CRANIO-FACIAL PAIN AND FUNCTIONAL NEUROIMAGING

From neuroimaging to patients’ bench: what we have learntfrom trigemino-autonomic pain syndromes

Massimo Leone • Alberto Proietti Cecchini •

Angelo Franzini • Giuseppe Messina •

Gennaro Bussone

� Springer-Verlag 2012

Abstract Trigeminal autonomic cephalalgias (TACs) are

primary headaches including cluster headache, paroxysmal

hemicrania, and short-lasting unilateral neuralgiform

headache attacks with conjunctival injection and tearing

(SUNCT). A number of neuroimaging studies have been

conducted in last decade showing involvement of brain

areas included in the pain matrix. Apart from pain matrix

involvement, other neuroimaging findings data deserve

special attention. The hypothalamic activation reported in

the course of TAC attacks coupled with the efficacy of

hypothalamic neurostimulation to treat drug-resistant TAC

forms clearly indicate the posterior hypothalamus as a

crucial area in TAC pathophysiology. In animal models

this brain area has been shown to modulate craniofacial

pain; moreover, hypothalamic activation occurs in other

pain conditions, suggesting that posterior hypothalamus

has a more complex role in TAC pathophysiology rather

than simply being considered as a trigger. In contrast,

hypothalamic activation may serve as a crucial area in

terminating rather than triggering attacks. It also could lead

to a central condition facilitating initiation of TAC attacks.

Keywords Neuroimaging � Trigeminal autonomic

cephalalgias � Pathophysiology � Trigeminal system �Hypothalamus

Introduction

The trigeminal autonomic cephalalgias (TACs) are primary

headaches characterized by short-lasting unilateral head

pain attacks associated with ipsilateral craniofacial auto-

nomic manifestations including cluster headache (CH),

paroxysmal hemicrania (PH), and short-lasting unilateral

neuralgiform headache attacks with conjunctival injection

and tearing (SUNCT) [1]. These three TAC forms are

mainly distinguished by duration of attacks.

Based on the belief that the pain and the autonomic

craniofacial phenomena arise, respectively, as the result of

simultaneous activation in the brainstem of the trigeminal

nerve and craniofacial parasympathetic nerve fibres (the

so-called trigeminofacial reflex), Goadsby and Lipton [2]

proposed the term of TAC for these forms.

Neuroimaging findings [3] and the introduction of

neurostimulation for the treatment of drug-resistant TAC

forms [4] has greatly improved our understanding of TACs

[5]. The clockwork regularity of attacks and seasonal

recurrence of cluster periods of CH [6], together with

earlier neuroendocrinological studies [7] supported the

hypothesis of hypothalamic involvement in this form. So

far, neuroimaging studies showed activation of the pos-

terior hypothalamus during CH attacks [8] and increased

neuronal density in the same brain area has been shown in

CH [9]. Activation of the posterior hypothalamus during

CH attacks could trigger activation of the trigeminofacial

reflex. In the last years neuroimaging studies on TACs as

well as data from long-term hypothalamic stimulation have

provided hints to a better understanding of the patho-

physiology of these primary headache forms. The aim of

this paper is to re-examine the central hypothalamic

hypothesis in the light of accumulated hypothalamic

stimulation and neuroimaging data.

M. Leone (&) � A. Proietti Cecchini � G. Bussone

Neuromodulation Unit and Neurological Department,

Headache Centre, Fondazione Istituto Neurologico

Carlo Besta, via Celoria 11, 20133 Milan, Italy

e-mail: leone@istituto-besta.it

A. Franzini � G. Messina

Neurosurgery Department, Fondazione Istituto Neurologico

Carlo Besta, via Celoria 11, 20133 Milan, Italy

123

Neurol Sci (2012) 33 (Suppl 1):S99–S102

DOI 10.1007/s10072-012-1051-8

Neuroimaging findings in cluster headache and TACs

In 1998, ipsilateral hypothalamic activation during acute CH

headache was demonstrated [8]. The anterior cingulate cor-

tex, the contralateral posterior thalamus, the ipsilateral basal

ganglia, the bilateral insulae and the cerebellar hemispheres

are also activated [8]. An increased cellular density in the

inferior posterior hypothalamus ipsilateral to the pain has

been shown [9] and proton magnetic resonance spectroscopy

studies have shown decreased N-acetylaspartate/creatine–

phosphocreatine and choline/creatine–phosphocreatine

ratios in the hypothalamus of CH patients compared to

migraine patients and healthy subjects [10, 11]. A hypome-

tabolism in the perigenual anterior cingulate cortex, pre-

frontal cortex and orbitofrontal cortex was found in both

cluster period and remission [12]. Again, CH patients showed

a disease duration-dependent decrease of opioid receptors in

the hypothalamus and anterior cingulate cortex and in the

pineal gland as well [13]. Taken together, these data indicate a

deranged top-down modulation of anti-nociceptive pathway

in CH. This could promote a permissive brain condition

leading to the initiation of CH attacks (or of cluster periods).

On the contrary, one cannot exclude that reduced opioid

receptor binding is just the consequence of the pain.

In PH, posterior hypothalamus activation was observed

contralaterally to the pain associated with activation of the

contralateral ventral midbrain, red nucleus and substantia

nigra [14].

In SUNCT hypothalamic activation was firstly reported

ipsilateral to the pain [15], but in five patients it was bilateral

and contralateral in two patients but no hypothalamic acti-

vation was observed in a patient with SUNCT due to a

brainstem lesion [16]. Activation of the ipsilateral hypo-

thalamus during attacks was reported in a patient whose

headache attacks varied in duration, and could be diagnosed

as trigeminal neuralgia, SUNCT, PH, or CH [17].

It is now clear that hypothalamic activation is not spe-

cific to CH and TACs: it has been reported in hemicrania

continua (contralateral to the pain) [18], in trigeminal

neuralgia (ipsilateral) [19], and in migraine (bilateral) [20].

Hypothalamic activation has also been reported in pain

conditions others than headache [21, 22].

It is helpful to remind that the hypothalamic brain areas

referred to in these various studies are not always identical

because stereotactic coordinates differ slightly.

Putative mechanism of action of hypothalamic

stimulation

After the observation that the posterior hypothalamus is

activated during a CH attack, a novel approach to CH

treatment was proposed based on the theory that high-

frequency stimulation would inhibit hypothalamic hyper-

activity [23]. Hypothalamic stimulation was successfully

started in 2000 to treat a chronic drug-resistant CH patient

[23]. So far, over 60 chronic drug-resistant CH patients

received hypothalamic stimulation at various centres, with

relevant clinical improvement in about 60 % of cases

showing complete control of attacks in about 30 % [24].

Stimulation must continue for weeks or months before

benefit is experienced [25–32], and acute stimulation is

unable to improve ongoing CH attacks [33]. Continuous

hypothalamic stimulation is also successful in SUNCT

[34–36] and in PH [37].

The mode of action of hypothalamic stimulation seems

rather complex and not the result of a mere inhibition of

hypothalamic neurons, as initially supposed. This is

because of inefficacy of acute stimulation and latency of

long-term stimulation necessary to improve the condition.

The increased cold pain threshold at the site of the first

trigeminal branch ipsilateral to the stimulated side suggests

that hypothalamic stimulation could exert its effect by

modulating the anti-nociceptive system [38].

Another putative mechanism of action of hypothalamic

stimulation is a modulation on pain matrix brain areas. In

fact, hypothalamic stimulation increases blood flow in

brain areas involved in the pain matrix, thalamus,

somatosensory cortex, precuneus, and anterior cingulate

cortex while deactivation occurs in the middle temporal

gyrus, posterior cingulate cortex, and insula [39]. Hypo-

thalamic stimulation seems to have the potential to restore

a deficient top-down modulation.

The past idea that the hypothalamus is the generator of

CH was attractive, but the recent findings and experience

with hypothalamic stimulation, suggest caution with this

interpretation [4]. Hypothalamic stimulation does not

trigger CH pain attacks nor block an ongoing attack: these

findings do not support the hypothesis that the hypothala-

mus is the trigger site in CH. It is possible that the hypo-

thalamus plays a major role in terminating rather than

triggering attacks in CH and TACs [4, 39]. Accordingly,

the hypothalamus could regulate the duration of a TAC

attack giving rise to the different TAC forms mainly dis-

tinguished by attack duration [4, 39].

Extensive studies on the autonomic nervous system in

hypothalamic stimulated patients suggest that it has little or

no role in the mechanism of action of hypothalamic stim-

ulation [40].

Integrating central and peripheral nervous system:

the hypothalamus and the trigeminal nerve

Anatomo-physiological studies in rats have demonstrated a

direct connection between the posterior hypothalamus and

S100 Neurol Sci (2012) 33 (Suppl 1):S99–S102

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the trigeminal nucleus caudalis (TNC) through the trige-

mino-hypothalamic tract (THT) [41]. Peripheral informa-

tion from trigeminally innervated areas reaches the

hypothalamus via the THT. Activity of TNC neurons is

modulated by the posterior hypothalamus as shown by

changes in neuronal TNC activity by the injection in the

posterior hypothalamus of orexins A and B, and the

GABAA receptor antagonist bicuculline. Orexins A and B

localize to neurons in and around the posterolateral hypo-

thalamus [42]. These studies point to the role that the

posterior hypothalamus has as physiological modulator of

TNC neurons [43]. A derangement in the hypothalamic

orexinergic system has been invoked in CH pathophysiol-

ogy and genetic studies give support to this idea [44], even

if a large multinational genetic study does not confirm this

[45].

In the 1970s Sano et al. [46] successfully treated

intractable facial pain with posteromedial hypothalamoto-

my showing that the posterior hypothalamus is involved in

pain control in humans. In recent years, a functional con-

nection between the hypothalamus and the trigeminal

system in humans has been demonstrated for the first time:

in a H215O PET study hypothalamic stimulation was shown

to induce activation in both the ipsilateral posterior inferior

hypothalamic gray at the site of the stimulator tip and the

ipsilateral trigeminal system [39]. The activation of the

trigeminal system was never accompanied by headache

attacks or autonomic craniofacial manifestations [39]. This

observation supports the notion that the trigeminal system

activation is not sufficient to explain CH attacks. This is

also in agreement with the well-known experience about

the persistence of CH attacks notwithstanding trigeminal

nerve lesioning [25, 47].

Conflict of interest We declare that we have no conflict of interest.

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