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C U R R E N T R E V I E W

Hypothalamic deep-brainstimulation: target and potentialmechanism for the treatment ofcluster headacheA MayDepartment of Systems Neuroscience, University of Hamburg, Hamburg, Germany

Recently, functional imaging data have underscored thecrucial role of the hypothalamus in trigemino-autonomicheadaches, a group of severe primary headaches. Thisprompted the application of hypothalamic deep-brainstimulation (DBS), with the intention to preventingcluster headache (CH) attacks in selected severetherapy-refractory cases. To date, a total of 50 operatedintractable CH patients, one patient with short-lastingunilateral neuralgiform headache attacks with conjunctivalinjection and tearing and three with atypical facial pain,have been reported. However, it is not apparent why thespontaneous bursts of activation in the inferior posteriorhypothalamus result in excruciating head pain, whereascontinuous electrical stimulation of the identical area isable to prevent these attacks. Recently, this issue has beenaddressed by examining 10 operated chronic CH patients,using H2

15O-positron emission tomography and alternatelyswitching the hypothalamic stimulator on and off. Thestimulation-induced activation in the ipsilateral posteriorinferior hypothalamic grey (the site of the stimulator tip)as well as activation and de-activation in several cerebralstructures belonging to neuronal circuits usually activatedin pain transmission. These data argue against anunspecific antinociceptive effect or pure inhibition ofhypothalamic activity as the mode of action ofhypothalamic DBS and suggest functional modulation ofthe pain-processing network.

Key words: deep-brain stimulation, DBS, hypothalamus, clusterheadache, TAC, PET, pain

INTRODUCTIONA comprehensive theory of cluster headache (CH) must explainthe unilateral headache, as well as the sympathetic impairmentand parasympathetic activation. In view of the striking relapsing–remitting pattern (1), seasonal variation (1) and the clockwiseregularity of the attacks (2), the concept of a central origin forCH has emerged. Consequently, the posterior hypothalamus was

identified early on as a crucial element in the pathogenesis of CH(3, 4). Neuroimaging of primary headache syndromes, such asCH and other trigeminal autonomic cephalalgias, has begun toprovide a better understanding of the neuroanatomical andphysiological basis of these conditions (5). Functional imagingwith positron emission tomography (PET) has shed light on thegenesis of several of the trigemino-autonomic syndromes,documenting activation in the hypothalamic grey in CH (6, 7),short-lasting unilateral neuralgiform headache attacks with con-junctival injection and tearing (SUNCT) (8, 9), paroxysmalhemicrania (10) and hemicrania continua (11). This area is notinvolved simply as a response to first division nociceptive painimpulses, but is inherent to each syndrome, probably in somepermissive or dysfunctional role (12, 13). Furthermore, a signifi-cant structural difference in grey matter density of the hypothala-mus has been found in patients with CH compared with healthyvolunteers (14). The co-localization of morphometric and func-tional changes demonstrates the precise anatomical location of aprobable central nervous system (CNS) lesion in CH. Given thatthis area is involved in circadian rhythms, sleep–wake cycles (15)and control of the autonomic system (16), these data suggestinvolvement of this hypothalamic area as a primum movens in theacute cluster attack. These findings prompted the use of deep-brain stimulation (DBS) in the posterior hypothalamic greymatter in a patient with intractable CH and led to complete relieffrom attacks (17). Based on these observations, DBS of theposterior hypothalamus was introduced with impressive clinicalresults in a refractory group of patients suffering from chronic,medically intractable chronic CH.

TARGETLittle is known about the circuits and mechanisms underlyingthe analgesic effect of DBS; however, it probably involves activa-tion of thalamo-cortical pathways and changes in cortical activity(18). The uniqueness of the DBS approach is that it allows in vivoinvestigation of the functional role of the underlying neuronalcircuits by switching the hypothalamic stimulator on and off. Itis unclear whether DBS causes:

1. Local blockade of the hypothalamic trigger activity2. A direct antinociceptive effect by activation of the periaque-

ductal grey (PAG) and/or rostral ventromedial medulla(RVM) or

3. Modulation of neuronal pain processing pathways.

Address correspondence to Assistant Professor Arne May, MD, Department of SystemsNeuroscience, Universitäts-Krankenhaus Eppendorf (UKE), Martinistreet 52, D-20246Hamburg, Germany. Tel. + 49 0404 2803 9189, fax + 49 0404 2803 9955,e-mail a.may@uke.uni-hamburg.de

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In order to unravel the brain circuitry mediating stimulation-induced effects, we applied PET, a relatively non-invasiveimaging technique that is sensitive to changes in regional cerebralblood flow, as an indirect measure of neuronal activity in humans(19, 20). Using a block design and alternately switching thehypothalamic stimulator on and off, each patient underwent 12consecutive H2

15O-water PET scans during two conditions: (i)baseline and (ii) during DBS. None of the patients suffered fromattacks during the time of the scanning. We therefore looked forchanges in brain activation patterns over time due to artificialstimulation of brain structures, but were not interested in CH orheadache attacks specifically. Functional imaging revealedstimulator-induced activations (ON > OFF) in the ipsilateralposterior inferior hypothalamic grey (the site of the stimulatortip), the ipsilateral thalamus, somatosensory cortex and praecu-neus, the anterior cingulate cortex and the ipsilateral trigeminalnucleus and ganglion. Significant deactivations (OFF > ON)

were found in the middle temporal gyrus, posterior cingulatecortex, inferior temporal gyrus bilaterally and contralateral ante-rior insula (21). Figure 1 demonstrates activation and deactiva-tion in hypothalamic DBS. These findings suggest thathypothalamic stimulation exerts its effect by modulating acomplex pattern of activation in some and deactivation in otherpain-processing areas distant from the hypothalamus. An exclu-sive focal block, e.g. depolarization effect of the posterior hypo-thalamic area as the sole therapeutic effector, is therefore unlikely.

This work can also not explain why it takes several weeks afterimplantation of the electrodes and stimulation to terminatecluster attacks and why it again takes several weeks after turningthe stimulator off until cluster attacks reappear. This time framesuggests that the hypothalamus may be best described as a ‘clock-pulse generator’, which must oscillate in a specific manner overtime to modulate distant autonomic and trigeminovascular areas,resulting in unilateral pain and autonomic symptoms (22).

A C

B

D

Figure 1 Comparison of hypothalamic stimulator ‘on’ and ‘off’ condition in 10 patients with chronic cluster headache. The activations during the

condition ‘stimulator on’ are displayed in yellow colour. Significant activation was detected in the ipsilateral posterior inferior hypothalamic grey

(the site of the stimulator tip) and the ipsilateral insula (A) and the ipsilateral trigeminal nucleus and ganglion (C,D). Additionally, significant

deactivations during the condition ‘stimulator on’ are displayed in blue colour. Deactivations occurred in the contralateral insula and the primary

somatosensory cortex (A) and in the inferior temporal cortex bilaterally (B). Both activations and deactivations are situated in cerebral structures

belonging to neuronal circuits usually activated in pain transmission. E magnifies the same axial view as C, to better visualize the finding. The right side

of the picture is the right side of the brain. Figure adapted from May et al. (21).

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Following this theory, the constant depolarization would dis-continue the biological clock-like impulses from the distanttrigeminal and autonomic ‘executers’, involving a certain timelag.

It is an intriguing finding that turning the stimulator oncauses ipsilateral activation of the trigeminal nucleus and gan-glion (see Fig. 1) in patients suffering from a syndrome conciselyascribable to the trigeminovascular system and not to somatic orchronic pain as such. Furthermore, the scanning was performedin the absence of any facial or head pain, and none of theoperated patients has ever reported any trigeminal negative orpositive sensation in association with the stimulator activity.Although this finding could represent local inhibition of thetrigeminal ganglion and nucleus, the clinical impression as well asrecent results of sensory testing in CH patients with hypotha-lamic DBS (23) argue for a more complex mechanism.

Some studies have assessed the nociceptive system in CHpatients using quantitative sensory testing. In non-stimulatedCH patients, Becser and colleagues (24) examined 22 patientssuffering from CH compared with a healthy control group. InCH patients, cephalic warm detection thresholds were signifi-cantly increased on both the affected and non-affected side,whereas cold thresholds were increased only at the thenar (painthresholds were not examined). In another study by Ellrich et al.(25), thermal detection thresholds in chronic (n = 8) and epi-sodic CH patients (n = 17) were compared with healthy controls.The authors found significantly increased warm and cold detec-tion thresholds on the affected side in chronic and episodic CH.In contrast, Ladda et al. (26) examined episodic (n = 8) andchronic (n = 8) CH sufferers and found bilaterally increasedwarm detection thresholds at the cheek and bilaterally increasedwarm detection and heat pain thresholds in the hand.

Schoenen et al. (27) were the first to describe neurophysi-ological changes after hypothalamic DBS. Increased pressure andelectrical pain thresholds were found extracephalically after 1month, whereas cephalic pain thresholds remained unchangedor were only slightly diminished after 1 month. The responsearea of the nociceptive blink reflex was significantly increasedipsilaterally to the stimulation electrode after 1 month. However,the sample was rather small, so the results should be regardedwith caution.

The anatomical basis for the connection between the hypo-thalamus and the trigeminal system has been described by Malicket al. (28). They discovered that non-nociceptive input was con-veyed directly to the hypothalamus neurons of the trigemino-hypothalamic tract, whereas nociceptive input was relayed via thetrigemino-hypothalamic as well as the reticulo-hypothalamictract. On a functional basis, a bidirectional connection betweenthe two structures exists. Electrical stimulation of the trigemi-nally innervated superior sagittal sinus in cats leads to activationof the posterior hypothalamus (29). The much discussed miss-ing link between the striking circadian rhythmicity and theexcruciating pain attacks could be the orexinergic system. The

neuropeptides orexin A and B (or hypocretin-1 and -2) are syn-thesized in the hypothalamus and have been associated withhomoeostasis (including the sleep–wake cycle). Orexinergic pro-jections have been found linking the suprachiasmatic nucleus(regarded as the ‘master clock’ in circadian regulation) with theposterior hypothalamus (30). In addition, the suprachiasmaticnucleus has a high density of orexin A receptors (31). Bartschet al. (32) found that nociceptive input to the trigeminal nucleuscaudalis (both dural and facial) could be modulated by differen-tial regulation of orexin A and B receptors in the posteriorhypothalamus. Thus, at least some clinical and neurophysiologi-cal effects of hypothalamic stimulation could be conveyed by theorexinergic system.

The fact that hypothalamic DBS is effective in nearly 60% ofotherwise intractable CH (33), that it has been reported to beeffective in SUNCT (34) but not in atypical facial pain (35)points towards a highly selective effect in terms of syndromaticresonse. It is not just pain or even trigeminally transmitted painthat will respond to hypothalamic stimulation. For the moment,we have to conclude that CH, and probably trigemino-autonomic headaches as a group, may respond and consequentlyshould be the only target population (36). However, given thatthe electrode is rather big compared with the target area, we alsohave to conclude that hypothalamic DBS circumscribes the factthat we are depolarizing an unknown number of cells of anunidentified cell population, whose function and neuronalnetwork are not precisely described. Furthermore, we have tostimulate for weeks, without any measurable effect, before somepatients will benefit. Further research offers great potential forunderstanding the mechanisms of action of DBS and underlyingpain generation. Until then, we need to be very restrictive withpatient inclusion (36).

POTENTIAL MECHANISMSAttempts to alleviate medically intractable pain through continu-ous stimulation of deep-brain structures have been reported fornearly half a century (37). Over the years, several brain regions,such as the ventroposterolateral nucleus and several other tha-lamic nuclei, the PAG and periventricular grey (PVG) matter andmotor cortex, have been targeted, with varying degrees of success(38). Some authors recommend PAG/PVG stimulation for thetreatment of peripheral pain (18, 39), whereas stimulation ofthalamic sensory relay nuclei ventral posterolateral or ventralposterior medial or the internal capsule has been suggested forthe alleviation of central pain (40, 41). Although animal experi-ments suggest the lateral hypothalamus to be involved in painmodulation (42, 43), serving as a relay station for nociceptivetransmission and autonomic function (44), electrical stimulationof the hypothalamus to produce analgesia has been used only inexperimental animals (45). Conversely, electrical stimulation ofthe superior sagittal sinus activates the supra-optic nucleus andposterior hypothalamic area (29), and a monosynaptic pathwayconnecting the hypothalamus and trigeminal nucleus has been

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documented (28). The posterior hypothalamus is able to bothdecrease and enhance nociceptive responses in the trigeminalnucleus caudalis (32). In humans, stereotactic thermocoagulationof the postero-medial hypothalamus has been successfullyemployed to treat otherwise intractable cancer pain (46).

Based on observations from earlier PET studies (6, 7, 47), itmay be hypothesized that the symptoms of CH are caused by alow threshold ‘oscillator’ that is generated by the hypothalamusand subsequently activates cortical structures of the paintransmitting system, leading to the characteristic short-livedtrigemino-autonomic pain. Nevertheless, it is thus far unclearhow the (deep brain) stimulation of this precise triggering areaprevents CH attacks from occurring. The fact that artificial hypo-thalamic stimulation activates not only the hypothalamus, butalso distinct members of the pain matrix, provides evidence thatDBS of the hypothalamus not only depolarizes this region (i.e.local depolarization and a local flow response to neuronal firing),but also bidirectionally modulates activity in fundamental struc-tures of the ascending pain pathway. The fact that key structuresof the descending antinociceptive system (PAG and RVM),although densely interconnected with the hypothalamus (48,49), were not influenced by hypothalamic DBS largely excludesa purely antinociceptive mode of action. From a clinical point ofview, it is noteworthy that it may take weeks or longer beforehypothalamic DBS is effective. Similar latencies from implanta-tion to a clinical effect were observed in the recently introducedoccipital stimulation of the greater occipital nerve (GON) inintractable CH. Although the clinical effects were rather modest,patient satisfaction was high (50, 51). Interestingly, pain attackswere positively affected, whereas thresholds for electrical andpressure pain did not change significantly within 1 month afterstimulation. However, similar to the findings in hypothalamicDBS, stimulation of the GON increased the nociceptive blinkreflex (51). In contrast to the central stimulation of the posteriorhypothalamus, peripheral GON stimulation probably acts locallyin the trigeminocervical complex, which is formed by the caudaltrigeminal nucleus and upper cervical afferents. However, therelatively long latency (the headaches did not ameliorate beforemonths of treatment) hints in both stimulation protocols at amore complex and central process, probably involving neuroplas-tic changes of the CNS, but further studies are needed to evaluateand understand both hypothalamic DBS and GON stimulationmore thoroughly.

Interestingly, none of the patients who received hypothalamicdeep brain stimulation developed trigeminal hypo- or anaesthe-sia, and hypothalamic stimulation did not affect anaesthesiadolorosa (22, 52). Considering the complex pattern of activationin some and deactivation in other pain processing areas distantfrom the hypothalamus, an exclusive focal block, e.g. depolariza-tion effect of the posterior hypothalamic area as the sole thera-peutic effector, is unlikely also. This observation, together withthe fact that trigeminal deafferentation does not influence clusterattacks (53), strengthens the hypothesis that the pain of CH does

not arise from a primary dysfunction of the trigeminal nerveitself, but is generated directly from the brain.

ACKNOWLEDGEMENTSThe author thanks M. Leone and T. Juergens for fruitful discus-sions. A.M. is supported by a grant of the Deutsche Forschungs-gemeinschaft (MA 1862/2).

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