Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 165

Functional anatomy of headache: hypothalamus

Anatomia funcional da cefaleia: hipotálamo

ABSTRACTABSTRACT

ABSTRACT

There is now compelling evidence that the hypothalamus exerts

a major role in the mechanism of headache triggering. Pain

and concomitant changes in the hormonal secretory pattern

occur during an attack of headache when hypothalamic

structures are involved. During spontaneous migraine or cluster

headache attacks activation of the hypothalamus is shown by

positron emission tomography. Over the past 10 years a

number of patients with refractory chronic cluster headache

have received neurostimulation of the posteroinferior

hypothalamus as a form of treatment. The clinical use of deep

brain stimulation (DBS) is based on the theory of posterior

hypothalamic nucleus dysfunction as the cause of cluster

headache attacks. In this article the authors review the

functional anatomy of the hypothalamic region and its

neighborhood, using silicone-injected cadaveric head and

MRI. In conclusion, a better understanding of the functional

anatomy of the hypothalamus and its neighborhood is

imperative for understanding the pathophysiology of several

of the primary headaches, particularly migraine and the

trigemino-autonomic headaches. Direct stimulation of the

posterior hypothalamic region using DBS devices is now the

"state of the art" form of treatment indicated for refractory chronic

cluster headache. The exact mechanism and the actual region

where the DBS may act are still unknown, and studies on the

functional anatomy of the hypothalamus are crucial to the

progress in this marvelous field of functional neurosurgery.

Keywords:Keywords:

Keywords: Anatomy; Hypothalamus; Cluster headache;

Migraine; DBS; MRI

FUNCTIONAL ANATOMYFUNCTIONAL ANATOMY

FUNCTIONAL ANATOMY

Marcelo Moraes Valença

, Luciana P. A. Andrade-Valença

, Carolina Martins

Neurology and Neurosurgery Unit, Universidade Federal de Pernambuco, Recife, PE, Brazil and

Hospital Esperança, Recife, PE, Brazil

Medical School of Pernambuco IMIP, Recife, PE, Brazil

Valença MM, Andrade-Valença LP, Martins C

Functional anatomy of headache: hypothalamus. Headache Medicine. 2011;2(4):165-72

RESUMORESUMO

RESUMO

Há agora evidência suficiente indicando exercer o hipotálamo

um importante papel no mecanismo de deflagração de uma

crise de cefaleia. Dor e alterações concomitantes no padrão

secretório hormonal ocorrem durante uma crise de cefaleia

quando o hipotálamo é envolvido. Ativação do hipotálamo

foi mostrada na tomografia por emissão de pósitrons durante

crises espontâneas de migrânea ou de cefaleia em salvas.

Durante a última década, um número de pacientes com

cefaleia em salvas crônica refratária recebeu neuroestimulação

no hipotálamo posterior como forma de tratamento. O uso

clínico de estimulação cerebral profunda foi baseado na teoria

de haver uma disfunção no núcleo hipotalâmico posterior

como causa das crises de salvas. Neste artigo, os autores

estão revisando a anatomia funcional da região hipotalâmica

e sua vizinhança, utilizando cabeça cadavérica injetada com

silicone e imagens de ressonância magnética. Concluindo,

um melhor entendimento da anatomia funcional do hipo-

tálamo e sua vizinhança é imperativo para compreender a

patofisiologia de várias das cefaleias primárias, em particular

da migrânea e das cefaleias trigêmino-autonômicas. Estimu-

lação direta da região hipotalâmica posterior é agora o "estado

da arte" no tratamento da cefaleia em salvas crônica refratária.

O mecanismo exato e a região onde a estimulação atuaria

ainda são desconhecidos; estudos no campo da anatomia

funcional do hipotálamo são críticos para que haja progresso

neste novo e encantador setor da neurocirurgia funcional.

alavrasalavras

alavras

chave:chave:

chave: Anatomia; Hipotálamo; Cefaleia em

salvas; Migrânea; Ressonância magnética; Estimulação

cerebral profunda

166

Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

INTRODUCTION

There is now compelling evidence that the

hypothalamus exerts a major role in the mechanism of

headache triggering.

(1-11)

Pain and concomitant changes

in the hormonal secretory pattern occur during an attack

of headache when hypothalamic structures are involved.

(5)

For instance, the hypothalamus, especially in the posterior

region, is activated during attacks of trigeminal autonomic

headaches, such as cluster headache, paroxysmal

hemicrania and short-lasting unilateral neuralgiform

headache attacks with conjunctival injection and tearing

(SUNCT), while during migraine attacks the activation

occurs preponderantly in the brainstem (e.g., dorsal

pontine region), but hypothalamic activation also

occurs.

(1,2)

The hypothalamus and the adjacent brainstem form

a complex interconnected structure responsible for the

chronobiological features of some types of primary

headache, especially sleep-related attacks, a characteristic

feature of trigeminal autonomic headaches, hypnic

headache and migraine.

(12)

The hypothalamus, through hormonal and autonomic

regulation, controls a number of physiological functions,

such as blood pressure, fluid and electrolyte balance, body

temperature, and body weight, maintaining a fairly

constant value known as the "set point".

(13,14)

The hypothalamic nuclei constitute part of the

corticodiencephalic circuitry activating, controlling, and

integrating the peripheral autonomic mechanisms,

endocrine activity, and many somatic functions, e.g.,

regulation of water balance, body temperature, sleep,

food intake, and the development of secondary sexual

characteristics.

(7)

The hypothalamus is wired in the brainstem to the

periaqueductal gray substance, the locus coeruleus, and

the median raphe nuclei, all of which are involved in

autonomic, sleep, and in the descending control of pain

perception mechanisms. The hypothalamus also receives

input from different locations of the central nervous

system, obtaining information on the state of the body,

thereby initiating compensatory physiological changes.

(7)

These inputs come from: (1) nucleus of the solitary

tract, with information on blood pressure and gut

distension; (2) reticular formation, receiving information

on skin temperature; (3) retina and optic nerve, whose

fibers go directly to the suprachiasmatic nucleus and are

involved in the regulation of circadian rhythms; (4)

circumventricular organs, nuclei located along the

ventricles, which lack a blood-brain barrier, allowing them

to monitor substances in the blood (e.g., organum

vasculosum of the lamina terminalis, which is sensitive to

changes in osmolarity, and the area postrema, which is

sensitive to toxins in the blood and can induce vomiting);

and

(5)

the limbic and olfactory systems. Structures such as

the amygdala, the hippocampus, and the olfactory cortex,

all of which are connected with the hypothalamus, regulate

a broad range of psychological and physiological

functions, including anger, fear, reproduction, learning

and memory, drinking, eating, autonomic activity and

pain.

(7,13,14)

The hypothalamus is continually informed of the

physiological changes occurring in the organism, and

immediate adjustments take place to maintain homeostasis

by means of two major outputs: first, neural signals to the

autonomic nervous system; and second, endocrine signals

working through the hypothalamic-pituitary axis.

The lateral hypothalamus projects onto cells that

control the autonomic systems located in the medulla.

These include the parasympathetic vagal nuclei and a

group of cells that descend to the sympathetic system in

the spinal cord. Thus the physiological functions of heart

rate and force of contraction; constriction and dilation of

blood vessels; contraction and relaxation of smooth

muscles in various organs; visual accommodation and

pupil size; and secretions from exocrine and endocrine

glands (i.e., digestion, lacrimation, sweating) are all also

influenced by the hypothalamus.

(7)

The master coordinator of hormonal endocrine activity

in mammals is the hypothalamus. Large hypothalamic

neurons positioned around the third ventricle send their

axons directly to the neurohypophysis, where the nerve

terminals release oxytocin and vasopressin into the

bloodstream. Smaller neurons located all over the

hypothalamus send their axons to the median eminence

in the medial basal hypothalamus, where they discharge

releasing factors [corticotropin-releasing hormone (CRH),

gonadotropin-releasing hormone (GnRH), growth

hormone-releasing hormone (GHRH), thyrotropin-

releasing hormone (TRH)] and inhibiting factors

(dopamine, somatostatin) into the hypophyseal portal

capillary. This specialized system of vessels connects the

base of the hypothalamus with the anterior pituitary gland

in order to regulate the secretion of hormones such as

ACTH, TSH, LH, FSH, and GH. In contrast, inhibiting

factors, such as dopamine and somatostatin, cause a

strong inhibition of prolactin (PRL) and GH secretions,

respectively.

(7,13,14)

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 167

FUNCTIONAL ANATOMY OF HEADACHE: HYPOTHALAMUS

The hormonal effects vary widely, including stimulation

or inhibition of growth; regulation of the metabolism;

preparation for a new activity (e.g. fighting, fleeing, or

mating); preparation for a new phase of life (e.g. puberty,

caring for offspring, menopause); controlling the

reproductive cycle; induction or suppression of apoptosis;

activation or inhibition of the immune system, among

others.

(7)

FUNCTIONAL ANATOMY

The hypothalamus (from the Greek hypo, meaning

"below" and thalamus, meaning "bed") is located at the

base of the brain, in the diencephalon, in an

anteroventral position in relation to the thalamus and

above the sella turcica and pituitary. The dimensions of

the hypothalamus are 1.5 cm in height, 1.5 cm in the

antero-posterior length and 1.3 cm in width. Its weight

varies from 2.5 to 5 g, considering a human brain of

1,200-1,300 g.

(13,14)

It also forms the roof, lateral walls and floor of the

third ventricle. The anatomical limits of the hypothalamus

are: anteriorly, the rostral border of the optic chiasm and

lamina terminalis; caudally, the posterior border of

mamillary nuclei; and rostrally and posteriorly, the

thalamus and the hypothalamic sulcus. The lateral

boundaries are less clear, varying with the level studied,

including the optic tract, internal capsule, pes pedunculi,

globus pallidus, ansa lenticularis and the subthalamic

region.

(13,14)

Because the boundaries between these areas

are disputable, in anatomy, it has been conventioned to

use a coronal plane at the level of mammillary bodies to

separate the hypothalamus, anteriorly, from the

subthalamic region, just behind.

(15)

The hypothalamic region includes the tuber

cinereum, the infundibulum, the optic chiasm,

mammillary bodies and the neurohypophysis. There are

two major tracts in the hypothalamus: (1) the

mamillothalamic tract (bundle of Vicq d'Azyr), which

emerges from the medial and lateral mamillary nuclei,

passing dorsally, and terminates at the anterior thalamic

nuclei. At the beginning, it forms a well-defined bundle

Figure 1. The hypothalamus and its neighborhood. Dissection of a silicone-injected cadaveric head has been performed at George Colter

International Microsurgical Lab - University of Florida, Gainesville. A sagittal cut through the head has been made and dissection with

preservation of the retrocomissural fornix has been undertaken. The path of the left column of fornix can be followed down to the mammillary

body. From the mammillary body, a fiber tract passes up along the lateral wall of the ventricle to the anterior nuclei of thalamus: the mammilothalamic

tract - involved in the circuitry of recent memory acquisition. The septum has been removed to expose the right lateral ventricle cavity. The

topographic limits of the hypothalamus are arbitrary. Anatomically, the hypothalamus is defined as the area including the lateral walls of the third

ventricle in front of a coronal plane passing posterior to the mammillary bodies. The anterior limit of this area is the anterior limit of the third

ventricle and is formed by the lamina terminalis. The hypothalamic sulcus can be seen as a groove on the lateral wall of the third ventricle,

between the foramen of Monro and the cerebral aqueduct. The hypothalamic sulcus is used as a landmark to divide the diencephalon. Posterior

to the sulcus is the pars dorsalis (dorsal thalamus and epithalamus), while anterior to the hypothalamic sulcus is the pars ventralis (hypothalamus

and subthalamus). Above the hypothalamic sulcus the walls of the third ventricle are united in 2/3 of the human brains by the interthalamic

adhesion, a portion of gray matter that signals the location of the medial nuclei of thalamus.

A.: Artery, Ant.: Anterior, I. A.: Interthalamic Adhesion, C.: Corpus, Car.: Carotid, Cav.: Cavernous, Cer.: Cerebral, Chor.: Choroid, Com.: Commissure,,

C.N.: Cranial Nerve, For.: Foramen, Int.: Internal, Lam.: Lamina, Lat.: Lateral, Pit.: Pituitary, Segm.: Segment, V.: Vein, Venous, Vent.: Ventricle.

168

Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

Figure 2. The sella turcica, infundibular stalk and optic quiasm.

Dissection of a silicone-injected cadaveric head has been performed

at George Colter International Microsurgical Lab - University of Florida,

Gainesville. A – Superior panel, anterior view of the optic quiasm and

infundibular stalk. B – Inferior panel, superior view of the sella turcica,

optic nerve, infundibular stalk, and neighborhood. This region is very

sensitive to stimuli that are painful, such as unruptured cerebral

aneurysms, pituitary adenomas, etc.

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

known as the principal mamillary bundle (fasciculus

mamillaris princeps). This bundle passes dorsally for a

short distance before dividing into two components: the

mamillothalamic tract (the larger) and the

mamillotegmental tract (the smaller); and (2) the

postcommissural fornix. The postcommissural fornix

extends from the fornical column, continues behind the

anterior commissure to reach the mamillary body. The

fornix group fibers connect the hippocampus to the

mammillary body. It is divided into fimbriae, crura,

commissure, body and columns. The columns, at the level

of the anterior commissure, divide into pre- and

postcommisural fibers. The former projects fibers to the

septal, lateral preoptic, diagonal and anterior

hypothalamic nuclei.

(13,14)

The Figures 1 and 2 show the

anatomy of the hypothalamic region and its

neighborhood, using silicone-injected cadaveric head.

Using the MRI scan in a sagittal view we can delineate

the hypothalamus using "imaginary lines" described by

Saleem et al.

(16)

The anterior boundary of the

hypothalamus, a "line" that extends from the anterior

commissure to the optic chiasm, corresponds to the lamina

terminalis. The posterior boundary, would extend from

the mamillary bodies to the posterior commissure (it is

imprecise because the hypothalamus blends into the

mesencephalic tegmentum) (Figures 3 and 4).

Superiorly the hypothalamic sulcus separates the

hypothalamus from the thalamus. The hypothalamic sulcus

extends from the interventricular foramen to the cranial

opening of the aqueduct. This sulcus is the remnant in the

adult of the sulcus limitans of the early development of

the neural tube. The sulcus limitans divides the neural tube

into a ventral lamina or basal plate – which will eventually

originate the motor nuclei of spinal cord and brainstem –

and a dorsal lamina or alar plate, that will differentiate

into input receiving structures.

(15)

Another practical way to

limit the hypothalamus from the thalamus in radiological

images is to draw a line between the anterior commissure

and the posterior commissure.

(16)

Inferiorly, the hypothalamus presents the tuber cinereum.

This is a tubular structure composed of gray matter and lies

between the two mamillary bodies (posteriorly) and the

optic chiasm (anteriorly). The lateral boundary of the

hypothalamus is, in its superior part, the medial thalamus.

The median eminence or infundibulum is a small

prominence in the tuber cinereum, formed by third ventricle

floor that continues downward to form the infundibular

stalk. The infundibular stalk is connected to the posterior

lobe of the pituitary gland (Figures 3 and 4).

(13,14,16)

Figure 2 A. Superior panel.

Figure 2 B. Inferior panel.

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 169

FUNCTIONAL ANATOMY OF HEADACHE: HYPOTHALAMUS

Figure 3. A – MRI scan (T1-weighted sagittal cut, 54-year-old woman)

showing the hypothalamic region (dashed line), based on Saleem

and colleagues.

B – MRI scan showing the different areas visualized

in the hypothalamic region. AC, anterior commissure; LT, lamina

terminalis; OQ, optic quiasm; IS, infundibular stalk; PG, pituitary gland;

TC, tuber cinereum; MB, mamillary body; HS, hypothalamic sulcus;

red line, postcommissural fornix; blue line, mamillothalamic tract.

The high-signal-intensity area in the posterior part of the sella turcica

is the posterior pituitary gland.

Cell proliferation in the posterior lobe and sprouting

of hypothalamic nerve fibers in humans result in closure

of infundibular recess – the path between the third ventricle

and the posterior lobe of the gland – kept naturally

opened in other mammals (e.g. cat). In conditions of high

ventricular pressure (e.g. hydrocephalus), the infundibular

recess can become patent. In this situation, the reddish

rue of the gland can be seen from inside the ventricle and

might be a cause of disorientation during endoscopic

ventriculostomies.

(17,18)

Several nuclei and fiber tracts are arranged

symmetrically in the hypothalami, into the floor and lower

medial surface of the third ventricle. To better identify the

Figure 4. MRI scan (T1-weighted coronal plane, 17-year-old girl four

years after surgical removal of a craniopharyngioma) showing the

different positions of the hypothalamic nuclei, based on Saleem and

colleagues.

AC, anterior commissure; LPO, lateral preoptic nucleus;

SC, suprachiasmatic nucleus; SO, supraoptic nucleus; MPO, medial

preoptic nucleus.

intrahypothalamic structures two imaginary axes are

used, the medial-lateral and the rostral-caudal axes. The

lateral and medial areas of the hypothalamus are

separated by the medial-lateral axis. The rostral-caudal

axis subdivides the hypothalamus into three regions:

anterior, tuberal, and posterior.

(16)

In the proximity of the hypothalamus there are the

optic nerves that ascend from the skull base toward the

chiasm at an angle of approximately 45 degrees with

the nasotuberculum line; the intracranial segment of the

optic nerve is 17 ± 2.4 mm in length, and the optic chiasm

sits about 10.7 ± 2.4 mm above the dorsum of the sella

turcica.

(19)

ROLE OF THE HYPOTHALAMUS ON THE

HEADACHE PATHOPHYSIOLOGY

rigeminal autonomic headachesrigeminal autonomic headaches

rigeminal autonomic headaches

The clinical manifestation of hemicrania continua

overlaps with that of other trigeminal autonomic headaches

and migraine, and activations observed in the hypothalamus

and dorsal rostral pons, respectively, appear to play an

important pathophysiological role.

(1,2,20-23)

Functional brain

imaging has demonstrated significant activation of the

ipsilateral dorsal rostral pons in association with the

headache attacks of hemicrania continua.

(20,21)

There was

also a significant activation of the contralateral posterior

hypothalamus and ipsilateral ventrolateral midbrain, which

extended over the red nucleus, the substantia nigra and

the pontomedullary junction. The distinction between two

170

Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

headache subtypes is that the ipsilateral hypothalamus

mediates cluster headache, while the contralateral

hypothalamus mediates hemicrania continua.

Proton MR spectroscopy of subjects with cluster

headache showed a reduction in the NAA marker of

neuronal integrity.

(10,11)

These results were confirmed by

Wang et al.,

(11)

who also found a decrease in the Cho/Cr

metabolite ratio, both during and between episodes. This

suggests that both neuronal dysfunction and changes in

the membrane lipids occur in the hypothalamus in cluster

headache patients.

During the last decade more than 50 patients with

refractory chronic cluster headache received neuro-

stimulation of the posteroinferior hypothalamus as a form

of treatment.

(24)

Clinical use of deep brain stimulation (DBS)

was based on the theory of posterior hypothalamic nucleus

dysfunction as the cause of cluster headache

attacks.

(1,2,10,11,20-22)

In a recent publication Seijo and colleagues

(24)

implanted five patients with a tetrapolar electrode (always

ipsilateral to the pain side) into the hypothalamus, using

the stereotaxic coordinates of 4 mm lateral to the third

ventricle wall, 2 mm behind the midintercommissural

point and 5 mm under the intercommissural line. An

improvement of the headache was obtained in all

patients. The authors postulated that the stimulated brain

area included a lateral hypothalamic area (LHA) and

the fasciculi mammillotegmentalis (FMTG), mammillo-

thalamicus (FMTH) and medialis telencephali (FMTL) or

medial forebrain bundle.

(24)

As a result of stimulation (target of a brain volume of

approximately 3 mm in radius) persistent myosis and

euphoria/well-being feeling were observed in 3 subjects.

Occasional dizziness (n=3), blurring vision/diplopia

(n=2), concentration difficulties (n=1), cervical dystonia

(n=1), generalized headache (n=1) and increase in

appetite (n=1) were symptoms transiently induced.

(24)

The "calming effect" was observed in three subjects.

(24)

In this regard, Sano and coworkers

(25)

reported their

experience with hypothalamic stimulation and lesion in

order to treat 51 patients with aggressive behavior. An

increase in blood pressure, tachycardia, and maximal

pupillary dilatation were provoked after stimulation in the

posteromedial hypothalamus (more than 1 mm and less

than 5 mm lateral to the lateral wall of the third ventricle),

a triangular area (ergotropic triangle) formed by the

midpoint of the intercommissural line, the rostral end of

the aqueduct, and the anterior border of the mammillary

body. Sano et al.

(25)

reported that sympathetic or

parasympathetic responses would depend on the region

of hypothalamic stimulation: an internal area of 0-1 mm

that has parasympathetic responses; a medial area of

1-5 mm that has sympathetic responses; a lateral area

of >5 mm, parasympathetic responses; and 3 mm under

the midintercommissural point and 5 mm from the lateral

wall of the third ventricle, parasympathetic responses.

Electrical stimulation of this ergotropic triangle

resulted in desynchronization of the electro-

encephalogram (EEG) with hippocampal theta waves,

or diffuse irregular delta waves of high voltage,

demonstrating that the hypothalamus may regulate the

cerebral cortex as well.

(25)

Interestingly, in the series of patients of Seijo and

colleagues

(24)

two typical cluster headache attacks were

triggered on the contralateral side after the performance

of the procedure in a 48-year-old woman. This is an

unquestionable indication that abnormalities in the

hypothalamus can induce cluster headache. Another

interesting fact was that all individuals were painfree up

to 2 weeks after the implantation of the DBS in the absence

of electrical stimulation. Probably related to a local

microlesion or a neuronal shock.

(24)

In another series, Fontaine and colleagues

(26)

studied

10 patients with refractory chronic cluster headache who

were implanted with DBS electrodes located in the

posterior and ventral wall of the third ventricle (theoretical

target 2 mm lateral to the midline, 3 mm posterior and

5 mm below the mid-commissural point). All of electrodes

were posterior to the mamillary body and the mamillo-

thalamic tract, at the diencephalo-mesencephalic junction

tract (retro-mamillary posterior hypothalamus?). In the 5

responder patients the electrodes were in the proximity

of the following structures: grey mesencephalic substance

(5/5), red nucleus (4/5, superficial; 3/5 core), fascicle

retroflexus (4/5), fascicle longitudinal dorsal (3/5), nucleus

of ansa lenticularis (3/5), fascicle longitudinal medial

(1/5) and the thalamus superficial medial (1/5), suggesting

a participation of some of these anatomical structures.

They admitted two possibilities to explain the pain relief

effect: a direct stimulation on a local cluster headache

generator, or through activation of an anti-nocioceptive

systems. Since there is a latent period after the onset of

DBS, neuroplastic mechanisms seem to play a role.

MigraineMigraine

Migraine

A disruption in the normal function of the hypothalamus

is implicated in the genesis of some prodromal symptoms

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 171

and signs of migraine, such as mood changes, drowsiness,

thirst, craving for food, and yawning.

(7)

Some of the migraine prodromal symptoms are

controlled by the limbic system.

(27)

In a study involving 97

patients, premonitory symptoms predicted migraine attacks

in 72%.

(28)

The most common premonitory symptoms were

feeling tired and weary, observed in 72% of attacks with

warning features, followed by difficulty in concentrating

(51%) and a stiff neck (50%). These signs and symptoms

may occur over several hours, or for even as long as 2

days, before the onset of pain.

During spontaneous migraine attacks activation of

the hypothalamus is shown by positron emission

tomography scanning.

(3)

During the headache Denuelle

and coworkers

(3)

reported significant activations in the

hypothalamus, midbrain and pons that persists after

headache relief by sumatriptan treatment. A theory

explaining the relationship between the hypothalamus and

migraine attacks is that the joint effect of several migraine

triggers may cause temporary hypothalamic dysfunction

and this will result in a migraine attack.

(4)

Furthermore, some of the hypothalamic peptides

appear to be involved in the physiopathology of

migraine.

(7)

Acute migraine headache attack can be

relieved by intravenous oxytocin administration.

(29)

addition, a lactational headache was attributed to

oxytocin surges in association with the milk-ejection

reflex.

(30)

A case of a woman suffering from brief attacks

of headache that happened on every occasion of

nursing was reported.

(30)

On the other hand, another

case was described when the apparent headache trigger

was breast overfulness, and not the oxytocin surge.

(31)

In this case the headaches were alleviated by putting

the baby to the breast by the activation of the milk-

ejection reflex.

(31)

Another indication that the hypothalamus is involved

during a migraine attack is the report of 6 subjects with

a history of increased urinary frequency during migraine

episodes.

(32)

An evident diuresis and natriuresis occurred

within 12 hours of the onset of the headache, associated

with a significant decrease in urinary arginine

vasopressin.

Intracranial lesions in the hypothalamic region and

its neighborhood (e.g. cerebral aneurysm and pituitary

adenomas)

(33,34)

may trigger headache with similar

features to those encountered in primary headaches.

Figure 5 shows an MRI scan of a man with a recent

history of headache caused by a hypothalamic cystic

tumor.

CONCLUSION

In conclusion, a more thorough understanding of the

functional anatomy of the hypothalamus and its

neighborhood is imperative for understanding the

physiopathology of several of the primary headaches,

particularly migraine and the trigemino-autonomic

headaches. Direct stimulation of the posterior

hypothalamic region, using DBS devices, is now the "state

of the art" form of treatment indicated for refractory chronic

cluster headache. The exact mechanism and the actual

region where the DBS may act are still unknown, and

studies on the functional anatomy of the hypothalamus

are crucial to the progress in this marvelous field of

functional neurosurgery.

REFERENCES

1. Iacovelli E, Coppola G, Tinelli E, Pierelli F, Bianco F. Neuroimaging

in cluster headache and other trigeminal autonomic cephalalgias.

J Headache Pain. 2012;13(1):11-20.

2. Friberg L, Sandrini G, Perrotta A. Neuroimaging and clinical

neurophysiology in cluster headache and trigeminal autonomic

cephalalgias. Handb Clin Neurol. 2010;97:413-20.

3. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Hypothalamic

activation in spontaneous migraine attacks. Headache.

2007;47(10):1418-26.

4. Alstadhaug KB. Migraine and the hypothalamus. Cephalalgia.

2009;29(8):809-17.

5. Peres MF, Sanchez del Rio M, Seabra ML, Tufik S, Abucham J,

Cipolla-Neto J, et al. Hypothalamic involvement in chronic

migraine. J Neurol Neurosurg Psychiatry. 2001;71(6):747-51.

FUNCTIONAL ANATOMY OF HEADACHE: HYPOTHALAMUS

Figure 5. The MRI scan (T1-weighted sagittal cut) of a 44-year-old

man with a 3-month history of headache, visual acuity decline,

hypothyroidsm and sexual impotence. The arrow shows a cystic

hypothalamic tumor.

172

Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

6. Benjamin L, Levy MJ, Lasalandra MP, Knight YE, Akerman S,

Classey JD, et al. Hypothalamic activation after stimulation of

the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis.

2004;16(3):500-5.

7. Prieto Peres MF, Valença MM. Headache endocrinological

aspects. Handb Clin Neurol. 2010;97:717-37.

8. Peres MF, Valença MM, Gonçalves AL. Misdiagnosis of hemicrania

continua. Expert Rev Neurother. 2009;9(9):1371-8.

9. Valença MM, Medeiros FL, Martins HA, Massaud RM, Peres MF.

Neuroendocrine dysfunction in fibromyalgia and migraine. Curr

Pain Headache Rep. 2009;13(5):358-64.

10.Lodi R, Pierangeli G, Tonon C, Cevoli S, Testa C, Bivona G, et

al. Study of hypothalamic metabolism in cluster headache by

proton MR spectroscopy. Neurology. 2006;66(8):1264-6.

11. Wang SJ, Lirng JF, Fuh JL, Chen JJ. Reduction in hypothalamic

1H-MRS metabolite ratios in patients with cluster headache. J

Neurol Neurosurg Psychiatry .2006;77(5):622-5.

12. Montagna P (2006). Hypothalamus, sleep and headaches.

Neurol Sci. 2006;27 (Suppl 2):S138-43.

13. Valenca MM, Martins MC, Antunes-Rodrigues J. Anatomia e

embriologia do hipotálamo e da glândula pituitária. In: José

Antunes-Rodrigues, Ayrton Moreira, Margarete Castro, Lucy

Elias, Eds. Neuroendocrinologia Básica e Aplicada. Rio de

Janeiro, 2004, p. 41-51

14. Valença MM, Ellias LLK, Elias PCL, et al. Anatomia e fisiologia

do hipotálamo e da glândula pituitária. In: Arthur Cuckier, Ed.

Neuroendocrinologia Clínica e Cirúrgica. 2002, p. 21-71.

15. Gray's Anatomy. The Anatomical Basis of Clinical Practice. 31

Ed, 2005.

16. Saleem SN, Said AH, Lee DH. Lesions of the hypothalamus: MR

imaging diagnostic features. Radiographics. 2007;27(4):1087-

108.

17. Cabanes J. Asymptomatic persistence of infundibularis recessus.

Case report. J Neurosurg. 1978;49(5):769-72.

18. Kuhne D, Schwartz RB. Persisting intrapituitary recessus

infundibuli. Neuroradiology. 1975;10(3):177-8.

19. Hayreh SS. Anatomy and physiology of the optic nerve head.

Trans Am Acad Ophthalmol Otolaryngol. 1974;78(2): OP240-

20. Matharu MS, Goadsby PJ. Functional brain imaging in hemicrania

continua: implications for nosology and pathophysiology. Curr

Pain Headache Rep. 2005;99(4): 281-8.

21. Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RS,

Goadsby PJ. Posterior hypothalamic and brainstem activation in

hemicranias continua. Headache. 2004;44(8):747-61.

22. May A, Bahra A, Büchel C, Frackowiak RS, Goadsby PJ.

Hypothalamic activation in cluster headache attacks. Lancet.

1998;352(9124):275-8. Comment in: Lancet.1998;352

(9124):253-5.

23. Valença MM, Andrade-Valença LP, da Silva WF, Dodick DW.

Hemicrania continua secondary to an ipsilateral brainstem lesion.

Headache. 2007;47(3):438-41.

24. Seijo F, Saiz A, Lozano B, Santamarta E, Alvarez-Vega M, Seijo E,

Fernández de León R, et al. Neuromodulation of the

posterolateral hypothalamus for the treatment of chronic

refractory cluster headache: Experience in five patients with a

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

Correspondence

Marcelo M. VMarcelo M. V

Marcelo M. V

alença, MDalença, MD

alença, MD

Neurology and Neurosurgery Unit,

Department of Neuropsychiatry

Universisdade Federal de Pernambuco

50670-420 – Recife, PE, Brazil

mmvalenca@yahoo.com.br

Received: 11/23/2011

Accepted: 12/20/2011

modified anatomical target. Cephalalgia. 2011;31(16):

1634-41.

25. Sano K, Mayanagi Y, Sekino H, Ogashiwa M, Ishijima B. Results

of timulation and destruction of the posterior hypothalamus in

man. J Neurosurg. 1970;33(6):689-707.

26. Fontaine D, Lanteri-Minet M, Ouchchane L, Lazorthes Y, Mertens

P, Blond S, et al. Anatomical location of effective deep brain

stimulation electrodes in chronic cluster headache. Brain.

2010;133(Pt 4):1214-23.

27. Raffaelli E Jr, Menon AD. Migraine and the limbic system.

Headache. 1975;15(1): 69-78.

28. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF,

Olesen J, et al. Premonitory symptoms in migraine: an electronic

diary study. Neurology. 2003. 60(6): 935-40.

29. Phillips WJ, Ostrovsky O, Galli RL, Dickey S. Relief of acute

migraine headache with intravenous oxytocin: report of two

cases. J Pain Palliat Care Pharmacother. 2006;20(3):25-8.

30. Askmark H, Lundberg PO. Lactation headache - a new form of

headache? Cephalalgia 1989; 9(2):119-22.

31. Thorley V. Lactational headache: a lactation consultant's diary. J

Hum Lact. 1997;13(1):51-3.

32. Poole CJ, Lightman SL. Inhibition of vasopressin secretion

during migraine. J Neurol Neurosurg Psychiatry. 1988;51(11):

1441-4.

33. Valença MM, Andrade-Valença LP, Martins C, de Fátima Vasco

Aragão M, Batista LL, Peres MF, et al. Cluster headache and

intracranial aneurysm. J Headache Pain. 2007;8(5):277-82.

34. Andrade-Valenca LP, Dodick D, Valenca MM. Alarm bell headache:

a sinister secondary headache. Cephalalgia. 2007; 27:715.