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두통, 얼굴의 통증, TM joint pain의 neural tissue origin pain을 이해하기 위해서는 Trigeminal Sensory System을 꼭 이해해야
두뇌, 얼굴의 통증은 삼차신경이 지배한다라는 단순한 사실과 함께 깊은 anatomy and pathophysiology를 이해할때 진정한 healing process를 도와주는 치료에 도달할 수 있다.
panic bird...
29 Trigeminal sensory system.pdf
Although generally considered part of the somatosensory system, the trigeminal sensory system has been assigned its own chapter for this second edition of the Human Nervous System. This chapter will address the unique anatomy of the pathway for facial sensations, involving the trigeminal ganglion and its associated nuclei within the brainstem. We will also comment on the innervation of specialized cranial structures such as the teeth, tongue, meninges, cornea, conjunctiva, and oral and nasal mucosa. Recent studies on the involvement of the trigeminal system in clinically relevant conditions such as toothache, headache, and trigeminal neuralgia are considered.
- 체성감각 시스템의 일부로서, 삼차 감각신경 시스템.
- 이 챕터에서는 얼굴감각을 위한 독특한 해부학을 탐구
- 이, 혀, 수막, 각막, 결막, 눈과 코의 점액의 감각을 담당하는 특별한 신경.
In outline, the trigeminal or fifth cranial nerve is a general sensory nerve carrying touch, temperature, nociception, and proprioception from the superficial and deep structures of the face. Trigeminal means literally “three twins” and refers to the three peripheral nerves that take origin together (i.e., are born) from each ganglion, the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions.
- 5번째 뇌신경 삼차신경은 촉각, 온도, 통각, 고유수용감각을 전달하는 일반적 감각신경.
- 삼차신경은 세가지 가지 "opthalmic, maxillary, mandibular division"으로 나뉨.
The central processes of the trigeminal ganglion cells form the trigeminal sensory root (or portio major), which enters the brainstem at midpontine level. Most fibers bifurcate to terminate in both the main sensory nucleus (Pr5, principal trigeminal nucleus) and the nuclei of the spinal trigeminal tract (Sp5, spinal trigeminal nuclei). A unique feature of the pathway is the location of proprioceptive neurons in the mesencephalic nucleus (Me5) in the brainstem, rather than in the trigeminal ganglion. From the trigeminal nuclei, second-order fibers concerned with sensation project via the dorsal and ventral trigeminothalamic tracts to several regions of the somatosensory thalamus, adjacent to projections from spinal inputs.
-
Facial inputs then run parallel to the spinal thalamocortical projections to supply somatosensory regions of the cortex. The trigeminal motor nucleus and nerve, innervating the muscles of mastication, the mylohyoid tensor veli palatini muscles, will not be considered here. For the development of the receptors, trigeminal nerves and ganglion, see Chapter 4.
RECEPTORS AND
THEIR INNERVATION
Receptors for the facial skin and scalp (reviewed Darian-Smith, 1973; Iggo, 1974) are similar to those in hairy skin of other body regions and are fully discussed in Chapter 28. For the glabrous skin of the lips,
a comparative study reported a variety of encapsulated
receptors, with the most complex structures
seen in primates including man (Kadanoff et al., 1980).
Muscle spindles in facial and jaw muscles are similar
in structure to those elsewhere in the body and are
only discussed with reference to the location of their
afferent somata and central connections. While innervation
of the temporomandibular joint also corresponds
to that for other synovial joints, it has attracted
considerable recent clinical interest and so is briefly
reviewed here.
Skin of the face is remarkable for its high tactile
sensitivity, with pressure thresholds lower than any
other body regions, in both men and women (Weinstein,
1968). The upper lip, nose, and tip of the tongue have
the lowest detection thresholds reported (Rath and
Essick, 1990). Regional differences in sensitivity to different
stimuli have been reported, with the glabrous lip
skin (vermilion) being especially sensitive to vibration
and motion, compared with adjacent perioral hairy
skin (Rath and Essick, 1990). For two-point discrimination,
fingers have rather lower values (2.1 mm) than
facial skin (3.3 mm, nose; 5–6 mm, upper perioral
skin), although the tip of the tongue was lowest at
0.99 mm (McNutt, 1975; Rath and Essick, 1990).
Recordings from the human infraorbital nerve by
microneurography, showed a high proportion of
receptive fields at the angle of the mouth, indicating
particularly dense innervation of perioral skin
(Johansson et al., 1988). Both slowly and rapidly
adapting responses were recorded, similar to those
reported for the hand (Vallbo et al., 1979). Receptive
fields for rapidly adapting units ranged from 2 to
118 mm2 (median 17 mm2) compared with 2 to 88 mm2
(median 7mm2) for slowly adapting responses. Rapidly
adapting thresholds were lower (median 0.5 mN) than
for slowly adapting responses (cutaneous units, median
1 mN; mucosal, median 1.5 mN). A recent study on
the tongue, also using microneurography to record
from single nerve fibers, indicates that receptive fields
(1–20 mm2, mean 2.4 mm2) and detection thresholds
(0.03–2 mN, mean 0.15 mN) may be lower there than
for any other body region (Trulsson and Essick, 1997).
Innervation of Specialized Cranial Structures:
Teeth and Periodontal Ligament
Human permanent incisors and canines each receive
about 360 myelinated fibers and some 1500–2000
unmyelinated afferents in adults (Johnsen and Johns,
1978). Small myelinated fibers include cholinergic
afferents, while many unmyelinated fibers contain
substance P and CGRP (Byers, 1984; Silverman and
Kruger, 1987). Galanin-immunoreactive fibers have
also been reported in several species including human
(Wakisaka et al., 1996). These fibers terminate mainly
in free nerve endings, especially within the dental
pulp (Fig. 29.1). Endings can extend for up to 200 μm
into the dentinal tubules in both monkey and human
teeth, particularly near the cusps of the crown (Byers
and Dong, 1983; Frank, 1968). Besides these afferent
fibers, unmyelinated sympathetic fibers supply blood
vessels within the tooth pulp (Anneroth and Norberg,
1968). Although innervation is mainly ipsilateral,
Byers and Dong (1983) used autoradiography to show
that some contralateral innervation occurs in monkey
mandibular incisors and canines. After tooth loss and
reimplantation, reinnervation of human teeth can occur,
although the number and caliber of regenerating fibers
is reduced (Ohman, 1965).
Electrical, chemical, mechanical, and thermal stimuli
can activate tooth receptors and usually give rise to the
sensation of pain (reviewed Schults, 1992). Pain can be
associated with dentinal, pulpal, gingival, or periodontal
receptors, each with particular but overlapping
characteristics (Sharav et al., 1984). For
dentinal receptors, pain is generally not spontaneous
but evoked by heat, cold, and sweet stimuli. The transduction
mechanism may involve odontoblasts, though
this matter is not resolved. Dull ache is thought to
arise from activity in unmyelinated axons, common
within the tooth pulp. Pulpal pain is associated with
inflammation, can be spontaneous, is generally poorly
localized, and may outlast the stimulus (Hensel and
Mann, 1956). The response of pulpal nerves to tooth
injury and inflammation has been reviewed by Fristad
(1997). In rodents, inflammation of the pulp and
periodontium results in up-regulation of substance P
and CGRP, as in other tissues.
Besides receptors within the tooth, the human
periodontal ligament is rich in free nerve endings and
a variety of coiled and Ruffini-type endings (Fig. 29.1;
Maeda et al., 1990; Lambrichts et al., 1992). Fibers
containing substance P have been demonstrated here
and are likely to be associated with periodontal pain (Fristad, 1997). Such pain is usually well localized and
exacerbated by pressure.
In addition to nociceptors, microneurography of the
inferior alveolar nerve in humans during applications
of forces to the teeth has confirmed the presence of
low-threshold, slowly adapting mechanoresponses
from the periodontium (Trulsson and Johansson, 1996).
These receptors encode food contact during biting and
continuously discharge when food is held between the
incisors. These response properties indicate that periodontal
receptors are likely to contribute to the sensation
of “dental touch” and the control of mastication,
particularly on initial contact with food and its manipulation.
Somata from periodontal afferents are found in
both Me5 and the trigeminal ganglion (reviewed Capra
and Dessem, 1992).
Temporomandibular Joint
The innervation of the temporomandibular joint
(TMJ) has attracted interest in recent years, at least in
part because of the involvement of the joint in a variety
of painful conditions (see later). Immunostaining with
neurospecific markers has shown that the human joint
capsule and peripheral disc is richly innervated
(Morani et al., 1994). Most studies in humans have
reported encapsulated receptors and free nerve
endings in the joint capsule (Griffin and Harris, 1975;
reviewed Zinny, 1988) and only free endings in the
disc (Fig. 29.2A). However, Morani et al. (1994) found
only free nerve endings in both locations. Reports on
corpuscular endings in animals are also inconsistent
with Ruffini-type and Paciniform endings described in
cat and sheep, but only with free nerve endings in the
mouse and rat (Dreessen et al., 1990; Ichikawa et al.,
1990; Tahmasabi-Sarvestani et al., 1996).
An interesting study on the fetal development of
innervation in the human TMJ showed that nerves
were present from around 9–10 weeks (Ramieri et al.,
1996). Innervation of the disc was particularly dense
by 20 weeks and included encapsulated endings; however,
this regressed during the third trimester. In adults,
disc innervation was restricted to the periphery and
only free nerve endings were present.
Oral Mucosa and Tongue
The oral mucosa in several primates, including
humans, contains Merkel cells and free nerve endings
(Fortman and Winkelmann, 1977; Luzardo-Baptista,
1973), although Ruffini endings were reportedly absent
(Halata and Munger, 1983). In the human gingiva,
fibers containing CGRP and substance P were seen in
the lamina propria, as well as fibers containing NPY,
tyrosine hydroxylase, and VIP in association with blood
vessels (Luthman et al., 1988). It was considered likely
that the CGRP and Substance P fibers were sensory,
probably associated with nociception.
In primate tongue, Meissner’s corpuscles are found
in the dermis close to the epidermal border, Ruffinitype
endings occur in deeper dermal regions, and free nerve endings terminate within the epidermis (Zahm
and Munger, 1985). Merkel cell complexes were not
seen, confirming results from a previous study (Munger,
1973). Trigeminal afferents also innervate tongue
papillae in primates and occasionally enter taste buds
where they have been suggested to serve a trophic
function (Zahm and Munger, 1985). Knock out studies
in mice indicate that the development of gustatory and
somatosensory afferents to the tongue require different
trophic factors, namely BDNF for gustatory nerves
and NT3 for trigeminal afferents (Nosrat, 1998).
The lingual nerve, a branch of the mandibular
division, supplies tactile sensation for the anterior
two-thirds of the tongue. A study of electrical activity
recorded from the human lingual nerve showed some
nerve fibers with low mechanical thresholds (mean
force 0.15 mN) and small receptive fields (mean area
2.4 mm2 ) considered to terminate near the tongue surface (Trulsson and Essick, 1997). As noted earlier,
these are lower than for any other site on the body. Both
rapidly adapting responses and two types of slowly
adapting units (SA I and SA II) were recorded, similar
to those reported from the glabrous skin of the human
hand. Generally, slowly adapting responses have been
considered to be associated with Merkel cells (SA I)
and Ruffini endings (SA II), so the lack of anatomically
identified Merkel cells in the tongue requires reassessment.
Besides these responses, lingual nerve responses
to mechanical and thermal (cold) stimuli have been
described (Kosar and Schwartz, 1990).
Two-point discrimination studies on the sides
and tip of the tongue showed the tip had the lowest
values (Ringel and Ewanowski, 1965; McNutt, 1975).
However, there was an interesting difference in two
point-discrimination values for the two sides in approximately
half of the adults, which was not present in the
children (McNutt, 1975). Either side could be more
sensitive, with equal frequency. Because laterality differences
were only noted in adults, they were attributed
to central neural changes rather than peripheral
mechanisms.
Cranial Vessels and Meninges
Major cranial blood vessels such as the middle
cerebral and scalp arteries are richly innervated by
trigeminal afferents, with fibers containing substance
P found in the media and adventitia (Helme and
Fletcher 1983; Chapter 37). Astudy of human temporal
arteries showed both CGRP and substance P in nerve
fibers in the adventitia and around the adventitia–
media border (Jansen et al., 1986). Two neuronal
ganglia have been described on the human internal
carotid artery (Suzuki and Hardebo, 1991). Although
the majority of cells within these ganglia were considered
to be parasympathetic, some contained CGRP
and substance P, and it was suggesting a sensory
function.
The dura of the anterior and middle cranial fossae
receives trigeminal innervation. Animal studies have
shown that the dural afferents contain substance P and
CGRP (Andres et al., 1987; Keller and Marfurt, 1991).
Most end simply as free nerve endings within the connective
tissue or adjacent blood vessels (rat, Knyihar-
Csillik et al., 1997). Release of peptides from these
endings has been implicated in migraine (see later).
Cornea, Conjunctiva, and Nasal Mucosa
Human cornea and conjunctiva, like those of other
mammals, are innervated by ophthalmic trigeminal
afferents as well as sympathetic and parasympathetic
efferents (Ruskell, 1985; Elsas et al., 1994). Fibers
containing CGRP, substance P, acetylcholine and
catecholamines have all been confirmed in human
cornea (Toivanen et al., 1987; Ueda et al., 1989; Uusitalo
et al., 1989). Radially oriented fiber bundles enter the
cornea from the sclera and then travel, mainly with a
temporonasal orientation (Fig. 29.2B), within the
stroma (Muller et al., 1997). Fibers penetrate Bowman’s
membrane and terminate between epithelial cells,
mainly in the deeper layers (Muller et al., 1996). Both
myelinated Aδ and unmyelinated C fibers have been
described in the peripheral cornea, although central
cornea contains only unmyelinated fibers (Muller et al.,
1996). In the living human, cornea innervation can be
studied with slit-scanning confocal microscopy (Auran
et al., 1995). This technique has been used to study
regeneration of corneal innervation after operative
procedures (Heinz et al., 1996; Ritcher et al., 1997).
The corneal innervation lacks any encapsulated
receptors, being innervated by free nerve endings only
(Weddell and Zander, 1950). Recordings in animals
indicate that both mechanosensitive and thermosensitive
afferents are present (Belmonte and Giraldez,
1981). The corneal responses are similar to those from
Aδ and C skin afferents, except that mechanical
thresholds are lower. In humans, most studies suggest
that the only sensation evoked by corneal stimulation is
pain (Beuerman and Tanelian, 1979). Lele and Weddell
(1956) showed subjects could distinguish touch, cold,
warmth and pain from the cornea; however, the
stimulus used was air streams, and it is difficult to
prevent the spread of air to adjacent conjunctiva or
eyelids (Schults, 1992). The dense innervation of eyelid
skin and eyelashes is well known, with Ruffini-type
endings, lanceolate terminals, and Merkel cell complexes
(monkey, Halata and Munger, 1980).
Trigeminal afferents also provide general somatic
afferents to the nasal mucosa, again with free nerve
endings only. Sensory fibers containing substance P
and CGRP have been described in nasal epithelium
(Hauser-Kronberger et al., 1997). For the nasal
vasculature, CGRP and neurokinin A fibers innervate
arterial vessel walls, along with parasympathetic and
sympathetic efferents (Baraniuk, 1992; Riederer et al.,
1995). Receptors for substance P (neurokinin 1) are
present in human airway epithelium and submucosal
glands (Shirasaki et al., 1998), and substance P has been
implicated in reflexes such as sneezing and allergic
reactions (Nieber et al., 1991; Baraniuk, 1992). Stimulation
of nasal mucosa commonly results in a tingling
sensation, which may outlast the duration of stimulation
(Melzack and Eisenberg, 1968). Besides mechanical
activation, many odorants stimulate trigeminal as well
as olfactory afferents, although trigeminal thresholds are generally higher (Doty, 1995). Such trigeminal sensations
are described as irritant or pungent and have
been shown to modify olfactory sensations.
TRIGEMINAL NERVES,
GANGLION, AND ROOT
Peripheral Nerves
The three main trigeminal nerve divisions—
ophthalmic, maxillary, and mandibular—together
constitute the largest of the cranial nerves (reviewed
Shankland, 2000). The mandibular division is the
largest with some 78,000 myelinated fibers, compared
with 50,000 fibers in the maxillary and only 26,000
in the ophthalmic divisions (Pennisi et al., 1991).
Myelinated fiber diameters range from 0.8 to 16 μ m,
with a similar bimodal distribution in each division
(although the motor component of the mandibular
division contains fibers with a larger diameter spectrum,
4–20 μ m). Each division supplies a distinct dermatome
on the head and face and the adjacent mucosal and
meningeal tissues (Brodal, 1965; reviewed Usunoff
et al., 1997). Unlike spinal dermatomes, trigeminal
nerve distributions show relatively little overlap.
There is, however, considerable overlap with inputs
from second and third cervical roots and vagal nerves
(monkey, Denny-Brown and Yanagisawa, 1973).
Communicating nerves between branches of the facial
and trigeminal nerves are common. The best known of
these is the chorda tympani, but others, such as the
auriculotemporal, have been described (Namking
et al., 1994).
Fibres from the autonomic nervous system frequently
join trigeminal nerves to reach peripheral
tissues. Thus sympathetic fibers from the superior
cervical ganglion travel with the external carotid
artery then join the peripheral trigeminal nerves to
reach sweat and mucosal glands in the facial skin and
oral and nasal cavities. Sympathetic fibers also supply
blood vessels in the connective tissue around the
ganglion and nerves, as recently described by Smolier
et al. (1998, 1999). Each trigeminal branch also receives
parasympathetic fibers: the ophthalmic nerve from the
ciliary ganglion, the maxillary from the pterygopalatine
ganglion, the mandibular nerve from submandibular
and otic ganglia. In addition, fibers from
the facial nerve (chorda tympani) join the lingual
nerve to provide the gustatory afferents for the
anterior tongue.
Each trigeminal nerve branch exits the skull
independently: the ophthalmic nerve through the
superior orbital fissure, the maxillary nerve via the
foramen rotundum and across the pterygopalatine
fossa, and the mandibular nerve through the foramen
ovale and the infratemporal fossa. Proprioceptive
inputs from muscle spindles in the jaw muscles and
some from the periodontal ligament travel with the
motor nerve branch and have somata located in Me5
in the brainstem, rather than in the trigeminal
ganglion. While the presence of muscle spindles is
well established for jaw-closing muscles (temporalis,
medial pterygoid, masseter; monkey, Kubota et al.,
1973; human, Voss, 1935; Freimann, 1954), their
existence in jaw opening muscles (lateral pterygoid,
digastric) was initially debated. They have been
confirmed in the human lateral pterygoid (Gill, 1971;
Rakhawy et al., 1971) and the anterior belly of the
digastic muscle in monkey and human (Voss, 1956).
Recordings from mesencephalic tract axons in monkeys
indicate that masseter muscle spindles are active
during muscle contraction, rather than preceding it
(therefore they are not gamma activated, Matsunami
and Kubota, 1972). Animal studies indicate that other
proprioceptive endings (e.g., Golgi tendon organs in
jaw muscles and extraocular muscle spindles) have
somata mainly in the ganglion; the location of any
extraocular muscle proprioceptors in Me5 is controversial
(reviewed Donaldson, 2000). For muscles of
facial expression, propriceptive fibers may travel to
the ganglion in the communicating nerves described
between the facial and trigeminal paths (Namking
et al., 1994).
Trigeminal Ganglion
The trigeminal (semilunar, Gasserian ganglion) is
crescent shaped and lies in Meckel’s cave adjacent to
the petrosal bone (Ferner, 1940). The gross morphology
of the human ganglion in relation to the dura and
the surrounding structures has been described in
detail elsewhere (Soeira et al., 1994; Kehrli et al., 1997).
In a study of ganglia from 64 subjects from 2 months to
81 years old, the mean neuronal count was 80,600 with
no significant age or sex difference (Ball et al., 1982).
However, there was a marked variation in individual
samples (range 20,000–157,000), which is surprising
and worth investigation. Ganglion cells are pseudounipolar
and invested by satellite cells, with some
showing complex interdigitations with the neuronal
membrane (Beaver et al., 1965). There is an approximate
somatotopy with ophthalmic somata lying
anteromedially, mandibular cells posterolaterally, and
maxillary in between (cat; Marfurt et al., 1989).
As in the dorsal root ganglia, trigeminal ganglion
cells can be classed as large, light (type A) cells and
smaller, dark (type B) cells (Lieberman, 1976). On the basis of ultrastructure, immunohistochemistry, and
cytochemistry, Kai-Kai (1989) included a third group
of small type C cells. A variety of peptides are known
to be present in the ganglion, particularly in the
smaller cells (see Chapter 30). For the human these
include CGRP, substance P, somatostatin, galanin, and
enkephalins (Del Fiacco and Quartu, 1994; Quartu and
Del Fiacco, 1994; Quartu et al., 1996). In the human
ganglion, nearly half of the cells contain CGRP, with
about 15% containing substance P, and some showing
colocalization (Helme and Fletcher, 1983; Quartu et al.,
1992). Such cells are thought to be associated with
nociceptive transmission (see later). CGRP fibers also
form pericellular baskets around some ganglion cells,
particularly in the fetal and newborn ganglion (Quartu
et al., 1992). In the rat, these fibers were shown to make
synaptic contacts with trigeminal ganglion cells
(Yamamoto and Kondo, 1989), but these were not seen
in the monkey and are not known for humans. As in
animals, discrete populations of human ganglion cells
have been shown to express trkA, trkB, and trkC,
receptors for the neurotrophins, often coexpressed on
substance P and/or CGRP immunoreactive cells
(Quartu et al., 1996). The percentage of neurotrophin
positive cells was lower in adults than in perinatal
ganglia.
Besides the peptides, another transmitter for the
trigeminal ganglion, like dorsal root ganglia, is likely
to be glutamate. Wanaka et al. (1987) reported that
about 45% of the rat trigeminal ganglion cells contain
glutamate, particularly the larger cells. However,
Kai-Kai and Howe (1991), also working in rat, found a
lower percentage with glutamate (32%), predominantly
localized in smaller cells, and this is in agreement
with Cangro et al. (1985). Glutamatergic terminals
are found throughout the trigeminal sensory complex
(rat, Clements and Beitz, 1991) and there is evidence
for involvement of glutamate in low-threshold
mechanoresponses as well as in nociceptive responses
from the tooth pulp and cornea (rat, Clements et al.,
1991; Bereiter and Bereiter, 1996). The percentage of
glutamatergic cells in the human ganglion is
unknown.
Kai-Kai and Keen (1985) confirmed the presence of
serotonin in type B neurons, and mast cells in the rat
trigeminal and spinal ganglia. The location of serotonin
in afferent termination zones in the dorsal horn has led
to its suggested role as a putative transmitter in primary
afferents (Kai-Kai, 1989).
Trigeminal Root and Tract
Central processes of trigeminal ganglion cells travel
posteriorly in the large sensory root (portio major,
radix sensoria) to enter the brainstem at midpontine
level. The smaller “motor” root (portio minor, radix
motoria) arises as two or more rootlets, which join
together and pass inferiorly to the sensory root and
ganglion, to travel with the mandibular nerve. The
total number of sensory root fibers has been estimated
as 140,000 (Young, 1977) and 170,000 (Pennisi et al.,
1991), similar to the number of peripheral nerve fibers
(154,000, Pennisi et al., 1991) but considerably higher
than the number of ganglion cells (80,000; Ball et al.,
1982). Whether this represents branching of fibers or
errors in counting is not known; the puzzlingly large
range of values reported for ganglion cells from different
individuals has already been noted. Approximately
50% of the root fibers are unmyelinated
(Young, 1977), less than the commonly quoted figure
for dorsal roots (70–80%); possible reasons for this,
such as the importance of discriminative sensations
from the face, are discussed by Young (1977).
Myelinated fibers are smaller (0.3–11 μ m) than in the
peripheral nerve (Kerr, 1967).
Within the sensory root, both electrophysiological
recordings in monkeys and results of lesions in
humans suggest that there is an approximate somatotopy,
with each division maintaining individual, but
overlapping, territories (Pelletier et al., 1974). However
there is no separation of modalities, with mechanical,
thermal, and nociceptive afferents being intermingled.
Similarly, in the motor root, responses from jaw
muscle spindles are intermingled with motor fibers.
Inputs are ipsilateral except for 2–3 mm of contralateral
skin at the tip of the nose (Cushing, 1904).
From the root, most fibers pass caudally to form the
spinal trigeminal tract in the dorsal and lateral
brainstem. The spinal tract lies adjacent to the spinal
trigeminal nucleus and extends from midpons to the
second cervical level, where it becomes continuous
with Lissauer’s tract (Fig. 29.3). Some, but not all, root
fibers bifurcate to give a short ascending branch to the
principal sensory trigeminal nucleus, which they enter
from the lateral, ventrolateral, and ventral aspects.
Within the spinal tract there is an approximate
topography, with ophthalmic fibers lying ventrally;
maxillary, intermediate; and mandibular, dorsally
(reviewed Capra and Dessem, 1992; Usunoff et al.,
1997) with all three divisions represented at all levels
(Kerr, 1963).
Tract axons are relatively small, with 90% having a
diameter of less than 4 μ m in man (Sjoqvist, 1938).
Comparison of rostral and caudal regions of the tract
shows fewer myelinated fibers caudally (Usunoff et al.,
1997). Golgi impregnation in humans and animal
studies in rat and cat (Cajal and Ramon, 1909; Hayashi,
1985 a, b; reviewed Capra and Dessem, 1992) show that individual axons in the tract give off a series of
collateral branches that enter the nucleus at different
levels. Collateral terminations in Sp5C show an
arrangement that has been likened to an onion-skin,
with midline and perioral face represented rostrally
and more lateral facial skin represented caudally.
Mandibular and ophthalmic trigeminal primary
afferents also cross the midline at caudal levels and
project to the contralateral spinal nucleus caudalis (rat,
Jacquin et al., 1990; Marfurt and Rajchert, 1991; cat,
Westrum and Henry, 1993), but this has not been
confirmed in primates. The trigeminal tract is joined by afferents from
other nerves, such as the nervus intermedius, glossopharyngeal,
vagal, and upper cervical nerves.
Trigeminal afferents project to other brainstem regions,
such as the nucleus of the solitary tract, and this has
been confirmed in humans (Usunoff et al., 1997). Projections
to the solitary tract encompass both the rostral
(gustatory) areas and caudal (cardiovascular, respiratory,
and gastrointestinal) regions (rat, Marfurt and
Rajchert, 1991). These inputs have been suggested to
play a role in the integration of sensory activity from
the mouth, pharynx, and oesophagus during mastication
and swallowing.
Trigeminal afferents also project to the reticular
formation, particularly alongside spinal nucleus
interpolaris (reviewed Usunoff et al., 1997). Direct
projections to dorsal column nuclei have been
reported, particularly to the cuneate nucleus and the
external cuneate nucleus (monkey, Porter, 1986;
Rhoton et al., 1966). Such inputs have been suggested
to be important in the integration of sensory inputs
from neck muscles and cutaneous cranial afferents and
for the coordination of head, neck, and eye movements
(Porter, 1986). Finally, trigeminal projections to the
paratrigeminal nucleus have been described in
animals and it has been suggested that this nucleus
plays a role in processing of nociceptive inputs
(reviewed, Usunoff et al., 1997). Trigeminal afferent
inputs to regions such as the supratrigeminal nucleus
and the motor trigeminal nucleus, as well as to
vestibular nuclei, have been reported in animal studies
but have not been substantiated in humans (reviewed
by Usunoff et al., 1997).
BRAINSTEM TRIGEMINAL
SENSORY NUCLEI
The brainstem trigeminal sensory nuclei consist of
the trigeminal sensory nuclear complex (the principal
and spinal trigeminal nuclei), the mesencephalic
nucleus, and a number of smaller collections of cells
(paratrigeminal and peritrigeminal nuclei) thought to
be predominantly sensory in function (see Chapter
10). These are all discussed later. Other trigeminal
brainstem areas such as the motor trigeminal and
intertrigeminal nuclei are associated with the motor
control of jaw muscles (Lund and Olsson, 1983) and
are not considered here. The supratrigeminal nucleus
described in the mouse and cat is not seen in the
human (Paxinos and Huang, 1995; Usunoff et al.,
1997), although Paxinos and Huang delineate a
peritrigeminal zone around the motor nucleus.
Trigeminal Sensory Nuclear Complex,
an Overview
The trigeminal nuclear complex is a long column of
cells in the dorsolateral brainstem that extends from
the rostral pons to the C2 level, a distance of
approximately 6 cm (Usunoff et al., 1997). The complex
is subdivided into four subnuclei (Fig. 29.3), the
principal or main sensory trigeminal nucleus (Pr5),
and three spinal trigeminal nuclei—oralis (Sp5O),
interpolaris (Sp5I), and caudalis (Sp5C) (Olszewski,
1950; reviewed Capra and Dessem, 1992).
Animal studies using anatomical labeling (Marfurt,
1981; Shigenaga et al., 1986), electrophysiological
recordings (Eisenman et al., 1963), and results of
lesions in humans indicate a somatotopic organization
throughout the complex, with the mandibular division
lying dorsally; maxillary, centrally; and the ophthalmic,
ventrally. Different facial regions are represented as
long rostrocaudal columns of cells extending through
the complex, with more midline regions (e.g., the nose)
represented medially and more lateral skin represented
laterally. However, particular facial regions
have relative differences in central representation at
the different levels, as noted later.
A major transmitter throughout the sensory
complex is glutamate, with NMDA and non-NMDA
receptors reported at all levels (rat, Petralia et al., 1994;
Tallaksen-Greene et al., 1992). In addition, peptides
such as substance P and CGRP are important transmitters,
particularly for small diameter afferents, and
may be colocalized with glutamate (Sessle, 2000).
Ultrastructurally, a feature of synaptic organization at
all trigeminal levels is the presence of synaptic
glomeruli, in which a primary axon is surrounded by
other terminals with axoaxonic synapses, with somewhat
different structure at different levels (rat,
Clements and Beitz, 1991).
Principal Sensory Trigeminal Nucleus
The principal sensory trigeminal nucleus is located
in the lateral pontine tegmentum and extends for
about 4 mm (from 17 to 20 mm rostral to the obex;
Paxinos and Huang, 1995), approximately level with
the motor trigeminal nucleus. In cross section, the
nucleus is narrow and elongated dorsoventrally (Fig.
29.3). Most neurones are small and generally oval with
some scattered medium-sized somata also present.
Large neurones (more than 35 μ m in diameter) are
seen along the lateral border. Usunoff et al. (1997)
describe a hint of dorsal and ventral subdivisions, with
ventral cells somewhat larger and in clusters, while
dorsal cells are smaller and more diffuse. However, these subdivisions are less marked than in the cat
(Shigenaga et al., 1986b), and the dorsoventral subdivisions
were not noted by Paxinos and Huang (1995).
Ultrastructurally, Pr5 in both the rat and cat contains
synaptic glomeruli (Gobel and Dubner, 1969; Gobel,
1971; Ide and Killackey, 1985).
Sections reacted for the enzyme acetylcholinesterase
(AChE) show a striking organization of densely
stained patches surrounded by paler regions. These
patches are also seen with histochemical techniques
for mitochondrial enzymes such as cytochrome
oxidase (Goyal et al., 1992). Animal studies indicate a
similar parcellated organization. The patches of
intense staining are particularly clear in rodents where
they have a distinctive pattern and are known to be
associated with the vibrissae (reviewed Waite and
Tracey, 1995). However, they are also seen in the dorsal
column nuclei in relation to the digits (Florence et al.,
1989). These patches have been considered to reflect
regions of high innervation density (Goyal et al., 1992).
In rodents, similar patches also occur in spinal
trigeminal nuclei Sp5I and Sp5C, but this has not been
seen in primates (Noriega and Wall, 1991).
Animal studies have shown that cells in Pr5 are
mechanoreceptive with low thresholds and small
receptive fields (Jacquin et al., 1988). Thus, Pr5 is
thought to be analogous to the dorsal column nuclei in
providing for discriminative tactile sensations for the
face. It contains many projection cells, with its predominant
projection being to the ventroposterior
medial nucleus (VPM) of the thalamus. In the cat and
rat, there is also a lesser projection to the posterior
complex, Po (Jones, 1985) renamed as part of regio
basalis (see Chapter 20), though this is unconfirmed in
humans. In rodents, 60–70% of the projection cells in
Pr5 contain glutamate (Magnusson et al., 1987), though
again this is not known for humans.
Pr5 also contains interneurones, many of which are
immunoreactive for GABA (rat, Haring et al., 1990).
Somatostatin immunoreactive cells have also been
described in the ferret (Boissonade et al., 1993). In
humans, somatostatin immunoreactive cells, fibers, and
receptors are only seen in low levels in Pr5 (Bouras et al.,
1987; Carpentier et al., 1996) and enkephalin-containing
cells are present in the newborn (Yew et al., 1991).
Spinal Trigeminal Nucleus Oralis
While all investigators agree that Sp5O extends
caudally from Pr5 (level with the caudal pole of the
motor trigeminal nucleus), its caudal boundary has
been placed at different levels. Paxinos and Huang
(1995) delineate an oblique caudal border level with
the caudal pole of the facial motor nucleus (13 mm
rostral to the obex), giving Sp5O a rostrocaudal extent
of some 4 mm (Fig. 29.3). However, Usunoff et al.
(1997) continue Sp5O to the level of the rostral pole of
nucleus ambiguus (~7 mm rostral to the obex), a
rostrocaudal distance of 10 mm. Sp5O is somewhat
peanut-shaped in cross section. Usunoff et al. (1997)
describe small (12–17 μ m) oval cells and mediumsized
oval, multipolar or fusiform cells (25–30 μ m long
and 10 μ m or less wide).
AChE staining shows a few dark patches within the
nucleus, especially within the central core (Paxinos
and Huang, 1995). Studies in the rat, cat, and ferret
have described subdivisions within the nucleus (e.g.,
dorsomedial and ventrolateral), but these were not
noted by Usunoff et al. (1997) or Paxinos and Huang
(1995). Many neurons in rodent Sp5O contain
glutamate, likely to be the excitatory transmitter
(Magnusson et al., 1986). In the ferret, both somatostatin
and enkephalin immunoreactive somata have
been described (Boissonade et al., 1993), and rodent
Sp5O contains dispersed GABAergic cells (Haring et al.,
1990). Human Sp5O and Sp5I are high in receptors for
somatostatin, although the functional significance of
this in sensory processing is not yet clear (Carpentier
et al., 1996). Like Pr5, Sp5O contains synaptic glomeruli,
often with glutamate immunoreactive profiles (rat,
Clements and Beitz, 1991).
Sp5O has been shown to receive extensive intraoral
projections (cat, Arvidsson and Gobel, 1981; Azerad
et al., 1982; rat, Marfurt and Turner, 1984; Takemura
et al., 1991) and this is consistent with loss of oral
sensation after vascular lesions in humans (Graham
et al., 1988). Responses generally have very widespread
receptive fields and can show modality convergence,
for instance from both cutaneous and tooth receptors
(rat, Jacquin and Rhoades, 1990). Indeed Sp5O has
been implicated in intraoral pain, as discussed later.
In the rat, Sp5O has extensive projections to the facial
motor nuclei and spinal cord with less dense projections
to the trigeminal motor nucleus, thalamus, and
cerebellum (rat, Ruggiero et al., 1981; Jacquin and
Rhodes, 1990).
Spinal Trigeminal Nucleus Interpolaris
Located in the medulla, Sp5I extends between
Sp5O and Sp5C. As noted earlier under Sp5O, there is
some discrepancy about the rostral border of Sp5I;
Paxinos and Huang (1995) delineate it as level with
the caudal pole of the facial nucleus, whereas Usunoff
et al. (1997) put the Sp5O/I border just rostral to
nucleus ambiguus. Thus the rostrocaudal extent varies
from 6 mm (Usunoff et al., 1997) to about 13 mm
(Paxinos and Huang, 1995).
With AChE staining, the nucleus stands out as an
area of moderate to high reactivity. Usunoff et al. (1997) describe a heterogeneous population of cells in human
brain; many are small to medium-sized (15–20 μ m)
and oval or spindle-shaped. There are also some large
scattered neurones (30–40 μ m). Paxinos and Huang
(1995) recognize a dorsomedial extension of Sp5I at
caudal levels. Like Sp5O, the nucleus is crossed by
prominent fiber bundles, for example from the glossopharyngeal
nerve.
Sp5I has extensive inputs from intraoral structures,
including tooth pulp, though these are generally less
dense than for Sp5O (cat, Azerad et al., 1982; rat,
Marfurt and Turner, 1984; Takemura et al., 1991). Cells
responsive to both low-threshold mechanoceptors and
nociceptors in the skin and periodontium have been
described in rats (Jacquin et al., 1989a). Glutamatergic
and GABAergic neurones are present in the rat
(Phelan and Falls, 1989; Usunoff et al., 1997;
Magnusson et al., 1986, 1987; Haring et al., 1990) as well
as somatostatin and enkephalin neurones in ferrets
(Boissonade et al., 1993). In the rat, Petralia et al. (1994)
described large multipolar neurons densely stained for
NMDA R1 receptor.
Intracellular recording and staining has provided
useful data on the detailed morphology of Sp5I cells in
the rat. The responses and structure of projection cells
(defined as cells that send axons outside the trigeminal
complex), as well as “local circuit” neurons (with axons
restricted to the trigeminal nucleus), were analyzed
(Jacquin et al., 1989a, b). The local circuit neurons often
had widespread intranuclear axonal connections
encompassing Pr5 and Sp5C, thus providing a
mechanism for integration between subnuclei.
Sp5I projects to the thalamus, cerebellum, superior
colliculus and spinal cord (rat, Kemplay and Webster,
1989; Huerta et al., 1983; Jacquin et al., 1989b; Phelan
and Falls, 1991), with single cells often having very
widespread connections (rat, Jacquin et al., 1986;
Patrick and Robinson, 1987; Bruce et al., 1987; Phelan
and Falls, 1991). In the rat, the thalamic projection is to
both VPM and the medial part of Po (Chiaia et al.,
1991), with many of these projection cells containing
glutamate (Magnusson et al., 1987). The projection of
Sp5I to the cerebellum has not been confirmed in the
human (Usunoff et al., 1997). Similarly, trigeminal
inputs to the human superior colliculus have not been
confirmed (for discussion see Chapter 28). Although
localized receptive fields were noted for local circuit
neurons, fields were generally widespread for projection
cells, particularly those projecting to the thalamus
(rat, Jacquin et al., 1989b).
Spinal Trigeminal Nucleus Caudalis
The spinal trigeminal nucleus caudalis extends
from the obex for approximately 15 mm to the C2 level
(Fig. 29.3), where it becomes continuous with the
dorsal horn. Its similar laminar organization to the
spinal dorsal horn (Chapter 7) has led to its alternative
name, the medullary dorsal horn (Gobel et al., 1981).
Thus Sp5C contains a marginal zone (subnucleus
zonalis, lamina 1), a substantia gelatinosa resembling
Rexed’s lamina 2, and a magnocellular layer, equivalent
to nucleus proprius (lamina 3 and 4) of the dorsal horn
(Fig. 29.3). In addition, some authors recognize a
deeper zone corresponding to laminae 5 and 6.
The marginal zone in human tissue consists of a
thin sheet of cells containing large multipolar neurones,
some over 60 μ m in diameter (Usunoff et al.,
1997) with small and medium-sized neurones also
present. In rat, cat, and monkey, fusiform, pyramidal,
and multipolar cells are described (Gobel, 1978; Zhang
et al., 1996; Yu et al., 1999), with different functional
properties for each (see later). Inputs to the marginal
zone arise mainly from small-diameter myelinated
fibers as well as unmyelinated afferents from all
cranial tissues (reviewed Craig, 1996).
The human substantia gelatinosa was rather aptly
described by Olszewski (1950) as horseshoe-shaped
in cross section (Fig. 29.3) and consists of relatively
densely packed small, oval, or fusiform cells
(10–20 μ m in diameter). This layer reacts strongly for
AChE and is rich in neuropeptides such as substance
P, CGRP, cholecystokinin, and somatostatin (Inagaki et
al., 1986; Clements and Beitz, 1987; Carpentier et al.,
1996). This region also contains the NGF receptor,
trkA, which is especially dense in pre and perinatal
human tissue, but is also present in adults (Quartu et
al., 1996). The region is rich in GABAergic somata and
fibers (rat, Haring et al., 1990; Ginestal and Matute,
1993). It receives predominantly small-diameter
myelinated and unmyelinated afferents. Synaptic
glomeruli, in which glutamatergic primary afferents
are both pre- and postsynaptic to GABAergic terminals,
have been described (rat, Clements and Beitz,
1987; cat, Iliakis et al., 1996).
The magnocellular zone has medium-sized diameter
(25 μ m) oval or fusiform cells with scattered
small and large neurones. In the rat, many cells here
contain glutamate, and some of these project to VPM
(Magnussen et al., 1986, 1987). Synaptic glomeruli are
present, often with scalloped glutamatergic profiles
(Clements and Beitz, 1991). The magnocellular zone
has a moderate level of AChE reactivity.
Low-threshold mechanical responses, high threshold
nociceptive specific responses, thermosensitive
specific (COLD) responses, HPC (heat, pinch, cold)
cells, and wide dynamic range (WDR) neurones are all
present in Sp5C (cat, Hu, 1990; monkey, Dostrovsky
and Craig, 1996; reviewed Sessle, 2000). Low-threshold
mechanical responses are found predominantly in the magnocellular zone along with some thermal specific
units (monkey, Price et al., 1976). In contrast, the
marginal zone contains nociceptive specific, COLD,
HPC, and WDR responses (monkey, Price et al., 1976;
Bushell et al., 1984; reviewed Sessle, 2000, and see later
section on trigeminal nociception). Intracellular
recordings from lamina 1 cells in cat spinal cord
suggest that there is a structure/function correlation:
fusiform and pyramidal cells correspond to nociceptive
specific and COLD responses, respectively, whereas
most multipolar cells showed HPC responsiveness
(Han et al., 1998). In monkey spinal cord, the fusiform
and multipolar cells express the substance P receptor
(neurokinin-1) supporting their role in nociception
(Yu et al., 1999). The role of trigeminal marginal zone
neurons in nociception and thermal discrimination has
been indicated by recordings in awake monkeys
(Dubner et al., 1981; Hayes et al., 1981; Bushnell et al.,
1984). The responses of COLD cells depended on the
behavioral significance of the stimuli, suggesting the
involvement of these cells in sensory discrimination,
rather than merely reflex activation.
Projections of Sp5C are extensive. Lamina 1 cells
project to several thalamic regions including VPM, Po,
and the midline and intralaminar nuclei (primate,
Ganchrow, 1978; cat and monkey, Burton and Craig,
1979; cat, Shigenaga et al., 1983; rat, Shigenaga et al.,
1979; Yoshida et al., 1991; Iwata et al., 1992; and see
Chapter 30, Fig. 30.8B) as well as a new nucleus
described by Blomqvist et al. (2000) as the posterior
part of the ventral medial nucleus (VMpo, referred to
as basalis nodalis in Chapter 20). Laminar 1 also gives
both direct hypothalamic projections (rats, Malick and
Burstein, 1998) and indirect projections through the
parabrachial area (Slugg and Light, 1994; Jasmin et al.,
1997). The substantia gelatinosa projections are
predominantly local, to the adjacent magnocellular
zone and reticular formation (primate, Tiwari and
King, 1974). The magnocellular zone projects to VPM,
zona incerta, the facial nucleus, trigeminal motor
nucleus, and adjacent reticular formation as well as
ipsilateral spinal cord (Iwata et al., 1992; Carpentier
et al., 1981). Magnocellular cells also project to more
rostral trigeminal nuclei, Sp5O and Sp5I (primate,
Tiwari and King, 1974; Price et al., 1976; cat, Hu and
Sessle, 1979; rat, Hallas and Jacquin, 1990). These intranuclear
connections are likely to modulate activity in
these rostral regions.
An interesting recent study has reported a discrete
thermospecific region in lamina 1 in the owl monkey
(Craig et al., 1999). Cells here responded to cold stimuli
(COLD cells) with small receptive fields on nasal and
labial regions and had a pyramidal morphology similar
to thermal cells in cats and rats. These cells project to
the posterior ventromedial nucleus (VMpo), identified
as a thermal and nociceptive region in monkey and
human thalamus (Craig et al., 1994, and referred to as
basalis nodalis, in Chapter 20 and see later). This region
of lamina 1 and the associated pathway was suggested
to provide specialized thermosensitivity, likely to be
relevant the nocturnal navigation and foraging
behavior of the owl monkey Craig et al. (1999).
Mesencephalic trigeminal nucleus
The mesencephalic trigeminal nucleus comprises a
band of scattered cells that extends from the level of
rostral Pr5 through the pons and midbrain, a distance
of some 22–24 mm (Olszewski and Baxter, 1954;
Paxinos and Huang, 1995). The cells lie at the outer
border of the periaqueductal gray in the midbrain and
the central gray of the pons (Fig. 29.3). Me5 cells have
a distinctive morphology, being mainly pseudounipolar
with large, regular, oval or round somata, like
that of other primary afferents. However, multipolar
cells have also been seen in the human (Olszewski and
Baxter, 1954) and identified in animal studies after
peripheral labeling (reviewed Capra and Dessem,
1992). Cells of Me5 are the somata of proprioceptive
afferents from the jaw muscles and periodontium.
Clustering of Me5 neurons with maculae adherens,
gap junctions and electrotonic coupling between cells
within a group have been described in the rat (Baker
and Llinas, 1971; Liem et al., 1991). Synapses on Me5
cells have been seen in rodents and cats, with a variety
of transmitters identified including serotonin and
dopamine (Liem et al., 1992; reviewed Capra and
Dessem, 1992), but the existence of synapses in
humans is unconfirmed. Somatostatin positive fibers
have been described around human Me5 cells (Bouras
et al., 1987). Besides these inputs, studies in rats show
bilateral projections to Me5 from parvocellular
reticular formation (Rokx et al., 1988).
Me5 cells project to the motor trigeminal nucleus
forming a monosynaptic reflex arc. In animals, Me5
also projects to the intertrigeminal and supratrigeminal
nuclei probably involved in masticatory
control (rat, Luo et al., 1991) although, as noted
previously, a human homologue of the supratrigeminal
nucleus has not been confirmed. There are
also projections to Pr5, which may provide a relay to
the thalamus for proprioceptive sensation (Luo et al.,
1991, 1995) although direct projections to the ventral
thalamus have been described (squirrel monkey,
Pearson and Garfunkel, 1983). Thalamic projections
were bilateral, but predominantly ipsilateral and may
have included VPO (see later). Projections to other
brainstem nuclei (the hypoglossal nucleus, nucleus of the solitary tract, extraocular motor nuclei, and
brainstem parvocellular reticular nucleus) as well as
the cerebellum and spinal cord have been identified
in animals (rat, Rokx et al., 1986; Raappana and
Arvidsson, 1993; cat, Matsushita et al., 1982; Shigenaga
et al., 1989, 1990).
Other Sensory Trigeminal Nuclei
Besides the trigeminal sensory complex of four
nuclei, the trigeminal sensory system also contains a
group of cells within the spinal tract, at the level of
caudal Sp5I and the Sp5I/C boundary (Fig. 29.3). There
is considerable confusion about the nomenclature of
this cell group (for discussion of this see Usunoff et al.,
1997). Originally described as interstitial cells by Cajal
and Ramon (1909), this cell group was later considered
part of the paratrigeminal nucleus of Chan-Palay
(1978). Paxinos and Huang (1995) used the term
“paratrigeminal” (Pa5), while Usunoff et al. (1997)
reintroduced the use of “interstitial nucleus.” In the
human these cells are small and chromophobic
(Usunoff et al., 1997). Animal studies have shown that
the interstitial/paratrigeminal nucleus receives a projection
from the tooth pulp and cornea, with responses
similar to those of the marginal zone of Sp5C (cat,
Shigenaga et al., 1986).
Other more scattered groups of cells, named by
Paxinos and Huang (1995) as the peritrigeminal
nucleus, lie lateral and ventral to the trigeminal tract at
the level of Sp5I. The connections and functions of this
group are unknown. A third group of large cells
extends between the inferior cerebellar peduncle and
the spinal and cuneate tracts, at the level of caudal
Sp5I and rostral Sp5C (Fig. 29.3). This latter group of
cells was named by Paxinos and Huang (1995) as the
lateral pericuneate nucleus (LPCu). The cells are
similar in appearance to those of the lateral cuneate
nucleus and may well be related to cuneate inputs
rather than the trigeminal system.
Brainstem Mechanisms in
Trigeminal Nociception
Pain from the trigeminal distribution (including
pain from the face, nasal sinuses, oral cavity and teeth,
TMJ, and meninges) is one of the most common and
distressing clinical symptoms known. In a study
performed in the United States (Lipton et al., 1993), it
was found that 12% of adults had experienced
toothache in the last six months, 5% had felt TMJ pain,
while 1.4% had noticed face or cheek pain over the
same period. Interestingly, there is a clear gender difference
in some of these craniofacial pain syndromes,
with women reporting a 28% higher incidence of pain
from the TMJ than men.
Despite this major clinical significance, much of
what we know about the nociceptive components of
the trigeminal system is derived from animal studies,
predominantly in rodents, although cat and primate
studies have also contributed (see Chapters 12 and 30).
Nevertheless, investigations in humans have usually
been in agreement with animal-based findings,
although some minor species differences in trigeminal
nociceptive pathways cannot be excluded.
Nuclear Localization of Nociceptive Responses
Clinical findings involving transection of the
trigeminal tract are consistent with findings in
experimental animals indicating that Sp5C is the most
important component of the trigeminal nuclear
complex for perception of noxious stimuli applied to
the craniofacial region (for review see Sessle, 2000).
Cells in lamina 1 respond to noxious mechanical,
thermal and chemical stimulation of structures such as
the cornea, cerebral vasculature, oral and nasal mucosa,
teeth, and TMJ. There is also evidence of the involvement
of the trigeminal complex, in particular Sp5C, in
the mediation of reflex responses to noxious craniofacial
stimuli, such as changes in sweating, respiration,
blood pressure, heart rate, and excitatory reflex effects
in jaw-opening muscles and inhibitory effects in jawclosing
muscles. On the basis of c-fos immunoreactivity
in the rat after noxious stimulation, Strassman
and Vos (1993) have suggested the Sp5I/Sp5c border
may be involved in these autonomic effects.
Besides the obvious involvement of Sp5C in
trigeminal nociceptive activity, recordings from Sp5O
and Sp5I indicate nociceptive responses are present in
more rostral levels of the spinal trigeminal complex.
Lesions or injections of analgesic chemicals into these
rostral levels can also interfere with nociceptive
behavior, particularly when the noxious stimulus is
applied to intra- or perioral regions (Dallel et al., 1998;
Takemura et al., 1993). Studies in awake monkeys
indicate that Sp5O responses to dental stimulation are
dependent on the behavioral state of the animal (Soja
et al., 1999). This indicates a role for the rostral, as well
as caudal, spinal nuclei in trigeminal nociceptive
mechanisms (Raboisson et al., 1989; Panneton and
Yavari, 1995). When the jaw-opening reflex is elicited
by tooth pulp or perioral stimuli, lesion studies
indicate that rostral subnuclei, such as Sp5O and Sp5I,
are more crucial to the reflex than Sp5C (Dallel et al.,
1989; Hannam and Sessle, 1994). Involvement of
rostral areas is also supported by clinical findings in
patients with brainstem lesions in the caudal pons
(Graham et al., 1988). It has recently been suggested, on the basis of the
distinctive responses of Sp5O nociceptive neurons to
noxious chemicals like formalin, that Sp5O is particularly
important for processing information about
short duration nociceptive stimuli, whereas Sp5C is
more important for processing tonic nociceptive
information (Raboisson et al., 1995). Studies involving
morphine administration in the superficial laminae of
Sp5C indicate that these analgesics may exert their
effect on Sp5O indirectly, by blocking C fiber inputs
that relay in the Sp5C (Dallel et al., 1998).
Nociceptive Transmitters, Response Characteristics,
and Projections
As indicated previously, small-diameter afferents
terminate mainly in the marginal zone and deep
laminae (5 and 6) of Sp5C. These afferents contain
neuropeptides and amino acids that have been
implicated as excitatory neurotransmitters or neuromodulators
(e.g., substance P, glutamate, nitric oxide)
in central nociceptive transmission (see Sessle, 1996,
2000, for reviews). Antagonism of the substance P
receptor mechanisms (NK1) blocks c-fos expression
induced by noxious chemical stimulation of dural
afferents (Shepheard et al., 1995). In addition to
substance P, studies indicate central involvement of
excitatory amino acids in trigeminal nociception
(Parada et al., 1997). Jaw-muscle activity associated
with TMJ nociception can be elicited by glutamate
injection into the TMJ and blocked by glutamate
receptor antagonists (Cairns et al., 1998).
As noted earlier in “Spinal Trigeminal caudalis,”
responses to nociceptive input include nociceptive
specific neurons, HPC cells and WDR neurons, all of
which can be recorded from the marginal zone and
deep laminae of Sp5C. The involvement of the marginal
zone in nociception is supported by functional
recordings as well as c-fos studies. However, comparable
neurons have been reported to be present in
rostral parts of the trigeminal spinal nucleus in both
Sp5O and Sp5I (see Sessle, 2000, for review). Electrophysiological
studies in all these regions often show a
pattern of convergence of inputs from different
regions, with cells responding to cutaneous
nociceptive stimulation as well as stimulation of
afferents supplying cranial blood vessels, dura,
cornea, TMJ, or tooth pulp (Boissonade and Matthews,
1993; Meng et al., 1997; also reviewed in Sessle, 2000).
There are substantial projections from the parts of
the trigeminal nuclear complex involved in nociception
to the thalamus (Craig and Dostrovsky, 1997;
Sessle, 2000). There is also electrophysiological evidence
for projections from nociceptive Sp5C neurons
to the periaqueductal gray and parabrachial region
(from which projections to the amygdala and hypothalamus
follow), as well as direct projections to the
hypothalamus (Malick and Burstein, 1998). These
ascending non-thalamic projections are likely to be
responsible for the affective aspects of nociception as
seen clinically.
Modulation of Nociceptive Responses, Inflammation
and Chronic Pain
As in the spinal cord (see Chapter 30), an important
aspect of nociception is that the activity can be
modulated by descending and afferent inhibitory
mechanisms that are known to suppress pain in both
humans and experimental animals. Projections from
the nucleus raphe magnus, periaqueductal gray,
sensorimotor cortex, pretectal area, and parabrachial
area are capable of influencing nociceptive responses
(for review see Sessle, 2000). Afferent induced modulation
also appears to be an important mechanism in
trigeminal nociception, studied, for instance, for
responses from cat tooth pulp (reviewed Soja et al.,
1999). The responses of neurons to inputs evoked by
deep and superficial noxious stimuli can be suppressed
by low-threshold stimuli that excite large afferent
fibers. Furthermore, noxious stimuli applied to other
parts of the body may inhibit trigeminal responses to
small fiber craniofacial nociceptive stimulation (i.e.,
“pain inhibits pain,” Sessle, 2000).
There is also a large body of literature concerning
the long-term effects of craniofacial injury and
inflammation on nociception in the trigeminal
complex. Deafferentation in the trigeminal system of
experimental animals (e.g., by transection of the
infraorbital nerve) is well known to lead to significant
morphological, neurochemical, and physiological
changes in the brainstem, thalamus, and somatosensory
cortex (Woolsey, 1990; Weinberger, 1995).
Endodontic removal of tooth pulps in adult animals
also induces morphological and physiological changes
in the trigeminal nuclear group, particularly in Sp5O
and Sp5C (Hu and Sessle, 1989). The sensitivity of
many nociceptive endings may increase after mild
forms of injury, such as when the threshold of
nociceptors is lowered as a result of repeated exposure
to noxious stimuli—a phenomenon known as
“peripheral sensitization” (see Levine and Taiwo,
1994, for review). Some of this sensitization may also
be the result of central factors.
Relatively little attention has been given to models
of chronic pain in the craniofacies. Chronic constrictive
infraorbital nerve injury has been applied in a
behavioral model of trigeminal neuropathic pain (Vos
et al., 1994) and has been shown to be associated with
some of the features of neuropathic pain behavior, but central effects of this model have not been fully
investigated as yet. However, neuroplasticity of
trigeminal nociceptive neurons has been found to be
induced by dermal or deep tissue injection of mustard
oil, which induces pain and other nociceptive
behaviors in humans and experimental animals (see
Sessle, 2000, for review). Accumulating evidence concerning
the role of NMDA receptor mechanisms in
these nociceptive processes has prompted the suggestion
that NMDA antagonists may be beneficial in the
treatment of chronic trigeminal injury and pain
(Dubner and Basbaum, 1994).
The Trigeminovascular System: Implications for the
Pathogenesis of Headache
The term “trigeminovascular system” refers to the
cranial vessels and their trigeminal innervation,
implying a functional network that may play an important
role both in normal cerebrovascular function
and in the aetiology of several types of headache.
Sensory fibers innervating the pial and dural vessels of
the anterior and middle cranial fossae arise from the
trigeminal nerve, mostly within the ophthalmic
division (Mayberg et al., 1981; Liu-Chen et al., 1984;
Moskowitz et al., 1983). On the other hand, the cell
bodies of sensory afferents innervating the posterior
cranial fossa and basilar arteries are located in the C1-
C3 dorsal root ganglia (Keller et al., 1985; Saito and
Moskowitz, 1989). Electrical stimulation studies of the
superior sagittal sinus have shown cells in Sp5C, the
cervical dorsal horn, and in the dorsolateral spinal
cord at the C2 level, which are responsive to dural
stimulation and may be involved in vascular headache
(Goadsby and Zagami, 1991; Angus-Leppan et al.,
1994). Convergence of inputs from facial skin and
intracranial vessels could explain the pattern of
referred pain seen in vascular headaches (Dostrovsky
et al., 1991).
For most of the 20th century, the prevailing theory
of pathogenesis of migraine held that the pain was the
result of abnormal dilation of intracranial dural and
pial blood vessels. This dilation was believed to result
in mechanical excitation of the sensory fibers
associated with the vessel adventitia (Graham and
Wolff, 1983). Recent studies have shown that vessel
dilation does not always coincide with the onset of
pain and that vessel constriction does not necessarily
coincide with pain relief. Alternative theories have
proposed a chemical mode of activation of meningeal
perivascular sensory fibers, one that also implicates
neurotransmitter release from the sensory fibers
themselves in the pathogenesis of the condition (socalled
neurogenic inflammation model of vascular
headaches; Moskowitz, 1992).
It is now clear that meningeal blood vessels share
some of the anatomical and physiological properties
seen in other body tissues (e.g., joints) where pain
commonly arises as a result of local sterile inflammatory
processes. Importantly for the neurogenic
inflammation model of vascular headaches, activation
of trigeminovascular fibers can lead to release of vasoactive
neuropeptides into the vessel wall (Goadsby et
al., 1988; Moskowitz et al., 1989; Sicuteri et al., 1990),
thereby promoting neurogenic inflammation. Orthodromic
and antidromic conduction along trigeminovascular
fibers is believed to facilitate the spread of the
inflammatory response to adjacent tissues, as well as
to transmit the nociceptive information to Sp5C.
Collaterals and higher order connections of these
central fibers of the trigeminovascular system also
terminate in centers associated with the generation of
other symptoms of vascular headaches (e.g., nausea,
emesis, autonomic activation, affective alterations;
Allen and Pronych, 1997).
The triggering factor may involve temporary
exposure to an unknown endogenous chemical agent
that alters the sensitivity of trigeminovascular fibers to
mechanical stimuli and leads to the sensation of head
pain. Strassman and co-workers have shown that
application of acidic and inflammatory agents to the
dura causes sensitization of dural trigeminovascular
fibers to mechanical stimuli that previously evoked
minimal or no response (intracranial sensitization;
Strassman et al., 1996). This sensitization can also lead
to enhanced responses of central neurons to stimuli
applied at extracranial sites, thereby explaining the
extracranial tenderness (mechanical and thermal
allodynia) experienced by migraineurs in the absence
of extracranial vascular pathology (Burstein et al.,
1998).
Agents that have been shown to be effective in the
therapy of either migraines or cluster headaches
(sumatriptan, ergotamine, somatostatin) may exert
their influence by receptor-mediated effects on fibers
of the trigeminovascular system. Both sumatriptan
and dihydroergotamine have been shown to reduce
the release of CGRP and inhibit increases in cranial
blood flow resulting from trigeminal ganglion stimulation
(Goadsby and Edvinsson, 1993). Somatostatin,
which inhibits the effects of release of substance P
from nerve terminals, is also effective in reducing
the pain of cluster headaches (Sicuteri et al., 1984).
Similarly, repeated application of capsaicin to nasal
mucosa leads to its desensitization, with a concomitant
decrease in intensity and duration of cluster
headaches. Experimental data support the idea that
sumatriptan activates an inhibitory receptor resembling
5-HT1D on perivascular fibers and by so doing blocks neuropeptide release and impulse conduction in the
trigeminovascular system (Moskowitz, 1992).
Pathophysiology of Trigeminal Neuralgia
Recent work concerning the debilitating condition
trigeminal neuralgia is worth commenting on here.
Trigeminal neuralgia (TN) is characterized by severe
unilateral paroxysmal pain of short duration and
restricted to the trigeminal distribution (Turp and
Gobetti, 2000). The symptoms are often triggered by
nonnociceptive stimuli to the face (e.g., chewing or
touching the face) applied to a trigger zone within the
trigeminal distribution. The paroxysms last only
seconds but may occur with varying frequency. Often
there is a remission of weeks to months, but this only
serves to heighten the patient’s anxiety, sometimes to
the point of suicide, as they wait for the next painful
paroxysm (Choi and Fisher, 1994). TN has an increased
prevalence among patients with multiple sclerosis, consistent
with the presumed importance of demyelination
in the pathophysiology.
The pathophysiology of TN remains controversial.
One postulated cause is demyelination within the
posterior trigeminal root entry zone and brainstem,
leading to repetitive firing of the nerve and its central
connection. A large proportion of patients with TN
show evidence of external vascular compression
(Hamlyn, 1997), with focal demyelination near the
compression site.
Two physiological mechanisms have been postulated
to explain how nerve compression may lead to
painful paroxysms (Choi and Fisher, 1994). In the first,
compression is believed to lead to selective demyelination
of large sensory fibers with relative sparing of
smaller nociceptive fibers. The segmental inhibitory
effect of larger fibers is lost while transmission of
painful impulses through the smaller undamaged
nociceptive afferents continues uninhibited. In the
other proposed mechanism, extra axon potentials are
believed to be initiated at the site of injury. Such
ectopic activity may arise by injury-induced repetitive
firing of nociceptive afferents. Alternatively, ephaptic
“cross-talk” between fiber classes has been proposed,
with action potential currents in low-threshold afferents
causing impulse generation in adjacent nociceptive
fibers.
Studies of the ultrastructure of trigeminal roots
removed during microvascular decompression surgery
for TN have shown zones of de- and dysmyelination,
juxtaposition of denuded axons, apparent axon loss
and degeneration, and collagen deposition (Rappaport
et al., 1997). Those authors’ observations of the
proximity of denuded axons support the hypotheses
of ectopic generation of impulses, ephaptic contacts,
and crossed after-discharge. They have proposed that
a small cluster of trigeminal ganglion cells (the
ignition focus) develops autorhythmicity as a result of
trigeminal root damage. Activity then spreads from
this focus to other parts of the ganglion by release of
neurotransmitter and potassium ions through the
extracellular space (Rappaport and Devor, 1994). The
effectiveness of phenytoin and carbamazepine in the
treatment of TN is consistent with the importance of
excitable membrane instability in the pathophysiology
of the condition (Choi and Fisher, 1994).
The effectiveness of surgical microvascular decompression
of the trigeminal root has long been taken as
an indication of the importance of compressive nerve
damage in the aetiology of TN. More recently, Tenser
(1998) has questioned this presumption, pointing to
the effectiveness of many other therapies for TN (e.g.,
glycerol or thermal rhizolysis, balloon compression,
blunt trauma to the trigeminal root, alcohol injury, and
radiation therapy), which probably produce controlled
injury to the ganglion. Tenser maintains that similar
effectiveness of a wide range of treatments for TN
suggest that these therapies act through a common
pathway (i.e., the induction of damage to trigeminal
ganglion cells with alteration in ganglion cell transcription).
He argues that altered ganglion cell function
(as reflected in the high frequency of herpes
simplex virus activation after these treatments), rather
than reduction in ephaptic transmission or the elimination
of ectopic signal generation, is responsible for
bringing relief. Nevertheless, it remains to be
explained how a general increase in ganglion cell transcription
diminishes pain—an issue not adequately
addressed by Tenser.
Correlation of with Clinical Features
Although much of the preceding discussion has
been derived from studies in experimental animals, it
is possible to correlate many of the results from animal
studies with clinical experience. For example, many
patients experiencing or anticipating craniofacial pain
(e.g., dental patients) undergo or experience diverse
effects including reflex changes in blood pressure, heart
rate, respiration, and sweating, as well as coactivation
of jaw-opening and -closing muscles. These phenomena
have been shown in experimental animals to involve
Sp5C. Effects on masticatory muscle tone may serve
an adaptive function by “splinting” the TMJ, as often
seen clinically after painful injury.
The poor localization of pain in most toothaches
and headaches, and the common feature of pain referral
in these conditions, probably reflects the extensive convergence
of nociceptive afferents from diverse sources
(tooth pulp, cranial vessels, and dura), as noted earlier in findings from experimental animals (Sessle and Hu,
1991; Strassman et al., 1994). Acute toothaches and
headaches are often associated with intense pain and
tenderness, often with radiation or referral to neighboring
craniofacial regions. These aspects are considered
to reflect convergence and peripheral sensitization
phenomena (see Sessle, 2000, for review).
Studies of trigeminal nociception in experimental
animals will continue to be an important area of
research. Nevertheless, more correlation of findings
from experimental animals with clinical experience is
necessary to realize the full benefits of animal studies.
Trigeminothalamic Projections
As noted previously, there is an extensive thalamic
projection from Pr5 to VPM. Both Sp5O and Sp5I also
project to VPM, but to a lesser extent than Pr5, while
Sp5I also gives projections to Po, at least in animal
studies. For Sp5C, there are projections to VPM, Po,
VMpo, and VPI as well as to the mediodorsal nucleus
and the intralaminar nuclei. Some cells in the marginal
zone also provide projections to VPI (Craig, 1996).
There are also thalamic projections from Me5 in the
squirrel monkey (Pearson and Garfunkel, 1983),
possibly to a region anterior to VPM designated VPO
by Percheron (Chapter 20) and VPS by Kaas and Pons
(1988; Chapter 28). This region receives inputs from
deep receptors (e.g. muscle spindles) mainly via the
external cuneate nucleus and is topographically
organized (Chapter 28).
Trigeminothalamic pathways have long been
recognized for their ability to show species differences
(Verhaart and Busch, 1960). Humans have both
dorsal and ventral trigeminothalamic tracts (reviewed
Usunoff et al., 1997). The ventral pathway, also called
the trigeminal lemniscus, arises from all levels of the
trigeminal nuclear complex. Fibers run through the
ventral pontine tegmentum and decussate to join
the dorsomedial side of the contralateral medial
lemniscus. They then travel with the medial lemniscus
to terminate in various thalamic sites (see later).
Lesions in the brainstem involving the trigeminal
lemniscus lead to contralateral sensory loss of both
touch and pain, supporting its crossed projection and
its involvement in both low- and high-threshold
responses (Kim, 1993).
The dorsal tract arises primarily from the dorsomedial
(intraoral) part of Pr5 (cat, Azerad et al., 1982;
cat and monkey, Burton and Craig, 1979). Fibers pass
dorsomedially in the dorsal pontine tegmentum, run
ventral and lateral to the periaqueductal gray in the
midbrain, and then pass laterally to enter the dorsomedial
part of the ipsilateral VPM.
THALAMIC SITES FOR TRIGEMINAL
SOMATIC SENSATIONS
Subdivisions of the thalamus are discussed by
Percheron (Chapter 20) and the somatosensory
thalamus is considered in detail by Kaas (Chapter 28).
Rather than repeat this information, we consider here
only those nuclei that are associated with cranial
somatic sensations.
Brainstem trigeminal nuclei provide a major input
to VPM, and also project to VPO and the midline and
intralaminar nuclei. In addition, there are inputs to a
region posterior and inferior to VPM and VPL, which
Percheron (Chapter 20) has called regio basalis. This
region includes, from medial to lateral, the suprageniculate,
the Po and VMpo areas described by
Blomqvist et al. (2000), and VPI. Regio basalis receives
inputs from laminar 1 cells of Sp5C and the spinal
cord (Hassler, 1959). For humans, information on
trigeminal responses is available only for VPM, VMpo,
and Po, and the following sections consider these. For
trigeminal inputs to VPO and VPI, the only details
available in the human, relate to somatotopy and are
considered by Kaas in Chapter 28. Somatic inputs to
the midline nuclei, such as the ventrocaudal part of the
mediodorsal nucleus (MDvc), with its projections to
the anterior cingulate cortex, are thought to be involved
in the affective-motivational aspects of nociception
(Rainville et al., 1997; Craig, 1996; Peyron et al., 2000).
Responses in these areas show widespread receptive
fields and modality convergence, which are not
specific to facial sensations, and consequently are not
considered further.
Ventroposterior Medial Nucleus
The (VPM) nucleus (also called Vci) lies medial to
VPL and is separated from it by a narrow band of
fibers sometimes referred to the arcuate lamina though
is really only an accumulation of lemniscal fibers. VPM
is characterized by relatively densely packed, small
to medium-sized cells and shows a high level of
parvalbumen immunoreactivity and, conversely, low
calbindin levels (Morel et al., 1997).
VPM is somatotopically organized, with the intraoral
surface, including the tongue, lying medially.
VPM is adjacent to, but excludes, the relatively parvocellular
area (VPMpc), which receives gustatory inputs,
also referred to as VMb or Varc. The most medial cells
of VPM have ipsilateral intraoral receptive fields. This
region receives input from dorsal (mandibular) Pr5 via
the ipsilateral dorsal trigeminothalamic tract (Smith,
1975). The remainder of VPM receives contralateral
inputs via the ventral trigeminothalamic tract, with intraoral and mandibular skin represented ventrally
and ophthalmic regions dorsally (Fig. 29.4). Adjacent
regions in VPL are responsive to finger and hand
stimulation. The close proximity of these regions is
indicated by the clinical finding that localized vascular
lesions in this boundary region can lead to the cheirooral
syndrome, in which there is a sensory disturbance
of the contralateral face and hand (Fisher, 1982;
Shintani et al., 2000).
Raussel and Jones (1991a) described monkey VPM
as consisting of cytochrome oxidase (CO)-rich rods
surrounded by a CO pale matrix (see Fig. 29.4 and
Table 29.1). The rods contain large and medium cells,
which are parvalbumen positive, as well as smaller
GABAergic cells. These areas also stain richly for
AChE and tachykinin immunoreactive fibers (e.g.,
substance P, neurokinin A and B, Liu et al., 1989). The
rods extend as anterior–posterior columns within the
nucleus, with all cells in a column having similar
receptive fields. They receive their major input from
Pr5 and project to cortical layer 4 of the primary
somatosensory cortex (Raussel and Jones, 1991b). In
contrast, the matrix lies around the rods and forms a
shell at the edges of VPM, which can extend into
adjacent nuclei (Jones, 1998). It contains small calbindin
positive cells and some GABAergic neurones. The predominant input to the matrix of VPM arises
from Sp5C, mainly the deeper laminae. The calbindin
positive matrix cells have widespread projections to
superficial cortical layers.
Response properties of human VPM cells have been
reported by a number of authors (Jasper and Bertrand,
1966; McComas et al., 1970; Ohye et al., 1972;
Donaldson 1973; Lenz et al., 1988). Most have reported
low-threshold, mechanoreceptive responses to hair or
skin stimulation. Besides cutaneous cells, responses to
deep pressure and/or joint movement have been
noted (Ohye et al., 1972; Lenz et al., 1988; Seike, 1993)
though these may have been located in VPO (see
Chapter 28, where it is referred to as VPS). In the rat,
VPM receives inputs from the TMJ and jaw muscles
and may be involved in proprioceptive sensations
(Luo et al., 1991; Ohya et al., 1993) via Pr5 and Sp5I
though this is not confirmed in humans.
All studies in humans agree that receptive fields are
contralateral and generally small, similar in size to
those on the fingers. There is a predominance of
responses from the lips and perioral area (Donaldson,
1973; Lenz et al., 1988). Many cells in VPM are
activated by speech movements; for instance, cells
with receptive fields on the lips may be activated
when the subject makes the sound “p” (McClean et al.,
1990). Two-thirds of the responses are slowly adapting
(Lenz et al., 1988) and spontaneous activity, at up to
40–50 impulses/s, is present in some cells (Jasper and
Bertrand, 1966). These results are similar to those in
the alert monkey where Bushnell and Duncan (1987)
found 90% of VPM cells had low-threshold cutaneous
receptive fields, usually within one trigeminal division.
Cells were activated by hair or skin stimulation,
and both rapidly and slowly adapting responses were
noted.
In most studies in primate VPM and VPL, responses
to noxious stimulation have been rare or absent. In
monkey VPM a small population of cells (10%) gave
nociceptive, WDR responses (Bushnell and Duncan,
1987). Similarly, a study by Lenz et al. (1993a) in
humans reported 6% of neurons in the ventrocaudal
thalamus responded to noxious heat as well as
innocuous thermal and mechanical stimuli, as for
WDR responses. Moreover microstimulation of this
region in humans evoked thermal and pain sensations
(Lenz et al., 1993b). Such sensations were more
common (30% of sites) from the posteroinferior region,
which may have corresponded to VPI, than from the
“core” region (5%). An extensive study by Dostrovsky
et al. (2000) found only 8% of sites evoked pain in
normal subjects though this was markedly increased
in patients with poststroke pain. Animal studies have
also reported innocuous thermal responses in VPM to
cooling of the tongue, but not other facial regions
(monkey, Poulos and Benjamin, 1968). Cells were
either cold-specific or responded to cooling and
mechanical stimuli; no responses to warming were
found. The paucity of thermal and nociceptive
responses in VPM suggests that these modalities may
activate additional thalamic sites and a major relay is
probably the adjacent region VMpo (see later).
Ventromedial Nucleus, Posterior Part and
Surrounding Po (Basalis Nodalis and Halo)
A relatively recently identified nucleus, thought to
be a relay for pain and temperature sensations, has
been described in monkey and human (Craig et al.,
1994; Blomqvist et al., 2000). VMpo lies posterior and
medial to VPM and VPL, ventral to the anterior
pulvinar and center median nuclei and dorsal to the
medial geniculate nucleus. It was designated the
posterior ventromedial nucleus by Paxinos and Huang
(1995), although Percheron (Chapter 20) considers it a
discrete nucleus “Nodalis” within the regio basalis.
VMpo contains small to medium-sized cells, loosely
aggregated in clusters (Blomqvist et al., 2000). In both
monkey and human, it stains richly for calbindin with
a dense plexus of immunopositive fibers (Craig et al.,
1994). Lamina 1 cells of Sp5C and the spinal dorsal
horn have been shown to project to this region in
monkeys (Craig et al., 1994). Double labeling has been
used to establish that the calbindin immunoreactivity
in these terminals colocalized with anterogradely
transported tracer from lamina 1 cells (Craig et al.,
1994). In human tissue, calbindin immunoreactive
fibers of the spinal lemniscus form dense patches of
terminals over VMpo neurons (Blomqvist et al., 2000).
Immunocytochemistry was used to show that fibers
containing substance P or CGRP terminated in VMpo.
Substance P staining frequently overlapped with that
of calbindin, but was less dense, suggesting that
substance P was present only in a subset of the
calbindin-positive fibers. In contrast, CGRP immunoreactivity
never overlapped with calbindin but lay
between calbindin-rich areas.
Recordings from this region in monkeys show
responses to innocuous thermal (cooling) or noxious
stimuli. Cells had small receptive fields on the contralateral
body surface, with clusters of adjacent cells
sharing similar response properties (Craig et al., 1994).
Both recording experiments and tracing studies in
monkeys indicate a topographic organization. Trigeminal
inputs are represented anteromedially, posterior
and ventromedial to VPM, whereas the limbs
are represented more posterolaterally, posterior and
ventromedial to VPL. As in monkeys, recordings from this site in humans
indicate that cold-specific (COLD) responses are
present (Dostrovsky and Craig, 1996). Stimulation of
this site in awake humans evoked cold sensations on
localized parts of the contralateral body surface,
including the face (Davis et al., 1999). Moreover,
imaging of the region shows activation with noxious
and thermal stimuli (Craig et al., 1996). Thus VMpo
has been suggested to be a specific thalamic relay site
for nociceptive and cold-specific responses from the
whole body surface, with the possible exception of the
tongue. Infarcts in this region are associated with
analgesia and loss of thermal sensibility (Leijon et al.,
1989). VMpo projects to a localized region of the
insula, which shows activation in PET studies with
noxious or cooling stimuli (Craig et al., 1996).
Blomqvist et al. (2000) have also identified a region
around VMpo that they call Po, though this should not
be confused with Po as described by Jones (1985).
Percheron (Chapter 20) describes it as a “halo” around
VMpo within the regio basalis (i.e., basalis halo, BH).
Po (BH) is a curved region forming the anterior, lateral,
and ventral aspects of VMpo. It contains patches of
CGRP positive fibers known to be associated with
visceral inputs (Blomqvist et al., 2000; de Lacalle and
Saper, 2000). Po (BH) has therefore been suggested to
act a general visceral afferent for inputs from the
glossopharyngeal, vagal and pelvic nerves (Blomqvist
et al., 2000).
Overview of Thalamic Relay Nuclei for
Cranial Sensations
The sites associated with somatic and gustatory
sensations in the human are summarized in Table 29.1.
Staining for the Ca-binding proteins parvalbumen and
calbinin has been included, although calretinin has
been omitted as it is generally low or absent in these
areas (Fortin et al., 1998; Cicchetti et al., 1998). In this
schema, the rod component of VPM (and VPL, though
not included here) forms the general somatic relay
nuclei for tactile information, with its main output to
area 3b the primary somatosensory cortex (Darian-
Smith et al., 1990; Chapter 28). In contrast, the matrix
has more diffuse projections to superficial cortical
layers and is suggested to have a modulatory role
(Jones, 1998). VPO is likely to provide for proprioceptive
sensation, although the extent of trigeminal
involvement in this is unclear. VPMpc acts as a special
visceral relay for taste, receiving inputs primarily from
the nucleus of the solitary tract (Beckstead et al., 1980;
Chapter 31). Po (BH), with its dense plexus of CGRP
fibers, may correspond to the relay for visceral
afferents (glossopharyngeal, vagal, and pelvic inputs;
Chapter 31), while VMpo, with its input of substance P
positive fibers, comprises the relay for general somatic
afferents for pain and temperature. VPI receives input
from both superficial and deep laminae and, like the
matrix of VPM and VPL, may have a more diffuse
modulatory role (Chapter 28). VMpo, Po, and VPI have
been considered part of the regio basalis by Percheron
(Chapter 20).
CRANIAL SOMATOSENSORY CORTEX
As for the thalamus, we will not attempt to repeat
here the organization and function of the whole
somatosensory cortex and associated areas involved
with somatosensory processing. These have been well
covered in Chapter 28. Rather we focus on recent data
addressing those aspects that are unique for cranial
somatic sensations.
Organization of Orofacial
Somatosensory Cortex
The overall organization of the primary somatosensory
cortex, with face located laterally adjacent to
the hand, has long been established. A recent report of
the facial representation in owl and squirrel monkeys
(Jain et al., 2001) shows a remarkable pattern of
myelin-dense patches within area 3b (Fig. 29.5). They
are separated from each other by myelin-light septa,
which mainly receive callosal inputs (Krubitzer and
Kaas, 1990). Jain et al. (2001) used electrophysiological
recordings to show that each patch represented a
specific region: upper face, upper lip, chin and lower
lip, contralateral teeth and tongue, and ipsilateral teeth
and tongue. These representations extended in an
orderly sequence from caudal to rostral in the cortex.
In addition, within each patch, receptive fields were
somatotopic; for example, for the upper face, the
upper forehead was caudal to the lower forehead.
Similar representations were also found in parallel
strips of cortex medial and lateral to area 3b and were
presumed to correspond to areas 3a and 1. A similar
organization is found in the macaque monkey
(Manger et al., 1995, 1996), although macaques have a
larger representation of the intraoral cheek pouches,
likely to reflect their use of these for food storage.
Like other body regions (Woolsey et al., 1979; Wood
et al., 1988), recordings of somatosensory-evoked
potentials after stimulation of trigeminal nerves have
been used to assess localization and topography of
orofacial responses in humans (Stohr and Petruch,
1979; Bennett and Jannetta, 1980; Findler and Feinsod, 1982; Badr et al., 1983). Response latencies for
somatosensory-evoked potentials from the orofacial
region are generally shorter than for the hand region
but otherwise show a similar series of waves (Ishiko et
al., 1980; Seyal and Browne, 1989). As found in animal
studies, face representation is lateral to the hand, with
an orderly progression of upper face, upper lip, lower
lip, and tongue, from medial to lateral (Penfield and
Rasmussen, 1950; McCarthy et al., 1993). In contrast to
most studies on the limbs, orofacial inputs have
generally been found to give bilateral responses
(Hashimoto, 1988).
Over the past decade or so, imaging techniques of
positron emission tomography (PET; Fox et al., 1987;
Bittar et al., 1999), magnetoencephalography (MEG;
Nakamura et al., 1988; Yang et al., 1993; Hoshiyama et
al., 1996) and functional magnetic resonance imaging
(fMRI; Sakai et al., 1995; Moore et al., 2000) have been
used to address the organization of the human
somatosensory cortex. These studies confirm the
overall topography reported from somatosensory
evoked potentials, with the orofacial representation
lying lateral to that of the hand (see Chapter 28, Fig
28.7). As for evoked responses, PET has demonstrated
the bilateral nature of the tongue representation
(Pardo et al., 1997).
Disbrow et al., (2000) have recently used fMRI to
show that besides SI, human cortex has both SII and
parietal ventral (PV) representations within the lateral
sulcus. Both regions are mirror-symmetrical and
topographically organised with face most lateral on
the lip of the upper bank of the lateral sulcus, similar
to the macaque (Krubitzer et al., 1995; Disbrow et al.,
2000; Chapter 28). They found that unlike areas 3b and
1, localized stimuli were less effective in SII and PV.
Stimuli over larger skin areas and stimuli moving
across the skin were particularly effective in SII and
PV, suggesting, indirectly, that cells in these areas may
have larger receptive fields. This was also supported
by the finding that unilateral stimuli caused bilateral
activation in both areas.
For intraoral representations, a recent PET study
has considered the issue of somatosensory versus
gustatory areas by using water as the stimulus (Zald
and Pardo, 2000). Intraoral water caused activation of
a large area of the pre- and post-central gyrus, insula,
and operculum. Voluntary swallowing was used to
eliminate areas thought to be associated with somatosensory
and motor processing, as compared with
gustation. Subtraction of activity associated with
voluntary swallowing reduced activation in all these
regions. Not surprisingly, the peak focus of somatosensory
activation occurred in the post-central gyrus,
in an area consistent with the representation of the
tongue and oral cavity.
Orofacial Response Characteristics
Responses of cells in areas 3b, 1, and 2 in orofacial
regions are similar to those from the limbs. Thus 3b
gives primarily cutaneous responses with small receptive
fields, while area 1 has larger, more complex
responses and area 2 contains both cutaneous and
deep receptors. These are discussed in Chapter 28.
Nociceptive responses have also been reported in SI
from trigeminal activation (Kenshalo and Isensee, 1983; Kenshalo et al., 1988; Chudler et al., 1990). Such
responses are found within SI as well as in SII and
adjacent regions (Dong et al., 1989).
Aseries of experiments in awake macaque monkeys
has provided the best information to date on responses
of cells within orofacial regions of the primate SI
cortex. Cells were located in areas 3b, 1, and 2. The
most frequently recorded responses were from cells
sensitive to stimulation of the lips, tongue and periodontium
(Lin et al., 1994a). Most cells were activated
by low-threshold stimulation and gave rapidly
adapting responses. Seventy-eight percent of the units
responded to contralateral stimuli; the others being
bilateral. The activity of many units was modified by a
protrusion of the tongue, and in some cases activity
could change significantly prior to the onset of EMG
activity associated with the movement. However,
biting movements did not change the firing pattern in
most of the cells. Modification of somatosensory
responses during facial movements would relate in
part to movement-activated stimulation within the
receptive field of the neuron. In addition, Lin et al.
suggested that these sensory cells may provide an
important input for controlling the movement or even
initiating it. The role of these cells in regulating tongue
movements was further supported by a study (Lin
et al., 1994b) in which monkeys were trained to protrude
the tongue in different directions. Over half of the
responses from areas 3b and 1 showed a difference in
response in relation to the direction of tongue protrusion.
Moreover it was shown that the response of
cells to stimulation of their receptive fields on the lips
or tongue were suppressed during a tongue protrusion
movement. This suppression was not generalized
across all the somatosensory cortex but rather was
dependent on the location of a particular receptive
field in relation to the movement being undertaken
(Lin and Sessle, 1994). The importance of responses
in SI for undertaking learned movements was shown
by Lin et al. (1993) by cooling of SI during a tongue
protrusion or biting task. During cooling, monkeys had
difficulty in maintaining the steady tongue protrusive
force during the holding period.
Plasticity of Trigeminal Responses
There is increasing evidence to support reorganization
of somatosensory responses following deafferentation,
for instance after nerve section or amputation.
This is widely reported from animal studies (Wall,
1988; Garraghty et al., 1994; Jain et al., 1998; Waite,
2000) where representation of a body part adjacent to
a denervated area expands into the deafferented representation.
There is now considerable evidence that
similar reorganization can occur in humans (Mogilner
et al., 1993; Ramachandran, 1993). Some of the most
extensive changes involve cortical regions originally
responsive to stimulation of the hand, becoming reorganized
to respond to facial stimuli. For example, MEG
imaging has shown an anatomical shift of the cortical
area activated by facial stimuli after amputation (Elbert
et al., 1994). The facial area was shifted medially into
the region normally associated with responses from
the hand. Such changes may explain the finding that
stimulation of the face evokes sensations on the
“phantom” hand (Ramachandran et al., 1992; Halligan
et al., 1993). Correspondingly, referral to the hand
occurred after the removal of the maxillary and
mandibular regions of the trigeminal ganglion (Clarke
et al., 1996). Some cortical reorganization occurs immediately
after deafferentation, although it is clear that
reorganization continues to become more extensive for
years after the injury (Pons et al., 1991).
The cortical reorganization reported in monkeys
can extend for 10 to 14 mm (Pons et al., 1991), well
beyond the known overlap in thalamocortical projections
(about 1.5 mm, Rausell and Jones, 1995).
Similarly in humans shifts of approximately 2 cm have
been demonstrated (Elbert et al., 1994). One possible
mechanism for such widespread remapping was
suggested to involve changes in horizontal intracortical
connections. However, Manger et al. (1997)
showed that there were few such horizontal connections
crossing the border between the hand and
trigeminal areas in macaques. In contrast, the hand
representation had extensive intracortical connections
with lower jaw and neck regions innervated by C2 and
C3 cervical nerves. These extended for some 3 mm and
may, at least in part, explain the remapping after
amputations or deafferentation. However, the limited
extent of intracortical connections indicates that they
are probably not sufficient to explain the total reorganization
seen.
Another mechanism likely to contribute to the
remapping that is seen at cortical level is the degree of
subcortical change that can occur. Plasticity at both
brainstem and thalamic levels have been documented
in animal studies (reviewed Kaas et al., 1999). For
example, in the brainstem, trigeminal inputs grow into
the cuneate nucleus after amputations or lesions of the
dorsal columns (monkey, Jain et al., 2000). There is now
evidence for plasticity in the human thalamus, both
immediately after a cold block of the receptive field of
a neuron (Dostrovsky, 1999) and chronically after
amputation (Kiss et al., 1994). Similarly after spinal
transections or surgery for chronic pain, expansions of
border zone responses into anaesthetic areas were
found (Lenz et al., 1994). These changes suggest that expansions from adjacent central representations can
occur at any level of a sensory path. Thus besides
cortical reorganization, changes in brainstem and
thalamus may underlie trigeminal expansions into
other central somatic territories. Similarly, limb inputs
can invade trigeminal territories at all central levels
after damage to trigeminal nerves or ganglion (rat,
Waite, 2000; human, Clarke et al., 1996).
FIGURE 29.2 (A) Diagram showing a sagittal section through the temporomandibular joint. Encapsulated and free nerve endings are present in the posterior capsule and tendon of lateral pterygoid muscle. Free nerve endings are distributed to the periphery of the disc but are absent from the central region. (B) Diagram to show the distribution of nerves within the cornea. Fibers initially enter radially and then assume a predominantly temporonasal orientation within the stroma (from Figure 7, Muller et al., 1997, Architecture of human corneal nerves. Invest. Ophthalmol. Vis. Sci. 38: 984–994, with permission from the copyright holder, the Association for Research in Vision and Ophthalmology, and the author).
FIGURE 29.3 The left-hand side shows a diagrammatic representation of the brainstem trigeminal complex, drawn to scale from a dorsal view. The entering trigeminal root, s5, and tract Sp5 are shown in black. The mesencephalic (Me5), principal (Pr5), and spinal nuclei (Sp5I, SP50, Sp5C) are shown as well as the paratrigeminal nucleus (Pa5). Subnuclear borders are indicated; the border between Sp50 and Sp5I is shown at two locations, as described by Paxinos and Huang (1995) and Usunoff et al. (1997). The right-hand side of the figure shows the cross-sectional appearance of each of the nuclei (gray shading) and adjacent structures at the levels indicated, as taken from the atlas of Paxinos and Huang (1995, copyright Academic Press, reprinted with permission).
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