The posterior part of the hypothalamus has been shown to be activated during acute cluster headache attacks in various studies, starting with early H
2O-PET studies and continuing to recent fMRI studies [
1‐
3,
16‐
18]. To date, no studies exist which investigated cluster headache patients using task related designs in functional imaging. Our data of 37 patients using trigeminal nociceptive input as a task (but outside the cluster headache attack) corroborate hypothalamic involvement in cluster headache pathophysiology. We note that trigeminal nociceptive input activates the posterior part of the hypothalamus, a brain area which is associated with cluster headache pathophysiology [
19], and not the hypothalamus proper. Whilst it is undoubted that it is indeed crucial for cluster headache pathophysiology [
20], the correct anatomical denomination is a much discussed issue [
21‐
23]. For the sake of convenience we keep the wording of the original report [
2] and consistently refer to this area as posterior hypothalamus. Regarding the site of activation, our data are in line with previous studies showing the activation ipsilateral to the site of cluster headache [
2,
16]. However, different from what we expected, hypothalamic activity levels following trigeminal nociceptive stimulation were highest in patients out of bout, i.e. with inactive cluster, and not within the active group. As there were patients taking medication within both cluster groups, it is rather unlikely that the difference we describe is simply due to an effect of medication. The hypothalamus is involved in processing and modulation of painful trigeminal stimuli via various fiber connections of different hypothalamic nuclei to the spinal trigeminal nucleus, the PAG, the posterior Raphe nucleus and others [
10,
18]. Additionally, there are efferent fiber connections of the spinal trigeminal nucleus that directly activate hypothalamic nuclei [
19] and the hypothalamus has been shown to be activated in response to trigeminonociceptive stimulation in healthy subjects [
10]. It is thus strategically positioned for integrating painful stimuli with signals of energy homeostasis and circadian rhythmicity. Cyclic activity changes within the hypothalamus might constitute the neuronal basis for the beginning of the cluster bout and especially the initiation of a cluster headache attack [
24]. Since the posterior hypothalamus is thus frequently activated in active cluster headache (eCH in bout and cCH), these frequent episodes of activation might lead to neurotransmitter exhaustion and hypo-excitability of this area to external stimuli. To our knowledge there are to date no studies directly investigating hypothalamic responses to external stimuli in cluster headache patient. One behavioral measure often discussed to be influenced by hypothalamic activity is the nociceptive blink reflex. Studies point towards altered habituation of the blink reflex in cluster headache patients in the bout and in one study also out of bout [
7,
25,
26], but findings are not homogeneous and partly contradicting [
27]. Hypothalamic involvement in this mechanism is therefore likely but not proven. The alterations in blink reflex habituation might thus point towards altered hypothalamic functioning in cluster headache but can not help us to explain the current results since other trigeminonociceptive sites of conduction might be involved in mediating blink reflex habituation. The theory of a hypothalamic exhaustion and hypoexcitability in active cluster headache is thus a viable explanation although there is currently no direct experimental evidence to support it. It could account for the fact that, other than expected, hypothalamic activation following nociceptive stimulation of the nasal mucosa was not highest within the active cluster group but within the group of inactive episodic cluster headache patients.