TRIGEMINOVASCULAR SYSTEM

Dept of Neurology

NIMS

HISTORY

•Vertebrate meninges have a rich trigeminal innervation and abundant bloodsupply.

•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.

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.

.

•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

•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).

Central projections of meningeal primary afferents

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

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.

•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

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

•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.

.

• 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

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.

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

•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 .

Projections from thalamic trigeminovascular neurons to the

cerebral cortex

•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 .

•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

•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

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 .

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

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

Brain areas expressing CGRP receptor

Substance P.

•Marked density around the superior sagittal sinus

•SP is a endothelium dependent

•Vasodialatation

•Protein extravasation

Neurokinin A.

•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

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

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

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.

If vasospasm is initiated cortical

neurons (trigger)

Trigeminal vascular system

activated

normalization of vascular tone

(by the release of CGRP ).

Trigeminovascular Activation

•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.”

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 .

Activation and sensitization of the Trigeminovascular Pathway

Electrophysiological recordings of CSD

•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

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.

•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

of the dermatome ,

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.

Schematic representation of peripheral sensitization andperiorbital throbbing pain in human beings.

Functional magnetic resonance imaging evidence showing activation of the trigeminal ganglion during migraine.

•Electrophysiological

recording of a neuron in the

trigeminal ganglion showing

increased responsiveness to

mechanical stimulation of the

dura after topical application

inflammatory mediators (IS).

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.

Sensitization of central

trigeminovascular neurons

in the TNC.

Functional magnetic

resonance imaging

evidence showing

activation of the spinal

trigeminal nucleus during

migraine.

Electrophysiological

recording of a neuron in the

SPVC showing increased

responsiveness to

mechanical stimulation of

the dura after topical

application of

inflammatory mediators (IS).

•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

Central mechanisms involved in exacerbation of

headache by light, and ocular discomfort/pain &

the role of TGVS

•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

•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.

• Convergence of

photic signals from the

retina onto the

Trigeminovascular

thalamo-cortical

pathway

•Neural mechanism for

the exacerbation of

migraine headache by

light

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

Brain regions associated with modulation of

migraine pain

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,

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

•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

•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 .

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.

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

Brainstem Nuclei

Superior salivatory nuclei

Rostroventral medulla(RVM)

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.

•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

PATHOPHYSIOLOGICAL SUBSTRATES OF MIGRAINE

Pain Trigeminovascular system

Throbbing

Unilateral

Pain producing innervation of cranial vesselsTrigeminal nerve/ nucleus processing

Nausea Trigeminal connections with NTS

Sensory sensitivityHead movement, Light, sound, smells

Abnormal brainstem modulation of sensory inputTGVS and optic N connections

Episodic attacks Channelopathic dysfunction in brainstemAminergic nociceptive control systems and trigeminovascularconnections

•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

The trigeminal autonomic reflex

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

CLUSTER HEADACHE AND OTHER TAC PATHOPHYSIOLOGY

ROLE OF TRIGEMINOVASCULAR SYSTEM

•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.

•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.

.

•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.

•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

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%.

Causation – blood vessel

compressing the

trigeminal nerve root as

it enters the brainstem

Peripheral pathology –

nervous compression

Central pathology –

hyperactivity of

trigeminal nerve nucleus

TRIGEMINAL NEURALGIA

•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

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CGRP SP VIP NK

5 HT RECEPTORS IN TRIGEMINOVASCULAR PATHWAY

Possible sites of cgrp antagonist

BRAIN STRUCTURES AS TARGET FOR PROPHYLAXIS OF MIGRAINE

Pathogenic mechanisms implicated in the action of migraine preventive drugs

•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

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

THANK YOU

Local vasodilation is an essential aspect of CH pathophysiology. Firstly, there is dilation of theophthalmic and middle cerebral arteries during attacks of CH Secondly, attacks can beinduced by specific vasodilators as a sign of increased neurovascular reactivity and thirdly,sumatriptan, a potent vasoconstrictor, gives prompt relief of pain. A prominent opinionis 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 isconcomitant 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 inCH 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 refractoryto nitroglycerine provocation . A most challenging issue is to clarify how CH pain isinduced by nitroglycerine and to clarify why thisoccurs only during the active cluster period