led to the theory of migraine being a syndrome of chronically low serotonin levels with transient increases during attacks. Providing further support for serotonergic involvement in migraine pathophysiology, previously used prophylactic treatments such as methysergide and pizotifen are 5-HT₂ antagonists (14) and the most efficient acute treatment to date – triptans – are selective 5-HT_1B/1D receptor agonists (15 –17).

Early studies of serotonin in patients employed measurements of the systemic serotonin levels and metabolism, but less is known about the serotonergic involvement in the brain of migraineurs (18). Here, we provide an overview of human studies investigating the serotonergic system in the migraine brain utilising molecular neuroimaging or electrophysiological methods as their primary tools. We discuss their methodological shortcomings and the implications of their findings for the understanding of the serotonergic involvement in migraine. Furthermore, we provide future perspectives on the continued search for serotonergic biomarkers in the migraine brain.

Investigating the serotonergic system in the brain

Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been used to investigate the serotonergic system in the migraine brain. With specific radioligands, these methods enable investigations of different aspects of the serotonergic system, such as synthesis, serotonin transporter (SERT) availability and the density of serotonin receptors. These measures will be reported in this review (see Table 2). Serotonergic neurotransmission is assumed to modulate sensory processing in the visual and auditory cortices. Electrophysiological investigations with event-related potentials (ERPs) and evoked potentials (EPs) generated with visual or auditory stimuli are therefore applied in the investigation of central serotonergic neurotransmission in migraine (see Table 3) (22,23). In this review, we focus on correlations between these measures and blood, platelet or plasma serotonin.

Materials and methods

This review is based upon articles found via PubMed searching combining free text and MeSH terms for migraine and migraine-abortive treatment (“migraine” OR “migraineurs” OR “primary headache disorder” OR “triptan” OR “triptans”), serotonin and serotonin receptor (“serotonin” OR “5-HT” OR “5-HT receptor” OR “5-HT ligand” OR “serotonin receptor”) and neuroimaging and EPs (“PET” OR “neuroimaging” OR “positron emission tomography” OR “functional neuroimaging” OR “evoked potentials”). This search was carried out on September 15, 2014.

Furthermore, a review of the reference lists from the included articles was performed in order to find additional articles that were not found during the original search protocol. Human studies using molecular imaging or electrophysiological methods reflecting the serotonergic system in the migraine brain (see Tables 2 and 3) were considered to be eligible for review. Non-English studies were excluded. The initial screening was conducted based on the titles and abstracts. The remaining articles were reviewed in full text in order to determine eligibility.

Results

The PubMed search returned 59 records, of which 13 were eligible for review (Figure 2).

Figure 2.

Results flowchart depicting the search protocol.

Given that migraine is a multiphasic disorder, we stratified and presented studies based on data collection timing (i.e. during interictal, preictal, ictal and postictal phases) (Figure 3). Furthermore, studies using serotonergic affecting drugs are presented.

Figure 3.

The migraine cycle. Migraine is characterised by recurrent attacks of headache (ictal) accompanied by symptoms such as nausea, vomiting and photo- and phono phobia (2). Between attacks (interictal), patients are pain free. In the preictal phase, some patients experience premonitory symptoms such as neck stiffness, yawning, mood swings and fatigue (32).

The results and their interpretations by their authors are presented in Table 4.

Discussion

Interictal investigations

Molecular imaging

Cerebral serotonin synthesis in vivo was investigated in PET studies using the brain trapping constant, K*, for α-[¹¹C] methyl-l-tryptophan (α-[¹¹C]MTrp) as a surrogate marker for serotonin synthesis. However, it has been questioned as to whether α-[¹¹C]MTrp is an appropriate radioligand for the measurement of serotonin synthesis (33), while other studies support the notion that it might reflect the serotonin synthesis capacity (34) (for a review, see Diksic and Young (35)). Studies using this radioligand yielded contradictory results by reporting higher values of mean global K* in migraine patients compared to controls (36) and no difference in mean global K* between patients and controls (24,37). A lower K* was found in migraine patients in their interictal phases than in their ictal phases (37). The discrepancy between the outcomes of the studies could be due to methodological differences, such as the composition of study groups, the timing of scans relative to migraine attacks or in the calculation of K*.

One study employed brain PET imaging of the 5-HT₂ receptors and the specific distribution volume as the quantification method and reported no difference in cortical binding between migraine patients and controls (38). The cortical density of the excitatory 5-HT₂ receptor, which is involved in pain processing (21), is thus not altered interictally in migraine patients. Similarly, there was no difference in 5-HT_1A receptor binding in a region of interest-based analysis between migraine sufferers and controls (39). In contrast, a voxel-based statistical parametric analysis of the same dataset found an increase in 5-HT_1A receptor binding in seven regions of the brain, including parieto-occipital, temporal and limbic areas, suggesting an increase in receptor density in these areas in migraine patients (39). Since the ligand used – 2’-methoxyphenyl-(N-2’-pyridinyl)-p-¹⁸F-fluoro-benzamidoethylpiperazine – is not sensitive to the endogenous release of serotonin (27), this could instead indicate a chronic low level of serotonin in these specific areas, causing an upregulation of the inhibitory 5-HT_1A receptor. The limitations of this study (39) were, however, a low number of participants (n = 10) and the use of historical data for controls. Furthermore, 5-HT_1A binding is higher with low age (40), and it is unclear how the results were corrected for the difference in mean age between the two groups (31.1 years in patients vs. 43.1 years in controls). The availability of SERT has been investigated with the SPECT radiotracer 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (¹²³I-ADAM) (41). SERT binding was found to be higher in the brainstem, but not in the thalamus, in migraine patients compared to controls. This was interpreted by the authors as a dysregulation of serotonin in the brainstem (41). A high level of SERT could cause a low synaptic level of serotonin, which would be in line with the theory of low brain serotonin levels in migraine patients. However, the ratio method used in this study as a kinetic model for the ¹²³I-ADAM ligand, which relates the standardised uptake value in a target region to that in a reference tissue region, may overestimate results (42), and these results would need to be replicated with a better radioligand or quantification method.

Table 1.

Overview of serotonin receptors.

Receptor family	Subtypes	Type	Function	Relevance for migraine
5-HT₁	5-HT_1A 5-HT_1B 5-HT_1D 5-HT_1E 5-HT_1F	G-protein coupled	Inhibitory auto- and hetero-receptor	Triptans – acute migraine medication – are 5-HT_1B/1D agonists 5-HT_1F agonists have proven effective in migraine (19)
5-HT₂	5-HT_2A 5-HT_2B 5-HT_2C	G-protein coupled	Excitatory heteroreceptor	5-HT₂ antagonists are effective as migraine prophylactics (15)
5-HT₃		Ligand-gated ion channel	Excitatory heteroreceptor	Involved in descending pain facilitation (20)
5-HT₄		G-protein coupled	Excitatory heteroreceptor	No known implication
5-HT₅	5-HT_5A	G-protein coupled	Inhibitory	No known implication
	5-HT_5B^a
5-HT₆		G-protein coupled	Excitatory	No known implication
5-HT₇		G-protein coupled	Excitatory	Coupled to pain processing (21)

Not expressed in humans.

Table 2.

Molecular imaging methods used in the reviewed articles.

Radioligand	Kinetic modeling	Analysis	Parameters	Interpretation
α-[¹¹C]-methyl-l-tryptophan	Time–radioactivity curve in plasma	Statistical parametric mapping	Trapping constant, K*	Surrogate for serotonin synthesis rate (24)
				Increased brain uptake indicates increased synthesis rate (25)
¹⁸F-4-(2’- methoxyphenyl)-1-[2’-(N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazin; 5-HT_1A receptor antagonist ligand (26)	Simplified reference tissue model	SPM	Binding potential, BP_ND	Increased BP_ND indicates increased receptor density, altered receptor affinity or increased endogenous serotonin levels (27)
¹⁸F-setoperone; 5-HT₂ and D₂ receptor antagonist ligand (28)	Radioactivity in the regions of interest less than the cerebellum activity	Ct/Cp = ∫ Ct/Cp (Ct = brain-specific radioactivity; Cp = free radioligand)	Specific distribution volume
¹²³I-ADAM; specific SERT ligand (29)	Ratio method	Counts in regions of interest = (target – reference)/reference	Count ratio	The higher the ratio, the higher the transporter availability
				Increased transporter availability decreases extracellular serotonin levels

¹²³I-ADAM: 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine; SERT: serotonin transporter; SPM: statistical parametric mapping; BP_ND: binding potential (non displacelable); D2: dopamin type 2 receptor.

Table 3.

Electrophysiological methods used in the reviewed articles.

Outcome	Components measured	Parameters	Stimuli	Interpretation
Visual evoked potential	N1, P1, N2, P2	Latency Amplitude	Checkerboards in different sizes: 8’, 31’, 65’	The cortical areas from which the potentials are generated are innervated by serotonergic neurons. Low serotonergic transmission leads to reduced cortical pre-activation, which causes lack of habituation (30)
		Habituation	Black and white checkerboards

Visual event-related potential	P2, N2, P3	Latency Amplitude Habituation	Active oddball stimulus paradigm with white and red flashes, red flashes being the stimuli to pay attention to
Auditory evoked potentials	N1, P1, N2, P2	Latency Habituation Amplitude Amplitude/stimulus intensity function	Binaural stimulation at 40, 50, 60 and 70 dB above hearing threshold	The cortical area from which the potentials are generated are innervated by serotonergic neurons. Pronounced intensity dependence of the auditory evoked N1/P2 component reflects low central serotonergic transmission (22)
Brainstem auditory evoked potential	Wave I–V	Latency Peak-to-peak amplitude Brainstem dispersion ratio (shape ratio IV–V) Amplitude/stimulus intensity function	Binaural stimulation at 40, 55 and 70 dB above hearing threshold	Indicators of brainstem dysfunction Serotonin modulates brainstem excitability (31)

Table 4.

Molecular imaging and electrophysiological studies on the brain serotonin system in migraine patients.

Authors, year of publication	Method	Results	Interpretation
Interictal investigations
Chugani et al., 1999	PET imaging of α-[¹¹C]MTrp brain uptake	Higher brain uptake in migraine patients without aura compared to controls	Increased 5-HT synthesis capacity in patients due to increased 5-HT turnover causing lower brain serotonin levels compared to controls
Sakai et al., 2014	PET imaging of α-[¹¹C]MTrp brain uptake	No difference in global brain uptake between patients and controls	5-HT synthesis rate does not differ between patients and controls
Sakai et al., 2008	PET imaging of α-[¹¹C]MTrp brain uptake	No difference in global brain uptake between patients and controls, but low uptake in some cortical areas in patients	Lower cortical serotonergic tone interictally in patients compared to ictal levels and compared to controls
		Lower interictal compared to ictal brain uptake
Chabriat et al., 1995	PET imaging of the 5-HT₂ receptor	Normal cortical binding in patients compared to controls	No difference in 5-HT₂ receptor density between patients and controls
Lothe et al., 2008	PET imaging of the 5-HT_1A receptor	Increased cortical binding in patients compared to controls	Low cortical serotonin level in patients between attacks
Schuh-Hofer et al., 2007	PET imaging of the SERT	Increased availability of the SERT in the brainstem in patients compared to controls	Dysregulation of the brainstem serotonergic system in migraine
Evers et al., 1999	VERP	Lower overall platelet 5-HT content in patients compared to controls, but no significant changes during the migraine interval	Lower 5-HT of central neurons in patients compared to controls
		Higher P3 latency in patients compared to controls and negative correlation between platelet 5-HT and P3 latency
Sand et al., 2008	BAEP	Lower overall platelet 5-HT content in patients compared to controls Lack of association between 5-HT and BAEP parameters No change in ASF slope during the migraine cycle	Dysregulation of the serotonin system, but normal brainstem auditory pre-activation in migraine patients
Sand et al., 2009	VEP	Lack of association between 5-HT in platelets and N1P1 amplitude for 31’ checks	The association between 5-HT and the generation of VEPs found in controls may be disrupted in migraine
		Increased VEP amplitude in MA patients compared to MO patients and to controls	Disturbed serotonin metabolism may be more pronounced in MA than in MO
		No difference in habituation between patients and controls
Sand et al., 2008	VEP	Lower overall platelet 5-HT content in patients compared to controls Increased VEP amplitude in MA patients compared to MO patients and controls No migraine cycle-related changes in habituation	A reduced level of serotonergic neurotransmission causes the increased VEP amplitude in MA patients
Preictal investigations
Sand et al., 2008	BAEP	No correlation between amplitude or SR IV–V and 5-HT	Dysregulation of the serotonin system is linked to migraine pathophysiology
		Trend towards a negative correlation between plasma 5-HT and wave I and V latency for 70 dB
Sand et al., 2009	VEP	Increased P1N2 amplitude compared to interictal Lack of association between 5-HT in platelets and N1P1 amplitude	Increased amplitudes in the pre-attack phase could be caused by decreased intracortical inhibition
Sand et al., 2008	VEP	Increased P1N2 amplitude compared to interictal No changes in serotonin concentrations compared to interictal levels	Increased amplitudes in the pre-attack phase could be caused by decreased intracortical inhibition
Ictal investigations
Demarquay et al., 2011	PET imaging of the 5-HT_1A receptor during odour-triggered migraine attacks	Higher binding in the brainstem in patients experiencing an attack compared to controls and to patients not experiencing an attack	The increased binding could be caused by a decrease in endogenous 5-HT
Sakai et al., 2008	PET imaging of α-[¹¹C]MTrp brain uptake	Increase in brain uptake compared to ictal levels	The serotonin synthetic activity increases during attacks, which leads to a normalisation of the low interictal 5-HT levels in the brain
Sand et al., 2008	BAEP	No attack-related changes in ASF slope No change in platelet 5-HT content compared to interictal levels Negative correlation between plasma 5-HT and habituation for wave IV-V and SR IV-V to 55 dB	Neither systemic 5-HT levels nor intensity dependence of BAEP change during attacks
Sand et al., 2009	VEP	Positive correlation between 5-HT in platelets and N1P1 amplitude in MA	The relationship between 5-HT and VEPs seems to be restored ictally in MA
Sand et al., 2008	VEP	Positive correlation between 5-HT in platelets and P1 and P1N2 amplitude habituation in MA	The serotonin metabolism changes ictally
		No change in platelet 5-HT content
Evers et al., 1999	VERP	Increased P3 latency compared to interictal	Serotonergic neurotransmission decreases ictally
		Decrease in platelet 5-HT content
Postictal investigations
Sand et al., 2008	BAEP	Positive correlation between 5-HT in plasma and wave V amplitude, SR IV–V and wave I latency to 70 dB and ASF slope	The normal relationship between 5-HT and BAEP parameters reappears postictally
Sand et al., 2008	VEP	No changes in platelet 5-HT content	Systemic 5-HT levels do not change during the migraine cycle
Post-interventional investigations
Chugani et al., 1999	PET imaging of α-[¹¹C]MTrp brain uptake before and after β-blocker treatment	Trend towards increased brain uptake after treatment with β-blockers	β-blockers increase the serotonin synthesis capacity in migraine patients
Sakai et al., 2014	PET imaging of α-[¹¹C]MTrp brain uptake before and after interictal administration of eletriptan	Significant decrease in brain uptake in migraine patients, but not in controls, after exposure to eletriptan	A chronic hyposerotonergic state in patients causes sensitisation of 5-HT_1B receptors and a negative feedback response to eletriptan
Sakai et al., 2008	PET imaging of α-[¹¹C]MTrp brain uptake after sumatriptan treatment of a migraine attack	Sumatriptan decreases brain uptake to a lower level than interictal and ictal	Sumatriptan reverses the ictal increases in brain 5-HT synthesis activity
Proietti-Cecchini et al., 1997	AEPs before and after zolmitriptan	Zolmitriptan increases the ASF slope. The effect is more pronounced in patients compared to controls	The effect of zolmitriptan is caused by an acute inhibition of 5-HT release. Patients are more responsive due to a chronic low level of serotonin
Ozkul et al., 2002	VEPs before and after fluoxetine	Treatment with fluoxetine corrected the lack of habituation found in patients before treatment	Patients have an interictal low level of serotonin, which normalises after fluoxetine treatment

-[¹¹C]MTrp: α-[¹¹C] methyl-l-tryptophan; AEP: auditory evoked potential; ASF: amplitude/stimulus intensity function; BAEP: brainstem auditory evoked potential; MA: migraine with aura; MO: migraine without aura; PET: positron emission tomography; SERT: serotonin transporter; SR IV–V: shape ratio IV–V; VEP: visual evoked potential; VERP: visual event-related potential.

Electrophysiology

In migraine patients, a negative overall correlation between the platelet content of serotonin and absolute latencies of the P3 component of visual ERPs was found (43). A loss of habituation of P3 latency was also found, but this was not associated with platelet serotonin content. These results suggest that serotonergic neurotransmission is linked to the latency of P3, but not to habituation in migraine patients, contrasting with reports of low serotonin causing a lack of habituation of auditory EPs (AEPs). In a longitudinal blinded study, the correlation between brainstem auditory EPs (BAEPs) and plasma serotonin levels was investigated. A positive correlation between amplitude and plasma serotonin was reported in controls, but not in migraine patients (31). The same group reported similar results for visual evoked potentials (VEPs), in which the N1P1 amplitude for medium-sized checks correlated positively with serotonin in plasma and platelets in controls, but not in migraine patients (44). Collectively, these data suggest an interictal disturbance of the association between systemic serotonin and EPs (31,44). This could indicate an altered serotonergic neurotransmission in migraine patients, but caution should be taken when comparing systemic and central serotonin levels, since serotonin is not transported from the periphery to the CNS (17).

Preictal investigations

Electrophysiology

For stimulations with 70 dB, a trend towards a negative correlation between BAEP wave I and V latency and plasma serotonin was observed preictally (31). No correlation was seen for amplitude or the brainstem dispersion ratio (SR IV–V; i.e. a measure of brainstem function). Two VEP studies did not report any correlations between serotonin levels or any parameters measured (44,45). These data suggest that the disturbance of the normal, positive correlation (see the section entitled ‘Interictal investigations’), which is found interictally in migraine patients, persists through the preictal phase, providing further support for the role of serotonin in migraine pathophysiology.

Ictal investigations

Molecular imaging

A small PET study of the 5-HT_1A receptor conducted during odor-triggered migraine attacks (46) showed higher binding in patients experiencing migraine attacks (n = 4) compared to both controls (n = 10) and to patients not developing a migraine attack (n = 6). The increased 5-HT_1A binding was found in both cortical areas and in the brainstem. These results could indicate an upregulation of the receptor or changes in receptor affinity during migraine attacks (46). A decrease in endogenous serotonin, as suggested by the authors, is not likely to cause the increase in binding (see the section entitled ‘Interictal investigations’). An increase in K* for α-[¹¹C]MTrp, which was found during migraine attacks, was suggested by the authors to reflect an increase in serotonin synthesis rate (37). The results are therefore in line with the theory of ictal increases in endogenous serotonin in the brain, but the reliability of the method and the number of participants (n = 6) should be taken into account.

Electrophysiology

Serotonin in plasma and habituation for wave IV–V amplitude and SR IV–V correlated negatively in the ictal phase (31). As in the preictal period, this was only found for one stimulus level of 55 dB, but not for 70 dB. A positive correlation between both P1N2 amplitude habituation (45) and N1P1 amplitude (44) in VEP and serotonin in platelets was found in a small group of patients (n = 8) with migraine with aura, but not in patients suffering from migraine without aura. The latter correlation was also found in controls (44,45). This indicates an ictal normalisation of the relationship between systemic serotonin and VEPs in migraine with aura.

During the migraine cycle, dynamic changes in both loss of habituation (i.e. no decrease in response after repeated stimuli) and in platelet serotonin content were observed (43). Interestingly, a decrease in platelet serotonin content coincided with an increase in habituation of the P3 latency during migraine attacks, but there was no correlation between the level of habituation and the serotonin level in platelets or in plasma. The increase in cognitive processing time, measured as P3 latency, reported during attacks was negatively correlated with the serotonin content in platelets. Based on these results, the authors suggested that the increase in cognitive processing time, but not the changes of habituation (using an oddball paradigm), during a migraine attack could be related to decreases in serotonergic neurotransmission. This is in contrast with data indicating an ictal increase in serotonergic neurotransmission (44,45). The authors did not report whether the same correlations were seen in controls, and it needs to be investigated further as to whether this is migraine specific or a common feature of the serotonergic system.

Postictal investigations

Electrophysiology

A positive correlation between wave I latency and plasma serotonin for 70 dB was found for BAEPs, in contrast to the negative correlation seen preictally. Furthermore, positive correlations between plasma serotonin and wave V amplitude, SR IV–V and amplitude/stimulus intensity function (ASF) slope were observed, which are similar to the correlations seen in controls (31). This indicates a normalisation of the correlations in migraine patients in the postictal period, which are suggested to reflect a normalisation of the serotonergic neurotransmission (31). However, these findings were derived from only one study and need to be replicated.

Investigations after treatment with serotonin-affecting drugs

Molecular imaging

In one small study (n = 5), α-[¹¹C]MTrp brain uptake was investigated in migraine patients before and after 12 weeks of treatment with β-blockers (either propranolol or nadolol, 5-HT_1A receptor antagonists and partial 5-HT_1B agonists) (36). Four out of five patients showed an increase in whole-brain uptake of the radioligand, suggesting an increase in serotonin synthesis capacity after treatment. This is consistent with 5-HT_1A antagonism, but contrasts with 5-HT_1B receptor agonism, since activation of 5-HT_1A and 5-HT_1B autoreceptors leads to a decrease in serotonin synthesis and release (47). Furthermore, the same study found a higher brain uptake in migraine patients before treatment compared to controls. Based on these results, it is surprising that prophylactic treatment causes further increases in brain uptake. However, the results should be interpreted with caution because of the small sample size. Eletriptan, a 5-HT_1B/1D receptor agonist that crosses the blood–brain barrier (BBB) (48), significantly decreased the α-[¹¹C]MTrp brain uptake in migraine patients in the interictal state, but had no effect in controls (24). This indicates a difference in response to 5-HT_1B receptor activation between the two groups. This difference could be due to sensitisation of 5-HT_1B autoreceptors in migraine patients, caused by low interictal serotonin levels in the migraine brain. In the ictal phase, sumatriptan, another 5-HT_1B/1D agonist, decreased the α-[¹¹C]MTrp brain uptake compared to both interictal and ictal levels in migraine patients (37). This suggests a central effect of sumatriptan on serotonin synthesis during migraine attacks, which could be exerted through 5-HT_1B autoreceptors (37).

Electrophysiology

An electrophysiological study with a limited number of subjects (49) demonstrated that treatment with both 5 mg (n = 8) and 10 mg (n = 6) zolmitriptan significantly increased the ASF slope of AEPs compared to both baseline and to placebo. The increase tended to be more pronounced in migraine patients compared to controls, but the difference did not reach statistical significance. Sumatriptan did not induce significant changes. The ASF slope reflects the intensity dependence of AEPs (IDAP), which is thought to be inversely related to serotonergic neurotransmission (50). The results, which are limited by the low number of subjects, thereby indicate that zolmitriptan decreases serotonergic neurotransmission, and this effect is more pronounced in migraine patients. This is in line with the effect of sumatriptan and eletriptan on α-[¹¹C]MTrp brain uptake and the hypothesis of chronic low serotonin in the migraine brain. In another electrophysiological study, the selective serotonin reuptake inhibitor fluoxetine was administered (20 mg daily) for 1 month (51). After treatment, migraine patients without aura (but not with aura) showed increased first block amplitude of VEPs compared to baseline. The treatment also corrected the lack of habituation observed in migraine patients during baseline. There was no longer a significant difference in mean amplitude changes in the fifth block expressed as a percentage of the first block between controls and migraine patients. These data suggest that VEPs are linked to serotonergic neurotransmission and that serotonergic neurotransmission is altered in migraine patients.

Methodological shortcomings

The results from existing investigations of the serotonergic system in the migraine brain are divergent (Table 4). Methodological shortcomings are pivotal factors causing these discrepancies. Several studies measure the platelet content of serotonin as a surrogate of neuronal transmission. Even though platelets have some resemblance to neurons with regards to the receptors, release, reuptake and storage of serotonin (52), platelet content of serotonin does not reflect the synaptic mechanisms between neurons. Plasma serotonin should not be directly compared to the serotonergic tonus in the brain either, since serotonin does not cross the BBB to any appreciable extent. Another point of concern with several of the reviewed studies is that headache diaries were not collected after the investigations (24,36 –39,49). Serotonin levels are thought to change in a cyclical manner in relation to the migraine cycle. Therefore, the time since the last migraine attack and the time to the next attack, relative to the time of the investigation, are highly important variables. The different subsets of subjects regarding age, gender, diagnosis and number are also highly discrepant between the studies. The stimulations used in the electrophysiological studies also differ in terms of, for example, check sizes of the alternating checkerboards for VEPs and sound frequencies and intensity levels for AEPs. Blinding of investigators is important, since three non-blinded electrophysiological studies found a lack of habituation in migraine patients (50,53,54), while blinded studies could not replicate these findings (55,56). However, a recent study comparing the habituation findings of blinded and non-blinded investigators found no differences in the results (57). Collectively, it is difficult to compare these results and draw any firm conclusions.

Brain PET studies using different serotonin receptor radioligands have limitations as well, especially due to the complex relationship between brain serotonin levels and the binding of serotonin receptor radioligands. Since the binding potentials depend on receptor affinity, neurotransmitter levels and receptor availability results must be interpreted with caution. The radioligands used in the reviewed studies are antagonists, which means that they are less sensitive to endogenous serotonin release compared to radioligands that are serotonin receptor agonists (27). Thus, the ictal increase in serotonin is less likely to be detectable with these ligands. Furthermore, the regulation of serotonin receptors is different from receptor to receptor (58,59). A low level of serotonin does not necessarily cause an upregulation of the receptor (60). Since serotonin is involved in the circadian rhythm (9), the timing of the scans should also be taken into consideration when interpreting binding potentials, as well as possible age differences between receptor distribution and density (61).

Possible serotonergic mechanisms in migraine pathophysiology

Even though the importance of serotonin in migraine pathophysiology is indisputable, the changes in the level of endogenous serotonin in the migraine brain have not yet been convincingly determined. The reviewed studies support the notion that migraine patients have alterations in the serotonergic system compared to non-migraineurs, and most likely they have a lower level between attacks, which then increases during a migraine attack (Table 4). How this difference in endogenous serotonin between migraine patients and controls and the sudden increases during attacks are linked to the sensation of head pain still remains to be fully elucidated. The headache phase in migraine depends on the activation of sensitised peripheral nociceptors and the trigeminal pathway (4), but central modulation of these signals is also involved. One prevailing theory relating serotonergic abnormalities to migraine is a central dysfunction of the pain-modulating system in migraineurs (62,63). Serotonin both facilitates and inhibits pain, depending on the site of action and the receptor subtype it activates (64). In the CNS, serotonin is predominantly analgesic, especially via mechanisms of descending inhibition (65), but a facilitatory role of serotonin has also been suggested (66). A low level of serotonin interictally could result in disinhibition of pain signals from peripheral nociceptors, thus lowering the threshold for the induction of headache. Furthermore, animal studies have shown that serotonin exacerbates pain in sensitised animals, whereas it inhibits pain in control animals (67). Low serotonergic tone could make migraine patients hypersensitive and more susceptible to stimuli, with sudden increases in serotonin during migraine attacks enhancing and maintaining the pain (e.g. through binding to proalgesic 5-HT_2A receptors) (64). Collectively, the function of serotonin in the pain-modulating system is dualistic and complex. It depends on receptor subtype, availability and affinity and the physiological or pathophysiological status, making it difficult to decipher the causality between serotonin and headache.

Supporting the theory of an increase in serotonin contributing to the headache are studies showing that treatment with serotonergic agonists acting on the cerebral excitatory 5-HT_2B and 5-HT_2C receptors or agents increasing synaptic serotonin causes headache (17,68,69). In contrast, intravenous infusion of serotonin relieved the pain in migraine patients (70) and inhibited sensory inputs from the dural vasculature in animals (71). This effect was most likely exerted through peripheral action sites, since serotonin does not cross the BBB (21). Evidence for central pain-relieving effects of serotonin is found in animal studies showing that the release of serotonin upon stimulation of the periaqueductal grey area causes analgesia through the stimulation of inhibitory interneurons acting on dorsal horn neurons (20,72). Since serotonin increases are observed after injury to nerves or to the spinal cord in animal models (73), one might also hypothesise that the increase in brain serotonin during a migraine attack could be a protective and pain-relieving mechanism.

PET studies reported brainstem activation during spontaneous migraine attacks (74,75). The activated areas include the raphe nuclei, suggesting activation of the serotonergic neurons. The low resolution of this method should, however, be taken into account when interpreting these results. Theoretically, an increased activation in the raphe nuclei could be associated with an increase in serotonergic signaling in the projection areas and activation of the endogenous anti-nociceptive system. Interestingly, the activation persisted following treatment with sumatriptan, indicating that brainstem activation is not necessarily coupled to pain processing and 5-HT_1B receptor-mediated serotonergic mechanisms (75).

The most efficient acute treatment of migraine – triptans – are 5-HT_1B receptor agonists (15,48). The 5-HT_1B receptor is present on the dural and cerebral vasculature, in the trigeminal ganglion and throughout the brain. It is both an autoreceptor inhibiting the release of serotonin from serotonergic neurons and also a heteroreceptor acting on non-serotonergic neurons (19,76). The central mechanisms of triptans are a subject of intense debate and have been investigated in several studies. Brain PET studies reported that zolmitriptan crosses the BBB and binds to central 5-HT_1B receptors with relatively low occupancy (77,78). It is still unknown whether sumatriptan has a central effect. Extracranial but not intracranial arteries constricted after sumatriptan treatment during a migraine attack (79), arguing against its penetration of the BBB. On the other hand, sumatriptan induces more CNS adverse events compared to placebo (80). A recent study reported that sumatriptan, but not acetylsalicylic acid, caused a decrease in trigeminal–cortical coupling in healthy volunteers after activation of the trigeminal nociceptive system (81). Furthermore, there is a discrepancy between the persistent brainstem activation (75) and the decreases in serotonin synthesis (37) after sumatriptan treatment. It could be speculated that 5-HT_1B receptor agonists modulate pain transmission in the CNS by primarily acting in the peripheral nervous system. On the other hand, if the pain relief is caused by central mechanisms, these could be explained by the existence of 5-HT_1B receptors in the descending pain-modulating pathways in the brainstem (82), with the inhibition of serotonin release and synthesis then being secondary. This further underlines the importance – and complexity – of serotonin in the migraine pathophysiology.

Future perspectives

The present review suggests that electrophysiological investigations are not optimal in the search for serotonergic biomarkers. Firstly, EPs and ERPs only indirectly reflect serotonergic neurotransmission. Secondly, the findings from electrophysiological studies are highly inconsistent. Interictal lack of habituation, which is the most consistent finding, is not reproducible in all studies. Recently, it has been disputed whether lack of habituation, also called the ‘neurophysiological hallmark of migraine’ (83), is even specific for migraine (56,84). Low first block amplitude and increased IDAP in migraine patients are additional controversial findings that are thought to be consequences of low serotonergic disposition (30,56). Reliable methods of elucidating the central serotonergic system in the migraine brain are therefore much needed. Future studies need to focus on more direct methods of investigating the serotonergic system in migraine. A recent study suggested that central 5-HT₄ receptor binding might serve as a biomarker of serotonergic tonus in the human brain (85). This method may be applied in migraine patients in order to accurately determine the differences in serotonergic levels between the migraine brain and controls. 5-HT₄ receptor binding is not affected by acute changes in endogenous serotonin levels, and other methods must be applied in order to obtain knowledge of the cyclical nature of the serotonin levels in the migraine brain. Currently, few PET studies have succeeded in measuring endogenous serotonin release (27). Studies with the 5-HT_1B receptor ligand [¹¹C]AZ10419369 in non-human primates have shown some potential, with decreases in binding after fenfluramine-induced serotonin release (86). Results from human studies have been less promising, with an increase in cortical binding after a single dose of escitalopram, a selective serotonin reuptake inhibitor (87). However, there was lower binding in the raphe nuclei, suggesting that the ligand is in fact sensitive to acute changes in endogenous serotonin, thus making it possible to detect changes in the serotonergic tonus during migraine attacks. In the future, these methods should be applied in migraine research in order to gain more knowledge of the pathophysiology and serotonergic mechanisms in the migraine brain.

Clinical implications

Migraine is most likely associated with low serotonin levels between attacks and transient increases during attacks.

The results of studies on the endogenous brain serotonin levels in migraine are divergent and brain serotonin levels have not yet been conclusively determined.

Electrophysiological studies yielded conflicting results and might not be optimal for investigating serotonergic biomarkers in the migraine brain.

Future studies should apply more direct methods of visualising the serotonergic system in the migraine brain, such as positron emission tomography with radiolabelled serotonin receptor agonists.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: this study was supported by the Lundbeck Foundation, grant number R-180-2014-3398.

References

Olesen

Gustavsson

Svensson

. The economic cost of brain disorders in Europe. Eur J Neurol 2012; 19: 155–162.

Headache Classification Committee of the International Headache Society (IHS) . The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

Steiner

Stovner

Birbeck

. Migraine: the seventh disabler. Cephalalgia 2013; 33: 289–290.

Olesen

Burstein

Ashina

. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 2009; 8: 679–690.

Goadsby

. Pathophysiology of migraine. Neurol Clin 2009; 27: 335–360.

Noseda

Burstein

. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain 2013; 154(Suppl.): S44–S53.

Törk

. Anatomy of the serotonergic system. Ann N Y Acad Sci 1990; 600: 9–34.

Celada

Puig

Artigas

. Serotonin modulation of cortical neurons and networks. Front Integr Neurosci 2013; 7: 25–25.

Hornung

. The human raphe nuclei and the serotonergic system. J Chem Neuroanat 2003; 26: 331–343.

10.

Sicuteri

Testi

Anselmi

. Biochemical investigations in headache: increase in the hydroxyindoleacetic acid excretion during migraine attacks. Int Arch Allergy Immunol 1961; 19: 55–58.

11.

Curran

Hinterberger

Lance

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

12.

Ferrari

Odink

Tapparelli

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

13.

Hamel

. Serotonin and migraine: biology and clinical implications. Headache Curr 2007; 27: 1293–1300.

14.

Hoyer

Clarke

Fozard

. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 1994; 46: 157–203.

15.

Saxena

Ferrari

. From serotonin receptor classification to the antimigraine drug sumatriptan. Cephalalgia 1992; 12: 187–196.

16.

Humphrey

. 5-Hydroxytryptamine and the pathophysiology of migraine. J Neurol 1991; 238(Suppl. 1): S38–S44.

17.

Ferrari

Saxena

. On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 1993; 13: 151–165.

18.

Panconesi

. Serotonin and migraine: a reconsideration of the central theory. J Headache Pain 2008; 9: 267–276.

19.

Tfelt-Hansen

Pihl

. Drugs targeting 5-hydroxytryptamine receptors in acute treatments of migraine attacks. A review of new drugs and new administration forms of established drugs. Expert Opin Investig Drugs 2013; 23: 375–385.

20.

Peng

Lin

Willis

. The role of 5-HT₃ receptors in periaqueductal gray-induced inhibition of nociceptive dorsal horn neurons in rats. J Pharmacol Exp Ther 1996; 276: 116–124.

21.

Viguier

Michot

Hamon

. Multiple roles of serotonin in pain control mechanisms – implications of 5-HT₇ and other 5-HT receptor types. Eur J Pharmacol 2013; 716: 8–16.

22.

Hegerl

Juckel

. Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 1993; 33: 173–187.

23.

Hegerl

Gallinat

Juckel

. Event-related potentials: do they reflect central serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J Affect Disord 2001; 62: 93–100.

24.

Sakai

Nishikawa

Diksic

. α-[11C] methyl-l tryptophan-PET as a surrogate for interictal cerebral serotonin synthesis in migraine without aura. Cephalalgia 2014; 34: 165–173.

25.

Chugani

Muzik

Chakraborty

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

26.

Plenevaux

Lemaire

Aerts

. [¹⁸F]p-MPPF: a radiolabeled antagonist for the study of 5-HT_1A receptors with PET. Nucl Med Biol 2000; 27: 467–471.

27.

Paterson

Tyacke

Nutt

. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab 2010; 30: 1682–1706.

28.

Blin

Pappata

Kiyosawa

. [¹⁸F]setoperone: a new high-affinity ligand for positron emission tomography study of the serotonin-2 receptors in baboon brain in vivo. Eur J Pharmacol 1988; 147: 73–82.

29.

Van De Giessen

Booij

. The SPECT tracer [¹²³I]ADAM binds selectively to serotonin transporters: a double-blind, placebo-controlled study in healthy young men. Eur J Nucl Med Mol Imaging 2010; 37: 1507–1511.

30.

Ambrosini

Schoenen

. The electrophysiology of migraine. Curr Opin Neurol 2003; 16: 327–331.

31.

Sand

Zhitniy

White

. Brainstem auditory-evoked potential habituation and intensity-dependence related to serotonin metabolism in migraine: a longitudinal study. Clin Neurophysiol 2008; 119: 1190–1200.

32.

Giffin

Ruggiero

Lipton

. Premonitory symptoms in migraine: an electronic diary study. Neurology 2003; 60: 935–940.

33.

Shoaf

Carson

Hommer

. The suitability of [¹¹C]-a-methyl-l-tryptophan as a tracer for serotonin synthesis: studies with dual administration of [¹¹C] and [¹⁴C] labeled tracer. J Cereb Blood Flow Metab 2000; 20: 244–252.

34.

Lundquist

Hartvig

Blomquist

. 5-hydroxy-l-[beta-¹¹C]tryptophan versus alpha-[¹¹C]methyl-l-tryptophan for positron emission tomography imaging of serotonin synthesis capacity in the rhesus monkey brain. J Cereb Blood Flow Metab 2007; 27: 821–830.

35.

Diksic

Young

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

36.

Chugani

Niimura

Chaturvedi

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

37.

Sakai

Dobson

Diksic

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

38.

Chabriat

Tehindrazanarivelo

. 5HT₂ receptors in cerebral cortex of migraineurs studied using PET and ¹⁸F-fluorosetoperone. Cephalalgia 1995; 15: 104–108.

39.

Lothe

Merlet

Demarquay

. Interictal brain 5-HT_1A receptors binding in migraine without aura: a ¹⁸F-MPPF–PET study. Cephalalgia 2008; 28: 1282–1291.

40.

Tauscher

Verhoeff

NPLG

Christensen

. Serotonin 5-HT_1A receptor binding potential declines with age as measured by [¹¹C]WAY-100635 and PET. Neuropsychopharmacology 2001; 24: 522–530.

41.

Schuh-Hofer

Richter

Geworski

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

42.

Frokjaer

Pinborg

Madsen

. Evaluation of the serotonin transporter ligand ¹²³I-ADAM for SPECT studies on humans. J Nucl Med 2008; 49: 247–254.

43.

Sand

White

Hagen

. Visual evoked potential and spatial frequency in migraine: a longitudinal study. Acta Neurol Scand Suppl 2009; 120: 33–37.

44.

Sand

Zhitniy

White

. Visual evoked potential latency, amplitude and habituation in migraine: a longitudinal study. Clin Neurophysiol 2008; 119: 1020–1027.

45.

Demarquay

Lothe

Royet

. Brainstem changes in 5-HT_1A receptor availability during migraine attack. Cephalalgia 2011; 31: 84–94.

46.

Evers

Quibeldey

Grotemeyer

. Dynamic changes of cognitive habituation and serotonin metabolism during the migraine interval. Cephalalgia 1999; 19: 485–491.

47.

Sharp

Serotonergic feedback control. In: Muller

Jacobs

(eds). Handbook of the Behavioral Neurobiology of Serotonin, 1st edn. London: Academic Press, 2009, pp. 233–247.

48.

Ferrari

Goadsby

Roon

. Triptans (serotonin, 5-HT_1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–658.

49.

Proietti-Cecchini

Áfra

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 5HT_1B/1D agonist zolmitriptan (311C90, Zomig®). Cephalalgia 1997; 17: 849–854.

50.

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: 1404–1409.

51.

Ozkul

Bozlar

. Effects of fluoxetine on habituation of pattern reversal visually evoked potentials in migraine prophylaxis. Headache J Head Face Pain 2002; 42: 582–587.

52.

Danese

Montagnana

Lippi

. Platelets and migraine. Thromb Res 2014; 134: 17–22.

53.

Ambrosini

Rossi

De Pasqua

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

54.

Afra

Proietti Cecchini

Sándor

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

55.

Omland

Nilsen

Uglem

. Visual evoked potentials in interictal migraine: no confirmation of abnormal habituation. Headache J Head Face Pain 2013; 53: 1071–1086.

56.

Omland

Uglem

Hagen

. Visual evoked potentials in migraine: Is the ‘neurophysiological hallmark’ concept still valid? Clin Neurophysiol 2016; 127: 810–816.

57.

Ambrosini

Schoenen

Magis

. EHMTI-0222. Habituation of visual evoked potentials in migraine: comparison between blinded and non-blinded analyses. J Headache Pain 2014; 15: E1–E1.

58.

Artigas

. Serotonin receptors involved in antidepressant effects. Pharmacol Ther 2013; 137: 119–131.

59.

Jacobs

Azmitia

. Structure and function of the brain serotonin system. Physiol Rev 1992; 72: 165–229.

60.

Saulin

Savli

Lanzenberger

. Serotonin and molecular neuroimaging in humans using PET. Amino Acids 2012; 42: 2039–2057.

61.

Nord

Cselenyi

Forsberg

. Distinct regional age effects on [¹¹C]AZ10419369 binding to 5-HT_1B receptors in the human brain. Neuroimage 2014; 103: 303–308.

62.

Panconesi

Bartolozzi

Guidi

. Migraine pain: reflections against vasodilatation. J Headache Pain 2009; 10: 317–325.

63.

Sicuteri

. Hypothesis: migraine, a central biochemical dysnociception. Headache 1976; 16: 145–159.

64.

Sommer

. Is serotonin hyperalgesic or analgesic? Curr Pain Headache Rep 2006; 10: 101–106.

65.

Stamford

. Descending control of pain. Br J Anaesth 1995; 75: 217–227.

66.

Suzuki

Rygh

Dickenson

. Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci 2004; 25: 613–617.

67.

Wei

Dubner

Zou

. Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci 2010; 30: 8624–8636.

68.

Sicuteri

Del Bene

Anselmi

. Fenfluramine headache. Headache 1976; 16: 185–188.

69.

Panconesi

Sicuteri

. Headache induced by serotonergic agonists – a key to the interpretation of migraine pathogenesis? Cephalalgia 1997; 17: 13–14.

70.

Kimball

Friedman

Vallejo

. Effect of serotonin in migraine patients. Neurology 1960; 10: 107–107.

71.

Lambert

Shimomura

Boers

. Serotonin infusions inhibit sensory input from the dural vasculature. Cephalalgia 1999; 19: 639–650.

72.

Cui

Feng

McAdoo

. Periaqueductal gray stimulation-induced inhibition of nociceptive dorsal horn neurons in rats is associated with the release of norepinephrine, serotonin, and amino acids. J Pharmacol Exp Ther 1999; 289: 868–876.

73.

Sommer

. Serotonin in pain and analgesia: actions in the periphery. Mol Neurobiol 2004; 30: 117–125.

74.

Afridi

Giffin

Kaube

. A positron emission tomographic study in spontaneous migraine. Arch Neurol 2005; 62: 1270–1275.

75.

Weiller

May

Limmroth

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

76.

Pierson

Andersson

Nyberg

. [¹¹C]AZ10419369: a selective 5-HT_1B receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain. Neuroimage 2008; 41: 1075–1085.

77.

Varnäs

Jučaite

McCarthy

. A PET study with [¹¹C]AZ10419369 to determine brain 5-HT_1B receptor occupancy of zolmitriptan in healthy male volunteers. Cephalalgia 2013; 33: 853–860.

78.

Wall

Kågedal

Bergström

. Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study. Drugs R D 2005; 6: 139–147.

79.

Amin

Asghar

Hougaard

. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 2013; 12: 454–461.

80.

Tfelt-Hansen

. Does sumatriptan cross the blood–brain barrier in animals and man? J Headache Pain 2010; 11: 5–12.

81.

Kröger

May

. Triptan-induced disruption of trigemino-cortical connectivity. Neurology 2015; 84: 2124–2131.

82.

Bartsch

Knight

Goadsby

. Activation of 5-HT_1B/1D receptor in the periaqueductal gray inhibits nociception. Ann Neurol 2004; 56: 371–381.

83.

Magis

Vigano

Sava

. Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia 2013; 33: 526–539.

84.

Stankewitz

May

. The phenomenon of changes in cortical excitability in migraine is not migraine-specific – a unifying thesis. Pain 2009; 145: 14–17.

85.

Haahr

Fisher

Jensen

. Central 5-HT₄ receptor binding as biomarker of serotonergic tonus in humans: a [¹¹C]SB207145 PET study. Mol Psychiatry 2014; 19: 427–432.

86.

Finnema

Varrone

Hwang

. Fenfluramine-induced serotonin release decreases [¹¹C]AZ10419369 binding to 5-HT_1B-receptors in the primate brain. Synapse 2010; 64: 573–577.

87.

Nord

Finnema

Halldin

. Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. Int J Neuropsychopharmacol 2013; 16: 1577–1586.

Serotonergic mechanisms in the migraine brain – a systematic review

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Investigating the serotonergic system in the brain

Materials and methods

Results

Discussion

Interictal investigations

Molecular imaging

Electrophysiology

Preictal investigations

Electrophysiology

Ictal investigations

Molecular imaging

Electrophysiology

Postictal investigations

Electrophysiology

Investigations after treatment with serotonin-affecting drugs

Molecular imaging

Electrophysiology

Methodological shortcomings

Possible serotonergic mechanisms in migraine pathophysiology

Future perspectives

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

References