Lateralized central facilitation of trigeminal nociception in cluster headache.
ABSTRACT To investigate whether central facilitation of trigeminal pain processing is part of the pathophysiology of cluster headache (CH).
Sixty-six patients with CH (18 episodic CH inside bout, 28 episodic CH outside bout, 20 chronic CH) according to the International Classification of Headache Disorders-II classification, as well as 30 healthy controls, were investigated in a case-control study using simultaneous recordings of the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1).
nBR latency ratio (headache side/nonheadache side) was decreased in all CH patients independent from CH subtype compared with healthy controls indicating central facilitation at brainstem level. Area under the curve ratio was increased in patients with episodic CH inside bout only. PREP showed decreased N2 latency ratio in patients with chronic CH indicating central facilitation at supraspinal (thalamic or cortical) level.
Asymmetric facilitation of trigeminal nociceptive processing predominantly on brainstem level was detected in patients with CH. This alteration is most pronounced in the acute pain phase of the disease, but appears to persist in remission periods. Only chronic CH patients show additional changes of PREP prompting to supraspinal changes of pain processing related to the chronic state of disease in regard to neuronal plasticity, which exceeds changes observed in episodic CH.
[show abstract] [hide abstract]
ABSTRACT: Cluster headache, one of the most severe pain syndromes in human beings, is usually described as a vascular headache. However, the striking circadian rhythmicity of this strictly half-sided pain syndrome cannot be readily explained by the vascular hypothesis. We aimed to assess changes in regional cerebral blood flow (rCBF) in patients with cluster headache. We used positron emission tomography (PET) to assess the changes in rCBF, as an index of synaptic activity, during nitroglycerin-induced cluster headache attacks in nine patients who had chronic cluster headache. Eight patients who had cluster headache but were not in the bout acted as a control group. In the acute pain state, activation was seen in the ipsilateral inferior hypothalamic grey matter, the contralateral ventroposterior thalamus, the anterior cingulate cortex, and bilaterally in the insulae. Activation in the hypothalamus was seen solely in the pain state and was not seen in patients who have cluster headache but were out of the bout. Our findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache. We suggest that a radical reappraisal of this type of headache is needed and that it should in general terms, be regarded as a neurovascular headache, to give equal weight to the pathological and physiological mechanisms that are at work.The Lancet 08/1998; 352(9124):275-8. · 38.28 Impact Factor
Article: Correlation between structural and functional changes in brain in an idiopathic headache syndrome.[show abstract] [hide abstract]
ABSTRACT: Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure. Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography. Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.Nature Medicine 08/1999; 5(7):836-8. · 22.46 Impact Factor
Article: Inhibition of the blink reflex R2 component after supraorbital and index finger stimulations is reduced in cluster headache: an indication for both segmental and suprasegmental dysfunction?[show abstract] [hide abstract]
ABSTRACT: Peripheral as well as central mechanisms are thought to play a role in cluster headache pathogenesis. We have studied recovery curves of the R2 component of the blink reflex after conditioning by supraorbital or index finger stimuli in 10 episodic cluster headache (CH) patients during a cluster period and in 10 healthy controls. There was no significant change of R2 threshold, latency or area in CH patients. After paired supraorbital stimuli, R2 recovered more rapidly in patients on the symptomatic side. After index stimulations, R2 recovery was more rapid on both symptomatic and non-symptomatic sides in patients compared to controls. Naloxone (0.4 mg) i.v. in two subjects partially reversed the R2 suppression induced by index finger stimuli. The unilateral decrease of R2 inhibition after a segmental supraorbital stimulus most likely reflects sensitisation in the spinal trigeminal nucleus. Whether the latter is due to irritation of the ophthalmic nerve within the cavernous sinus region, which is thought to be pivotal in CH pathogenesis, remains to be proven. In addition, we propose that the bilateral deficit of R2 inhibition after an extrasegmental exteroceptive stimulus might reflect hypoactivity of reticular nuclei, possibly because of reduced central opioid activity.Pain.
; Published online before print March 14, 2012;
D. Holle, C. Gaul, S. Zillessen, et al.
Lateralized central facilitation of trigeminal nociception in cluster
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Lateralized central facilitation of trigeminal
nociception in cluster headache
D. Holle, MD
C. Gaul, MD
S. Zillessen, MD
S. Naegel, MD
H. Kaube, MD, PhD
Z. Katsarava, MD, PhD
Objective: To investigate whether central facilitation of trigeminal pain processing is part of the
pathophysiology of cluster headache (CH).
Methods: Sixty-six patients with CH (18 episodic CH inside bout, 28 episodic CH outside bout, 20
chronic CH) according to the International Classification of Headache Disorders–II classification,
as well as 30 healthy controls, were investigated in a case-control study using simultaneous
recordings of the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) follow-
ing nociceptive electrical stimulation on both sides of the forehead (V1).
Results: nBR latency ratio (headache side/nonheadache side) was decreased in all CH patients
independent from CH subtype compared with healthy controls indicating central facilitation at
brainstem level. Area under the curve ratio was increased in patients with episodic CH inside bout
only. PREP showed decreased N2 latency ratio in patients with chronic CH indicating central
facilitation at supraspinal (thalamic or cortical) level.
Conclusions: Asymmetric facilitation of trigeminal nociceptive processing predominantly on
brainstem level was detected in patients with CH. This alteration is most pronounced in the acute
pain phase of the disease, but appears to persist in remission periods. Only chronic CH patients
show additional changes of PREP prompting to supraspinal changes of pain processing related to
the chronic state of disease in regard to neuronal plasticity, which exceeds changes observed in
episodic CH. Neurology®2012;78:985–992
ACC ? anterior cingulate cortex; AUC ? area under the curve; BR ? blink reflex; CH ? cluster headache; nBR ? nociceptive
blink reflex; PREP ? pain-related evoked potentials; TSEP ? trigeminal somatosensory evoked potentials; WDR ? wide
Cluster headache (CH) is a rare primary headache disorder characterized by strictly unilateral
headache attacks accompanied by ipsilateral autonomic symptoms. Pain attacks occur in clus-
ters over periods of weeks or months (inside bout). In between, patients are usually pain free
(outside bout). Despite this episodic course of disease 10%–20% of patients develop chronic
CH without longer attack-free time periods.1
The underlying pathophysiologic mechanisms in CH remain unresolved. Functional and
structural neuroimaging studies pointed to an alteration of the posterior hypothalamus to be
one key mechanism in the pathophysiology of CH.2–4Investigations of trigeminal sensory
pathways of CH, especially in regard to nociceptive processing, are rare and results are rather
diverse.5–9Some studies suggested a facilitation of trigeminal processing on the headache side
compared to the nonheadache side,10–12some did not observe any alterations,13whereas other
studies even observed a decreased excitability.8,9Inconsistent results might at least partly result
from the different study techniques (e.g., conventional blink reflex [BR] vs nociceptive blink reflex
[nBR], trigeminal somatosensory evoked potentials [TSEP] vs pain-related evoked potentials
From the Department of Neurology (D.H., C.G., S.Z., S.N., S.K., H.-C.D., Z.K., M.O.), University of Duisburg-Essen, Essen; and Interdisciplinary
Pain Center (H.K.), University of Freiburg, Freiburg, Germany.
Study funding: Supported by the IFORES grant of the University Duisburg-Essen.
Disclosure: Author disclosures are provided at the end of the article.
Correspondence & reprint
requests to Dr. Holle:
Copyright © 2012 by AAN Enterprises, Inc.
Published Ahead of Print on March 14, 2012 as 10.1212/WNL.0b013e31824d58ce
[PREP]) involving different reflex arches after
nociceptive and innocuous stimulation or by
different modulation from higher pain process-
ing centers or medication influence.
Data on alterations depending on the stage
of disease (inside bout vs outside bout) are not
available. This, however, seems important as
the trigeminal nociceptive system presumably
acts very differently in pain compared to non-
The aim of this study was to assess trigemi-
nal nociceptive processing in patients with ep-
isodic and chronic CH inside and outside
bout compared with healthy controls to inves-
tigate the presence or absence of facilitation
processes in the patient group. To assess the
trigeminal nociceptive system, we used the
nBR and trigeminal PREP. These noninva-
sive electrophysiologic study techniques allow
a nociception-specific stimulation of the pain
processing system14and are highly sensitive
for the detection of changes of trigeminal pro-
cessing15at brainstem (nBR) as well as su-
praspinal (thalamic, cortical) level (PREP).
METHODS Standard protocol approvals, registra-
tions, and patient consents. The study protocol was re-
viewed and approved by the Medical Ethics Committee of the
University of Duisburg-Essen and written informed consent ac-
cording to the Declaration of Helsinki was obtained from all
participants prior to investigation.
Patients and healthy controls. Sixty-six patients with CH
according to the International Classification of Headache Disor-
ders–II criteria (code 3.1) were investigated in a case-control
study design. Forty-six patients had episodic CH (code 3.1.1),
18 of them were inside bout at the time of recording (mean age
43 ? 12 years; range 19 to 60 years), 28 outside bout (mean age
42 ? 11 years; range 19 to 67 years), 20 patients had chronic
CH (mean age 47 ? 12 years; range 19 to 65 years) (code 3.1.2).
Patients inside bout and outside bout were different persons.
Additionally, 30 healthy controls without medical or family his-
tory of primary headache disorder or any other psychiatric, neu-
rologic, or severe somatic disease were investigated (mean age
44 ? 14 years; range 20 to 68 years). The diagnosis of CH was
reconfirmed in a face-to-face interview by a headache-
experienced neurologist (C.G., D.H.) between January 2009
and February 2010. One chronic CH patient reported a side
shift of headache attacks within a bout in the past. However, the
vast majority of headache attacks occurred on the same side,
which was considered to be the headache side. In the last 2 years
before participating in this study he reported no side shifting of
headache attacks at all. Two patients had their last headache
attacks 10 days prior to study participation. However, they still
reported attacks with trigeminal autonomic symptoms and were,
therefore, considered to be still inside bout. None of the patients
had had an attack within the last 4 hours prior to recording.
Cluster-related acute and prophylactic medication was main-
tained and prescribed independently from study participation
according to current therapy guidelines (table 1). Additional
information on prior and concomitant headache medication,
clinical symptoms, and course of disease were inquired. Comor-
bidities as well as additional medications were determined. All
smokers (patients and healthy controls) were instructed not to
smoke at least 4 hours before examination. Last smoking time as
well as smoking history (number of cigarettes/day, begin) was
Electrophysiologic settings. Two planar concentric elec-
trodes (Walter Graphtek GmbH, Lu ¨beck, Germany; http://
www.walter-graphtek.com/) were attached to the skin 10 mm
above the entry zone of the supraorbital nerve. The outer rim of
the first electrode was placed 1 cm from the forehead midline,
the second electrode approximately 2 cm apart and lateral. Left
side and right side were stimulated 15 times per session in each
patient and control subject (triple pulse, monopolar square wave,
duration 0.5 msec, pulse interval 5 msec, interstimulus interval:
12 to 18 seconds, pseudorandomized). Perception and pain
thresholds were determined on the forehead with an ascending
and descending sequence of 0.2 mA intensity steps. The stimulus
intensity was set at 2 times the individual pain threshold. Stimuli
were delivered to each side in pseudo random order in terms of
start site (i.e., left or right side of the forehead).
NBR and PREP were recorded simultaneously following tri-
geminal stimulation of the forehead. The nBR was recorded us-
ing surface electrodes placed infraorbitally referenced to the
orbital rim. Recording parameters were as follows: bandwidth 1
Hz to 1 kHz, sampling rate 2.5 kHz, sweep length 300 msec
(1401 plus, Signal, Cambridge Electronic Design, UK). PREP
were recorded with electrodes placed at Czreferenced to linked
earlobes (A1-A2) according to the international 10–20 system.
Signal analysis was performed by an investigator blinded to
the diagnosis. The first sweep was rejected to avoid contamina-
tion by startle response. The remaining 14 sweeps were averaged.
For nBR onset latencies waveforms were rectified and analyzed
for each sweep separately. A mean value for each session was
calculated. Areas under the curve were calculated between 27
and 87 msec. Concerning PREP N2 (negative peak), P2 (posi-
tive peak) latencies, and PPA (peak-to-peak) amplitudes were
Intraindividual mean ratios for latencies, PPA, and area un-
der the curve (AUC) were determined in all CH patients. For
this purpose, values of all parameters measured after stimulation
of the headache side (CH) or right side (healthy controls) are
reported as percentage of the nonheadache side or left side, re-
spectively (ratioCH[%] ? [result headache side/result nonhead-
ache side] ? 100 and ratiohealthy controls[%] ? [result right side/
result left side] ? 100).
Mean values of the stimulation blocks for each subject and
subsequent mean values for the group were calculated. Offline
analysis was performed with a custom-written PC-based software
using Matlab (Matlab 7, The MathWorks, Natick, MA).
Statistical analysis. Based on the small sample size, nonpara-
metric statistical methods were applied. Mann-Whitney U test for
independent samples was used to compare thresholds, AUC, AUC
ratios latencies, latency ratios, amplitudes, and amplitude ratios.
Planned contrasts were applied (each group of CH patients vs
healthy controls; CH inside bout and outside bout; CH inside bout
vs chronic CH). All statistics were calculated with SPSS 16 (SPSS
Inc., Chicago, IL). The level of significance was set to p ? 0.05.
Neurology 78March 27, 2012
RESULTS Clinical characteristics. Demographics
and patients’ clinical characteristics are displayed in
table 1. More patients than healthy controls were
smokers: episodic inside CH 78%, episodic outside
CH 79%, chronic CH 50%, healthy controls 13%.
Age was comparable in all patient groups as well as in
the healthy controls group. Disease duration and
pain intensity was similar in all subgroups of CH.
Chronic CH patients had slightly more headache at-
tacks per day compared with episodic CH patients
inside bout (3.1 ? 2.7 vs 1.2 ? 1.0).
Nociceptive blink reflex. Electrophysiologic results of
means are summarized in table 2. Representative
nBR responses are shown in figure e-1, A1–D1, on
the Neurology®Web site at www.neurology.org.
Latency ratio of all CH patient groups (ratioCH?
[latency headache side/latency nonheadache side] ?
tiohealthy control? [latency right side/latency left side] ?
p ? 0.001; episodic CH outside bout: 92% ? 7, Z ?
?3.988, p ? 0.001; chronic CH 91% ? 8, Z ?
?4.145 p ? 0.001; healthy controls: 101% ? 7])
only increased in episodic CH patients inside bout
(ratioCH? [AUC headache side/AUC nonhead-
ache side] ? 100) compared with healthy controls
(ratiohealthy control? [AUC right side/AUC left side] ?
100 [episodic CH inside bout: 147% ? 57, Z ?
?2.178, p ? 0.029; episodic CH outside bout:
116% ? 36, NS; chronic CH 128% ? 59, NS,
healthy controls: 109% ? 27]) (figure 1B). These
observations demonstrate altered nociceptive pro-
cessing in CH with a shift of the ratio between head-
ache and nonheadache side. This might hint at
selective facilitation of the trigeminal nociceptive sys-
tem in CH on the affected painful side. Analysis be-
tween CH subgroups (episodic CH inside bout vs
Table 1Demographics and clinical characteristics
Episodic CH: inside boutEpisodic CH: Outside bout Chronic CHHealthy controls
7/11 6/22 4/1610/20
Age, y (range)
43 ? 12 (19–60) 42 ? 11 (19–67)47 ? 12 (19–65) 44 ? 14 (20–68)
78 7950 13
Disease duration, y (range)
14 ? 11 (1–40) 14 ? 10 (1–40)15 ? 9 (2–35)—
No. of attacks/day (range)
1.2 ? 1.0 (0.5–4.0)0 3.1 ? 2.7 (0.5–10.0)—
Last attack, h (range)
64 ? 79 (5–240)7,200 ? 4,620 (1,800–15,120) 36 ? 67 (4–240)—
Acute medication, %
Prophylactic medication, mg, %;
dosage median (range)
44; 240 (40–480) 18; 120 (40–240)70; 240 (120–480)
5; 675 (225–1,800)025; 900 (225–1,800)
11; 100 (25–400) 4; 100 (12.25–150)45; 100 (25–400)
Abbreviation: CH ? cluster headache.
Table 2Results of nociceptive blink reflexa
Area under the
?V ? ms,
Area under the
?V ? ms,
mean ? SD
45.3 ? 5.152.6 ? 5.6b
1040.1 ? 542.7 821.2 ? 549.0
45.1 ? 5.3 49.9 ? 7.1 966.0 ? 394.5 880.4 ? 445.5
43.2 ? 4.7 47.3 ? 6.41,130.3 ? 458.51,015.8 ? 400.0
45.6 ? 6.4 45.3 ? 5.51,077.5 ? 520.3 1,034.0 ? 515.5
Abbreviation: CH ? cluster headache.
aIn healthy controls headache side is assigned right side.
bp ? 0.05; Mann-Whitney U test.
Neurology 78March 27, 2012
episodic CH outside bout vs chronic CH) did not
reveal any significant differences of latency ratio and
AUC ratio. No differences were observed comparing
primary values of latency and AUC between con-
trols, episodic CH inside bout, episodic CH outside
bout, and chronic CH. Only latency of the nonhead-
ache side in episodic CH patients inside bout was
longer compared with healthy controls (52.6 msec ?
5.6 vs 45.3 msec ? 5.5; Z ? ?3.578, p ? 0.001)
Pain related evoked potentials. Electrophysiologic re-
sults are presented in table 3. Representative PREP
responses are illustrated in figure e-1, A2–D2.
In chronic CH patients we observed a decreased
N2 latency ratio (ratioCH? [N2 latency headache
side/N2 latency nonheadache side] ? 100) compared
with healthy controls (ratiohealthy control? [N2 la-
tency right side/N2 latency left side] ? 100) (95% vs
102%, Z ? ?2.864, p ? 0.004) showing a side shift
of trigeminal processing. This observation points to-
ward supraspinal facilitation in the chronic course of
disease, which was not detected in episodic CH in-
side and outside bout (100%, 99%) (figure 1C). P2
ratio as well as PPA ratio showed no significant dif-
ferences between patient groups or healthy controls.
Perception and pain thresholds as well as stimula-
tion intensities did not differ between groups (table
e-1). No differences were observed comparing pri-
mary values of N2 latency, P2 latency, and PPA be-
tween controls, episodic CH inside and outside bout,
and chronic CH.
DISCUSSION Our data demonstrate lateralized
central facilitation of trigeminal nociception in CH.
This asymmetry within trigeminal pain processing
comparing headache and nonheadache side in CH
regardless of the state of disease suggests that central
facilitation is a persistent pathophysiologic correlate
of this primary headache disorder. The observed
changes were most pronounced at brainstem level
represented by nBR and during periods with acute
pain attacks (inside bout). Only in chronic CH was ad-
ditional facilitation at supraspinal level represented by
Figure 1 Cluster headache (CH) patients compared with healthy controls
Results are shown as ratio of headache side/nonheadache side in CH patients (ratioCH?
[result headache side/result nonheadache side] ? 100) or right/left side in healthy controls
(ratiohealthy controls? [result right side/result left side] ? 100). (A) Nociceptive blink reflex (nBR)
latency ratio is decreased in CH patients compared to healthy controls (*p ? 0.001). Be-
tween the several patient groups no significant effects can be observed. (B) Area under the
curve (AUC ratio) is increased in episodic CH patients compared with healthy controls (*p ?
0.029). (C) N2 latency ratio is reduced in chronic CH patients compared with healthy con-
trols (*p ? 0.004). cCH ? chronic cluster headache; eCH ? episodic cluster headache;
PREP ? pain-related evoked potentials.
Table 3Results of pain-related evoked potentialsa
N latency, ms,
N latency, ms,
P latency, ms,
P latency, ms,
52.9 ? 30.953.9 ? 26.8 127.4 ? 14.4 127.2 ? 12.1182.1 ? 21.5 183.8 ? 19.9
40.5 ? 15.242.7 ? 22.4 127.8 ? 15.5 134.9 ? 17.5184.0 ? 18.6 184.2 ? 23.4
58.1 ? 22.152.8 ? 22.3 133.9 ? 9.5 135.3 ? 8.1 189.8 ? 12.5 189.1 ? 14.3
44.3 ? 20.049.2 ? 24.0128.9 ? 14.4125.8 ? 14.4178.7 ? 18.9177.6 ? 19.0
Abbreviations: CH ? cluster headache; PPA ? peak-to-peak amplitudes.
aIn healthy controls headache side is assigned right side.
Neurology 78March 27, 2012
PREP observed, which most likely reflects neuroplastic
changes as result or consequence of chronic pain.
Nociceptive trigeminal processing was previously
evaluated investigating the corneal reflex in CH pa-
tients without showing differences of absolute values
of latency and amplitude which is in line with our
observations.13In agreement with our data, Busch et
al.12reported an at least subtle lateralization of in-
creased nBR AUC and shortened latency to the
headache side in chronic CH patients. Unfortu-
nately, the authors did not report on ratio values and
did not include a healthy age-matched control group
in this study, making a true comparison of the results
and an evaluation of possible unilateral facilitation
TSEPs allow the investigation of trigeminal pro-
cessing after nonpainful cutaneous electrical stimula-
tion at supraspinal level similar to PREP. In contrast
to our results, TSEP latencies were prolonged in CH
patients compared with healthy controls, predomi-
nantly during the cluster attack period7and acute
pain16attacks most pronounced on the symptomatic
side7,17whereas PREP were only altered in the
chronic CH. Although TSEP studies also suggest an
asymmetry of pain processing the study results rather
indicate a decreased excitability on the headache side.
Differences might be based on the different stimula-
tion modalities (painful vs nonpainful) that were
used in PREP/TSEP.
The observed asymmetry in CH pain processing
compared with healthy controls is in line with the
clinical presentation showing clear side dependency
of pain and ipsilateral accompanying trigeminal au-
tonomic features1as well as with previous imaging
studies.3The most likely explanation of this ratio
shift is a mainly side-specific facilitation and subse-
quent sensitization of anatomic structures involved
in trigeminal processing (e.g., wide dynamic range
[WDR] neurons in the ipsilateral trigeminal nucleus
caudalis) in regard to the headache side (figure 2).
Figure 2 Possible central facilitation mechanisms at brainstem level and antinociceptive supraspinal
modulation in cluster headache
(A) Healthy control. Without any central facilitation area under the curve (AUC) and latency show no lateralization of values
facilitated on headache side leading to increased AUC and decreased latency. AUC ratio is increased, latency ratio de-
creased compared with healthy controls. (C) Cluster headache with descending pain control. Antinociceptive mechanisms
of descending pain modulation lead to deceleration of latency and decrease of AUC on the headache side. As central
counter regulation affects both sides of the face equally the nonheadache side is also slowed down and AUC is decreased.
Despite central facilitation primary values on the headache side are within normal boundaries compared with healthy con-
trols whereas primary values of the nonheadache side even appear inhibited. HA side ? headache side of the cluster
headache; Lat ? nociceptive blink reflex latency.
Neurology 78 March 27, 2012
Antinociceptive descending pain modulation might
be responsible for keeping the primary values of nBR
and PREP within certain physiologic boundaries in
regard to homeostatic neuronal plasticity.18These
countermeasures are presumably very effective and
together with prophylactic medication effects possi-
bly disguise a more pronounced central facilitation
effect. This hypothesis is supported by the observa-
tion of increased nBR latency on the nonheadache
side in CH inside bout compared with healthy con-
trols as central deceleration effects would affect both
sides of the brain simultaneously and thus lead to
normalization of the facilitated nBR and PREP re-
sponses on the headache side and further decrease of
nBR and PREP responses on the nonheadache side
(figure e-1). Descending antinociceptive influ-
ences have become of major interest in the last
years and were subject to many electrophysiologic,
anatomic, and pharmacologic studies.19Several su-
praspinal brain centers including the somatosensory
cortex, thalamus, hypothalamus, and periaqueductal
gray are thought to form an integrated network that
modulates trigeminal and spinal cord excitability in a
top-down manner. These descending inhibitory in-
fluences converge on relay neurons in the rostroven-
tral medulla, including the median raphe nucleus,
and in turn attenuate nociceptive processing di-
rectly,19probably by inhibition of medullary WDR
CH patients inside bout showed the most promi-
nent increase of nBR AUC ratio and smallest nBR
latency ratio, suggesting that facilitation at brainstem
level is most pronounced in acute pain episodes (in-
side bout), as described previously in acute pain
states.15Only in chronic CH was additional PREP
alteration detected. This is similar to results from
previous studies in chronic headache conditions like
chronic tension-type headache,20medication overuse
headache,21and chronic trigeminal neuralgia.22
PREP facilitation might be a possible adaptive mech-
anism in the development of chronic pain with re-
spect to neuronal plasticity.22In this regard, central
sensitization at second or third order neuron level
was shown to be very important in the development
of chronic pain in animal models23as well as hu-
mans.24The anterior cingulate cortex (ACC) is as-
sumed to be the main generator of PREP.25
Modifications of ACC synapses appear to regulate
afferent signals that may be important for the transi-
tion from acute to chronic pain conditions in terms
of cortical plasticity.26
Impairment of trigeminal nociceptive processing
not only during the active cluster bout but also in
remission periods, therefore, suggests permanent al-
teration of the trigeminal system including pain-free
periods which is in line with previous studies using
magnetic resonance spectroscopy and VBM.3,27,28It
remains unclear whether these changes are causal in
the pathophysiology of CH and therefore may dis-
play a trait marker for CH, whether they represent a
reaction of the trigeminal system to pain, or whether
they are merely incidental epiphenomena.
In regard to the clinical treatment of CH patients
in general it seems to be crucial to avoid the progres-
sion from an episodic course of disease into chronic
CH not only in terms of prevention of pain attacks
for the patients but also in terms of prevention of
pain-related potentially irreversible neuroplastic al-
terations in regard to cortical plasticity and perma-
nent malfunction of pain regulation with all the
consequences well known to be associated with
chronic pain in general.
Prophylactic and acute pain medication might in-
fluence our results. Alterations of trigeminal pain
processing were also present outside bout with less or
no prophylactic medication and no acute medication
influences, so that our findings cannot be reduced to
that effect alone. Moreover, because we compared
headache side vs nonheadache side we expected
global medication effects similar on both sides. Sepa-
ration into smaller, medication-adjusted groups is
virtually impossible owing to the large number of
different medications and medication combinations.
Nevertheless, reduction of lateralized facilitation
might be one essential mode of action of pain medi-
cation that has shown efficacy in CH.
Nicotine has to be considered as additional con-
founder as more patients than healthy controls were
smokers. To minimize its possible effects all patients
were instructed not to smoke for at least 4 hours
before study participation. Studies on the effects of
nicotine on laser evoked potentials showed a reduc-
tion of neuronal excitability within the pain process-
ing network.29Additionally, withdrawal effects in
heavy smokers have to be considered in affecting our
results. However, as we did not detect any significant
correlation between smoking frequency and electro-
physiologic results its impact on the observed results
should be rather small.
One methodologic problem has to be mentioned.
For pain stimulation the pain was applied in the tri-
geminal area of V1. This might cause eyelid move-
ments, which might superimpose the reflex signal of
the PREP and therefore contaminates the detected
reflex answer at the vertex. However, this stimulation
method using the same paradigm was used in many
previous studies and has proven its feasibility.21,22
Furthermore, the observed reflex responses showed
typical curves which are in line with previously
reported results regarding their shapes. We, there-
Neurology 78March 27, 2012
fore, are convinced to report genuine cortical
Taken together we detected asymmetry of trigem-
inal nociceptive processing in patients with CH com-
paring headache and nonheadache side that indicates
side-specific lateralized central facilitation primarily
on brainstem level. This lateralization varies in mag-
nitude between different stages of disease (i.e., epi-
sodic inside/outside, chronic). Our findings suggest
persistent alteration of trigeminal nociceptive pro-
cessing in CH. Additional supraspinal central facili-
tation in chronic CH demonstrates supplemental
pathophysiologic mechanisms associated with the
development of chronic disease in regard to neuronal
plasticity, which supports the importance of early
and effective treatment in CH to avoid long-lasting
Dr. Holle: study design, acquisition of data, statistical analyses, interpreta-
tion of data, drafting the manuscript. Dr. Gaul: acquisition and analysis of
data. Dr. Zillessen: acquisition and analysis of data. S. Na ¨gel: acquisition
and analysis of data. S. Krebs: acquisition and analysis of data. Dr. Diener:
study design, revising the manuscript. Dr. Kaube: study design, revising
the manuscript. Dr. Katsarava: study design, statistical analyses, revising
the manuscript. Dr. Obermann: study design, interpretation of data, re-
vising the manuscript.
Dr. Holle reports no disclosures. Dr. Gaul has received research support
from Deutsche Gesellschaft fu ¨r Muskelkranke, Roux-Program of the Uni-
versity of Halle-Wittenberg, Merck, Sharp & Dohme, Berlin Chemie,
Medtronic, Inc., and Boehringer Ingelheim. Dr. Zillessen, S. Naegel, and
S. Krebs report no disclosures. Dr. Diener has received honoraria for
participation in clinical trials, contribution to advisory boards, and/or oral
presentations from Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer
Vital, Berlin Chemie, CoLucid, Boehringer Ingelheim, Bristol-Myers
Squibb, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Lilly, La Roche,
3M Medica, Minster, MSD, Novartis, Johnson & Johnson, Pierre Fabre,
Pfizer, Schaper and Brummer, Sanofi-Aventis, and Weber & Weber; and
has also received financial support for research projects from Allergan,
Almirall, AstraZeneca, Bayer, GlaxoSmithKline, Jannsen-Cilag and
Pfizer. Headache research at the Department of Neurology in Essen,
where Dr. Diener is professor, is supported by the German Research
Council (DFG), the German Ministry of Education and Research
(BMBF), and the European Union. Dr. Kaube serves on a scientific advi-
sory board for Merck, Sharp & Dohme; has received speaker honoraria
from Merck, Sharp & Dohme, Boehringer Ingelheim, Pfizer Inc, Boston
Scientific, Medtronic, Inc., St. Jude Medical, Linde AG, Berlin-Chemie
AG, MD HORIZONTE GmbH, and Gru ¨nenthal GmbH; estimates that
5% of his clinical practice is spent administering IV infusion of aspirin for
outpatient and inpatient headache patients; and receives research support
from Boston Scientific, Medtronic, Inc., and St. Jude Medical. Dr. Kat-
sarava serves as an Associate Editor for Headache and the Journal of Head-
ache and Pain; serves as a consultant for Allergan, Inc.; and has received
research support from Allergan, Inc., Bayer Schering Pharma, Biogen
Idec, Merck, Sharp & Dohme, the German Research Council (DFG), the
German Ministry of Education and Research (BMBF), and the European
Union. Dr. Obermann receives research support from the German Fed-
eral Ministry of Education and Research BMBF.
Received August 3, 2011. Accepted in final form November 14, 2011.
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Neurology 78March 27, 2012
; Published online before print March 14, 2012;
D. Holle, C. Gaul, S. Zillessen, et al.
Lateralized central facilitation of trigeminal nociception in cluster headache
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