Convergence of cervical and trigeminal sensory afferents

Abstract

Cranial nociceptive perception shows a distinct topographic distribution, with the trigeminal nerve receiving sensory information from the anterior portions of the head, the greater occipital nerve, and branches of the upper cervical roots in the posterior regions. However, this distribution is not respected during headache attacks, even if the etiology of the headache is specific for only one nerve. Nociceptive information from the trigeminal and cervical territories activates the neurons in the trigeminal nucleus caudalis that extend to the C2 spinal segment and lateral cervical nucleus in the dorsolateral cervical area. These neurons are classified as multimodal because they receive sensory information from more than one afferent type. Clinically, trigeminal activation produces symptoms in the trigeminal and cervical territory and cervical activation produces symptoms in the cervical and trigeminal territory. The overlap between the trigeminal nerve and cervical is known as a convergence mechanism. For some time, convergence mechanisms were thought to be secondary to clinical observations. However, animal studies and clinical evidence have expanded our knowledge of convergence mechanisms. In this paper, the role of convergence mechanisms in nociceptive physiology, physiopathology of the headaches, clinical diagnosis, and therapeutic conduct are reviewed.

Full text

Convergence of Cervical and
Trigeminal Sensory Afferents
Elcio J. Piovesan, MD*, Pedro A. Kowacs, MD, and Michael L. Oshinsky, PhD
Address
*Jorge Manços do Nascimento Teixeira 868, São José dos Pinhais,
83005-500 Brazil.
E-mail: piovesan1@hotmail.com or piovesan@avalon.sul.com.br
Current Pain and Headache Reports 2003, 7:377–383
Current Science Inc. ISSN 1531–3433
Copyright © 2003 by Current Science Inc.
Introduction
The transmission and modulation of pain in the nervous
system is complex and involves different pathways and
levels of modulation. The activation of nociceptors from
the dura mater and cranial vessels is considered to be the
substrate of pain in primary headaches, such as migraine
and cluster headache [1]. In these headaches, the pain
frequently exceeds trigeminal innervations to the back
of the head, which is territory innervated by the greater
occipital nerve (GON), a branch of the C2 [2]. For exam-
ple, stimulation of the upper cervical roots by posterior
fossa tumors [3], direct cervical roots [3], infratentorial
dura mater [4], and subcutaneous tissue innervated by
the GON [5••] produces frontal head pain. These clinical
features suggested an overlap between trigeminal and
cervical sensory afferents projections in the central nervous
system (CNS), probably in the upper cervical segments
such as the trigeminal nucleus caudalis (TNC).
The meninges and cranial vessels are richly innervated
by nociceptors (C-fibers and α-δ fibers) from the first
division of the trigeminal nerve. Stimulating these fibers
induces the release of neuropeptides, such as substance
P (SP) [6], calcitonin gene-related peptide (CGRP) [7], and
neurokinin A. These neuropeptides induce cell activation
within the medullary dorsal horn of the TNC [8–11] that
extends to the C2 spinal segment [9,10] and within the
dorsolateral area (DLA), which contains the lateral cervical
nucleus (LCN) [12,13]. This activation occurs within the
superficial lamina (I and II) of the TNC, where many of the
afferents synapse on projection neurons to other brain
stem sites or the thalamus [14]. Upper cervical root stimu-
lation (ie, GON manipulation) produces changes in the
TNC [15,16] and LCN [17] neurons. Moreover, the LCN
also receives input from other receptive fields, which
included some parts of the arm and trunk [18]. This is the
reason why some headaches are associated with limb pain
[18]. The authors have described a patient with migraine
who showed recurrent extratrigeminal stabbing and burn-
ing sensation with allodynia on different parts of the body
[19]. These features support the view that the perception of
cranial pain is caused by a functional continuum between
trigeminal and cervical fibers that converge on neurons in
the TNC and upper cervical segments [15]. The TNC also
receives afferents from the autonomic nervous system
(vagus nerve) [20,21] and the hypoglossal nerve [22].
To review this convergence mechanism, the authors
of this paper used published reports of referred pain,
trigeminocervical convergence in clinical studies, animal
research that used headache and other pain models, and
therapeutic responses to blocking the trigeminal afferents
or the GON.
Basic Science Evidence
The evidence for convergence between trigeminal and
cervical nociception in the TNC is from electrophysiologic
studies and other methods of detecting neuronal
Cranial nociceptive perception shows a distinct topo-
graphic distribution, with the trigeminal nerve receiving
sensory information from the anterior portions of the
head, the greater occipital nerve, and branches of the
upper cervical roots in the posterior regions. However,
this distribution is not respected during headache attacks,
even if the etiology of the headache is specific for only one
nerve. Nociceptive information from the trigeminal and
cervical territories activates the neurons in the trigeminal
nucleus caudalis that extend to the C2 spinal segment and
lateral cervical nucleus in the dorsolateral cervical area.
These neurons are classified as multimodal because they
receive sensory information from more than one afferent
type. Clinically, trigeminal activation produces symptoms in
the trigeminal and cervical territory and cervical activation
produces symptoms in the cervical and trigeminal territory.
The overlap between the trigeminal nerve and cervical
is known as a convergence mechanism. For some time,
convergence mechanisms were thought to be secondary
to clinical observations. However, animal studies and
clinical evidence have expanded our knowledge of conver-
gence mechanisms. In this paper, the role of convergence
mechanisms in nociceptive physiology, physiopathology
of the headaches, clinical diagnosis, and therapeutic
conduct are reviewed.

378 Cervicogenic Headache
activation. These include the measurement of c-fos with
immunohistochemistry, metabolic activity with 2-deoxy-
glucose, and single-cell electrophysiologic techniques. The
studies are based on animal headache models, which
provide anatomic and physiologic knowledge of cranial
nociceptive pathways.
Immunohistochemical detection of the protein
product fos of the c-fos immediate-early gene
Electrical stimulation of the superior sagittal sinus (SSS) in
cats and rats has provided a useful means to study trigemi-
nal vascular pain mechanisms. SSS stimulation produces
neuronal chances within the TNC and medullary dorsal
horn, which increases c-fos immediate-early gene
expression. Electrical stimulation over the SSS induces fos-
positive cells in lamina I and II of the medullary dorsal
horn of the upper cervical spinal cord [10]. In model exper-
iments using macaca nemestrina, electrical stimulation
over the SSS produced expression of fos-positive cells in
the caudal superficial lamina of the trigeminal nucleus and
in the superficial lamina of the dorsal horn at the C1 level
of the upper cervical spinal cord [23]. Because of the close
anatomy of cranial structures of monkeys to humans, it is
likely that the cells described in this study represent
(for primates) the nucleus that mediates the pain of
migraine, suggesting a convergence process [23]. Mechani-
cal stimulation of the transverse sinus and SSS produced
a predominantly ipsilateral increase in the number of fos-
positive neurons in the TNC (lamina I) and upper cervical
dorsal horn [24]. Other studies using mechanical and
electrical stimulation of the SSS also evoked significant
increases in fos-positive cells in the lamina I and II of
the superficial dorsal horn of C1–C3 cervical spinal cord
and TNC [25].
Using chemical stimuli (injection of autologous blood
or carrageenin subdurally into the cisterna magna), Nozaki
et al. [26] introduced fos-like positive cells in the super-
ficial lamina of the medullary dorsal horn. Electrical
stimulation of the middle meningeal artery also produces
fos-positive cells in the dorsal horn of the caudal medulla
(TNC) and the upper two divisions of the cervical spinal
cord on the ipsilateral and contralateral sides [27].
Although the c-fos method is a good way to identify
cell activation after sensory stimulation, it does not
allow for the differentiation of the origin of activation of
the secondary sensory neurons. Because there is an increase
in c-fos positive neurons in both of these nuclei after
SSS stimulation or GON stimulation, we are not able
to predict the source of the sensory activation based on
pattern of c-fos expression. Therefore, c-fos studies are an
indirect method for identifying convergence mechanisms.
Metabolic mapping approach and other studies
Electrical stimulation over the SSS induces neuronal activa-
tion within the TNC and LCN followed by vascular
changes. Blood flow and metabolic activity increases in the
TNC and LCN after electrical stimulation over the SSS in
cats [28]. Stimulation of a purely cervical input, such as the
GON, also increases metabolic activity in both typically
cervical regions of the spinal cord and in the TNC [29].
The exact nature of this activation cannot be detected using
2-deoxyglucose methods. One shortcoming of this method
is that increased activity can be excitatory or inhibitory.
After stimulation, trigeminal nociceptors produce
neuropeptides (ie, CGRP, SP, and neurokinin A) [6,7].
SP is a neurotransmitter released in the lamina I and II of
the TNC and spinal cord neurons, which then can diffuse
to laminas III to V depending on the intensity of the
stimuli [30]. Teeth extraction of the incisor and molar
induces SP release in bilateral and unilateral neurons,
respectively, of the TNC and cervical spinal cord [31]. The
authors of this study propose that bilateral activation
occurs because the incisor tooth receives bilateral trigemi-
nal afferents. Other studies show that bilateral activation
of the TNC and LCN was not caused by multiple afferents,
but by the same afferent sending bilateral projections to
the TNC and LCN [27].
Electrophysiologic studies
Electrophysiologic studies are versatile methods of assess-
ing nociceptive responses and studying the overlap
between trigeminal and cervical nociception. These stud-
ies measure the progression of nociceptive responses over
time in one experiment. They produce important infor-
mation concerning convergent mechanisms. Time course
for inducing convergence mechanisms, intensity of
the stimuli, sensitization of neurons involved in sensory
processing, and therapeutic actions have been studied
using these methods.
The trigeminocervical reflex in humans is used to
measure convergent mechanisms between trigeminal and
cervical nociceptors. This method consists of electrical
stimulation over the supra-orbital nerve, which produces a
sternocleidomastoid muscle contraction (cervical inputs).
The reflex occurs with motoneuron participation (inter-
neurons) within the TNC [32]. This test has been used
for patients with headache to assess nociceptive processing
of the TNC [33].
Stimulation of nociceptive afferents from the trigemi-
nal [8] and cervical [34] territories can produce changes
that are reflected in an increase in excitability of CNS
neurons. Chemical and electrical stimulation over upper
cervical roots (GON) produces an increase in the excit-
ability of the meningeal neurons, which coincides with
a central trigeminal sensitization [35•]. In this study,
convergent neurons were found in deep layers of the
dorsal horn (lamina V–VI) that correspond with the C2
neurons (superficial layers [lamina I–II] from cervical
neurons) [35•]. These data provide clear evidence of
functional coupling between nociceptive meningeal affer-
ents and cervical afferents, with central trigeminal sensiti-
zation secondary to GON stimulation.

Convergence of Cervical and Trigeminal Sensory Afferents • Piovesan et al. 379
The time course and intensity of changes in excitability
in neurons that receive convergent inputs was determined
by recent studies. Stimulation of the upper cervical
roots (GON) produces an initial decreased excitability of
the trigeminal neurons and then a subsequent increased
excitability [35•]. These results are consistent with results
in our laboratory in experiments using chemical stimula-
tion of the dura (unpublished results).
Secondary sensory neurons in the TNC can receive
ipsilateral and contralateral inputs from the GON or
trigeminal afferents [10,35•,38]. Severe injury of trigemi-
nal nociceptive afferents, such as extraction of the incisor
tooth, produces activation in bilateral neurons of the
TNC and spinal cord [31]. The bilateral activation after
unilateral stimulation may correspond to the sensation
of a dull and poorly localized quality of pain spread
from deep somatic afferents in the trigeminocervical
regions (c-fibers) [37].
Clinical Evidence
Several clinical studies have demonstrated an overlap in
nociceptive processing between the trigeminal and cervical
systems [3,4,38]. The authors have studied (three cases)
the clinical behavior of convergence in these systems [5••].
Patients were administered upper cervical stimulation with
intradermal sterile water over the GON. The intensity of
the pain was mapped and measured using a visual
analogue scale (VAS) during stimulation and 10, 30, and
120 seconds after stimulation: at 10 seconds after GON
stimulation, all of the patients developed severe pain at the
site of the injection; in two patients (case 1 and 3), the
pain spread from the right GON territories to the areas
innervated by the first branch of the trigeminal nerve (V1)
on the ipsilateral to the intradermal injection; after 30
seconds, the pain increased and spread to the periorbital
region head innervated by the trigeminal nerve (case 1). In
cases 2 and 3, the intensity of the pain increased, but did
not spread. These patients developed ipsilateral facial
flushing and conjunctival injection and tearing, which
subsided after 60 seconds; at 2 minutes after the stimula-
tion, the intensity of the pain decreased in the ipsilateral
trigeminal region and kept the same intensity in the
cervical territories (case 1 and 2); in the third patient, the
pain maintained the same intensity in both territories.
The pain was described as lancinating with intermingled
paroxysms that lasted for approximately 2 to 3 seconds.
For all of the patients, the occipital pain was perceived
to be more intense than the trigeminal pain. Ipsilateral
occipital pain lasted an average of 4 hours and was the
only pain that the second patient experienced. The time
course of spread of the pain from the occipital to the
trigeminal region is very fast, which is shown in the study
by the authors. This process cannot be explained by central
sensitization, which generally begins at least 45 minutes
after the stimuli.
Using pressure algometry, the authors studied
the influence of light stimulation on pain perception in
the cervical and trigeminal territories in migraineurs and
control subjects. Migraineurs presented a significant and
persistent drop in pain thresholds in the trigeminal and
cervical region after light stimulation. These results
indicate that light may have a relevant role in modulating
trigeminal and cervical pain perception [39].
Another headache type that displays convergence of
trigeminal and cervical areas is cervicogenic headache.
Cervicogenic headache is a final common pathway for
several neck disorders [40]. Pain stemming from the neck
usually spreads to the oculofrontal area (trigeminal
region). The most characteristic features are symptoms
and signs of neck involvement (such as mechanical precip-
itation of attack). Blocking the GON can improve these
symptoms. The distribution of these symptoms over the
trigeminal territory and the response after a GON block
can be explained by the convergence of trigeminal and
cervical afferents in the TNC or LCN.
Therapeutic Evidence
Laboratory studies
Acute abortive migraine medications used to treat primary
headaches, such as sumatriptan and dihydroergotamine
(DHE), can inhibit the expression of c-fos positive cells
in the TNC and LCN [41,42]. Using electrophysiologic
techniques, it has been shown that neurons in the TNC
are inhibited by parenteral administration of DHE [43].
The pharmacologic mechanisms of the 5-HT1D receptor
agonist (sumatriptan) may be mediated peripherally,
whether by inhibition of plasma extravasation or by direct
vasoconstriction [42]. In addition, it was shown that trip-
tans act centrally within the trigeminocervical complex.
Microiontophoretic injections of ergometrine or sumatrip-
tan into this site produced inhibition of neuronal activa-
tion from the SSS nociceptors [43].
These studies suggest that triptans, which are serotonin 5-
HT1B/1D receptor agonists, inhibit evoked trigeminovascular
nociceptive activity in the trigeminocervical complex.
Sumatriptan (after blood-brain barrier disruption), eletrip-
tan, naratriptan, rizatriptan, 4991W93, and zolmitriptan
block evoked trigeminal nucleus activity [44]. Opioid
receptors also are involved in cardiovascular nociception,
specifically within the trigeminocervical complex. Studies
using microiontophoresis determined that ␮-receptor ago-
nists inhibit neurons in the TNC post-synaptic to trigeminal
afferents [45]. Valproic acid, an inhibitor of γ aminobutyric
acid (GABA) aminotransferase, when applied to the rat in the
trigeminocervical nociceptive models, reduced the expres-
sion of c-fos-positive cells in the TNC [46] after trigeminal
stimulation. Electrophysiologic studies, combined with
microiontophoresis, also suggested that GABA receptors
modulate trigeminovascular nociceptive transmission in the
trigeminocervical complex [47].

380 Cervicogenic Headache
These studies suggest that the trigeminal nociceptive
system in the trigeminocervical complex is modulated by
several neurotransmitter systems, such as 5-HT, GABA,
opioid, and others (Fig. 1).
Clinical studies
Some headaches, in which the etiology is trigeminal activa-
tion, benefit from anesthetic blockage of the upper cervical
roots (GON) [2,48–50]. This therapeutic response can be
explained only by a convergence mechanism between
trigeminal and cervical roots. However, other studies
showed that blocking the GON did not influence migraine
attacks [52] or other primary headaches [51]. Electrical
stimulation of the GON or the suboccipital regions
produces improvement in chronic headaches, such as
cluster (unpublished data) and chronic migraine [53].
The authors’ experience with GON blockage with
bupivacaine 0.5% for migraine prophylaxis showed
increased headache intensity for the first 30 days [54].
The migraine attacks improved after this time and this
improvement was maintained for more than 60 days.
Studies that used prilocaine hydrochloride 2% over the
GON [55] and bupivacaine 0.5% over the GON and
supraorbital nerve [56] showed reduced intensity during
attacks. In an isolated study with a limited number of
patients, GON blockage did not reduce the intensity of
acute migraine attacks [52].
Greater occipital nerve manipulation is a good
therapeutic option for some chronic headaches. Cluster
headache attacks were improved after blocking the GON
[49]. Patients with chronic migraine who received subcuta-
neous suboccipital neurostimulation showed headache
improvement after activation of this device [53]. Less
effective responses occurred for chronic paroxysmal hemi-
crania and hemicrania continua, in which GON block did
not reduce the pain [51].
Those headaches that we know have an etiology
restricted to the trigeminal afferents show a good response
after the upper cervical roots (GON) are blocked. There is
good evidence that trigeminocervical convergence mecha-
nisms exist. GON block produced improvement of the
frontal pain that occurs in some headaches with a cervical
etiology. Perhaps the best example for this is that the
diagnostic criteria for cervicogenic headache include
significant headache improvement after GON block [40].
In a study by Piovesan et al. [57], patients suffering from
cervicogenic headaches with chronic presentation showed
a positive response after GON block.
Other Connections with
Trigeminocervical Complex
Autonomic-trigeminocervical connections
The TNC is a nociceptive structure that exerts fundamental
control over inputs from cervical and trigeminal nocicep-
tors. However, it also receives other inputs that participate
in head pain control. The parasympathetic system (vagus
nerve), together with the TNC and LCN (trigeminocervical
Figure 1. Convergence mechanisms and neuro-
transmitters involved in pain modulation. PR—
prejunctional receptors; pos-R—post-junctional
receptors; 5-HT1B/1D receptors for triptans [46];
5-HT1 receptors for dihydroergotamine;
opioids—receptor [47]; GABA-A—receptors
[48,49]; trigeminocervical complex—trigeminal
nucleus caudalis and lateral cervical nucleus
[10,15–17,23,44,45]; hypoglossal afferents [22];
simpato afferents [20,21].

Convergence of Cervical and Trigeminal Sensory Afferents • Piovesan et al. 381
structures), could increase or decrease the pain signals.
Vagus nerve stimulation produces inhibitions in the
trigeminothalamic projection neurons from the TNC [58]
and in tooth pulp-responsive units (trigeminal) in ventro-
posteromedial nucleus of the thalamus [59,60]. Low-
intensity stimulations of cervical vagal afferents facilitate
nociceptive reflexes such as the jaw-opening reflex [61] or
the tail-flick reflex [62].
Continuous vagal nerve stimulation (VNS) for 24
hours in awake rats produced significant antinociceptive
effects in a model of trigeminal pain [64]. This showed
that VNS stimulation significantly inhibits activation of
second-order nociceptors in the TNC and pain-related
behavior on the side of the facial nociceptive stimulus
during the early and late phase. Vagal afferent stimulation
predominantly inhibits sensory processing in the
TNC [58,65] and in the ventral posteromedial thalamic
nucleus [59] (Fig. 2).
Hypoglossal-trigeminocervical
Chemical and electrical stimulation of the distal hypo-
glossal (12th) nerve trunk produced a significant increase
in fos-positive neurons in the dorsal paratrigeminal
nucleus and laminae I and II of the TNC and upper cervical
dorsal horn in rats [22].
Projections from the trigeminocervical
nociceptive complex
The TNC sends nociceptive information to the ventro-
posteromedial (nucleus of the ventrobasal complex) of
the thalamus and to other medial nuclei [66]. It also
relays information from the hypothalamus in the
trigeminohypothalamic pathway [67], which may explain
some of the premonitory symptoms that are associated
with primary headaches disorders. Some studies specu-
late that there may be convergence of trigeminal sensory
information and sensory information from other areas in
the thalamus.
Conclusions
The first step of complex central modulation of
cranial pain syndromes starts in the TNC and upper
cervical horn. The TNC and LCN are the main nuclei that
receive nociceptive information and together they form
the trigeminocervical complex. These nuclei are anatomi-
cally separated, but functionally connected between the
convergent mechanisms. Recent clinical and laboratory
evidence suggests that this complex is involved in noci-
ceptive modulation during migraine, cluster, and other
headache attacks. Cells inside these nuclei are considered
to be multimodal neurons. One multimodal cell can
receive two or more inputs from distinct origins (ie, from
the trigeminal nerve, cervical roots, parasympathetic
nerve, or other nociceptive areas). These physiologic
properties produce divergent symptoms, which are mani-
fested by diffuse pain without regard to topographic
anatomic nerve distribution. Some of the neurotransmit-
ters that regulate these mechanisms include 5-HT, GABA,
opioid, norepinephrine, and other substances. Under-
standing the anatomy, physiology, and pharmacology
of convergence mechanisms may help understand the
Figure 2. Anatomic and physiologic distribu-
tion of elements involved in the convergence
mechanisms. TNC—trigeminal nucleus
caudalis; LCN—lateral cervical nucleus;
trigeminocervical complex—TNC and LCN;
V1—branch from the trigeminal first division;
C1–C3—branch from the upper cervical roots;
empty circle—secondary nociceptive neurons
that receive input from the trigeminal territory;
colored circle—secondary neurons that
receive input from the cervical territory;
partially colored circle—secondary neurons
that receive inputs from the trigeminal and
cervical territory (multimodal cells).

382 Cervicogenic Headache
clinical features and future treatments for headache and
other facial pain.
This review shows that convergence of trigeminal and
cervical afferents, which are located within the trigemino-
cervical complex, produce diffuse painful symptoms and
are responsible for the first step in nociceptive modulation
in patients with primary headaches.
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