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Review
Serotonergic mechanisms in the
migraine brain – a systematic review
Marie Deen
1,2,3
, Casper Emil Christensen
1
, Anders Hougaard
1
,
Hanne Demant Hansen
2
, Gitte Moos Knudsen
2,3
and
Messoud Ashina
1,3
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 develop-
ment of future migraine drugs.
Keywords
Serotonin, neurobiology of migraine, molecular imaging, electrophysiology, brain
Date received: 28 October 2015; revised: 3 January 2016; 16 February 2016; accepted: 26 February 2016
Introduction
Migraine is a common, disabling and socioeconomi-
cally costly disorder characterised by recurrent attacks
of throbbing, severe headache accompanied by multi-
sensory 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 mechan-
isms, such as sensitised perivascular trigeminal nocicep-
tors (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, seroto-
nergic neurons project to nearly every region of the
central nervous system (CNS) (Figure 1), including
the primary sensory cortex, the thalamus, the trigem-
inal nuclei and the dorsal horns of the spinal cord (7).
Serotonin acts through several different receptor sub-
types (see Table 1) (8) and is involved in many psycho-
physiological functions such as sleep, mood, appetite
and pain modulation (9).
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 excre-
tion of the main metabolite of serotonin, 5-hydroxyain-
doleacetic 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 syn-
drome of chronically low serotonin levels with transient
increases during attacks. Providing further support for
1
Danish Headache Center, Department of Neurology, The Neuroscience
Centre, Rigshospitalet, Denmark
2
Neurobiology Research Unit and Center for Experimental Medicine
Neuropharmacology, Department of Neurology, The Neuroscience
Centre, Rigshospitalet, Denmark
3
Faculty of Health and Medical Sciences, University of Copenhagen,
Denmark
Corresponding author:
Messoud Ashina, Danish Headache Centre and Department of
Neurology, The Neuroscience Centre, Rigshospitalet – Glostrup, Faculty
of Health and Medical Sciences, University of Copenhagen, Nordre
Ringvej 57, DK-2600 Glostrup – Copenhagen, Denmark.
Email: ashina@dadlnet.dk
Cephalalgia
0(0) 1–14
!International Headache Society 2016
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DOI: 10.1177/0333102416640501
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serotonergic involvement in migraine pathophysiology,
previously used prophylactic treatments such as methy-
sergide and pizotifen are 5-HT
2
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 meth-
ods as their primary tools. We discuss their methodo-
logical 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 seroto-
nergic biomarkers in the migraine brain.
Investigating the serotonergic system in the brain
Molecular imaging such as positron emission tomog-
raphy (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 investiga-
tions of different aspects of the serotonergic system,
such as synthesis, serotonin transporter (SERT) avail-
ability and the density of serotonin receptors. These
measures will be reported in this review (see Table 2).
Serotonergic neurotransmission is assumed to modu-
late sensory processing in the visual and auditory cor-
tices. 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
Table 1. Overview of serotonin receptors.
Receptor
family Subtypes Type Function Relevance for migraine
5-HT
1
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-HT
2
5-HT
2A
5-HT
2B
5-HT
2C
G-protein coupled Excitatory heteroreceptor 5-HT
2
antagonists are effective as migraine
prophylactics (15)
5-HT
3
Ligand-gated ion channel Excitatory heteroreceptor Involved in descending pain facilitation (20)
5-HT
4
G-protein coupled Excitatory heteroreceptor No known implication
5-HT
5
5-HT
5A
G-protein coupled Inhibitory No known implication
5-HT
5Ba
5-HT
6
G-protein coupled Excitatory No known implication
5-HT
7
G-protein coupled Excitatory Coupled to pain processing (21)
a
Not expressed in humans.
Thalamus
Hypothalamus Raphe nuclei
Cerebellum
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.
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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 recep-
tor’’ OR ‘‘5-HT ligand’’ OR ‘‘serotonin receptor’’)
and neuroimaging and EPs (‘‘PET’’ OR ‘‘neuroi-
maging’’ 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 elec-
trophysiological 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).
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 seroto-
nergic affecting drugs are presented.
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 trap-
ping constant, K*, for a-[
11
C] methyl-L-tryptophan (a-
[
11
C]MTrp) as a surrogate marker for serotonin synthe-
sis. However, it has been questioned as to whether a-
[
11
C]MTrp is an appropriate radioligand for the meas-
urement 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 con-
trols (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 out-
comes of the studies could be due to methodological
differences, such as the composition of study groups,
Table 2. Molecular imaging methods used in the reviewed articles.
Radioligand Kinetic modeling Analysis Parameters Interpretation
a-[
11
C]-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 syn-
thesis rate (25)
18
F-4-(2’- methoxyphe-
nyl)-1-[2’-(N-2-pirydy-
nyl)-p-fluorobenza-
mido]-ethylpiperazin; 5-
HT
1A
receptor antag-
onist ligand (26)
Simplified reference
tissue model
SPM Binding potential,
BP
ND
Increased BP
ND
indicates
increased receptor
density, altered recep-
tor affinity or increased
endogenous serotonin
levels (27)
18
F-setoperone; 5-HT
2
and D
2
receptor antag-
onist ligand (28)
Radioactivity in the
regions of interest less
than the cerebellum
activity
Ct/Cp ¼RCt/Cp
(Ct ¼brain-specific
radioactivity; Cp ¼free
radioligand)
Specific distribution
volume
123
I-ADAM; specific SERT
ligand (29)
Ratio method Counts in regions of
interest ¼(target – ref-
erence)/reference
Count ratio The higher the ratio, the
higher the transporter
availability
Increased transporter
availability decreases
extracellular serotonin
levels
123
I-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.
Deen et al. 3
the timing of scans relative to migraine attacks or in the
calculation of K*.
One study employed brain PET imaging of the 5-
HT
2
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-HT
2
recep-
tor, 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 suf-
ferers and controls (39). In contrast, a voxel-based stat-
istical 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-
18
F-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 (n¼10) 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 radiotra-
cer 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodo-
phenylamine (
123
I-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 sero-
tonin, 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
123
I-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 repli-
cated with a better radioligand or quantification
method.
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 serotoner-
gic 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 para-
digm 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 seroto-
nergic transmission (22)
Brainstem auditory
evoked potential
Wave I–V Latency
Peak-to-peak ampli-
tude
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 dysfunc-
tion
Serotonin modulates brainstem
excitability (31)
4Cephalalgia 0(0)
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 con-
trols, 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 inter-
ictal 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 pre-
ictally (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
Aura∗
Headache
Preictal lctal Postictal Interictal
72 h 4−72 h
nEP = 4
nPET = 0
nEP = 4
nPET = 2
72 h
nEP = 4
nPET = 0
nEP = 4
t
nPET = 6
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).
*A third of migraine patients report that the headache is preceded by transient central nervous system symptoms called ‘auras’. The
most common is visual aura.
n
EP
: number of articles using electrophysiology in the different time points of the migraine cycle; n
PET
: number of articles using positron
emission tomography in the different time points of the migraine cycle.
Records identified through
initial database search protocol
n = 59
Records screened
n = 59
Full text assessed for eligibility:
n = 15
Records included in review
n = 13
Records excluded:
n = 2
Records excluded:
n = 44
1 observational study
3 investigations in HC1
1 case study
1 MOH2 study
1 hemiplegia study
3 blood flow studies
3 editorial comments
19 reviews
4 non English
8 animal studies
2 no measurement of 5-HT
Figure 2. Results flowchart depicting the search protocol.
HC: healthy controls. MOH: medication overuse headache.
Deen et al. 5
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 a-[
11
C]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 sero-
tonin levels compared to controls
Sakai et al., 2014 PET imaging of a-[
11
C]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 a-[
11
C]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-HT
2
receptor
Normal cortical binding in patients
compared to controls
No difference in 5-HT
2
receptor dens-
ity 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 sero-
tonergic 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 con-
trols
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
(continued)
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Table 4. Continued.
Authors, year of
publication Method Results Interpretation
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 concentra-
tions 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-trig-
gered 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 a-[
11
C]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 inter-
ictal 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 a-[
11
C]MTrp
brain uptake before and after
b-blocker treatment
Trend towards increased brain uptake
after treatment with b-blockers
b-blockers increase the serotonin syn-
thesis capacity in migraine patients
Sakai et al., 2014 PET imaging of a-[
11
C]MTrp
brain uptake before and after
interictal administration of
eletriptan
Significant decrease in brain uptake in
migraine patients, but not in con-
trols, after exposure to eletriptan
A chronic hyposerotonergic state in
patients causes sensitisation of 5-
HT
1B
receptors and a negative feed-
back response to eletriptan
Sakai et al., 2008 PET imaging of a-[
11
C]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
(continued)
Deen et al. 7
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 experi-
encing migraine attacks (n¼4) compared to both con-
trols (n¼10) and to patients not developing a migraine
attack (n¼6). 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 investiga-
tions’). An increase in K* for a-[
11
C]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 (n¼6) 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 amp-
litude (44) in VEP and serotonin in platelets was found
in a small group of patients (n¼8) with migraine with
aura, but not in patients suffering from migraine with-
out 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 sero-
tonin 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 cog-
nitive processing time, but not the changes of habitu-
ation (using an oddball paradigm), during a migraine
attack could be related to decreases in serotonergic
neurotransmission. This is in contrast with data indi-
cating an ictal increase in serotonergic neurotransmis-
sion (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 pre-
ictally. 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,
Table 4. Continued.
Authors, year of
publication Method Results Interpretation
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
a-[
11
C]MTrp: a-[
11
C] 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.
8Cephalalgia 0(0)
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 (n¼5), a-
[
11
C]MTrp brain uptake was investigated in migraine
patients before and after 12 weeks of treatment with b-
blockers (either propranolol or nadolol, 5-HT
1A
recep-
tor 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 treat-
ment 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 a-[
11
C]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 a-
[
11
C]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 (n¼8) and 10 mg (n¼6) zol-
mitriptan 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 sig-
nificant 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 a-[
11
C]MTrp brain uptake and the hypothesis of
chronic low serotonin in the migraine brain. In another
electrophysiological study, the selective serotonin reup-
take 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 seroto-
nergic 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 neur-
onal 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 mech-
anisms 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 cyc-
lical 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 dif-
ferent subsets of subjects regarding age, gender, diag-
nosis and number are also highly discrepant between
the studies. The stimulations used in the electrophysio-
logical 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 habitu-
ation 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.
Deen et al. 9
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 sero-
tonin 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 sero-
tonin 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 dens-
ity (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 noci-
ceptors and the trigeminal pathway (4), but central
modulation of these signals is also involved. One pre-
vailing theory relating serotonergic abnormalities to
migraine is a central dysfunction of the pain-modulat-
ing system in migraineurs (62,63). Serotonin both facili-
tates 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 facili-
tatory role of serotonin has also been suggested (66). A
low level of serotonin interictally could result in disin-
hibition 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 hyper-
sensitive and more susceptible to stimuli, with sudden
increases in serotonin during migraine attacks enhan-
cing 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 patho-
physiological 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 cere-
bral 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 periph-
eral action sites, since serotonin does not cross the BBB
(21). Evidence for central pain-relieving effects of sero-
tonin is found in animal studies showing that the release
of serotonin upon stimulation of the periaqueductal grey
area causes analgesia through the stimulation of inhibi-
tory 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 sero-
tonin 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 asso-
ciated with an increase in serotonergic signaling in the
projection areas and activation of the endogenous anti-
nociceptive system. Interestingly, the activation per-
sisted following treatment with sumatriptan, indicating
that brainstem activation is not necessarily coupled to
pain processing and 5-HT
1B
receptor-mediated seroto-
nergic mechanisms (75).
The most efficient acute treatment of migraine – trip-
tans – are 5-HT
1B
receptor agonists (15,48). The 5-
HT
1B
receptor is present on the dural and cerebral vas-
culature, in the trigeminal ganglion and throughout the
brain. It is both an autoreceptor inhibiting the release
10 Cephalalgia 0(0)
of serotonin from serotonergic neurons and also a het-
eroreceptor 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 dis-
crepancy 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 import-
ance – and complexity – of serotonin in the migraine
pathophysiology.
Future perspectives
The present review suggests that electrophysiological
investigations are not optimal in the search for sero-
tonergic biomarkers. Firstly, EPs and ERPs only
indirectly reflect serotonergic neurotransmission.
Secondly, the findings from electrophysiological stu-
dies 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 ampli-
tude and increased IDAP in migraine patients are add-
itional controversial findings that are thought to be
consequences of low serotonergic disposition (30,56).
Reliable methods of elucidating the central serotoner-
gic 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-
HT
4
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-HT
4
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 measur-
ing endogenous serotonin release (27). Studies with the
5-HT
1B
receptor ligand [
11
C]AZ10419369 in non-
human primates have shown some potential, with
decreases in binding after fenfluramine-induced sero-
tonin release (86). Results from human studies have
been less promising, with an increase in cortical bind-
ing after a single dose of escitalopram, a selective sero-
tonin 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 ser-
otonergic 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 seroto-
nergic 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.
Deen et al. 11
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 sup-
port for the research, authorship and/or publication of this
article: this study was supported by the Lundbeck
Foundation, grant number R-180-2014-3398.
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