This document summarizes the trigeminovascular system, which senses real or impending tissue injury in the meninges and dural blood vessels. It has three main parts: 1. The trigeminal ganglia houses the cell bodies of trigeminal neurons that innervate the meninges and dural blood vessels. These neurons release vasodilatory peptides like CGRP and substance P in response to noxious stimulation. 2. The spinal trigeminal nucleus transmits nociceptive signals from the meninges into the brain. It has ascending projections to thalamic and brainstem nuclei. 3. Higher brain regions like the thalamus and cortex modulate pain processing. The trigeminov

1. TRIGEMINOVASCULAR SYSTEM
Dept of Neurology
NIMS

2. HISTORY
•Vertebrate meninges have a rich trigeminal innervation and abundant blood
supply.
•Vesalius was the first to remark on the close
Similarity between the distribution of nerves
and blood vessels at the macroscopic level.
•At the microscopic level, this close association
evolved in part to protect the contents of the cranial
vault at entry points such as the blood vessels and the skull.
•This network senses real or impending tissue injury.
•With noxious stimulation blood flow to the meninges increases and blood
vessels leak.

5. Anatomical substrate of the trigeminovascular pain pathways
•The brain has a sparse sensory innervation
•Meninges and dural vessels are the most
significant pain producing intracranial tissues.
• Innervation is Primarily by V1
•These fibres therefore provide a pathway
for pain signal transmission from meningeal
blood vessels into the brain where
headache pain is registered.
This system has been described collectively as the ‘trigeminovascular’
system.

6. •Trigeminal innervation is
predominantly to the forebrain and
extends posteriorly to the rostral
basilar artery
•Caudal vessels are innervated by the
C2 and C3 dorsal roots, which also
synapse with the central trigeminal
neurons
•Sole sensory innervation of the
cerebral vessels

7. Central projections of meningeal primary afferents
•Central processes of
meningeal sensory afferents
enter the brainstem via the
trigeminal tract
•They pass caudally
giving off collaterals that
terminate in the spinal
trigeminal nucleus (SpVC) and
upper cervical spinal cord
(C1–C3).

8. Three types of nociceptive neurons are
described
1. C fibres -Small calibre, unmyelinated ,
slow conducting
 Slow buildup of aching , throbbing,
burning pain
2 . A delta nociceptors – small diameter ,
lightly myelinated, rapid conducting fibres
 sharper initial pain sensations
3 . Silent nociceptors – remain quiet during
in normal nociceptive process and fire only
to high intensity noxious stimulation

9. TRIGRMINO CERVICAL COMPLEX
• Using c-Fos-immunocytochemistry, a
method for looking at activated cells, after
meningeal irritation with blood, expression
is reported in the Trigeminal nucleus
caudalis .
• After stimulation of the superior sagittal
sinus, Fos-like immunoreactivity is seen in
monkey cat and Rat subjects in the
trigeminal nucleus caudalis and in the
dorsal horn at the C1 and C2 levels.

10. •Trigeminal nucleus extends beyond the
nucleus caudalis to the dorsal horn of the
high cervical region in a
functional continuum that includes a
cervical extension that could be regarded as
TRIGEMINAL NUCLEUS CERVICALIS.
•The entire group of cells can be usefully
regarded as
TRIGEMINO CERVICAL COMPLEX
•Integrative role of these neurons in
in head pain

11. Convergence of Trigeminal and Cervical inputs
•The Trigeminocervical neurons show a
convergent synaptic input from the
•trigeminal cutaneous fibers
•supratentorial dura
•deep paraspinal neck musles,
•cutaneous dermatome served by
the greater occipital nerve.
•This anatomic arrangement may be
responsible for dull and poorly localized
quality of head and neck pain

12. •The TCC is a key relay center for
the transmission of nociceptive
information from the cranial
vasculature to the brainstem and
higher pain-processing structures.
•Anatomically, the TCC makes
ascending and receives descending
connections with many higher brain
structures.

13. .
• Nociceptive signaling from the dural
vasculature, processed via the TCC is relayed
to the third-order neurons in the thalamus via
the ‘quintothalamic tract.’
• Trigeminovascular dural nociceptive inputs
predominantly processed in
•Ventroposteromedial (VPM) nucleus
•Ventral periphery of the VPM,
•Posterior thalamic nucleus,
•Medial nucleus of the posterior complex
•Intralaminar Nuclei

14. Ascending projections of trigeminovascular neurons
•Trigeminovascular neurons from SpVC project into to the
parabrachial area (PB),
anterior hypothalamic (AH),
lateral hypothalamic (LH), and
lateral preoptic nucleus (LPO), hypothalamic areas,
ventral posteromedial (VPM),
posterior (Po), and parafascicular (Pf) thalamic nuclei.

16. The ventrolateral area of the
upper cervical and
medullary dorsal horn, an
with majority of 2nd
trigeminovascular neurons ,
projects to the
•Ventrolateral periaqueductal
gray matter (vlPAG),
•NTS
•brainstem reticular areas,
•superior salivatory nuclei,
• cuneiform nuclei

17. Projections from thalamic trigeminovascular neurons to the
cerebral cortex
•Human functional imaging
studies that show
activation of posterior/dorsal
thalamus have identified
trigeminovascular neurons
•Posterior (Po),
• Lateral posterior/dorsal
(LP/LD),
•Ventral posteromedial (VPM)
Thalamic nuclei .

18. •Cortical projections of such neurons
are defined by their
thalamic nucleus of origin.
• VPM dura-sensitive neurons
in VPM project to trigeminal areas of
the primary and secondary
somatosensory (S1/S2) cortices,
insula,
•suggest a role in sensory-discriminative
components of migraine
location, intensity, and quality of
pain .

19. •Dura-sensitive
neurons in Po, LP, and LD
project to multiple cortical areas such
as motor, parietal association,
retrosplenial,
somatosensory,
auditory, visual and
olfactory cortices
• Suggests a role in motor
clumsiness, difficulty focusing,
transient amnesia,
allodynia, phonophobia,
photophobia & osmophobia

20. •Diverse pattern from
trigeminovascular neurons of
higher-order relay thalamic
nuclei are projected to
disseminate information to
many cortical areas
simultaneously and directly
• Explain the diversity of
neurological disturbances
associated with migraine

22. Trigeminovascular physiology
trigeminal ganglion section
Resting cerebral blood flow.
Hypercapnia and hypoxia.
Autoregulation
Responses observed resulted from the axon-reflex part of the trigeminovascular
system, since root section does not eliminate the effect whereas ganglionectomy
does so .

23. Transmitters
•Vasodilator peptides are found in cellbodies within the trigeminal neurons
that innervate blood vessels.
• Calcitonin gene-related peptide(CGRP)
• Substance P (SP)
• Neurokinin A (NKA),
• PACAP (pituitary adenylate cyclase activating Polypeptide)
found in various combinations of neurons so that any combination may
characterize a particular neuron

24. CGRP
•Most potent and the most interesting of the neuropeptides in the trigeminal
system.
•It is derived by alternative processing of the calcitonin gene messenger .
•The trigeminal ganglion contains numerous CGRP immunoreactive cells (40)%
•CGRP-containing fibers on cerebral vessels are not found after trigeminal
nerve section.
•CGRP act as neuromodulator at multiple areas in the nervous system and
regulate the flow of nociceptive signals

26. Brain areas expressing CGRP receptor

27. Substance P.
•Marked density around the superior sagittal sinus
•SP is a endothelium dependent
•Vasodialatation
•Protein extravasation
NeurokininA.
•Similar profile of action and localization in the trigeminal system .
•Both SP and NKA coexist in perivascular nerve fibers in peripheral
and cerebral vessels .
•Neurokinin A vasodilatation only 1/10th of SP

28. PACAP (pituitary adenylate cyclase activating Polypeptide)
•In the human trigeminal ganglion, PACAP-containing cell bodies amounting to
15–20% of trigeminal cells.
•PACAP co-localises with CGRP in some cell bodies in the trigeminal ganglion.
•PACAP dilates cerebral arteries and can increase cerebral blood flow
•This peptide may participate in antidromic vasodilatation following activation of the
trigeminovascular reflex

33. Neurogenic plasma
extravasation
•Seen during stimulation of the
trigeminal ganglion in
along with structural changes in
dura mater includes
• Mast cell degranulation
• Changes in post-capillary
venules including platelet
aggregation

35. THE TRIGEMINO VASCULAR REFLEX
•Denervation of the trigeminovascular system did not alter the regional cerebral
blood flow or metabolism, the cerebral vascular responses to carbon dioxide, or
the cerebral autoregulation.
•Vasoconstrictor responses elicited by Noradrenaline ,alkaline pH,
PGF2α, BaCl2, and subarachnoid blood were modified.
•Following denervation, there was no alteration in the contractile response to
agents, but the time to attain initial basal tone was markedly prolonged.

37. Trigeminovascular Activation
If vasospasm is initiated cortical
neurons (trigger)
Trigeminal vascular system
activated
normalization of vascular tone
(by the release of CGRP ).

38. •The Trigeminal doesnt play a
significant role in the regulation
of blood flow under resting
conditions.
•The system acts in times of
stress and has been described
as the “watchdog.”

39. Activation and sensitization of the Trigeminovascular Pathway
Cortical spreading depression
•First identified by Leao
•CSD (reversible transient coritcal
event)
• Slowly propagating wave (2–6 mm/min)
of neuronal and glial depolarization
followed by a prolonged inhibition
(15– 30 minutes) of cortical activity.
•Correlated with the visual aura that
precedes the onset of
headache in migraine .

41. Electrophysiological recordings of CSD

43. •Genetic factors are likely to
play a role in individual CSD
susceptibility
•FHM mutations show
increased susceptibility to
CSD & altered synaptic
transmission
•Dysfunction of these
channels might impair
serotonin release and
predispose patients to
migraine

44. SENSITIZATION IN MIGRAINE
•Sensory sensitization is manifested in patients in two ways:
Hyperalgesia
Allodynia.
•Non -nociceptive. Stimulus (hair brushing,
wearing a hat, showering, and resting the head on a pillow.) can be
percieved as increasingly painful stimulus .
•As the attack progresses, cutaneous allodynia developes in the region of pain
and then outside at extracephalic locations .
• Sensitization is important because
patients with allodynia often fail to respond to triptans.

45. •Sensitization of nociceptors,
• secondary sensory neurons in the trigeminal nucleus caudalis, or projected neurons
in the thalamus
for initiation and maintenance of the of allodynia.
The afferent / central neurons process the sensory information
Increase in spontaneous discharge rate / increased responsiveness to both painful
and nonpainful stimuli.
The receptive fields of these neurons expand, resulting in pain felt over a greater part

46. Peripheral sensitization
•Measured in minutes, up to 1 hour,
•Peripheral sensitization produces an increase in pain sensitivity that is
restricted to the site of inflammation—in the case of migraine, this is the dura.
• This results in the throbbing quality of migraine pain and its activation by
movement.
• Sensitization of these neurons reduces their threshold to a level where blood
vessel and cerebrospinal fluid pulsations are painful.

47. Schematic representation of
peripheral sensitization and
periorbital throbbing pain in
human beings.
Functional magnetic resonance
imaging evidence showing
activation of the trigeminal
ganglion during migraine.

48. •Electrophysiological
recording of a neuron in the
trigeminal ganglion showing
increased responsiveness to
mechanical stimulation of the
dura after topical application
inflammatory mediators (IS).

49. Central sensitization
•Activity-dependent increase in the excitability of neurons responsive to
nociceptor inputs in the dorsal horn of the spinal cord.
•The increase in activity outlasts the initial afferent stimulation.
•Central sensitization is initiated by nociceptor afferent activation and is
characterized by a reduction in activation threshold induced in the neuron of the
deep lamina of the dorsal horn (laminae III to V )
•Results in increases in the magnitude of responsiveness, and an increase in
receptive field.

50. Sensitization of central
trigeminovascular neurons
in the TNC.
Functional magnetic
resonance imaging
evidence showing
activation of the spinal
trigeminal nucleus during
migraine.

51. Electrophysiological
recording of a neuron in the
SPVC showing increased
responsiveness to
mechanical stimulation of
the dura after topical
application of
inflammatory mediators (IS).

52. •Whole-body allodynia (cannot wear tight clothing, cannot use heavy
blanket, cannot take a shower) is an extracephalic allodynia during migraine.
•Sensitization Thalamic Trigeminovascular neurons located in VPM, Po, LP
subdivision of the pulvinar nucleus in the posterior thalamus

56. Central mechanisms involved in exacerbation of
headache by light, and ocular discomfort/pain &
the role of TGVS

57. •The perception of migraine headache is intensified during exposure to
ambient light in migraine pts with normal eyesight .
•Clinical observations in blind migraine pts suggest that the exacerbation
of headache by light depends on photic signals from the eye that
converge on trigeminovascular neurons along its path.
•In migraine patients with complete damage of the optic nerve, no
photophobia observed as they lack any kind kind of visual perception
•Conversely, exacerbation of headache by light is preserved in blind
migraine pts with intact optic nerve, partial light perception, but no sight
because of severe degeneration of rod and cones

58. •Integrating the knowledge of the neurobiology of the
Trigeminovascular system and the anatomy of visual pathways
Conclusions available:
1. light enhances the activity of thalamic Trigeminovascular neurons
2. Light/ dura-sensitive neurons located mainly in the LP/Po area of the
posterior thalamus receive direct input from Retinal ganglion cells
3. the axons of these neurons project to cortical areas involved in the
processing of pain and visual perception.

59. • Convergence of
photic signals from the
retina onto the
Trigeminovascular
thalamo-cortical
pathway
•Neural mechanism for
the exacerbation of
migraine headache by
light

62. Dura/light-sensitive neurons (red ) closely apposed to retinal afferents (green in the
posterior thalamus

63. Brain regions associated with modulation of
migraine pain

64. Cerebral cortex - Major source of trigeminovascular
modulation
•Endogenous modulation of trigeminal nociception originates from the cortex
•Cortical dysexcitability major factor for the susceptibility to migraine .
•Cortico-trigeminal projections originate mainly from the contralateral primary
somatosensory and insular cortices, and innervate both deep and superficial
layers of the SpVC,

65. Hypothalamic modulation of the trigeminovascular system
•Most of the functional imaging studies showing increased hypothalamic activity
have been obtained from trigeminal autonomic cephalalgias (TACs) .
•The hypothalamus plays a critical role in autonomic and endocrine regulation
and has been involved in the premonitory symptoms of migraine.
such as sleep–wake cycle disturbances, changes in mood, appetite, thirst, and
urination

67. •The reciprocal
connections between the
hypothalamus and SpVC
• The presence of neurons
expressing c-fos in several
hypothalamic nuclei after
dural stimulation
supports the role of the
hypothalamus in different
aspects of migraine and its
connections with
Trigeminovascular
system

68. •Trigemino-parabrachial-hypothalamic
circuit
•Noxious stimulation of the dura
activates parabrachial and
ventromedial hypothalamic nucleus
(VMH) neurons that expresses the
receptor of the anorectic peptide
cholecystokinin,
•Mediate the loss of appetite during
migraine .

69. Orexinergic projections with importance to the modulation of trigeminovascular
nociceptive processing
Orexin A inhibits trigeminovascular
activation at the level of the dural
vasculature and in TCC when
administered intravenously
Orexin B has no known effect on
trigeminovascular activation when
administered intravenously, but
demonstrates a facilitatory role when
microinjected directly into the posterior
hypothalamus.
Further possible mechanisms include a
direct action on the PAG and LC.

70. The A11 nucleus and the trigeminovascular system
•. The hypothalamic A11
nucleus is the sole source of
dopamine to the spinalcord
• provides direct inhibitory
projections.
•Stimulation of A11 inhibits
nociceptive trigeminal afferent
responses through the D2
receptor

71. Brainstem Nuclei
Superior salivatory nuclei
Rostroventral medulla(RVM)

72. The trigeminal brainstem
nuclear complex
A descending inhibitory
neuronal network
Frontal cortex
Hypothalamus
PAG
RVM
Medullary and spinal dorsal
horn.
The RVM may be involved
in modulation of
trigeminovascular
nociceptive traffic
in migraine.

73. •Three classes of neurons have been identified
in RVM & PAG
• “OFF” cells pause
immediately before the nociceptive reflex,
and “ON” cells are activated.
•Increased “ ON “ cell activity in the brainstem’s
pain modulation system enhances the response
to both painful and nonpainful stimuli
•Headache may be caused, in part, by
enhanced neuronal activity in the nucleus
caudalis as a result of enhanced ON cell or
decreased OFF cell activity

78. PATHOPHYSIOLOGICAL SUBSTRATES OF MIGRAINE
Pain Trigeminovascular system
Throbbing
Unilateral
Pain producing innervation of
cranial vessels
Trigeminal nerve/ nucleus
processing
Nausea Trigeminal connections with NTS
Sensory sensitivity
Head movement, Light, sound,
smells
Abnormal brainstem modulation
of sensory input
TGVS and optic N connections
Episodic attacks Channelopathic dysfunction in
brainstem
Aminergic nociceptive control
systems and trigeminovascular
connections

79. The trigeminal autonomic reflex
•The trigeminal autonomic brainstem
reflex afferent limb- the trigeminal nerve
efferent limb-facial/greater superficial
petrosal (parasympathetic) dilator
pathway.
•It stems from the superior salivatory
nucleus in the pons and supplies lacrimal
glands and blood vessels in the upper
part of the face

80. Sufficient painful stimulation of the
V1 produces reflex activation of
the cranial parasympathetic
outflow, with associated
vasodilation of the internal carotid
artery and watering and redness
of the eye or nasal congestion

81. CLUSTER HEADACHE AND OTHER TAC PATHOPHYSIOLOGY
ROLE OF TRIGEMINOVASCULAR SYSTEM

82. •Trigeminovascular system and the trigeminoautonomic reflex are activated in
CH and other TAC
•Increased concentrations of CGRP and VIP in jugular venous blood during
spontaneous CH attacks
•There is a decrease of CGRP concomitant with pain relief after treatment with
vasoconstrictors like oxygen and sumatriptan but not after injection of pethidine.

83. .
•Hypothalamus is a key area for the
pathophysiology of CH and TACs
•The brain areas involved in a CH attack
are mainly those of the pain matrix, and
they overlap areas involved in cognitive,
affective, and autonomic functions.
•A dysfunction or a disturbance in the
interactions between them, might give rise
to a permissive state, resulting in
disinhibition of the hypothalamo-trigeminal
pathway, which is
necessary for a pain attack to begin.

85. •Dual activation of the
trigeminovascular
cranial parasympathetic
systems
by
•Central or peripherally-acting
triggers at a permissive time,
called “cluster period”
• Determined by a
dysfunctional hypothalamic
pacemaker.

87. •The distinction between the TACs and other headache syndromes is the
degree of cranial autonomic activation and not its presence.
•The cranial autonomic symptoms may be prominent in the TACs due to a
central disinhibition of the trigeminal–autonomic reflex.
•Hypothalamus regulates the duration of an attack, may be responsible for
the different phenotypic expressions of the TACs

88. Hypothalamic stimulation: mechanism of action and
implications for TAC pathophysiology
•high-frequency hypothalamic stimulation might inhibit apparent hyperactivity
of this brain area.
•Hypothalamic implantation and stimulation is used treat chronic drug-resistant
patient with CH.
•Accumulated experience patients with drug-resistant chronic CH who have
received implantation indicates that the technique produces notable clinical
improvement in 60% of cases, with complete control of attacks recorded in about
30%.

89. TRIGEMINAL NEURALGIA
Causation – blood vessel
compressing the
trigeminal nerve root as
it enters the brainstem
Peripheral pathology –
nervous compression
Central pathology –
hyperactivity of
trigeminal nerve nucleus

91. •A marked increase in CGRP levels was
seen in the jugular vein ipsilaterally during
the flushing with no change in substance P,
NPY, or VIP.
•After cessation of the stimulation, the
peptide levels returns to normal.
•This change was also seen in venous
blood from the cubital fossa to a lesser
degree.
•Thus, CGRP is apparently released from a
cranial source and is linked with unilateral
head pain of trigeminal neuralgia
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
CGRP SP VIP NK

93. 5 HT RECEPTORS IN TRIGEMINOVASCULAR PATHWAY

94. Possible sites of cgrp antagonist

95. BRAIN STRUCTURES AS TARGET FOR PROPHYLAXIS OF
MIGRAINE

96. Pathogenic mechanisms implicated in the action of migraine preventive drugs

97. •BTX-A could cause relaxation of the
corrugator muscles, with pain relief
during migraine attacks .
•BTX-A may exert its prophylactic
action in migraine through the
inhibition of peripheral sensory
neurons .
•Through inhibition of peripheral
sensitization, BTX-A leads to an
indirect reduction in central
sensitization, which underlies pain
maintenance in migraine

98. REFERENCES :
1. WOLF S HEADACHE AND OTHER FACIAL PAIN 7TH EDITION
2. PAIN (2013) S44–S53 :Anatomy of the trigeminovascular pathway and
associated neurological Symptoms, cortical spreading depression,
sensitization, and modulation of pain
3 . Lancet Neurol 2009; 8: 755–64 : Pathophysiology of trigeminal
autonomic cephalalgias
4. Headache ISSN 0017-8748 ,2006 by American Headache Society
Functional Imaging of Migraine and the Trigeminal System

99. THANK YOU

101. Local vasodilation is an essential aspect of CH pathophysiology. Firstly, there is dilation of the
ophthalmic and middle cerebral arteries during attacks of CH Secondly, attacks can be
induced by specific vasodilators as a sign of increased neurovascular reactivity and thirdly,
sumatriptan, a potent vasoconstrictor, gives prompt relief of pain.
A prominent opinion
is that the vasodilation is mainly a secondary phenomenon due to pain and activation of the
trigeminoautonomic reflex, since a similar distribution of vasodilation is seen in experimental
studies of induced pain. Notably, vasodilation per se is not painful, but if there is
concomitant sensitization of vascular pain receptors caused by local processes or centrally
induced mechanisms it may contribute to pain.
The role of the vasodilator nitric oxide (NO) in CH is not clear. Basal levels of nitrite, a
metabolite and marker of NO, have been reported to be higher in
CH patients (either in remission or in the active period) than in controls as a possible sign of a
hyperactive L-arginine NO pathway or to be normal (in the active period between attacks)
.The increase of nitrite after nitroglycerine provocation did not differ between healthy
controls and patients who suffered an induced CH attack . Other factors, at present not
clarified, may render the CH patient hypersensitive to NO and other vasodilators but not all
the time, since a few hours immediately after a spontaneous attack patients appear to be
refractory
to nitroglycerine provocation . A most challenging issue is to clarify how CH pain is
induced by nitroglycerine and to clarify why this
occurs only during the active cluster period