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.