Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine?
ABSTRACT Habituation of the nociception-specific blink reflex (nBR) is reduced interictally in migraine patients. This could be related to the habituation deficit of evoked cortical responses, a reproducible abnormality in migraine which has a familial character, or to central trigeminal sensitization due to repeated attacks. We compared nBR habituation in healthy volunteers devoid of personal or family history of migraine (HV), in migraine without aura patients (MO) and in healthy volunteers with a family history of migraine in first degree relatives (HV-F). We elicited the nBR by stimulating the right supraorbital region with a custom-built electrode in 16 MO between attacks, 15 HV and 14 HV-F. Habituation was measured as the percentage area-under-the-curve decrease in 10 consecutive blocks of five averaged rectified responses. nBR habituation was clearly reduced in MO and HV-F compared to HV. Percentage area under the curve decreased between the 1st and the 10th block by 55.01% in HV, 25.71% in MO (P = 0.001) and 26.73% in HV-F (P = 0.043). HV-F had the most pronounced abnormality with potentiation instead of habituation in the second block. We found a positive intraindividual correlation between attack frequency and habituation in MO (r = 0.621; P = 0.010). Migraine patients have interictally a deficient habituation of the nBR which is inversely related to attack frequency, suggesting that it is not due to trigeminal sensitization. Surprisingly, the most pronounced habituation deficit is found in asymptomatic individuals with a family history of migraine. Deficient nBR habituation could thus be a trait marker for the genetic predisposition to migraine.
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Interictal habituation deficit of the nociceptive
blink reflex: an endophenotypic marker for
L. Di Clemente,1,3G.Coppola,4D. Magis,1A.Fumal,1,2V. De Pasqua,1V. Di Piero3and J. Schoenen1,2
Headache Research Unit,University Departments of1Neurology and2Neuroanatomy,University of Lie ' ge, Lie ' ge, Belgium,
3Department of Neurological Sciences,University ‘La Sapienza’ and4Department of Neurophysiology of Vision
and Neurophthalmology,G.B. Bietti Eye Foundation-IRCCS, Rome, Italy
Correspondence to: Professor Jean Schoenen,University Department of Neurology,CHR Citadelle, Bld. du12e 'me
de Ligne1, B^4000 Lie ' ge, Belgium
E-mail: firstname.lastname@example.org; email@example.com
Habituation of the nociception-specific blink reflex (nBR) is reduced interictally in migraine patients.This could
be related to the habituation deficit of evoked cortical responses, a reproducible abnormality in migraine which
has a familial character, or to central trigeminal sensitization due to repeated attacks. We compared nBR
habituation in healthy volunteers devoid of personal or family history of migraine (HV), in migraine without
aura patients (MO) and in healthy volunteers with a family history of migraine in first degree relatives (HV-F).
We elicited the nBR by stimulating the right supraorbitalregionwith a custom-built electrodein16 MObetween
attacks, 15 HVand 14 HV-F. Habituation was measured as the percentage area-under-the-curve decrease in 10
consecutive blocks of five averaged rectified responses. nBR habituation was clearly reduced in MO and HV-F
compared to HV . Percentage area under the curve decreased between the 1st and the 10th block by 55.01% in
HV , 25.71% in MO (P¼0.001) and 26.73% in HV-F (P¼0.043). HV-F had the most pronounced abnormality with
potentiation instead of habituation in the second block.We found a positive intraindividual correlation between
attack frequency andhabituation in MO (r¼0.621;P¼0.010).Migraine patients have interictally a deficient habit-
uation of the nBR which is inversely related to attack frequency, suggesting that it is not due to trigeminal
sensitization. Surprisingly, the most pronounced habituation deficit is found in asymptomatic individuals with a
family historyof migraine.Deficient nBR habituation could thus be a trait marker for the genetic predisposition
Keywords: sensory processing; brain circuits; migraine
Abbreviations: HV¼health volunteers devoid of personal or family history of migraine; HV-F¼healthy volunteers with
a family history of migraine in first degree relatives; MO¼migraine without aura patients; nBR¼nociception-specific blink
Received August14, 2006. Revised November 5, 2006. Accepted November16, 2006
Lack of habituation is a reproducible abnormality found
studies (Schoenen, 1996; Schoenen et al., 2003). It was also
recently described in migraineurs for a brainstem reflex, the
nociceptive blink reflex (nBR) (Katsarava et al., 2003;
Di Clemente et al., 2005). Contrary to the classical blink
reflex which has two components (R1 and R2) and sometimes
a third one (R3), the nBR is elicited by a special stimu-
lation electrode with high current density activating
rather selectively Ad fibres and has only a R2 component
(Kaube et al.,2000; Katsarava et al.,2002a). Whilethe classical
blink R2 reflex habituates normally in migraine patients
(De Tommaso et al., 2002), habituation of the nBR is reduced
interictally (Katsarava et al., 2003). During a migraine attack
doi:10.1093/brain/awl351Brain (2007), Page1of 6
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the nBR habituates normally, a change also reported for
cortical evoked responses (Afra et al., 2000), while its global
amplitude increases (Kaube et al., 2002).
The habituation deficit of cortical evoked potentials
may have a familial character and was proposed as an
endophenotypic marker of migraine (Sa ´ndor et al., 1999;
Siniatchkin et al., 2000). In migraine families it was found in
asymptomatic subjects at risk of developing the disorder
(Siniatchkin et al., 2000).
We searched therefore for an abnormal habituation
pattern of the nBR in healthy asymptomatic subjects
having a first degree relative affected by migraine, and we
compared them with healthy volunteers and migraine
Material and methods
Twenty-nine healthy volunteers without personal history of
migraine or any other recurrent headache were recruited among
students, hospital personnel and relatives of patients consulting
our Headache Clinic. They were separated in two groups of
comparable age and sex distribution: 15 subjects without family
history of migraine (HV: mean age: 23.9 years; 10 women, 5 men)
and 14 subjects (HV risk: mean age: 24.2 years; 9 women, 5 men)
having at least one first degree relative who suffers from migraine
and consults our clinic. These healthy volunteers were compared
to 16 patients suffering from migraine without aura according to
ICHD-II criteria (Headache Classification Subcommittee of the
International Headache Society, 2004) (MO; ICHD-II code 1.1;
mean age: 27.6 years; 11 women, 5 men). Recordings in patients
were obtained interictally at least 2 days after the last and before
the next migraine attack. All subjects were devoid of any other
pathology, were non-smokers, and were not allowed to take drugs
on a regular basis, nor caffeine or alcohol containing beverages
54h before the recording. Written informed consent was obtained
from all participants in accordance with the Declaration of
Helsinki and the study protocol was approved by the local Ethics
The nociception-specific blink reflex was elicited according to the
methods described by Kaube et al. (2000) and Katsarava et al.
(2002a). Briefly, a custom-built planar concentric electrode
(central cathode: 1mm D; insert: 8mm; anode: 23mm OD)
providing a high current density at low intensities over a
?40mm2area was used to stimulate the supraorbital region.
Perception and pain thresholds were determined on both sides of
the forehead with ascending and descending sequences of 0.2mA
intensity steps. For the patients’ comfort and to avoid a too
lengthy procedure the electrophysiological study was restricted to
a unilateral right-sided stimulation. The stimulus intensity was set
at 1.5 times the individual pain threshold. Monopolar square
pulses of 0.3ms of duration were delivered with pseudorando-
mized interstimulus intervals (ISI) of 15–17s. With surface
electrodes we recorded bilaterally over orbicularis oculi muscles
10 blocks of six rectified EMG responses with an interblock
interval (IBI) of 2min using a CEDTM1401 signal averager
(Cambridge Electronic Design, Cambridge, UK). The 2-min IBI
was chosen because it produces the most pronounced habituation
in normal subjects (Katsarava et al., 2002).
For each sweep, 150ms of the poststimulus period were collected
and off-line filtered (1 Hz–1kHz). Five responses were rectified
and averaged for each block (Fig. 1), as the first sweep was
excluded from the signal analysis to avoid contamination with
startle responses (Kaube et al., 2000; Katsarava et al., 2002a). In
order to evaluate the global EMG activity generated during the R2
reflex, we measured the area under the curve (the response area:
RA) in mV?ms.
For each averaged block, the R2 onset latency, visually
determined as the take-off point from baseline, and the RA
between 27 and 87ms (Ellrich and Treede, 1998) (Fig. 1) were
measured off-line by an investigator (GC or LDC) blinded to the
subjects’ identities. Habituation of the nBR R2 was defined as the
percentage change of the R2 area between the 1st and the 10th
block of recordings (IBI: 2min). Since the study by Katsarava
et al. (2003), showing reduced nBR habituation interictally in
migraineurs was based on five responses obtained with short
ISIs, we also measured the amplitude change in the five sequential
responses recorded in the 1st block with an ISI of 15–17s.
Results are presented as means?standard deviations except in
Fig. 4 where standard errors are shown for a better visual
identification of the different curves. Group differences in mean
pain threshold and nBR latency were calculated with one-way
analysis of variance (ANOVA). Habituation of the nBR responses
was assessed by ANOVA for repetitive measurements with
Scheffe ´’s post hoc analysis, considering the different blocks (2 to
10) as within subject factors and the diagnostic groups (HV, MO
and HV-risk) as between subject factors. Results were considered
significant at P50.05.
We found no significant difference in mean perception or
pain threshold between the three subject groups on
Fig.1 Nociception blink reflex recording: one block of five
rectified and averaged responses with an ISI of15^17s.
Page 2 of 6Brain (2007)L. Di Clemente et al.
by guest on June 3, 2013
either side of the forehead, or between the left and right
side in any group (data not shown). The mean stimulus
intensities (1.5?pain threshold) used for studying the
nBR were thus similar between groups: 2.09?0.44mA
for HV; 2.04?0.66mA for HV-risk and 2.15?0.77mA
On all recordings the R2 component of the blink reflex
was clearly identified and there was no R1 component.
Mean R2 latency was slightly shorter in migraineurs than in
both groups of healthy volunteers (MO: 36.55?5.66ms;
HV: 40.74?7.37ms; HV-risk: 38.81?4.54ms), but these
differences were not significant [F(1,29)¼2.919, P¼0.10
versus HV; F(1,28)¼1.162, P¼0.29 versus HV-risk].
There was no significant side difference in first block
nBR response area or in its habituation over 10 blocks in
any of the three groups (Table 1).
The response area in the first block of stimuli was
greater in healthy controls than in migraineurs or healthy
volunteers with an affected first degree relative, but
P¼0.37; Table 1, Fig. 2].
There was a large interindividual variation of both first
block nBR RA and habituation in the three groups of
subjects (see standard errors in Fig. 4). Habituation of the
nBR RA was nonetheless on average clearly different
between the HV group on the one hand and the HV-risk
and MO group on the other. In HV there was a strong
habituation with an amplitude decrease exceeding 50%
between the first and the 10th block of five averagings.
This contrasted with a less than 28% habituation in the
MO [F(1,29)¼13.317, P¼0.001 versus HV] and HV-risk
[F(1,27)¼4.527, P¼0.043 versus HV] groups (Table 1,
Fig. 3). Habituation steadily increased in successive blocks
in all the three groups of subjects up to the 10th block of
stimuli (Fig. 4). The difference in the degree of nBR RA
habituation between healthy volunteers and the other two
groups, however, was already significant in the second block
nBR RA (%)
Blocks of responses
Fig. 4 Habituation of the R2 response area of ipsi- and
contralateral nBR in10 blocks of five averagings (interstimulus
interval:15^17ms; interblock interval: 2min) expressed as
percentage of the1st block.
T able1 Mean values of electrophysiological findings
Subject groups First block nBR RA (mV?ms)
Habituation10th/1st block (%)
27 .36? 40.76?
Healthy subjects (HV; n¼15)
Healthyþ1st deg mig
Migraine without aura
nBR RA 1st block (mV x ms)
Ipsilateral R2 Contralateral R2
Fig. 2 R2 response area in the first block of averaged responses
AIpsilateral R2Contralateral R2
Habituation 1st vs 10th block (%)
Fig. 3 Habituation of the R2 response area in the last block of
averaging relative to the1st block (%).
Interictal habituation deficit of the nociceptive blink reflexBrain (2007)Page 3 of 6
by guest on June 3, 2013
of five averagings (Fig. 4): 24.1% habituation in HV, –8.4%
(i.e. potentiation) in HV-risk [F(1,27)¼7.730, P¼0.010
versus HV] and 1.5% habituation in MO [F(1,29)¼5.145,
P¼0.031 versus HV].
We found a positive intraindividual correlation between
attack frequencyand habituation in MO (r¼0.621;
Single response areas within the 1st block of stimuli and
their habituation in individual subjects greatly varied. There
was nonetheless a significant reduction in habituation
between the first and fifth response in the HV-risk group.
For instance, on the ipsilateral side the amplitude change
was –36.9% (potentiation) in HV-risk, compared to
þ41.5% (habituation) in HV [F(1,27)¼4.701; P¼0.04].
Habituation was also lower in MO (29.7%) than in HV,
but this difference was not significant [F(1,29)¼0.751;
Our results showing that habituation of the nBR is
significantly reduced interictally in migraineurs compared
to healthy volunteers are in line with those reported by
Katsarava et al. (2003). The two studies, however, differ in
several aspects. While in Katsarava et al.’s (2003) study the
habituation was assessed only on five single responses with
an ISI of 15–17s, i.e. over a maximal time span of 68s, we
measured the R2 habituation on 10 successive blocks of five
averaged responses with the same ISI but with an IBI of
2min, i.e. over a maximal period of 32min (10th versus 1st
block) or a minimal period of 256s (2nd versus 1st block).
We chose this method for two reasons.
habituation deficits reported in migraine for evoked and
event-related potentials have been determined without
exception on averaged responses and thus over long time
periods reaching 30min in some studies (Schoenen et al.,
2003). Second, Katsarava et al. (2002a) themselves have
shown in healthy volunteers that habitutation of the nBR2
is much more pronounced (475%) over 10 averaged blocks
of five responses separated by 2min, the IBI chosen here,
than between five single responses with an ISI of 15–17s
(19–24%) (Katsarava et al., 2002b). The short and long-
term habituation phenomena may be related, insofar as the
intrablock habituation may increase in successive blocks,
but this was not mentioned in a study where two blocks of
five responses were analysed (Katsarava et al., 2003) and
not examined in our study. To allow a better comparison of
results, however, we also measured the nBR habituation
over the five 1st block responses and were not able to
totally confirm Katsarava et al.’s (2003) data. Although the
intrablock habituation values were smaller in migraineurs
significant, possibly because standard deviations were too
large and groups too small. The mechanisms underlying
short and long-term habituation of the nBR may thus
be partly different. The difference in nBR response area
habituation between patients and healthy volunteers is
significant as early as the 2nd block of averages. It increases
with repetition of stimuli and tends to become maximal in
the 10th block, i.e. after 32min of recordings, a time at
which habituation was found to be maximal in normal
subjects (Katsarava et al., 2002a). Our stimulation method
was similar to the one published by the abovementioned
group (Kaube et al., 2000) with the notable exception that
we used a custom-built electrode with a slightly larger
stimulation area. As stimuli elicited no R1 responses, it is
likely that they activated chiefly Ad fibres like in Kaube
et al.’s study. Our study was not designed to assess changes
in pain perception thresholds simultaneously
nBR habituation, as perception thresholds were measured
only once at the beginning of the recording session
(see Material and methods).
Although the R2 component of the classical blink
reflex and the nociceptive R2 are elicited by activation of
different populations of trigeminal fibres, they probably
share some common features. They are both bilateral
responses and involve polysynaptic neural networks com-
prising the spinal trigeminal nucleus, interneurons of the
bulbopontine lateral reticular formation and motoneurons
of the facial nucleus innervating the orbicularis oculi
muscles (Holstege, 1990; Esteban, 1999). Habituation is a
classical phenomenon in polysynaptic activities (Desmedt
and Godaux, 1976). There are, however, striking differences
betweenthe classical and
in migraine. For instance, the classical R2 does not
habituate with IBI intervals as low as 15s either in healthy
volunteers or in migraineurs (Penders and Delwaide, 1971;
de Marinis et al., 2003). As mentioned, the classical R2
is essentially normal interictally, but it is less influenced by
the warning of the stimulus in migraine (de Tommaso
et al., 2002) and, at short IBI, its habituation was found
reduced in migraineurs who developed an attack within
72h after the recording (de Marinis et al., 2003). It remains
to be determined if the nociceptive BR is modulated
by dopamine like the classical R2. Lack of habituation
of this response is a typical finding in Parkinson’s
(Penders and Delwaide, 1971). If so, the fact that the
nBR2 habituation is decreased in migraine would not
favour the hypothesis that the disorder is associated with
dopaminergic hypersensitivity (see for a review Mascia
et al., 1998).
The rather low nBR amplitude in the first block of five
averaged responses we found interictally in migraineurs
contrasts with the 680% nBR RA increase reported during
the migraine attack (Kaube et al., 2002) which is considered
to reflect ictal sensitization of spinal trigeminal nucleus
neurons and not found in sinus headaches (Katsarava et al.,
2002b). The low nBR amplitude in our study does not
favour such sensitization and rather suggests that the R2
interneurons and circuit could be hypoexcitable in between
migraine attacks. This is reminiscent of our previous
Page 4 of 6Brain (2007)L. Di Clemente et al.
by guest on June 3, 2013
interictal findings with evoked cortical potentials where low
1st block amplitude and lack of habituation are found in
concert (Schoenen et al., 2003). We have provided indirect
evidence (Bohotin et al., 2002; Coppola et al., 2005) that
both abnormalities might be a consequence of reduced
serotoninergic transmission (Wang et al., 1996; Juckel et al.,
Interestingly, it has been shown in cat that the serotoni-
nergic raphe magnus nucleus is a pivotal relay between the
basal ganglia and the trigeminal neurons mediating the
blink reflex; theloss of
Parkinson’s disease is thought to disinhibit the blink
reflex by causingalack
magnus neurons (Basso and Evinger, 1996). The habit-
uation deficit might thus represent a trait marker for
migraine patients and their low serotonin disposition
(Ferrari et al., 1989), and play a role in its pathomecha-
nisms (Schoenen, 1998). It does not seem to be a
consequence of repeated attacks and persistent attack-
related sensitization (Kaube et al., 2002), as in this case
one would expect a more pronounced deficit in patients
with frequent attacks. As a matter of fact, we find the
opposite in our study: nBR habituation increases, rather
than decreases, with increasing attack frequency, which
confirms our previous results (Di Clemente et al., 2005).
Few correlations have been found between neurophysio-
logical results and attack frequency in migraine. In a study
of laser-evoked cortical responses, the habituation deficit
found interictally in migraineurs was positively correlated
with attack frequency (de Tommaso et al., 2005) and in a
evoked potentials the N20m amplitude increase in migrai-
neurs was linked to the frequency of attacks (Lang et al.,
2004). We have therefore no satisfactory explanation for
our finding of a negative correlation between the habitua-
tion deficit on the nBR and attack frequency. It could,
however, be related to the fact that nBR short-term
habituation (Katsarava et al., 2003), akin to habituation
of evoked cortical potentials (Schoenen et al., 2003),
normalizes during the attack period. One might thus
speculate that patients with high-attack frequencies were at
greater risk of being recorded in closer vicinity to an attack.
Our most striking finding is that asymptomatic subjects
with a first degree migrainous relative present the same
nBR abnormalities as patients with full-blown migraine
between attacks. Compared to healthy volunteers without a
family history of migraine, they tend to have smaller first
block nBR response areas and, more significantly, reduced
habituate more and that of migraineurs who habituate
less, but the difference is significant respective to the
former, but not to the latter. Healthy subjects at risk
also have a significant reduction of habituation within the
1st block of five responses, which differs from the findings
in migraineurs. The possible relation between intra- and
dopaminergic neurons in
ofactivation of raphe
interblock habituation remains to be determined. Whatever
it may be, our finding raises the possibility that subjects
with a familial predisposition for migraine may present a
response habituation. A similar suggestion was made for
increased amplitudes and lack of habituation of contingent
negative variation, an event-related potential (Siniatchkin
et al., 2000). Although certain rare migraine subtypes such
as familial hemiplegic migraine are monogenic diseases,
there is increased evidence that the common forms of
migraine are polygenic multifactorial diseases, where the
genotype determinesa migraine
modulated by internal (e.g. hormonal) and environmental
factors (Montagna, 2000; Sandor et al., 2002; Haan et al.,
2005). It seems evident from the previous studies and from
our results that not all subjects with a first degree relative
having migraine have abnormal CNV or nBR patterns, as
likely not all of these subjects are genetically predisposed to
migraine. This may explain why standard deviations and
variance for nBR habituation values are largest in the
HV-risk group. One may hypothesize, however, that
subjects who show the same habituation deficit as migraine
patients are at risk of developing migraine. To verify this
hypothesis it seems worthwhile to conduct a longitudinal
follow-up study of healthy subjects at high risk and to
compare the genotypes, and, if ethically acceptable, the
sensitivity to glyceryl trinitrate administration (Olesen et al.,
1993) between those who have a normal habituation
pattern and those who have not. It would be of even
greater interest to determine which factors such as
personality traits, life events, environment or comorbidity
can protect subjects with a family history of migraine
against developing migraine.
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