Hypothalamic Deep-Brain Stimulation: Target and Potential Mechanism for the Treatment of Cluster Headache

Abstract

Recently, functional imaging data have underscored the crucial role of the hypothalamus in trigemino-autonomic headaches, a group of severe primary headaches. This prompted the application of hypothalamic deep-brain stimulation (DBS), with the intention to preventing cluster headache (CH) attacks in selected severe therapy-refractory cases. To date, a total of 50 operated intractable CH patients, one patient with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and three with atypical facial pain, have been reported. However, it is not apparent why the spontaneous bursts of activation in the inferior posterior hypothalamus result in excruciating head pain, whereas continuous electrical stimulation of the identical area is able to prevent these attacks. Recently, this issue has been addressed by examining 10 operated chronic CH patients, using H₂ ¹⁵O-positron emission tomography and alternately switching the hypothalamic stimulator on and off. The stimulation-induced activation in the ipsilateral posterior inferior hypothalamic grey (the site of the stimulator tip) as well as activation and de-activation in several cerebral structures belonging to neuronal circuits usually activated in pain transmission. These data argue against an unspecific antinociceptive effect or pure inhibition of hypothalamic activity as the mode of action of hypothalamic DBS and suggest functional modulation of the pain-processing network.

INTRODUCTION

A comprehensive theory of cluster headache (CH) must explain the unilateral headache, as well as the sympathetic impairment and parasympathetic activation. In view of the striking relapsing–remitting pattern (1), seasonal variation (1) and the clockwise regularity of the attacks (2), the concept of a central origin for CH 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 as CH and other trigeminal autonomic cephalalgias, has begun to provide a better understanding of the neuroanatomical and physiological basis of these conditions (5). Functional imaging with positron emission tomography (PET) has shed light on the genesis of several of the trigemino-autonomic syndromes, documenting activation in the hypothalamic grey in CH (6, 7), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) (8, 9), paroxysmal hemicrania (10) and hemicrania continua (11). This area is not involved simply as a response to first division nociceptive pain impulses, but is inherent to each syndrome, probably in some permissive or dysfunctional role (12, 13). Furthermore, a significant structural difference in grey matter density of the hypothalamus has been found in patients with CH compared with healthy volunteers (14). The co-localization of morphometric and functional changes demonstrates the precise anatomical location of a probable central nervous system (CNS) lesion in CH. Given that this area is involved in circadian rhythms, sleep–wake cycles (15) and control of the autonomic system (16), these data suggest involvement of this hypothalamic area as a primum movens in the acute cluster attack. These findings prompted the use of deep-brain stimulation (DBS) in the posterior hypothalamic grey matter in a patient with intractable CH and led to complete relief from attacks (17). Based on these observations, DBS of the posterior hypothalamus was introduced with impressive clinical results in a refractory group of patients suffering from chronic, medically intractable chronic CH.

TARGET

Little is known about the circuits and mechanisms underlying the analgesic effect of DBS; however, it probably involves activation of thalamo-cortical pathways and changes in cortical activity (18). The uniqueness of the DBS approach is that it allows in vivo investigation of the functional role of the underlying neuronal circuits by switching the hypothalamic stimulator on and off. It is unclear whether DBS causes:

1. 1.

   Local blockade of the hypothalamic trigger activity

2. 2.

   A direct antinociceptive effect by activation of the periaqueductal grey (PAG) and/or rostral ventromedial medulla (RVM) or

3. 3.

   Modulation of neuronal pain processing pathways.

In order to unravel the brain circuitry mediating stimulation-induced effects, we applied PET, a relatively non-invasive imaging technique that is sensitive to changes in regional cerebral blood flow, as an indirect measure of neuronal activity in humans (19, 20). Using a block design and alternately switching the hypothalamic stimulator on and off, each patient underwent 12 consecutive H₂ ¹⁵O-water PET scans during two conditions: (i) baseline and (ii) during DBS. None of the patients suffered from attacks during the time of the scanning. We therefore looked for changes in brain activation patterns over time due to artificial stimulation of brain structures, but were not interested in CH or headache attacks specifically. Functional imaging revealed stimulator-induced activations (ON > OFF) in the ipsilateral posterior inferior hypothalamic grey (the site of the stimulator tip), the ipsilateral thalamus, somatosensory cortex and praecuneus, the anterior cingulate cortex and the ipsilateral trigeminal nucleus and ganglion. Significant deactivations (OFF > ON) were found in the middle temporal gyrus, posterior cingulate cortex, inferior temporal gyrus bilaterally and contralateral anterior insula (21). Figure 1 demonstrates activation and deactivation in hypothalamic DBS. These findings suggest that hypothalamic stimulation exerts its effect by modulating a complex pattern of activation in some and deactivation in other pain-processing areas distant from the hypothalamus. An exclusive focal block, e.g. depolarization effect of the posterior hypothalamic area as the sole therapeutic effector, is therefore unlikely.

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).

This work can also not explain why it takes several weeks after implantation of the electrodes and stimulation to terminate cluster attacks and why it again takes several weeks after turning the stimulator off until cluster attacks reappear. This time frame suggests that the hypothalamus may be best described as a ‘clock-pulse generator’, which must oscillate in a specific manner over time to modulate distant autonomic and trigeminovascular areas, resulting in unilateral pain and autonomic symptoms (22). Following this theory, the constant depolarization would discontinue the biological clock-like impulses from the distant trigeminal and autonomic ‘executers’, involving a certain time lag.

It is an intriguing finding that turning the stimulator on causes ipsilateral activation of the trigeminal nucleus and ganglion (see Fig. 1) in patients suffering from a syndrome concisely ascribable to the trigeminovascular system and not to somatic or chronic pain as such. Furthermore, the scanning was performed in the absence of any facial or head pain, and none of the operated patients has ever reported any trigeminal negative or positive sensation in association with the stimulator activity. Although this finding could represent local inhibition of the trigeminal ganglion and nucleus, the clinical impression as well as recent results of sensory testing in CH patients with hypothalamic DBS (23) argue for a more complex mechanism.

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

Schoenen et al. (27) were the first to describe neurophysiological changes after hypothalamic DBS. Increased pressure and electrical pain thresholds were found extracephalically after 1 month, whereas cephalic pain thresholds remained unchanged or were only slightly diminished after 1 month. The response area of the nociceptive blink reflex was significantly increased ipsilaterally to the stimulation electrode after 1 month. However, the sample was rather small, so the results should be regarded with caution.

The anatomical basis for the connection between the hypothalamus and the trigeminal system has been described by Malick et al. (28). They discovered that non-nociceptive input was conveyed directly to the hypothalamus neurons of the trigemino-hypothalamic tract, whereas nociceptive input was relayed via the trigemino-hypothalamic as well as the reticulo-hypothalamic tract. On a functional basis, a bidirectional connection between the two structures exists. Electrical stimulation of the trigeminally innervated superior sagittal sinus in cats leads to activation of the posterior hypothalamus (29). The much discussed missing link between the striking circadian rhythmicity and the excruciating pain attacks could be the orexinergic system. The neuropeptides orexin A and B (or hypocretin-1 and -2) are synthesized in the hypothalamus and have been associated with homoeostasis (including the sleep–wake cycle). Orexinergic projections have been found linking the suprachiasmatic nucleus (regarded as the ‘master clock’ in circadian regulation) with the posterior hypothalamus (30). In addition, the suprachiasmatic nucleus has a high density of orexin A receptors (31). Bartsch et al. (32) found that nociceptive input to the trigeminal nucleus caudalis (both dural and facial) could be modulated by differential regulation of orexin A and B receptors in the posterior hypothalamus. Thus, at least some clinical and neurophysiological effects of hypothalamic stimulation could be conveyed by the orexinergic system.

The fact that hypothalamic DBS is effective in nearly 60% of otherwise intractable CH (33), that it has been reported to be effective in SUNCT (34) but not in atypical facial pain (35) points towards a highly selective effect in terms of syndromatic resonse. It is not just pain or even trigeminally transmitted pain that 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 consequently should be the only target population (36). However, given that the electrode is rather big compared with the target area, we also have to conclude that hypothalamic DBS circumscribes the fact that we are depolarizing an unknown number of cells of an unidentified cell population, whose function and neuronal network are not precisely described. Furthermore, we have to stimulate for weeks, without any measurable effect, before some patients will benefit. Further research offers great potential for understanding the mechanisms of action of DBS and underlying pain generation. Until then, we need to be very restrictive with patient inclusion (36).

POTENTIAL MECHANISMS

Attempts to alleviate medically intractable pain through continuous stimulation of deep-brain structures have been reported for nearly half a century (37). Over the years, several brain regions, such as the ventroposterolateral nucleus and several other thalamic nuclei, the PAG and periventricular grey (PVG) matter and motor cortex, have been targeted, with varying degrees of success (38). Some authors recommend PAG/PVG stimulation for the treatment of peripheral pain (18, 39), whereas stimulation of thalamic sensory relay nuclei ventral posterolateral or ventral posterior medial or the internal capsule has been suggested for the alleviation of central pain (40, 41). Although animal experiments suggest the lateral hypothalamus to be involved in pain modulation (42, 43), serving as a relay station for nociceptive transmission and autonomic function (44), electrical stimulation of the hypothalamus to produce analgesia has been used only in experimental animals (45). Conversely, electrical stimulation of the superior sagittal sinus activates the supra-optic nucleus and posterior hypothalamic area (29), and a monosynaptic pathway connecting the hypothalamus and trigeminal nucleus has been documented (28). The posterior hypothalamus is able to both decrease and enhance nociceptive responses in the trigeminal nucleus caudalis (32). In humans, stereotactic thermocoagulation of the postero-medial hypothalamus has been successfully employed to treat otherwise intractable cancer pain (46).

Based on observations from earlier PET studies (6, 7, 47), it may be hypothesized that the symptoms of CH are caused by a low threshold ‘oscillator’ that is generated by the hypothalamus and subsequently activates cortical structures of the pain transmitting system, leading to the characteristic short-lived trigemino-autonomic pain. Nevertheless, it is thus far unclear how the (deep brain) stimulation of this precise triggering area prevents CH attacks from occurring. The fact that artificial hypothalamic stimulation activates not only the hypothalamus, but also distinct members of the pain matrix, provides evidence that DBS 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 structures of the ascending pain pathway. The fact that key structures of the descending antinociceptive system (PAG and RVM), although densely interconnected with the hypothalamus (48, 49), were not influenced by hypothalamic DBS largely excludes a purely antinociceptive mode of action. From a clinical point of view, it is noteworthy that it may take weeks or longer before hypothalamic DBS is effective. Similar latencies from implantation to a clinical effect were observed in the recently introduced occipital stimulation of the greater occipital nerve (GON) in intractable CH. Although the clinical effects were rather modest, patient satisfaction was high (50, 51). Interestingly, pain attacks were positively affected, whereas thresholds for electrical and pressure pain did not change significantly within 1 month after stimulation. However, similar to the findings in hypothalamic DBS, stimulation of the GON increased the nociceptive blink reflex (51). In contrast to the central stimulation of the posterior hypothalamus, peripheral GON stimulation probably acts locally in the trigeminocervical complex, which is formed by the caudal trigeminal nucleus and upper cervical afferents. However, the relatively long latency (the headaches did not ameliorate before months of treatment) hints in both stimulation protocols at a more complex and central process, probably involving neuroplastic changes of the CNS, but further studies are needed to evaluate and understand both hypothalamic DBS and GON stimulation more thoroughly.

Interestingly, none of the patients who received hypothalamic deep brain stimulation developed trigeminal hypo- or anaesthesia, and hypothalamic stimulation did not affect anaesthesia dolorosa (22, 52). Considering the complex pattern of activation in some and deactivation in other pain processing areas distant from the hypothalamus, an exclusive focal block, e.g. depolarization effect of the posterior hypothalamic area as the sole therapeutic effector, is unlikely also. This observation, together with the fact that trigeminal deafferentation does not influence cluster attacks (53), strengthens the hypothesis that the pain of CH does not arise from a primary dysfunction of the trigeminal nerve itself, but is generated directly from the brain.